Virtual Library

Background:
Nivolumab is an immune check point inhibitor becoming a major tool in the treatment of Non-Small cell lung cancer (NSCLC). Its side effects are specific from its pharmacological class. General practitioners (=GP) may manage cancer patients and they would like to receive information about side effects of anticancer drugs. In our cancer center three oncologists prescribe nivolumab for NSLC. They use three different methods to inform the GP about Nivolumab expected side effects: a letter directly for the GP, an information sheet and/or a personal drug's card (OPDIVO® card) given to the patients. A survey has been conducted to assess GP satisfaction of information.

Method:
A complete list of all patients treated by nivolumab since its commercialization was obtained by medical prescription writing software (CHIMIO). Their GP have been identified with computer-based patient record (DX-Care). Through this same process, any information given about nivolumab side effects has been queried. A questionnaire has been drawn up, made up of 4 open questions and 1 closed question. All GP have been contacted by phone.

Result:
121 patients have been identified. 5 patients were excluded because they died a few days after the first administration or because we could not find their GP. 103 GP were phoned over a one-month period and 86 GP responded to the survey. GP received 63 Nivolumab side effects letters and patients received 31 information sheets and 2 OPDIVO® cards. For 18 patients there was no evidence of information transmission. According to the survey, only 9 GP received information. For six of them in a letter, for two in an information sheet, and for one a patient showed its OPDIVO® card. They were satisfied with information. Most GP would like to be informed by secure messaging.

Conclusion:
No evidence of information was found in 21% of the electronic patient care. In the future, information must appear for all patients. Only 10% of GP could remember to have information, this may be partly explained by recall bias. As regards the desired method, they were different views. It was decided to harmonize oncologist practices. Nivolumab side effects are now systematically described in the letter for GP. All patients receive two information sheets with an OPDIVO® card. Patients are instructed to make an appointment with their GP to give one information sheet. In this way, we reinforce the communication between the hospital and the GP and thus hope to optimize patient’s care

Background:
Non-small-cell lung cancer (NSCLC) can be identified by precise molecular subsets based on genomic alterations that drive tumorigenesis and include mutations in EGFR, KRAS, and various ALK fusions. However, despite effective treatment for EGFR and ALK, promising therapeutics have not been developed for patients with KRAS mutations. Therefore, novel therapeutic strategies for KRAS mutated cancer based on molecular mechanisms are needed to improve their prognosis. It has been reported that one way the RAS-ERK pathway contributes to tumorigenesis is by affecting stability and localization of FOXO3a protein, an important regulator of cell death and the cell cycle.

Method:
We used NSCLC cells with RAS mutation to evaluate the effect of a MEK inhibitor in combination with a HDAC inhibitor through the expression and localization of FOXO proteins in vitro and in vivo. Protein expression was examined by Western blotting.

Result:
Combined treatment with a MEK inhibitor and a HDAC inhibitor showed synergistic effects on cell viability of RAS mutated lung cancer cells through activation of FOXOs, with a subsequent increase in BIM and cell cycle inhibitors. Moreover, in a mouse xenograft model, the combination of belinostat and trametinib significantly decreases tumor formation through FOXOs by increasing BIM and increase in cell cycle inhibitors p21 and p27.

Conclusion:
These findings demonstrate that FOXOs might be one of the critical pathways in RAS driven lung cancer cells, suggesting that the dual molecular targeted therapy for MEK and HDACs may be promising as novel therapeutic strategy in NSCLC with specific populations of RAS mutations.

Background:
Taxane-based chemotherapy including paclitaxel, docetaxel, paclitaxel-albumin was wildly used in solid tumors. ABCB1 (P-glycoprotein, multidrug resistance 1) is a trans-membrane protein that acts as an energy-dependent drug efflux pump for chemotherapeutic drugs, including taxanes. In addition, ABCB1 has been suggested to have a role in the prediction of treatment response and toxicity of chemotherapy in breast cancer, gastric cancer et.al. In this retrospective study, we explore the influence of ABCB1 polymorphism on toxicity and taxane-based chemotherapy.

Method:
118 patients (lung cancer 103, others 15) with taxane-based chemotherapy (paclitaxel 56 cases, docetaxel 55 cases, paclitaxel-albumin 7 cases) treatment were included in this study. Fluorescence in situ hybridization (FISH) was used for ABCB1 polymorphism detection. Statistical analysis was performed using SPSS 20.0.

Result:
The frequency of the ABCB1 3435 site homozygous mutation (TT genotype), heterozygous mutation (TC genotype) and wild type (CC genotype) was 11.0%(13/118) , 45.8%(54/118) and 43.2%(51/118) respectively. The occurrence of neurotoxicity was higher in patients had TT genotype (62.9%) compared with patients had TC (25.9%) and CC genotype (37.3%)(P=0.310). Especially in the docetaxol subgroup, the difference of chemotherapy-induced neurotoxicity was statistically significant (TT 75.0%, TC 9.5%, CC 11.5%, P=0.007). There was not significant difference between the three ABCB1 genotypes with regarding to other chemotherapy-induced toxicity, including diarrhea, constipation, leukocytes, neutrophils, anemia and thrombocytopenia. For non-small cell lung cancer (NSCLC) patients in this study, patient harboring ABCB1 3435 site CC genotype had longer median progression free survival (PFS) (5.1 months) than TC genotype (4.7 months) and TT genotype (2.6 months)(P=0.42). Especially in the paclitaxel subgroup (n=21), the median progression was significantly longer in patients with CC genotype when compared with TC and TT genotype (9.8 months vs. 4.5 months vs. 1.6 month, P=0.06). We failed to find the difference in either response rate or disease control rate between the different genotype, even in subgroup analysis.

Conclusion:
ABCB1 3435 site polymorphism is associated with neurotoxicity of taxane-based chemotherapy. It can also predict clinical outcomes for NSCLC.

Background:
Adenosquamous lung carcinoma (ASC) is a hybrid tumor made of adenocarcinoma and squamous cell carcinoma in one tumor. It is a rare disease with poorer prognosis comparing with the other common variants of non-small cell lung cancer (NSCLC). There is a persisting need for identifying more effective targeted therapy methods. Our previous study had examined the EGFR mutation status in lung ASC, the results showed that its mutation rate is similar with that of lung adenocarcinoma. Because the rarity of lung ASC, little is known about its gene rearrangement status and its relationship with the clinical characteristics.

Method:
ALK, ROS1, RET and NTRK1 gene rearrangement in lung ASC were examined by next generation sequencing methods, and further confirmed by fluorescent in situ hybridization (FISH) and/or immunohistochemistry methods. Tissue microarrays (TMAs) containing formalin fixed paraffin embedded (FFPE) lung ASC cases were used in this study.

Result:
This study included 53 cases of lung ASC totally. ALK/EML4 gene rearrangement was detected in 3 cases (5.7%), ROS1 fusion gene was detected in 1 cases (1.9%), RET gene rearrangement was detected in 1 case (1.9%). One of the ALK/EML4 rearrangement case had a concurrent EGFR exon 21 L858R mutation. All the rearrangement results can be further confirmed by FISH and/or immunohistochemistry methods. No association were identified between ALK/EML4 rearrangement and patient age, tumor size, clinical stage, positive pleural invasion, lymphovascular invasion, smoking status, lymph node metastasis, therapy methods, recurrence free survival (RFS) time or overall survival duration.

Conclusion:
The gene rearrangement rate of lung ASC is similar with that of lung adenocarcinoma, which further support our suggestion that lung ASC is a peculiar subtype of lung adenocarcinoma with a poorer prognosis than lung adenocarcinoma.

Background:
Primary lung enteric adenocarcinoma is a rare type of invasive lung carcinoma. This study mainly discusses the clinicopathological characteristics, diagnosis and treatment of primary lung enteric adenocarcinoma.

Method:
Retrospectively analysed clinical records of 6 cases admitted in hospital from Feb. 2013 to May 2016, and reviewed the literature of primary lung enteric adenocarcinoma.

Result:
Two patients were male and four patients were female with the age ranged from 25 to 78 years. Their symptoms consisted mainly of cough chest stuffy with 4 patients, neck mass with 1 case, dizziness nausea vomiting with 1 case; imagining scan showed mass of lung and or mediastinal, pathology form and the immunochemistry showed all positive for intestinal immune phenotypes and some positive for lung cancer immunophenotypic. But no tumor was found by gastrointestinal endoscopes; 1 case recurrence and metastasis after radical operation; 1 patient underdone palliative surgery, 1 patient with brain solitary metastasis onset received Cyber Knife and without system treatment, and 5 patients underwent chemotherapy. At the end of follow-up, 4 patients died, over survival time as long as 32 months.

Conclusion:
The primary lung enteric adenocarcinoma is easily confused with pulmonary metastases from colorectal cancer, confirmed diagnosis need to rule out intestinal lesion, the main early treatment is surgery, and systematic treatment programs need to be further studied.

Background:
Anlotinib hydrochloride is a novel TKI targeting the VEGFR, FGFR, PDGFR and c-Kit. ALTER0303 trial (NCT02388919), phase III study has demonstrated that Anlotinib significantly prolonged OS and PFS in advanced NSCLC patients as 3[rd] line treatment. Here we report the efficacy of anlotinib in patients with or without EGFR gene mutations from the ALTER0303 trial.

Method:
Eligible adult IIIB/IV NSCLC patients who progressed after at least 2 lines of prior therapies were randomized 2:1 to receive Anlotinib or placebo (12 mg QD from day 1 to 14 of a 21-day cycle) till progression. Patients harboring EGFR or ALK mutations must had received previous targeted therapies. Primary endpoint is OS.

Result:
Among patients with sensitive EGFR mutations, the PFS was 0.83 months for control arm and 5.57 months for anlotinib arm (p<0.0001, HR=0.15, 95%CI: 0.09-0.24). Accordingly, OS was found 4.43 months longer in anlotinib group (6.27 vs 10.70, p=0.0227, HR=0.59, 95%CI: 0.37-0.93). On the other hand, in the subgroup of patients with wild-type EGFR gene, remarkable advantages in PFS and OS were observed as well. Specifically, PFS in control arm was 1.57 months which is 3.80 months shorter than that in anlotinib group (1.57 vs 5.37, p<0.0001, HR=0.29, 95%CI: 0.22-0.39). As to OS, superiority of 2.40 months was found in anlotinib arm (6.47 vs 8.87, p=0.0282, HR=0.73, 95%CI: 0.55-0.97). In the patients treated with Anlotinib, the most common (≥ 3 grade) and significantly differ from placebo group AEs were hypertension (13.61%), dermal toxicity (3.74%) and hypertriglyceridemia (3.06%). These results indicate that either the patient with EGFR mutation or not, they can both benefit from Anlotinib treatment.

Conclusion:
In ALTER0303 trial, significant advances in OS and PFS were found in anlotinib treated patients from both subgroups (sensitive EGFR mutations and wild EGFR gene type), indicating that, independent of the EGFR gene status, anlotinb treatment led to a consistent improvement in OS and PFS for advanced NSCLC patients and may be an appropriate option for this difficult-to-treat population as 3[rd] line treatment.

Background:
The Lung Cancers Mutation Consortium (LCMC) is a multi-institutional effort where 16 sites identify oncogenic drivers and pool data to assess the impact of targeted therapies in patients with lung adenocarcinomas. We now report the results of the second patient cohort (LCMC2) with an expanded multiplex molecular panel to include RET and ROS1 and tumor suppressors.

Method:
904 patients with centrally confirmed stage IV lung adenocarcinomas who were candidates for therapy had at least one of 14 oncogenic drivers assessed in a CLIA-compliant laboratory using genotyping, FISH, massively parallel sequencing (NGS), and immunohistochemistry (IHC) analyses.

Result:
Among 423 patients tested for all 14 targets, we found a driver in 65%. Mutated KRAS was found in 31%, sensitizing EGFR in 14%, MET amplification in 5%, ALK rearrangements in 4%, BRAF V600E in 3%, and HER2 in 3%. Rearrangements in RET and ROS1 were each found in 2% (CI 1 to 3%). Using IHC, PTEN loss was found in 8% (CI 6 to 11%) and MET expression in 58% (CI 55 to 61%). Use of targeted therapies in patients with EGFR, HER2, or BRAF mutations, ALK, ROS1, or RET rearrangements, and MET amplification was associated with a gain in overall survival of 1.5 years relative to those with the same drivers not receiving targeted therapy and a gain of 1 year relative to those without an actionable driver. Current and former cigarette smokers derived a survival benefit from targeted therapies similar to never smokers (p=0.975). Among 154 patients who had all drivers assessed and NGS testing in addition, any TP53 mutation was associated with poorer survival among those with EGFR, ALK, or ROS1 (p=0.014). STK11 was detected in 11%, all in patients with KRAS mutations.

Conclusion:
Using an expanded testing panel, LCMC2 demonstrates the survival benefit of matching targeted treatments to oncogenic drivers in patients with lung adenocarcinomas, identifies additional prognostic factors, and supports the performance of multiplex molecular testing on specimens from all individuals with lung adenocarcinomas irrespective of clinical characteristics. We detected either MET amplifications or HER2 mutations in 7%, together more than the 4% with ALK. A targeted drug is available in the United States for 35% of patients with lung adenocarcinomas. The routine use of massively parallel sequencing (NGS) detects both targetable drivers and tumor suppressor genes that have significance for therapy selection and prognosis. Supported by Free to Breathe

Background:
The difficulty of establishing lung squamous cell carcinoma (LUSC) derived cell lines have posed significant challenges for identifying potential therapeutic targets and understanding the complexity of this disease. We have previously developed a LUSC patient-derived xenograft (PDX) platform in which over 50 models have been characterized on the genomic and transcriptomic level. We describe a method to culture and establish LUSC organoids from PDX models and demonstrate their utility for drug testing.

Method:
Surgically resected LUSC were implanted into the subcutaneous flank of NOD/SCID mice to establish PDXs. To generate organoids, PDX tissue was dissociated into single cells using Liberase and TypLE and plated in growth factor reduced matrigel dome with media overlay. Organoids were processed for histological and immunohistochemical marker characterization. Organoids and matched PDX were subjected to shallow next generation sequencing for mutation and copy number analysis. Drug screening was performed in 384 well plates and viability was determined by Celltiter Glo 3D assay.

Result:
Of the 17 LUSC PDX models attempted, organoid lines from 3 PDX models were propagated beyond 20 passages for over 100 days. The success rate of organoid establishment is 18%, which is higher than establishing LUSC cell lines. Organoids exhibited various doubling rates ranging from 38 to 48 hours. Organoid tumor cells faithfully recapitulated the immuno-phenotypes of the matched PDX, expressing p63 and CK5/6 and were EpCAM positive and H2K negative by flow cytometry analysis. Organoids implanted in NOD/SCID mice formed tumors that reflected the histology of the matched PDX. Shallow sequencing revealed similar copy number status between the organoid and matched PDX. RNA sequencing analysis is pending and will be reported. Organoids were amenable for drug testing and exhibited varying sensitivities to the PI3K inhibitors BKM120 and BYL719 based on each model’s PI3K pathway status.

Conclusion:
We describe a method of developing LUSC PDX-derived organoids that can be propagated long term and faithfully recapitulate the histological and molecular characteristics of the original tumor. Additionally, we demonstrate their utility for in vitro drug testing. Organoids may be useful for preclinical modeling and therapeutic evaluation of LUSC.

Background:
Development of targeted NGS technology resulted in more attention to be given in identifying cancer-related driver gene pathways, which precisely illustrate how different driver genes collaborate simultaneously to induce carcinogenesis and progression.

Method:
We profiled 165 solid tumor samples, including 9 cancer types and 4 sample types, by using amplicon-based next-generation sequencing panel covering 48 highly mutated tumorigenesis-related genes that were deep sequenced at an average coverage of 2000×.

Result:
Both tumor and sample types had significant effect on tumor genetic mutational profiles. Concurrent driver mutations were frequently detected in solid tumor, concentrating on both modes of action driver genes (activating or loss of function). Furthermore, in non-small cell lung cancer (NSCLC), concurrent driver mutations were also significantly correlated with the lymph node metastasis status and pathological types. Higher frequency of lymph node metastasis was observed in patients with NSCLC with concurrent mutations on at least two driver genes. In addition, patients with lung adenocarcinoma were more likely to harbor concurrent driver mutations than patients with lung squamous and large cell carcinoma. Multiple mutations in the epidermal growth factor receptor gene were more frequently detected in patients with refractory NSCLC compared to untreated naive ones.

Conclusion:
Therefore, concurrent multiple driver mutations, rather than a single genetic mutation, should be investigated extensively to probe novel genetic biomarkers with clinical benefits.

Background:
Oncogenic fusions of the RET kinase gene, which was discovered by us in 1‒2% of LADCs (Kohno et al, Nat Med, 2012), have been suggested as a therapeutic target for existing tyrosine kinase inhibitors (TKIs). Actually, several clinical trials investigating RET tyrosine kinase inhibitors (TKIs) for the therapy of RET-positive LAD showed promising clinical outcome. However, the cancer inevitably acquires resistance to TKI like other driver oncogene positive LAD.

Method:
To identify a mechanism of TKI resistance in RET-driven lung cancer, we generated resistant cells to several RET-TKIs using LC-2/Ad cells that are RET-rearranged lung cancer cell lines. In addition, we established cells stably expressing RET fusion cDNA and RET-rearranged cells edited by CRISPR/Cas9, and generated resistant cells using these cells. We performed targeted sequencing covering 50 genes on a pair of resistant and pre-treatment cells. To identify the bypath track, then we performed antibody array and investigated change of mRNA expressions.

Result:
No genetic alteration was found in resistant cells by targeted sequencing. Antibody array found the activation of other tyrosine kinase, including EGFR and other HER family. Actually, the addition of the growth factors activating the kinases reduced the inhibitory effect of the TKIs. In addition, the TKI to suppress signaling of the kinase in combination with RET TKI reduced the cell viability in resistant cells.

Conclusion:
The inhibition of bypath track in combination of RET signaling could be an effective therapy for RET-rearranged lung cancer. In the meeting we plan to report the progress.

Background:
BRAF mutations is one of the important driver oncogene in non-small cell lung cancer (NSCLC), and are known to give the petients worse prognosis as same as KRAS mutations. However, we experienced that a patient with BRAF V600E positive lung adenocarcinoma was responsive to pemetrexed treatment. The patient has been followed for over 7 years without recurrence and metastasis.

Method:
Here, we introduce a pemetrexed well respond patient with BRAF mutation positive lung adenocarcinoma. Clinical presentation, radiological features, histopathologic findings and genetic findings of the patient are reported.

Result:
A 64 years-old never smoker female who complained bloody sputum visited our hospital. Chest X ray examination showed protrusion of the right first aortic arches. Transbronchial lung biopsy was performed and primary lung adenocarcinoma was diagnosed. Brain metastasis was suspected by magnetic resonance imaging. The patient was initially given combined chemotherapy with CDDP+VNR and Radiation therapy (60Gy). But after six months, tumor progression was found. Therapeutic agent was changed to 600mg single pemetrexed as outpatient chemotherapy for 14 months. Computed tomography showed reduction of tumor mass. Then, the patient has been still followed without any anti-cancer treatment. It passed for 7 years after diagnosis. The oncogenic driver mutations of the present patient were investigated in another study. Immunohistochemistry and DNA sequencing analysis showed the existence of BRAF mutation V600E in the present case.

Conclusion:
BRAF mutation in NSCLC was reported not associated with enhanced chemosensitivity. However, pemetrexed was effective to the present BRAF V600E positive lung adenocarcinoma patient.

Background:
KRAS is frequently mutated in non-small cell lung cancer (NSCLC). However, direct targeting of KRAS has proven to be challenging, and inhibition of KRAS effectors has resulted in limited clinical efficacy. Wee1 kinase is an important regulator of the G2 checkpoint and is overexpressed in various cancers. Inhibition of Wee1 exerts anticancer effects as a monotherapy or in combination with DNA-damaging agents when cancer cells harbor TP53 mutations. However, its role in KRAS-mutant NSCLC, especially as a single agent, has not been explored.

Method:
Here, we investigate the anticancer potential of Wee1 inhibitor AZD1775 as a monotherapy and uncover a possible cellular context underlying sensitivity to AZD1775. Eight KRAS-mutant NSCLC cell lines were treated with AZD1775 and cell viability, proliferation, and cell cycle were analyzed. Target modulation was assessed by Western blotting and immunohistochemistry.

Result:
Our data show that treatment with AZD1775 significantly inhibited cell survival, growth, and proliferation of TP53-mutant (TP53[MUT]) compared to TP53 wild-type (TP53[WT]) in KRAS-mutant (KRAS[MUT]) NSCLC cells. In KRAS[MUT]/TP53[MUT] cells, AZD1775 treatment led to DNA damage, a decrease of survival signaling, and cell death by apoptosis. Interestingly, cell death through apoptosis was found to be heavily dependent on specific cellular genetic context, rather than inhibition of Wee1 kinase activity alone. In addition, AZD1775 treatment was well tolerated and displayed single-agent efficacy in a mouse xenograft model.

Conclusion:
This study provides rationale for inhibiting Wee1 using AZD1775 as a potential anticancer therapy against the TP53[MUT] subgroup of KRAS[MUT] NSCLC.

Background:
Recent advances in high-throughput genetic analysis revealed that single lung cancer cells harbour a number of genetic and epigenetic changes. Nevertheless, findings from cancer epidemiology and the experimental models of the multi-step lung carcinogenic process, which were developed by our group and others, suggested that only a handful of changes are ‘drivers’ whereas others are only ‘passengers’. Thus, it is very important to identify those that truly contribute to the oncogenic properties of cancer cells by performing functional screening. To this end, we performed screening with a pooled shRNA library in search for genes that are critical for the survival and/or proliferation of lung cancer cells using a lung cancer cell line.

Method:
NCI-H460 cell line was used for semi-genome-wide dropout viability analysis using a pooled shRNA library that targeted 5,043 genes. Two Cdk4/hTERT-immortalised normal human bronchial epithelial cell lines, HBEC3 and HBEC4 were used as controls. Pathway analysis was done using NIH-DAVID. Microarray gene expression analysis was done using Illumina Human WG-6 v3.0 Expression BeadChip for 163 non-small cell lung cancer (NSCLC) cell lines and 59 normal control cell lines. DNA copy number analysis with array CGH was done for 108 NSCLC cell lines. Proteasome activity was measured using a 20S proteasome activity assay kit. 20 pairs of resected lung cancer and matched normal lung samples were used for immunohistochemistry of PSMA6. Cell growth was evaluated by WST-1 colorimetric proliferation assay. Cell cycle analysis was done using FACS for cells stained with propidium iodide.

Result:
shRNA screening targeting 5,043 genes in NCI-H460 identified 51 genes as candidates for therapeutic targets. Pathway analysis revealed that the 51 genes were enriched for the five pathways, including ribosome, proteasome, RNA polymerase, pyrimidine metabolism and spliceosome pathways. We focused on the proteasome pathway that involved six candidate genes because its activation has been demonstrated in diverse human malignancies, including lung cancer. Microarray expression and array CGH data showed that PSMA6, a proteasomal subunit of a 20S catalytic core complex, was highly expressed in lung cancer cell lines, with recurrent gene amplifications in some cases. Therefore, we further examined the roles of PSMA6 in lung cancer. Silencing of PSMA6 induced apoptosis or G2/M cell cycle arrest in cancer cell lines but not in an immortalised normal lung cell line.

Conclusion:
Our data suggested that PSMA6 serves as an attractive target with a high therapeutic index for lung cancer.

Background:
Apatinib is a specific tyrosine kinase inhibitor that targets VEGFR-2. Treatment of primary lung cancer patients with apatinib is a new promising paradigm. In addition to hypertension and hand-foot syndrome, tumor cavitation and increase in CEA value are frequently noted in these patients. However, there are limited literatures regarding whether they could be used as potential biomarkers for anti-angiogenic therapy. This study was to evaluate the frequency and clinical outcome of primary lung cancer patients who developed tumor cavitation or showed increase in CEA value following apatinib treatment.

Method:
This was a retrospective analysis of primary lung cancer patients treated with apatinib in the Affiliated Hospital of Qiingdao University between 2/1/2015 and 5/19/2017. Clinical data were retrieved from medical records, and chest imaging findings were documented. Survival data were analyzed with Kaplan-Meier estimates and compared with log-rank test.

Result:
A total of 38 primary lung cancer patients received oral apatinib as the third-line or beyond therapy at an initial dose of 250 mg (n=37) or 500 mg (n=1) per day. During treatment, tumor cavitation was developed in 20 of the 38 (52.6%) patients. No significant difference was observed between patients with and without cavity formation in age, gender, tumor histology, tumor stage, history of pulmonary surgery and apatinib typical adverse events. Cavity formation was accompanied with temporary increase in CEA value (65.0% vs. 5.6% in patients with and without cavitary lesions; P=0.0001). The progression-free survival (PFS) of patients with cavitary lesions was 11.25 (95% CI, 10.16-13.64) months, which was significantly longer compared with those without (6.11 [95% CI, 6.01-6.71] months; P<0.0001). Besides, patients with a temporary increase in CEA had a longer PFS than those without (10.64 [95% CI, 10.09-14.14] vs. 6.14 [95% CI, 6.07-8.13] months), but the difference was not significant (P=0.0703).

Conclusion:
Cavitation formation induced by apatinib is common in primary lung cancer patients, and is not correlated with age, gender, tumor histology, tumor stage, history of pulmonary surgery and common adverse events. Cavitation might have significant effects on the temporary increase in CEA value and PFS prognosis.

Background:
ROS1 is a receptor tyrosine kinase that belongs to insulin receptor family.It acts as a driver oncogene in 1 to 2% of NSCLC patients. ALK and ROS1 Kinase domain share 77% amino acid identity within the ATP-binding sites. Crizotinib binds with high affinity to both ALK and ROS1, Crizotinib is approved for patients with the ROS1 translocation including those who have received chemotherapy and those who are treatment naive. This is based on a phase 1 expansion study which enrolled 50 patients with ROS1 rearrangement. Over 80 percent of patients had received one or more prior chemotherapy treatment regimens. The objective response rate was 72 percent. The median duration of response was 17.6 months, and the median progression-free survival was 19.2 months.A retrospective series from Europe which included 32 patients reported 80% response rates and a PFS of 9.1 months.In this paper, we report our experience with ROS1 rearranged NSCLC from India.

Method:
Advanced NSCLC with the presence of ROS1 fusion (FISH) patients whose demographic data were retrieved from prospective lung cancer audit database Response by RECIST 1.1 criteria, side effects using CTCAE v 4.02

Result:
Among 11 patients more than 1/4[th] of patients had PS of ≥2. Nearly 1/2 of patients had comorbidities and extrathoracic disease while none with brain or adrenal metastasis.Eight received platinum-based doublet chemotherapy, two oral EGFR TKI, and one upfront crizotinib. Four patients among those who received platinum doublet were subsequently exposed to crizotinib Among the 4 patients platinum-based doublet, 2 (PR)and 2 (SD).Out of 5 patients who received crizotinib, 3 patients experienced grade ½ fatigue and grade ½ vomiting. Grade ½ transaminitis, visual symptoms, grade ½ diarrhea, grade ½ neutropenia and asymptomatic bradycardia, grade ½ neutropenia and thrombocytopenia were seen in 1 patient each. Out of 8 patients who received chemotherapy 3 patients had grade ½ anemia, grade ½ vomiting. There was one mortality in non-crizotinib group.Out of 5 patients who received crizotinib, 4 patients had PR (80%).With a median follow-up of 9 months, median PFS and OS were 5.4 months and 8.5 months respectively for the entire cohort.Median PFS and OS was not reached for those who received crizotinib compared to median PFS of 2.5 months and median OS of 4.2 months(<0.01).Estimated 1 year OS was 80% for those who received crizotinib and 18% for who did not.

Conclusion:
In conclusion, Crizotinib is effective with acceptable side effect profile in patients with ROS1 rearranged NSCLC in our population

Background:
The advent of genotype-directed therapy in personalized medicine requires the identification of driver-mutations that are often under-diagnosed due to limitations in tissue biopsy and high false negative rates associated with genomic tests. Studies have demonstrated that the mutation status of cancer cells correlates with changes in cellular morphology. The automated Cell-CT[®] platform produces isometric, high-resolution 3D images of cells in liquid biopsies, such as sputum, where published studies have demonstrated 92% sensitivity to biopsy confirmed lung cancer with 95% specificity. This study reports the development of cell classifiers for lung cancer cell lines that harbor known mutations, helping pave the way to driver-mutation targeted therapy.

Method:
Non-invasive sputum specimens from patients without lung cancer (“normal cells”) and the following cell lines were analyzed using the Cell-CT[®] platform: Small Cell Lung Cancer cell line NCI-H69 Adenocarcinoma cell lines A549 (EGFR wild-type, -c.1_471del471, KRAS- p.G12S) NCI-H1650 (EGFR- p.E746_A750del, CDKN2A- c.1_471del471, TP53- c.673-2A>G) NCI-H1975 (EGFR-T790M, CDKN2A- p.E69*, PIK3CA- p.G118D, TP53- p.R273H) NCI-H2228 (EML4-ALK+, CDKN2A- c.1_471del471, RB1- p.E204fs*10, TP53- p.Q331* high PD-L1).

Result:
15,000 normal cells from sputum and 500 malignant cells from each of the five cancer cell lines were analyzed using Cell-CT[®] platform, measuring 704 structural biomarkers to sub-classify the cancer cells by mutation status. Cell classifiers were operated to drive the highest specificity (avoidance of false positives) while maintaining sensitivity above 50%. The area under ROC (aROC), sensitivity and specificity for each classifier were:

Cell Classifiers	aROC	Sensitivity %	Specificity %
Small cell lung cancer (NCI-H69)	0.991	74.8	99.98
Adenocarcinoma, EGFR wild-type (A549)	0.950	58.8	99.94
Adenocarcinoma, EGFR – pE746_A750del (NCI-H1650)	0.993	59.6	99.99
Adenocarcinoma, EGFR -T790M (NCI-H1975)	0.972	66.0	99.99
Adenocarcinoma, ALK+ (NCI-H2228)	0.992	76.8	99.97

Conclusion:
This study demonstrates the feasibility of processing non-invasive sputum specimens by the Cell-CT[®] platform to accurately identify driver mutations in cancer cells to promote mutation-directed targeted therapy for the treatment of lung cancer.

Background:
Anlotinib hydrochloride, an oral multi-target TKI targeting VEGFR, FGFR, PDGFR and c-Kit, have demonstrated noticeable effects for advanced NSCLC as 3[rd] line treatment in phase III trial (ALTER0303). Anlotinib significantly improved OS (9.63 vs. 6.30 months, p=0.0018, HR=0.68) and PFS (5.37 vs 1.40 months, p<0.0001, HR=0.26) comparing to placebo. Here, we applied ctDNA-based NGS to investigate the association between baseline molecular signature and clinical parameters.

Method:
Blood samples were collected from patients who enrolled in Anlotinib arm in ALTER0303 trial. Total of 92 samples were analyzed by capture-based targeted ultra-deep sequencing using a panel consisting of critical exons and introns of 168 NSCLC-related genes for the baseline genetic profiling.

Result:
At baseline, ctDNA was detected in 85% samples (78/92), driver mutation was found in 58% (53/92) samples. POM121L12 and CDKN2A mutations showed a tendency of co-occurrence with TP53, and mutually exclusivity was found between KEAP1 and TP53. The correlation between baseline molecular signature and treatment efficacy measured by PFS or best response was also investigated. Maximum mutation allele frequency (MAF) at baseline was inversely correlated with PFS (P=0.006, HR=0.612, 95%CI: 0.402-0.932). Patients achieving SD or PR had a significantly lower MAF comparing to patients having PD as their best response (p=0.018). Tumor mutation burden (TMB) is positively correlated with age (p=0.016) and gender (p=0.01). POM121L12, TP53 and MYC statuses are correlated with metastases burden. Moreover, as an important drive gene, EGFR mutation and/or EGFR amplification was found in 36 patients at baseline. In 27 patients with sensitizing EGFR mutation (L858R or 19 del), no significant differences was found in PFS compare to those without this mutation (n=65) (5.53 vs 5.53 months, p=0.495, HR=1.16, 95%CI: 0.73-1.85). As well, no significant difference was found in PFS between the patients with (n=17) or without EGFR T790M mutation (5.53 vs 5.53 months, p=0.253, HR=1.35, 95%CI: 0.75-2.41). Interestingly, in patients with EGFR amplification (n=10), the PFS is significantly shorter than those with normal EGFR copy number (2.12 vs 5.57 months, p=0.002, HR=2.70, 95%CI: 0.99-7.36). However, a tendency of PFS benefit is still observed in patients with EGFR amplification treated by Anlotinib comparing placebo arm in ALTER0303 (1.40 months).

Conclusion:
According to available data, no correlation was found between PFS and EGFR sensitizing mutations or T790M in anlotinib treatment. The negative correlation of EGFR amplification and PFS is still need verification to eliminate the bias caused by the disparity and limitation of samples. A larger scale analysis is ongoing.

Background:
Apatinib, a specific tyrosine kinase inhibitor targeting VEGFR-2, shows anti-angiogenesis effects in multiple solid tumors including lung cancer. Correlation between cavitation formation and outcome of some anti-angiogenic drugs is evaluated in patients with pulmonary cancer. However, the onset of cavitation in lung metastases in solid tumor patients following apatinib treatment has not been mentioned yet.

Method:
The clinical data of solid tumor patients with lung metastasis treated with apatinib in the Affiliated Hospital of Qiingdao University between 4/1/2015 and 6/17/2017 were collected from medical records, and chest imaging findings were documented. Survival data were analyzed with Kaplan-Meier estimates and compared with log-rank test.

Result:
Sixty-four eligible patients were identified (Table). The main primary tumor sites were stomach (n=23, 35.9%), colorectum (n=14, 21.9%) and liver (n=10, 15.6%). 93.8% patients received 250 mg/day of apatinib orally. Tumor cavitation formation in lung metastases occurred in 20 (31.3%) patients. None of these patients had preexisting cavity, which demonstrated that all cavitary lesions were developed during apatinib administration. There was no significant difference in age, gender, primary tumor site, histology and stage of lung metastases, history of pulmonary surgery and typical adverse events of apatinib between patients developed cavity or not. Compared with those without cavitary lesions, patients with cavitary showed higher rate of temporary increase in CEA (85.0% vs. 34.1%, P=0.0002) and longer progression-free survival (PFS; 15.44 [95% CI, 12.12-20.65] months vs. 6.71 [95% CI, 6.11-8.13] months, P<0.0001). However, patients with temporary increase in CEA showed longer but not significant PFS (11.15 [95% CI, 6.71-15.44] vs. 8.13 [95% CI, 6.31-15.57] months; P=0.3047).

Table Baseline characteristics

Characteristics		Cavitation (n=20)	No Cavitation (n=44)
Age, years	mean±SD	58.65±10.35	61.27±13.86
Gender, n (%)	Male	13 (65.0)	33 (75.0)
	Female	7 (35.0)	11 (25.0)
Primary tumor site, n (%)	Stomach	4 (20.0)	19 (43.2)
	Colorectum	5 (25.0)	9 (20.5)
	Liver	6 (30.0)	4 (9.1)
	Other	5 (25.0)	12 (27.3)
Histology of lung metastases, n (%)	Adenocarcinoma	16 (80.0)	38 (86.4)
	Squamous cell ca	2 (10.0)	2 (4.6)
	Other	2 (10.0)	4 (9.1)
Stage of lung metastases, n (%)	IIIA	0 (0.0)	2 (4.6)
	IIIB	3 (15.0)	13 (29.6)
	IVA	10 (50.0)	20 (45.5)
	IVB	7 (35.0)	9 (20.5)
History of pulmonary surgery, n (%)		8 (40.0)	8 (18.2)
Treatment lines, n (%)	2	4 (22.2)	5 (11.6)
	3	12 (66.7)	33 (76.7)
	4	1 (5.6)	2 (4.7)
	5	1 (5.6)	3 (7.0)

Conclusion:
Cavitation development in lung metastases is accompanied with temporary elevation of CEA in patients treated with apatinib, and might be used as a potential biomarker for survival free of progression.

Background:
Challenges in Precision and Personalized Medicine with interpatient variation needs individualized protocols. PARP Inhibition may be one modality of treatment of NSCLC, as coadjutant to chemotherapy.

Method:
A 66 years old male has been diagnosed with lung adenocarcinoma since 02-06-2016, c T4 c N1 c M1a (pleura and pericardium), had been exposed to carboplatin and pemetrexed for 6 cycles (January to March 2016) with disease progression, and peripheral neuropathy. He didn’t have EGFR mutation, ALK translocation, MET/RET or ROS-1 FISH alterations. He had been treated with radiation therapy from September to November 2016 with 60 Gy, IMRT, and after he received Nivolumab, from November 2016 to Abril 2017 with radiological progression. He had been tested by RCGG in May 2017 looking for circulating tumor cells in vitro (the culture contains all substances measured to apoptotic ability using oncogene apoptosis kit; the result is confirmed by cultures of the tumor or circulating tumor cells), Idengen (inherited hot-spot mutations), and Guardiant 360 by liquid biopsy (circulating DNA sequencing somatic mutations).

Result:
With the Idengene test, he has had PALB2 inherited mutation germline with possible pathogenic significance, BRCA1 and BRCA2 with unknown pathogenic significance. Also, he had NBN, PTCH2, and PTEN as possible pathogenic significance. With the Guardiant 360 test, he had BRCA1, C24Y, NF1, R416Q somatic mutations. With the RGCC test, the specific tumor appears to have resisting populations because of the MDR1 overexpression that can be reversed using inhibitors of ABCG2 pumps. Also, the neoplastic cells have the greatest sensitivity in the alkylating agent (cisplatin, mitomycin), in the tubulin dimmer polymerization inhibitors (Vinorelbine). Inhibitor of Akt/mTOR pathway can be used, as Everolimus, temsirolimus. He has partial sensibility to nucleus spindle stabilizer I (paclitaxel, docetaxel), II (vincristine, vinblastine), and nucleoside analogues (methotrexate, gemcitabine, pemetrexed). Therefore he has been exposed to oral Olaparib 300 mg BID, intravenous Gemcitabine 600 mg/m2, and oral vinorelbine 60mg/m2 weekly both., with good tolerability, and improvement of Performance Status.

Conclusion:
PARP Inhibitor can be a target therapy in personalized medicine, guided by PALB2 / BRCA 1 / 2 mutations in codons inherited and / or somatic mutations, in addition to gemcitabine and vinorelbine in lung adenocarcinoma resistant to platinum/pemetrexed. The addition of Olaparib was possible in this patient, and feasible with a good tolerability, maybe impacting the outcome. More studies related to PARP inhibitor and NSCLC need to be developed.

Background:
Oncogenic driven mutation is the key to develop targeted therapy in lung cancer. Different ethnicity might have the different prevalence of molecular alteration. This study aimed to explore the unique molecular profile of lung adenocarcinoma in Thai population.

Method:
We studied 120 lung adenocarcinoma patients’ molecular profile by FFPE DNA extraction and using Next Generation Sequencing (NGS) on 45 genes lung cancer panel (Ion Torrent system).

Result:
We found 64% (77/120) of EGFR mutation, 13%(16/120) of BRAF V600E,32% (38/120) of KRAS mutation, 11% (13/120) of MET exon14 splice site, 7.5% (9/120) of AKT mutation (E17K), 2.5% (3/120) of ROS1 mutation, 0.8% (1/120) of PIK3CA mutation (H1047R), and 0.8% (1/120) of PTEN mutation by NGS method using the allele fraction cutoff at 2%. We also found 46 patients (38.3%) who had more than one mutation in each person. The validations by the other technique are on-going and will be presented at the WCLC 2017.

Conclusion:
Adenocarcinoma of the lung in Thai population had the unique molecular profile with high prevalence of BRAF V600E and MET exon 14 splice site comparing to the other populations. High prevalence of KRAS and dual different gene mutations in each patient are needed to be confirmed by the other technique because it could be from the artifact of formalin fixation for G12D, G12S, G13D, and G13S of KRAS mutation.

Background:
We have developed a high-purity patient-derived cell (HP-PDC) method for primary culture of malignant effusions from non-small cell lung cancer (NSCLC) patients with oncogenic driver mutations. We updated the results of HP-PDC with mutation test and drug response.

Method:
HP-PDCs were established by a multistep isolation protocol. Malignant effusions were cultured and examined with a light microscope to identify spheroid-forming cells. Immunofluorescence (IF) and flow cytometry were used to evaluate the purity of tumor cell in PDCs. EGFR, ALK or ROS mutation of PDCs was analyzed with direct or PCR-based sequencing and RT-PCR. The sensitivity of target agent to HP-PDCs were tested using a cell viability assay.

Result:
Consecutive series of 79 malignant effusion samples was collected from 61 patients with advanced NSCLC. Spheroid-forming cells were detected in 41 samples which were cultured in AR5 media to establish PDCs. IF analysis revealed that TTF-1 was upregulated in 17 PDCs (21.5%), which also showed EpCAM-positive cell population in flow cytometry with high purity of over 70%. Time spent for establishment of HP-PDCs ranged from 26 days to 132 days. There were 9 PDCs (53%) which harbored active EGFR mutations. Three PDCs with ALK fusion and four with ROS1 fusion were established. Twelve PDC cases were from patients who experienced disease progression while on treatment with EGFR- (9) and ALK- (3) tyrosine kinase inhibitors. Four PDCs with ROS1 fusion were obtained before anti-cancer treatment. Three of PDCs with EGFR mutations were established from patients, who progressed on both gefitinib and the 3[rd] generation EGFR inhibitors. All of them showed in vitro resistance to both gefitinib and 3[rd] generation EGFR inhibitors. PDC from a patient with ROS1 fusion was sensitive to ROS1 inhibitors (entrectinib, crizotinib and ceritinib) in vitro test. The patient has been treated with entrectinib and showed partial response.

Conclusion:
HP-PDCs provide useful in vitro platforms of preclinical studies which predicts responses to targeted therapies in a short period of time and may provide an excellent platform for personalized therapies in NSCLC patients.

Background:
Young patients with Non-small cell lung cancer (NSCLC) represent a distinct subset of patients. There are few reports describing younger patient’s characteristics and survival. Therefore, we conducted a retrospective study, in which we gathered clinical features of NSCLC patients under the age of 50 and matched patients who were older than 60 years at diagnosis.

Method:
Retrospective data of NSCLC patients was collected in a single tertiary hospital between January 2010 and December 2015. Patients were divided into 2 age groups according to the age at diagnosis: younger than 50 years (N=62) and older than 60 years (N=124). Their clinico-pathological characteristics, disease course and survival rate were analyzed.

Result:
The median age was 44 and 68 years of the younger and older cohort respectively. There were more never smokers (36% vs. 24%, p=0.08) and more brain metastasis (40% vs. 25%, p =0.04) in the younger group. Interestingly enough, upper lobes were more involved in the older vs. the younger cohort (p<0.001). A similar percentage of patients underwent NGS testing in both groups, but driver mutations were more common in the younger cohort: Epidermal Growth Factor Receptor (EGFR) mutations (32% vs. 25%, NS), Anaplastic Lymphoma Kinase (ALK) rearrangement (22% vs. 3%, p =0.002). Accordingly, the clinical impact of molecular testing on treatment decision was greater in the young vs. the older group (61% vs. 31%, p=0.002). Median survival was longer in the younger cohort, although not significantly different (34 vs. 21 months, p =0.1).

Conclusion:
Young patients with NSCLC have more driver mutations, more brain metastases and a trend of better survival. Therefore, this group of patients should undergo intensive mutation investigation and brain MRI on initial assessment.

Background:
There is growing awareness that tumor-associated fibroblasts (TAFs) play critical roles in both tumor progression and response to therapies in solid tumors including non-small cell lung cancer (NSCLC). Nintedanib (NTD) is a multi-kinase inhibitor of VEGF, FGF and PDGF receptors that has been recently approved to treat advanced lung adenocarcinoma (ADC) patients in combination with docetaxel. The main goal of this study was to assess how TAFs contribute to the selective therapeutic effects of NTD in lung ADC.

Method:
Because TAFs are largely activated in vivo, patient derived lung TAFs from ADC and squamous cell carcinoma (SCC) patients as well as paired control fibroblasts from non-malignant pulmonary tissue were activated with TGF- β1 in the presence of increasing concentrations of NTD. Conditioned medium was also collected and used to stimulate the growth and invasion of several cancer cell lines. A panel of activation markers indicative of fibrosis were analyzed in TAFs, including alpha-smooth muscle actin, collagen-I/III and P4HA2.

Result:
Nintedanib dose-dependently inhibited the TGF-β1-induced expression of all activation markers in both ADC-TAFs and control fibroblasts derived from uninvolved lung parenchyma, whereas such inhibiton was very modest in SCC-TAFs, suggesting that TAF activation is regulated by different mechanisms in ADC and SCC. Remarkably, nintedanib abrogated the stimulation of growth and invasion in a panel of carcinoma cell lines induced by the conditioned medium from activated TAFs in ADC but not SCC. These results reveal that the pro-tumorigenic effects of ADC-TAFs in vitro are markedly reduced in the presence of NTD.

Conclusion:
These results reveal that nintedanib is an effective inhibitor of fibrosis and its associated tumor-promoting effects in ADC, and that the poor antifibrotic response of SCC-TAFs to nintedanib may contribute to the differential clinical benefit observed in both subtypes. Our findings also support that preclinical models based on carcinoma-TAF interactions may help defining the mechanisms of the poor antifibrotic response of SCC-TAFs to nintedanib and testing new combined therapies to further expand the therapeutic effects of this drug in solid tumors.

Background:
Targeted therapy is becoming increasingly important and has improved the overall survival for patients with NSCLC. BRAF[V600E] mutations (Val600Glu) are observed in 1-2% of lung cancer and play a major role in targeted therapy by providing an opportunity for affected patients as possible allocable target. In Austria an effective therapy is available with Dabrafenib and Trametinib. The aim of this retrospective analysis was to support ongoing research on the frequency of this promising genetic alteration by determining the prevalence of BRAF[V600E] mutations among Austrian NSCLC patients. We also examined clinical characteristics of these patients.

Method:
Patient characteristics including age, sex, race, smoking history and localization of biopsy were collected. Tumor tissue from bronchoscopy, CT- and ultrasound guided biopsies as well as surgical specimen with histological type of adenocarcinoma and NSCLC NOS (Not Otherwise Specified) excluding large cell carcinoma and neuroendocrine carcinoma was reflex tested independent of the tumor stage and clinical characteristics (like sex, smoking history, demography) for BRAF mutations. The BRAF mutation detection was performed since February 2017 with the BRAF/NRAS Mutation Test Kit from Roche on a COBAS[®] z 4800 Analyzer.

Result:
BRAF alterations were found in 11 of 118 tested patients (9.3%), of which 7 patients (5.9 %) showed a BRAF[V600E] positive mutation. Out of these patients with BRAF[V600E] positive mutation, 4 were women and 3 men. 3 patients were Never-Smoker, 2 were former smokers and 2 smokers. Biopsies in 5 patients were taken from the primary tumor, in 1 patient from the lymph nodes and in 1 patient the analysis was performed by drainage of pleura effusions. Median age was 69 years. All patients were Caucasian.

Conclusion:
The prevalence of BRAF[V600E] mutation in this real-world data, assessed in a cohort of 118 people, was higher than BRAF[V600E] mutation rates previously reported by other published data, and thus underline the importance of reflex testing for this druggable target independent of clinical characteristics.

Background:
Although a growing list of mandatory genomic/immune-based biomarkers are now routinely integrated into the management of advanced non-small-cell lung cancer (NSCLC), few reports have detailed the evolution of NSCLC predictive biomarker assessment in routine clinical practice.

Method:
We retrospectively probed 1,000+ NSCLC-patient pairs analyzed for predictive biomarkers from 2004 to 2017 at our institution and evaluated patterns of testing as well as correlation with clinical-pathologic characteristics.

Result:
The majority of 1,009 patient-tumor pairs had advanced adenocarcinoma with most specimens obtained from lung, mediastinal/hilar nodes, and pleura and with a similar distribution between surgical, small biopsy, and cytology specimens. All were tested for EGFR mutations, 895 for ALK rearrangement, 841 for KRAS mutation, 537 for ROS1 rearrangement, and 179 using comprehensive genomic profiling. Implementation of near-universal genomic biomarker testing for EGFR, ALK, ROS1 and PD-L1 occurred within the first year following evidence of activity/approval of a paired therapy. The failure rate after use of the best specimen for the most common tests was ≤5.5%. A quarter of tumors had a driver oncogene (EGFR/ALK/ROS1/BRAF-V600E) with an approved oral therapy, with the highest prevalence in patients with ≤15 pack-years tobacco use.

Conclusion:
Tumor biomarker testing in routine clinical NSCLC specimens at our institution evolves rapidly following approval of new therapies linked to diagnostic assays. Our practice’s decade-plus experience indicates that it will be feasible for the thoracic oncology community to continue to expand the use of predictive genomic and immune biomarkers using currently available clinical specimens.

Background:
Chemoprevention could have a great impact on lung cancer prevention. While Iloprost treatment has shown a significant reduction of dysplasia in former smokers, the identification of patients who would benefit from the drug is seriously hampered due to the need to use invasive diagnostic procedures in patients who are typically asymptomatic. Published clinical data shows that non-invasive sputum analysis using the Cell-CT platform detects early stage lung cancer with high sensitivity (92%) and specificity (95%). This abstract reports the development of cell classifiers that distinguish cultured human lung dysplastic explants from malignant and normal sputum cells. This study represents a first important step toward developing a non-invasive diagnostic test for detecting patients with moderate to severe bronchial dysplasia who may then be treated with chemopreventive drugs such as Iloprost.

Method:
To achieve diagnostic classifications, sputum from patients without lung cancer (“normal cells”), small cell lung cancer and five adenocarcinoma cell lines, and cultured bronchial explants from three patients with moderate to severe dysplasia were analyzed using the Cell-CT.

Result:
15,000 normal cells from sputum, 500 malignant cells from each of the five lung cancer cell lines and 264 cells from patient dysplastic explants were analyzed using Cell-CT platform, measuring 704 structural biomarkers to sub-classify the cancer cells by abnormality and dysplastic status. Cell classifiers were operated to drive the highest specificity (avoidance of false positives). The area under ROC (aROC), sensitivity and specificity for each classifier were:

Cell Classifiers	aROC	Sensitivity %	Specificity %
Lung Cancer cell lines	0.999	93%	99.99
Cells from patient dysplastic explants	0.995	86%	99.99

Conclusion:
These results show strong discrimination by the Cell-CT in classifying normal cells from sputum versus cells from lung dysplastic explants and lung cancer cell lines grown in culture. These data suggest that a non-invasive test using sputum liquid biopsy analyzed on the Cell-CT platform could enable the detection of dysplasia in patients who would benefit from chemoprevention drug therapy.

Background:
LKB1 is a protein kinase that is mutated and down-regulated in 20-30% of non-small cell lung cancer (NSCLC). LKB1 mutations co-occur with KRAS alterations in 7%-10% of NSCLC, resulting in an aggressive phenotype with short survival. Because LKB1 activates AMPK, the master sensor of cellular energy, many of the best known functions of LKB1 are attributed to its ability to control metabolic alterations in the cells. However LKB1 also plays an important role in regulating angiogenesis, likely as a strategy to overcome energetic depletion of tumor microenvironment. Bevacizumab, the human anti-VEGF antibody, improves the PFS and OS of NSCLC patients combined with chemotherapy, but often the benefit is transient and therapeutic resistance occurs. Our laboratory has previously identified alterations in cell metabolism and in vasculature of LKB1-deficient tumors when compared to LKB1 wild type in NSCLC.

Method:
LKB1 KO murine NSCLC cell lines were generated using CRISPR/Cas9 system in a KRAS[G12D] mutant background (LKR10 & LKR13). Syngeneic NSCLC models were established via s.c. injection of LKB1 intact and KO murine cells in immunocompetent mice. After tumors reached 150 mm[3] mice were randomly assigned to treatment groups consisting of vehicle, mouse anti-VEGF and nintedanib. Tumor volumes were measured and compared using student’s t test and samples were collected for vasculature analysis. Survival curves will be calculated using log rank test. Hypoxia experiments were preformed and apoptosis was measured using annexin V and 7ADD staining.

Result:
Treatment with anti-VEGF or nintedanib significantly inhibited tumor progression in LKB1 wt KRAS[G12D] mutant mouse model (p<0.001) but did not show any therapeutic effect in the LKB1 KO KRAS[G12D] group. Furthermore in the LKB1 wt group, the median survival of anti-VEGF and nintedanib treated mice was 111 days and 84 days respectively and 37 days in the vehicle group. No improvement in survival was detected in the LKB1 KO group after treatment with anti-VEGF. In vitro studies showed that LKB1 loss is associated with a decrease in oxygen consumption and enhanced glycolysis. Furthermore LKB1 KO NSCLC cells showed a decrease in apoptosis under hypoxic and low nutrient conditions compared to LKR13 LKB1 wt cells.

Conclusion:
NSCLC LKB1-deficient tumors showed resistance to anti-angiogenic therapy and this effect is driven by the regulation of metabolic adaptations that allow cells to survive under hypoxic and low nutrient conditions.

Background:
Patient-tailored therapy based on tumor genomics is limited to 30-40% of the patients whose tumor harbor actionable DNA mutations or amplifications.

Method:
WINTHER is an international open label non-randomized clinical trial developed by the WIN consortium. Matched tumor and normal tissue biopsies are collected and analyzed by NGS (Foundation Medicine) or by functional genomics utilizing a prediction model of efficacy developed at Ben Gurion University.

Result:
56 patients were biopsied. 29 (52%) had lung cancer. Successful biopsies yielding sufficient material for full genomic analyses were achieved in 29 subjects (53%). Lung biopsy success rates were 71% and 61% respectively for normal and tumor specimens. To date, 11 lung cancer patients were treated with chemotherapy (1) or biologic agents (11). Targeted genomic alterations included EGFR (3), RET (2), KRAS (2), ALK (1), ErbB2 (1), ErbB3 (1), BRAF (1). Clinical benefit rate (CBR) was 55% (6/11) with 1 subject achieving compete response, 2 partial response and 3 stable disease. Response durations were 7, 14 and 18 months.

Conclusion:
Tumor genomic analysis based on the comparison of matched tumor and normal biopsies is acceptable and feasible. The experience of the multidisciplinary team is an important contributor to the program’s success.

Background:
ROS1 rearrangements define a distinct molecular subset of lung adenocarcinoma and patients (pts) experience significant improvements with oncogene-directed therapies. Break-apart/Split Fluorescence in situ hybridization (FISH) is a commonly used detection method for rearranged genes as well as the copy number variation (CNV). Based upon FISH, we aimed to thoroughly evaluate the prognostic role of ROS1 alterations in lung adenocarcinoma.

Method:
Between 1997 and 2016, 634 pts with complete FISH test data were enrolled and followed for outcome research. According to ratios of separated signals, ROS1 rearrangement status were dichotomized into positive and negative. Due to combinative patterns of the signals, positive ones were divided into typical (separation), atypical (single 3' signal) and rare patterns (single 5' signal), and CNV were divided into normal, amplification and deletion.

Result:
ROS1 rearrangement was present in 24 (3.8%) pts, including 17 (2.7%) typical or atypical patterns and 7 (1.1%) rare patterns. ROS1 rearranged pts confer sensitivity to treatment with ALK/ROS1/MET inhibitor crizotinib as the overall response rate (ORR: CR+PR) is 37.5% and the overall disease control rate (DCR: CR+PR+SD) is 75.0%; for 1st line therapy, these rates are 50.0% and 83.3%, respectively. However, the ORR and DCR were dramatically decreased in 2nd or 3rd line therapy as 25.0% and 25.0%. Overall survival rates differ among three kinds of rearranged patterns; rare pattern pts tend to have the worst prognosis. Multivariate Cox regression analysis indicated that ROS1 rearrangement (hazard ratio [HR], 0.49) was significantly associated with improved overall survival (OS) while disease free survival (DFS) was equivocal (HR=0.66; p=0.22), and CNV was not an independent prognostic factor for both OS and DFS. ROS1-negative pts had worse fatigue and lung cancer symptoms than positive ones, while CNV did not predict recent QOL. Younger age (<60 years), female gender, non-smoker and advanced stage (IIIb-IV) were significant indicators for ROS1 rearrangement.

Conclusion:
ROS1 rearrangement confers favor OS and QOL in lung adenocarcinoma pts and crizotinib induced preferable clinical remission, while CNV showed no exact implications, which might only act as an minor aspect of genetic heterogeneity in tumor cells. Therefore, our results highlight the importance of screening for ROS1 rearrangement in pts with lung adenocarcinoma, which should help to prolong pts’ survival time and maintain or improve QOL.

Background:
EGFR-TKIs are recommended first-line treatment for patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC). Most patients develop resistance after an average of approximately 12 months. Among various mechanisms, about half are acquired with T790M in EGFR exon 20. Little is known about the mechanisms in patients progressed within 6 months after first-line treatment of EGFR-TKIs. Therefore, we prospectively designed this study to investigate the possible mechanisms of resistance in this group of patients.

Method:
NSCLC patients with sensitive EGFR mutations who treated with first-line EGFR-TKI in Zhejiang Cancer Hospital from Jun 2014 to Jan 2017 were screened prospectively. Tissue samples pre-TKI and after disease progression (RECIST1.1) were collected. Blood samples were collected after disease progression. The study was approved by hospital research ethics committees. Of the total 50 patients enrolled for the study, 21 patients were included and further divided into two groups: patients suffered disease progression within six months after taking EGFR-TKI were classified as Group A (rapid progress group, n=13); patients took EGFR-TKI more than two years were classified as Group B (long term survival group, n=8). Patients with a PFS between 6 months to two years were excluded. We performed NGS of ~416 cancer related genes from the primary cancer samples collected before TKI treatment. Differences of gene alterations between two groups were analyzed.

Result:
The median age was 55 years old (range: 34-75 years). There were 47.6% female and 53.8% non-smokers. All patients in Group A carried TP53 mutation before treatment, none was found in Group B. The average cancer-related genetic mutations is 6.46 (range 3-16, 6 in Group A, 5.6 in Group B, P>0.05). There was enrichment for co-alterations in TP53 (100%), RB1 (38%), NKX2-1 (31%), BIM (30.8%) in pre-treated tissues from Group A. ERCC2 (38%), JAK3 (38%), BRCA2 (25%) were enriched in pre-treated tissues from Group B. Mutation rate of EGFR T790M after resistance was lower in Group A (2/13,15.4%) than in Group B (2/5, 40%). Three patients (3/8) are still benefit from first-line EGFR-TKI without disease progression in Group B. The median PFS was 3 months for Group A (range 1-5 months) and 26.5 months for Group B (range 24-52 months).

Conclusion:
This data highlights a model of genetic collectives as potential mechanisms of rapid progression in first-line EGFR-TKIs treatment. TP53 mutation reduced responsiveness to TKIs and worsen prognosis in EGFR-mutated NSCLC patients, contributing to rapid disease progression. EGFR T790M mutation seems uncommon in rapid progression patients.

Background:
Although non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations are responsive to EGFR-tyrosine kinase inhibitors (EGFR-TKIs), drug resistances are always inevitable. Concurrent multiple mutations and bypass mechanisms both can contribute to development of resistance to EGFR-TKIs. Preclinical and clinical evidences suggest a role for MET activation as a secondary driver of resistance to targeted therapy. Activation of the MET pathway can occur through a diverse set of mechanisms including MET amplification, MET exon 14 alterations, MET overexpression. As partial overlap of these biomarkers occurs, whether one is purely a surrogate for the other, or if both can represent true oncogenic driver states continues to be explored. Cases of MET inhibitor sensitive NSCLC harboring exon 14 alterations without co-incident amplification have already been described. But concurrent EGFR-mutation and MET overexpression in one case is rare. Whether MET overexpression can be served as a driver alteration in NSCLC and its cut-off value need to be explored.

Method:
A NSCLC patient with EGFR mutation who took first line EGFR-TKI therapy was described in this report. The chest enhanced CT examination, whole-body PET/CT, coarse needle biopsy on right clavicle and bronchoscopy were taken to assess the disease condition before treatment. ARMS, IHC, FISH, ddPCR and NGS were used to detect gene alterations including gene mutation, overexpression and amplification, in cancer tissue samples obtained before TKI and after disease progression.

Result:
In this case, we described a 56-year-old male NSCLC patient with EGFR Ex21 L858R mutation who underwent refractory after first line EGFR-TKI therapy and was confirmed having concurrent c-MET overexpression (ICH: +++, 95%) before treatment. Disease progression was occurred after taking first-line EGFR-TKI for 4 months. Patient was then further confirmed having c-MET overexpression (ICH: +++, 90%) but without EGFR T790M mutation, c-MET amplification and MET exon 14 alterations in progressed cancer samples. Crizotinib was added to the treatment from Aug 8, 2016 after disease progression. And the recent chest enhanced CT examination on May 5, 2017 confirmed complete response (CR) to crizotinib in this patient.

Conclusion:
Our case report uncovered the underling mechanism of c-MET overexpression in EGFR-TKI resistance, and crizotinib may assist to overcome this resistance to EGFR-TKI. In this case, MET overexpression and EGFR mutation were concurrent before treatment. Thus, whether simultaneously applied EGFR-TKI and MET inhibitor in first-line treatment could result a better outcome was needed to be further demonstrated. The ideal cut-off value of MET overexpression is also waiting for determination.

Abstract not provided

Background:
For patients with metastatic EGFR mutated NSCLC, 1[st] line treatment with EGFR TKIs such as erlotinib result in a median PFS of about 10 months. In patients with a limited number of progressing lesions, local ablation therapy (LAT) of progressive lesions followed by re-initiation of TKI has shown promise in retrospective studies but to date this strategy has not been testing in prospective fashion.

Method:
As part of an IRB approved open label prospective phase II trial, patients with EGFR mutated NSCLC and immediate progression on a TKI in < 5 locations were treated with stereotactic radiosurgery (SRS) to progressing lesions followed by re-initiation of erlotinib. Our primary endpoint was PFS, and we hypothesized that it would be at least 3 months.

Result:
25/40 planned patients were enrolled; data are available on 23 and will be updated prior to the conference to include 25. By local reporting, 14 had exon 19, 5 had exon 21, 1 had compound exon 18 and exon 20, 1 had compound exon 19 and EML4/ALK and 2 were unknown. 65% were female, all were non-Hispanic white, median age 62.5, PS0 65.2%/PS1 34.8%, median Charlson Comorbidity Index 6, and 71.4% were never smokers. Median number of lesions treated was 1 (range 1-3). There were no G3-4 AEs to SRS. Two subjects had grade 3 rash on erlotinib. Median PFS post treatment was 5.8 months (95% CI, 2.5 to 11.3) and median OS was 2.9 years (95% CI 1.1 to 2.9). Serum proteomics showed a Veristrat good signature for all but one subject; this result changed to good following LAT. No signatures turned to poor at progression.

Conclusion:
LAT resulted in a modest extension in the duration of targeted therapy, supporting retrospective data in this population. Accrual to this study has been challenging due to the availability of 3[rd] generation EGFR TKIs and because LAT is often done outside of a clinical trial.

Background:
This Study will assess the stability of the ProLung China Test classification algorithm when used as an adjunct to CT scan. Also, we will assess whether there are any potential safety concerns of the ProLung China Test when used to evaluate patients with a positive CT scan for lung cancer.

Method:
This study is a multicentre, prospective, open, self-control study which aims to evaluate the utility of the ProLung China Test in diagnosis of lung cancer (ClinicalTrials.gov ID: NCT02726633 ). The subject whose age is between 18 and 80 years old and CT result shows a 4 ~ 50 mm nodule within 30 days is our object. In these objects, we will exclude those people who has TB, pulmonary edema, chronic lung infection, abnormal anatomy, skin disease effecting bioconductance and other tumors.The expected sensitivity and specificity of Prolung China Test are 70 % and 61%, and non-inferiority margin is 10 %. Based on these statistical information, four clinical trial centers, in the study, will enroll at least 452 samples with 20 % dropout rate. These samples must contain at least 182 effective malignant sample and 194 benign samples.

Result:
According to the inclusion and exclusion criteria, excision biopsy or follow-up examination will perform on enrolled subjects. Before these examination, a Prolung China test will be operated on these subjects. The subject in follow-up will be followed at least 24 months. The pathology result and follow-up result will be the gold standard in this study. The diagnosis result and adverse event will be recorded during the experiment.

Conclusion:
To demonstrate safety and efficacy of the ProLung China Test in the risk stratification of patients with pulmonary lesions identified by CT that are suspicious for lung cancer.

Background:
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by worsening dyspnea and progressive loss of lung function. Acute exacerbation of IPF is associated with high morbidity and mortality. Several studies have provided evidence of an association between lung cancer and IPF, with a prevalence of lung cancer in IPF patients ranging from 9.8% to 38%. Although the efficacy of nintedanib for IPF has been demonstrated, it has remained unknown whether this agent also reduces the risk of chemotherapy-induced acute exacerbation of IPF. Patients with interstitial pneumonia have been excluded from most prospective clinical trials for NSCLC because of the risk of acute exacerbation, with only two prospective single-arm phase II studies having been reported. In addition, it has been difficult to perform a randomized prospective clinical trial for patients with advanced NSCLC and IPF because of their rarity. The optimal chemotherapy regimen for advanced NSCLC with IPF has thus remained unclear.

Method:
Chemotherapy-naïve patients with advanced NSCLC associated with IPF (enrollment target of n = 170) are randomized at a 1:1 ratio to receive four cycles of carboplatin (AUC 6 on day 1) plus nab-paclitaxel (100 mg/m[2] on days 1, 8, and 15) administered every 3 weeks either without (arm A) or with (arm B) nintedanib (150 mg b.i.d., daily), to be followed in arm B by single-agent administration of nintedanib (150 mg b.i.d., daily). The primary end point of the study is time to acute exacerbation of IPF.Figure 1



Result:
Section not applicable

Conclusion:
J-SONIC is the first randomized controlled study for treatment of NSCLC associated with IPF. The goal of the study is to demonstrate that nintedanib in combination with carboplatin plus nab-paclitaxel prolongs time to acute exacerbation of IPF compared with carboplatin plus nab-paclitaxel alone. Study enrollment began in May 2017 and is to continue for 3 years.

Background:
More than 40,000 US patients per year present with stage III NSCLC. These patients are of particular interest in that most are not resectable and while they can be treated with curative intent with excellent initial responses, only approximately 25% will be cured by conventional chemoradiotherapy. This, together with the generally better health of this cohort compared to patients with metastatic NSCLC, makes these patients ideal candidates for studies of immunotherapy to increase cure rates. The combination of checkpoint inhibition to counter tumor related immunosuppression along with standard chemoradiotherapy that depletes T-regulatory cells should create immunologic “space” to facilitate clonal expansion of effector T-cells in an environment that fosters improved tumor immunogenicity by blocking PD-L1. Responses to immunotherapy seem to be higher in patients for whom significant cytoreduction can be achieved, such as with radiation of all known disease. Further, both chemotherapy and radiation may expose otherwise hidden antigens that can present additional targets to the reconstituting immune system.

Method:
This phase II single arm Alliance Foundation study (NCT03102242) will evaluate safety and efficacy of atezolizumab before and after definitive chemoradiotherapy. 63 patients with stage III NSCLC, PS 0-1, no active autoimmune disease, adequate cardiopulmonary function and no underlying organ dysfunction will be enrolled at 15 Alliance sites in the US. Treatment consists of 4 cycles of neoadjuvant atezolizumab 1200 mg IV q 21 days before chemoradiotherapy with restaging after cycles 2 and 4. Nonprogressing patients undergo weekly carboplatin and paclitaxel concurrent with 60 Gy thoracic radiotherapy followed by 2 cycles of carboplatin and paclitaxel consolidation followed by completion of one year of atezolizumab. The primary endpoint of this pilot study is disease control (CR+PR+SD) after neoadjuvant atezolizumab. Secondary endpoints include ORR, PFS and OS, safety and QoL assessed by the EORTC QLQ-30. Translational endpoints seek to define the role of PD-L1 biomarker testing in selecting the population most likely to respond to neoadjuvant and adjuvant immunotherapy together with standard chemoradiotherapy and to study the association of biomarkers, including immunologic signatures, with response and survival. Tumor tissue will be assessed at study entry and, where possible, at progression. Plasma and immune cells will be assessed at baseline, post neoadjuvant atezolizumab, post chemoradiotherapy, during adjuvant atezolizumab and at study completion or progression. Analyses may include multipanel immunohistochemistry, gene expression profiling, whole exome and T cell receptor sequencing, cytokine/chemokine analysis, flow cytometry immunophenotyping, and T cell function.

Result:
Section not applicable

Conclusion:
Section not applicable

Background:
50%-60% of patients after the first-generation EGFR-TKI, gefitinib and erlotinib showed acquired resistance of T790M mutation and osimertinib is a standard regimen for this population. However, the median PFS by osimertinib alone is 8-10M and a better strategy is needed. One promising option is a combination of osimertinib and chemotherapy, and previous trials have suggested the promising efficacy by the combined treatment of EGFR-TKI with pemetrexed. We here present the treatment rationale and study design of TAKUMI trial, a multicenter randomized phase Ⅱ study of of osimertinib (Tagrisso) alone versus osimertinib plus carboplatin/pemetrexed for patients with locally advanced or metastatic non-small cell lung cancer whose disease has progressed with previous epidermal growth factor receptor tyrosine kinase inhibitor therapy and whose tumours harbour a T790M mutatIon within the epidermal growth factor receptor gene.

Method:
Figure 1schema of this study



Result:
Section not applicable

Conclusion:
Section not applicable

Background:
This study will investigate whether PD-L1 and other immuno-markers will be influenced by osimertinib treatment in advanced EGFR T790M positive advanced NSCLC patients，who have progressed on an EGFR-TKI.

Method:
This study is an ASTRIS companion study. Major eligibility criteria include locally advanced (stage IIIB) or metastatic (stage IV) EGFR sensitive mutation NSCLC, not amenable to curative surgery or radiotherapy, with confirmation of the presence of the T790M mutation, prior therapy with an EGFR-TKI, PS 0-2, and the patients are willing to provide tumor specimens before osimertinib treatment and at the time of disease progression. The FFPE tissue samples will be collected at the time of baseline and disease progression. PD-L1 and CD8+ T cell will be detected by IHC (Ventana SP263). Immune-related gene will be detected by ThermoFisher Oncomine[TM] Immune Response Panel (398genes). The plasma samples will be collected at the time of baseline and disease progression, and tumor mutational burden will be detected by QIAGEN Mix-561-Match Panel (561 genes). A sample size of 62 will provide a power of 80% to detect the change at an alpha level of 0.05 based on Wilcoxon rank sum test. Assuming re-biopsy will be obtained from 40% patients at disease progression, the total number of patients will be 155. Estimated date of first subject enrollment will be before March 2017, and last subject last visit will be at June 2018. (NCT03029858)

Result:
The clinical trial is open for enrollment.

Conclusion:
The study points are not reached now.

Background:
Pain is common in malignant pleural mesothelioma (MPM) and tends to be poorly responsive to analgesia. Radiotherapy has traditionally been used for pain control, without robust supportive evidence. ‘SYSTEMS’ was the first prospective study to use validated endpoints to assess pain response to a standard dose of palliative radiotherapy (20Gy/5#). This multicentre, phase II trial demonstrated clinically meaningful improvements in pain in one third of patients at week 5, with minimal toxicity. The SYSTEMS-2 study is comparing pain control at week 5 in the standard arm (20Gy/5#) with that in the dose escalated arm (36Gy/6#).

Method:
Recruitment target is 112 patients across 15-20 UK hospitals. Eligible patients have: • MPM diagnosis • ECOG PS 0-2 • Pain score ≥ 4/10 after analgesia optimisation • CT scan with contrast within 8 weeks of starting radiotherapy • Radiotherapy plan compatible with dose escalated arm prior to randomisation. Wire markers are used to indicate sites of pain at radiotherapy planning and doses to organs at risk (OAR) are minimised through advanced planning techniques (e.g. intensity modulated radiotherapy- IMRT). (Figure 1) The primary outcome is pain control at the radiotherapy site at week 5. A clinically significant response is defined as a drop of ≥ 2 points in a validated numerical rating scale. Radiological response will be assessed at week 9. Figure 1



Result:
SYSTEMS-2 opened to recruitment in August 2016. More than 30 patients have been screened across a total of 5 UK sites and 15 patients have been randomised. A further 19 sites are currently in set-up. PTV coverage and OAR doses have been consistently achieved, despite large treatment volumes and nearby radiosensitive structures. Radiological responses have been seen across both cohorts.

Conclusion:
This study will provide robust and accurate symptom response data for palliative radiotherapy in MPM and help to establish the optimal dose and fractionation.

Background:
Small cell lung cancer (SCLC) is an aggressive and invasive variant of lung tumors，and its treatment strategy is poor. Apatinib is an oral TKI against VEGFR-2. We determined the efficacy of Apatinib as third- or later-line treatment in advanced SCLC.

Method:
The study was expected to enroll 30 patients diagnosed with advanced SCLC. Patients received oral Apatinib 500mg QD and make an efficacy evaluation after first cycle, then every two cycles once again. The primary endpoint was progression-free-survival (PFS).

Result:
From November 10, 2016 to June 18, 2017, 10 patients were enrolled. 1 patient showed PR when make efficacy evaluation the first time, 8 patients were evaluated SD and 1 patient showed PD due to liver metastasis. Although only one patient showed PR, all the patients’ target lesions were reduced, as figure 1. Figure 1 Up to June 18, 4 patients out of the group due to PD, the PFS is 28 weeks, 19.8 weeks, 13 weeks and 4.7 weeks respectively. Another 6 patients are still investigated, as figure 2, the blue bars are their PFS . Figure 2





Conclusion:
Apatinib in advanced SCLC is worth expecting.To further investigate the role of Apatinib in SCLC patients, large sample and additional clinical trials are needed.

Background:
Daratumumab (DARA), a human CD38 monoclonal antibody, is approved for the treatment of patients with relapsed/refractory multiple myeloma (RRMM). DARA produces deep clinical responses in RRMM and induces T-cell expansion through the reduction of immune suppressive cell populations, such as CD38[+] myeloid-derived suppressor cells and regulatory T and B cells. Atezolizumab (atezo) is a humanized programmed death-ligand 1 (PD-L1) monoclonal antibody that blocks the interaction between PD-L1 and the programmed death-1 and B7.1 receptors, reinvigorating anticancer immune responses. Atezo was recently approved for patients with metastatic NSCLC that progressed on or during platinum therapy based on data showing improved overall survival (OS) in the atezo vs docetaxel treatment arm in two clinical trials. The combination of DARA and atezo may improve clinical responses in NSCLC by enhancing anti-tumor T-cell responses facilitated by checkpoint inhibition. This study will assess the anti-tumor activity and safety profile of DARA plus atezo vs atezo alone in patients (pts) with previously treated advanced or metastatic NSCLC.

Method:
This is an ongoing phase 1b/2 randomized, open-label, multicenter study of DARA (16 mg/kg intravenous [IV] weekly for 3 cycles [Days 1, 8, and 15] and then Day 1 of each 21-day cycle thereafter) in combination with atezo (1200 mg IV; Day 2 of Cycle 1 and Day 1 of each 21-day cycle thereafter) versus atezo alone (1200 mg IV; Day 1 of Cycle 1 of each 21-day cycle). Eligible pts (≥18 years) must have advanced or metastatic NSCLC and have received 2 or more cycles of standard platinum-based therapy with disease progression or intolerance to therapy. Eastern Cooperative Oncology Group performance status of ≤1 and known PD-L1 tumor status are required. Pts previously treated with anti-CD38 therapy, including DARA, CD137 agonists, or immune checkpoint inhibitors are excluded. The primary endpoint is overall response rate. Secondary outcomes include safety, duration of response, clinical benefit rate (≥16 weeks duration), progression-free survival, OS, and pharmacokinetics and immunogenicity of DARA and atezo when given in combination. Approximately 96 pts will be enrolled; 6 pts will receive combination therapy in a safety run-in cohort for evaluation of dose-limiting toxicity followed by 90 pts randomly (1:1) assigned to the 2 treatment arms. ClinicalTrials.gov number, NCT03023423.

Result:
Section not applicable

Conclusion:
Section not applicable

Background:
PD-1/PD-L1 axis inhibition and comprehensive stereotactic body radiation (SBRT) treatment to all gross disease have both been independently associated with improved outcomes for patients with oligometastatic NSCLC in randomized trials. Interest has increased in the use of dual immune checkpoint inhibition in NSCLC, which adds targeting of CTLA-4 to PD-1/PD-L1 inhibition, as this has showed improved outcomes in melanoma, though with increased side effects. Recent appreciation for the immunostimulatory effects of SBRT and possible synergy with checkpoint inhibition therapies has prompted interest in combining these treatments, however the toxicity of this combination is unknown. This is the first trial evaluating the sequential combination of comprehensive SBRT and dual immune checkpoint inhibition.

Method:
This phase I trial will assess the safety and preliminary outcomes for a 21 patient cohort undergoing SBRT to all sites of oligometastatic (EGFR/ALK wildtype) NSCLC followed by combined duvalumab and tremelimumab immune checkpoint inhibition. Patients with 1-6 extracranial sites of disease will undergo SBRT from 30-50 Gy in 5 fractions. One week after radiation they will receive 4 cycles of combination Durvalumab 1500mg/Tremelimumab 75mg every 4 weeks followed by Durvalumab 1500mg monotherapy q 4 weeks. The primary endpoint of this study is safety. Secondary endpoints include overall survival (OS) and (PFS). Correlative studies of PD-L1 expression on post SBRT biopsy and circulating tumor cells are incorporated into the protocol.

Result:
Section not applicable

Conclusion:
The study is currently undergoing IRB review and FDA IND approval. This study will open to accrual in August 2017.

Background:
Current state-of-the-art lung cancer early screening utilizes low-dose CT scan to identify lung nodules smaller than 3 cm in diameter. However, it's still a clinical challenge to differentiate between malignant and benign nodules. In previous studies, we had taken the approach of methylation profiling by high- throughput bisulfite DNA sequencing to learn methylation patterns that differentiate malignant vs. benign lesions from tissue samples by in-depth data mining, and then used pattern matching to classify plasma samples. We were able to achieve a preliminary sensitivity of 94.3% for identification of malignancies, with a preliminary specificity of 93.6% against all benign specimens in the training set (129 malignant specimens and 101 benign specimens). From an independent validation set of 145 plasma samples (79 malignant specimens and 66 benign specimens from asymptomatic normal individuals and patients), this assay obtained a preliminary sensitivity of 78.5% and a preliminary specificity of 83.3% for differentiating patients with malignant tumor. Specifically, the assay is demonstrated to be highly sensitive towards early‐stage lung cancer detection, with a preliminary sensitivity of 71.1% in 38 patients with stage Ia lung cancer and 87.5% in 16 patients with stage Ib lung cancer. In this multi-center clinical study, we aim to validate the accuracy of ctDNA methylation test for diagnosing early-stage lung cancer by comparing the pre-operational ctDNA methylation test results with the surgical pathology results. (NCT03181490，CCTC-1701)

Method:
Patients who are diagnosed with solitary pulmonary nodules (<=3cm) by LDCT/CT scans and have decided to undergo surgery will be recruited in this study. All blood samples are collected before surgery. We take the approach of targeted methylation profiling by high-throughput bisulfite DNA sequencing of plasma samples to identify lung cancer specific methylation signatures. By comparing the results of the methylation test and the histopathological diagnostic results, we calculate the specificity and sensitivity of the methylation test on differentiating patients with malignant lesions from benign diseases. The laboratory technicians and analysts who perform the methylation tests are blinded to this study. Sample size determination: expected specificity and sensitivity is 80% based on pre-clinical study, permissible error is ±5%, α=0.05, β=0.10. According to the study design, patients with benign nodules make up ~20% of all patients. Therefore, the estimated sample size for each of the benign and malignant group is estimated to be at least 246.

Result:
Section not applicable

Conclusion:
Section not applicable

Background:
Recent advances in imaging technology and the widespread use of low-dose computed tomography screening have greatly increased the chance of detecting small-sized non-small cell lung cancer (NSCLC) with indolent features (radiologically ground-glass opacity and histopathologically lepidic pattern adenocarcinoma). This change in the disease pattern of NSCLC has led to a resurgence of interest in sublobar resection. The purpose of this study is to determine the outcome of patients with clinical stage IA NSCLC treated by 3 types of surgical resection (wide wedge resection, segmentectomy, or lobectomy) according to the institutional decision-making algorithm.

Method:
In this study, we are planning to prospectively enroll 1,000 patients with clinical stage IA NSCLC undergoing curative-intent surgical resection. Our decision-making algorithm regarding the optimal extent of pulmonary resection has been developed based on our institutional consensus building meetings. We are planning to prospectively measure radiologic features such as tumor diameter and consolidation/tumor (CT) ratio. For ≤ 2cm tumors with CT ratio of ≤ 0.25, wide wedge resection needs to be performed. For ≤ 2cm tumors with CT ratio of 0.25 to 0.5 or 2-3cm tumors with CT ratio of ≤ 0.5, segmentectomy should be chosen. When CT ratio is larger than 0.5, lobectomy is required regardless of tumor size. When either parenchymal or bronchial resection margin is found to be insufficient during surgery, segmentectomy or lobectomy should be done even when a lesser resection was planned. Resection margins greater than the maximal tumor diameter (lesions less than 2cm) or at least 2cm gross margins (lesions larger than 2cm) should be achieved. Hilar and mediastinal lymph node dissection or at least systematic lymph node sampling is strongly recommended for any kind of pulmonary resection.

Result:
The primary objective is to determine disease-free survival following sublobar resection and lobectomy. The secondary objectives are (1) to determine overall survival following surgery, (2) to determine rates of loco-regional and systemic recurrence following surgery, (3) to compare postoperative pulmonary function between 3 different resection types, (4) to explore the relationship between radiologic parameters and pathologic subtypes, and (5) to determine the predictors of unexpected nodal involvement.

Conclusion:
This study is registered with ClinicalTrials.gov, number NCT03066297 (“OREX-IA” study) and we started recruiting patients in February, 2017 and will also be planning to follow up patients for at least 5 years to analyze their survival and recurrences.

Background:
In patients with metastatic EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC), resistance to EGFR tyrosine kinase inhibition arises from the T790M EGFR mutation in over half of cases; up-regulation of “bypass track” activity in non-EGFR signaling pathways is observed in other cases. Up-regulation of expression of the AXL tyrosine kinase has been observed in EGFRm NSCLC patients experiencing disease progression on erlotinib, and xenograft studies have explored the role of AXL inhibition in combination with EGFR TKI treatment in overcoming such resistance. DS-1205c is a novel, orally administered, specific small molecule inhibitor of AXL.

Method:
Trial Design: This is a multicenter, open-label, Phase 1 study of DS-1205c in combination with osimertinib in metastatic or unresectable EGFR-mutant NSCLC subjects experiencing disease progression during treatment with erlotinib, gefitinib, or afatinib, and without T790M resistance mutation. Eligible subjects are at least 18 years of age, have ECOG PS 0 or 1, have radiological documentation of disease progression while receiving continuous treatment with erlotinib, gefitinib, or afatinib, have at least one measurable lesion per RECIST v1.1, do not have spinal cord compression or clinically active brain metastases, and do not have any factors that increase the risk of QTc prolongation. This study includes two parts: Dose Escalation and Dose Expansion. In Dose Escalation, subjects receive DS-1205c during a run-in period, followed by continuous combination treatment with DS-1205c and osimertinib. Escalation of DS-1205c dosing between subjects is determined from dose-limiting toxicity data in subjects, guided by the modified Continuous Reassessment Method (mCRM) using a Bayesian logistic regression model (BLRM) following the escalation with overdose control (EWOC) principle. In Dose Expansion, subjects receive DS-1205c at the recommended dose for expansion determined in Dose Escalation, in combination with osimertinib. Primary objectives are to determine the safety, tolerability, and recommended dose for expansion of DS-1205c in combination with osimertinib. Secondary objectives are to assess the pharmacokinetic parameters of DS-1205a (free form of DS-1205c), osimertinib, and osimertinib active metabolites, and to assess antitumor activity (RECIST v1.1).Clinicaltrials.gov identifier: NCT03255083

Result:
Section not applicable

Conclusion:
Section not applicable

Background:
While the treatment of EGFR-mutant NSCLC has significantly improved with the use of EGFR tyrosine kinase inhibitors, there remain limited treatment options for many patients who develop resistance to these agents. The HER3/ERBB3 oncogene is overexpressed in many cancers, including NSCLC, and higher expression is correlated with poorer outcomes. U3-1402 is a novel antibody-drug conjugate (ADC) comprised of a recombinant fully human anti-HER3 antibody (patritumab) covalently conjugated via a cleavable peptide linker to a derivative of the topoisomerase I inhibitor exatecan. After U3-1402 binds to HER3 on the tumor cell surface, it is internalized and leads to apoptosis via inhibition of topoisomerase I. This ADC achieves a high drug-to-antibody ratio of ~8:1.

Method:
Trial Design: This is a multicenter, open-label Phase 1 study of U3-1402 in metastatic or unresectable non-squamous NSCLC subjects harboring EGFR-activating mutation who (a) are T790M mutation-negative after disease progression during treatment with erlotinib, gefitinib, or afatinib or (b) develop disease progression while on osimertinib. Eligible subjects are at least 18 years of age, have ECOG PS 0 or 1, have radiological documentation of disease progression while receiving continuous treatment with erlotinib, gefitinib, afatinib, or osimertinib, have at least one measurable lesion per RECIST v1.1, have adequate bone marrow and organ function, do not have LVEF < 45% by either ECHO or MUGA scan, do not have mean QTc prolongation to > 470 ms for females and >450 ms for males, and do not have spinal cord compression or clinically active brain metastases. This study includes two parts: Dose Escalation and Dose Expansion. In Dose Escalation, subjects receive U3-1402 via intravenous infusion in 21-day cycles. In Dose Escalation, escalation of U3-1402 dosing between subjects is based on dose-limiting toxicity data in subjects, guided by the modified Continuous Reassessment Method (mCRM) using a Bayesian logistic regression model (BLRM) following the escalation with overdose control (EWOC) principle. In Dose Expansion, subjects receive U3-1402 at the recommended dose for expansion determined in Dose Escalation. Primary objective is to determine the safety, tolerability, and recommended dose for expansion of U3-1402. Secondary objectives are to assess the pharmacokinetic parameters of U3-1402, total anti-HER3 antibody, and MAAA-1181a (drug payload), and to assess antitumor activity of U3-1402 (RECIST v1.1).Clinicaltrials.gov identifier: NCT03260491

Result:
Section not applicable

Conclusion:
Section not applicable

Background:
Mesothelioma is an incurable, apoptosis-resistant cancer caused in most cases by previous exposure to asbestos and is increasing in incidence. It represents a growing health burden but remains under-researched, with limited treatment options. Despite a significant number of clinical studies in the second line setting, no randomized study has been positive. Early promising signals of activity relating to both PD-L1 and PD-1 targeted treatment in mesothelioma implicate a dependency of mesothelioma on this immune checkpoint, and support the development of a randomized phase III trial to evaluate the efficacy of nivolumab. CONFIRM is the first ever placebo controlled, randomized phase III trial of a PD-1/PD-L1 immune checkpoint inhibitor in mesothelioma.

Method:
The primary objective is to determine whether nivolumab increases overall survival (OS) in relapsed mesothelioma. Secondary objectives are to determine whether nivolumab a) increases progression-free survival, b) increases response rate, c) has good safety/tolerability, and d) results in acceptable patient quality of life and cost per quality adjusted life year. A translational study will be undertaken to determine the correlation between OS and i) PD-L1 expression, ii) mutational burden (estimated by genome-wide analysis of copy number alterations), iii) immunotranscriptomic profile. Developed by researchers at the Universities of Leicester and Southampton on behalf of the UK NCRI Lung Clinical Studies Group the trial is co-ordinated by the Cancer Research UK Southampton Clinical Trials Unit in the UK, within the Centre of Cancer Immunotherapy. The trial will recruit 336 patients with pleural or peritoneal mesothelioma who have received at least two prior lines of therapy, from UK sites between March 2017 and 2021. We are also investigating opening recruitment to international sites. Patients will be randomized 2:1 (treatment: control), stratified according to epithelioid vs. non-epithelioid and center, to receive 240mg nivolumab (anti PD-1 antibody) monotherapy or saline placebo as a 30-minute intravenous infusion. Allocation will be double-blind. Treatment will be on day one of each 14-day cycle, until disease progression for a maximum of 12 months. Trial follow up will continue for 6 months after the last participant has progressed, or completed or discontinued treatment. The trial is powered (80%, with 2-sided 4% significance level) to detect a hazard ratio of 0.7 using an adjusted Cox regression model (time-to-event) and will be analyzed using intention-to-treat. This trial is funded by Cancer Research UK (C16728/A21400) and Bristol Myers Squibb (CA 209-841). Trial registrations: NCT03063450 and ISRCTN79814141.

Result:
Section not applicable

Conclusion:
Section not applicable

Background:
Tumor Treating Fields (TTFields) are non-invasive, loco- regional, anti-mitotic treatment modality, based on low intensity alternating electric fields. Efficacy of TTFields in non-small cell lung cancer (NSCLC) has been demonstrated in multiple in vitro and in vivo models, and in a phase I/II clinical study. TTFields treatment to the brain was shown to be safe and to extend overall survival in newly-diagnosed glioblastoma patients.

Method:
TRIAL DESIGN [NCT02831959] The study objectives are to test the efficacy, safety and neurocognitive outcomes of TTFields in this patient population. Patients (N=270) with 1-10 brain metastases (BM) from NSCLC are randomized in a ratio of 1:1 to receive stereotactic radio surgery (SRS) followed by either TTFields or supportive care alone. Patients are followed-up every two months until 2[nd] cerebral progression. Patients in the control arm may cross over to receive TTFields at the time of 2[st] cerebral progression. Key inclusion criteria: Karnofsky performance status (KPS) of 70 or above, 1 inoperable or 2-10 brain lesions amenable to SRS, optimal standard therapy for the extracranial disease, no brain-directed therapy, no signs of significantly increased intracranial pressure, and no electronic implantable devices in the brain. Endpoints: Time to 1[st] cerebral progression based on the RANO-BM Criteria or neurological death (primary); time to neurocognitive failure based on the following tests: HVLT, COWAT and TMT; overall survival; radiological response rate; quality of life; adverse events severity and frequency (secondary). Treatment: Continuous TTFields at 150 kHz for at least 18 hours per day are applied to the brain within 7 days of SRS. The treatment system is a portable medical device allowing normal daily activities. The device delivers TTFields to the brain using 4 Transducer Arrays, which may be covered by a wig or a hat for cosmetic reasons. Patients receive the best standard of care for their systemic disease. Statistical Considerations: This is a prospective, randomized, multicenter study for 270 patients. The sample size was calculated using a log-rank test (based on Lakatos 1988 and 2002) and has 80% power at a two sided alpha of 0.05 to detect a hazard ratio of 0.57.

Result:
Section not applicable

Conclusion:
Section not applicable

Background:
There is an urgent need for methods to detect lung cancer earlier. If detected early, over half of lung cancer patients could be cured with existing treatments. Therefore, our greatest opportunity lies in increasing rates of early diagnosis through improved cancer screening. Exhaled breath contains over 1,000 Volatile Organic Compounds (VOCs), which are the products of metabolic activity, hence they directly reflect the current state of cells and represent a valuable source of information about the health of an individual. As the earliest stages of tumour development are characterized by profound changes in cellular metabolic activity, VOCs are potential non-invasive biomarkers for early detection of lung cancer. The LuCID study aims to collect breath samples and evaluate VOCs in exhaled breath as non-invasive biomarkers for early detection of lung cancer.

Method:
LuCID is an international multi-centre prospective case-control cohort study (ClinicalTrials.gov ID NCT02612532) currently in progress, evaluating breath VOCs in patients with a clinical suspicion of lung cancer. A clinical suspicion is based on symptoms and/or suspicious finding on incidental imaging. Using tidal breathing, patients breathe into the ReCIVA Breath Sampler for 7 minutes to collect alveolar- and bronchial-enriched breath fractions on stable sorbent tubes for later analysis by Gas Chromatography-Mass Spectrometry and Field Asymmetric Ion Mobility Spectrometry (FAIMS, Owlstone Medical Ltd). A classification algorithm will be constructed from chemical spectral data, and undergo internal and external blinded validation to provide a ROC-curve detailing diagnostic accuracy. The LuCID study has an adaptive trial design, recruiting up to 2,600 patients depending on interim results.

Result:
The LuCID study has recruited 980 patients to date from 20 centres (mean age 67.5, SD 12.0). Of patients with completed follow-up (n=802), 33% have histologically confirmed lung cancer (of those with lung cancer: 40% early stage 1a-2b, 60% advanced stage 3a-4). Non Small Cell Lung Cancer (NSCLC) comprised 87% of these cancers, and Small Cell Lung Cancer 9%. NSCLC were further categorized as adenocarcinoma (50%), squamous cell carcinoma (38%), with the remaining 12% belonging to other categories.

Conclusion:
The LuCID study is evaluating the analysis of exhaled VOC biomarkers as a new diagnostic modality for early detection of lung cancer. Successful completion of the LuCID study will pave the way for the development of a non-invasive, easy-to-implement test that could markedly improve screening and early detection rates, reducing lung cancer morbidity and mortality.

Background:
The LuCED® test is based on analysis of sputum by the Cell-CT® platform that computes 3D images of cells with isometric resolution, allowing orientation-independent measurements of 704 3D structural biomarkers to generate a probabilistic score to identify abnormal cells. that was consistent by tumor histology and stage. Early stage tumors are generally smaller in size. One view is that smaller tumors might exfoliate fewer abnormal cells into sputum, making early stage tumor detection less likely. Here, we test the hypothesis that tumor size is a primary determinant of LuCED sensitivity.

Method:
Sputum samples from 74 biopsy confirmed non-small cell lung cancer cases were studied. The tumor size (mm) was characterized as the maximum tumor dimension supplied by the clinic. The numbers of bronchial epithelial cells and abnormal cells in sputum were measured and confirmed by cytological review. Tumor cell prevalence was characterized as (abnormal cells)/(bronchial epithelial cells) and plotted versus tumor size to assess any trend towards lower abnormal cell prevalence with decreasing tumor size.

Result:
The figures show the abnormal cell prevalence and the log of prevalence versus tumor size. Figure 1



Conclusion:
No trend was observed that might support the hypothesis that lower abnormal cell prevalence would occur with smaller tumor size. Moreover, variance in abnormal cell prevalence for any tumor size is large, suggesting that factors other than tumor size are more important in determining prevalence. There is no evidence to suggest that the LuCED test sensitivity decreases for smaller tumors, and this further suggests that early stage cancer, where tumors might be smaller, can still be detected. Published data shows that the LuCED test is 92% sensitive to stage 1 lung cancer.

Background:
Non-invasive diagnostic biomarkers for patients with suspicious non-small cell lung cancer (NSCLC) may provide needed guidance on invasive diagnostic and therapeutic decisions. Thioredoxin reductase 1 (TrxR1) is a pivotal intracellular redox sensor and antioxidant enzyme, and plays an important part in tumor growth, progression, metastasis, and chemotherapy resistance. The goal of this study is to test the feasibility of developing plasma TrxR1 as a novel diagnostic biomarker for NSCLC.

Method:
The plasma TrxR1 activity was determined spectrophotometrically by monitoring the NADPH-dependent production of 2-nitro-5-thiobenzoate at 412nm and at 37℃. A random forests method was adopted to identify and measure the important diagnostic variables for NSCLC. A nomogram that allowed more accurate prediction of probability for NSCLC was developed.

Result:
In this study, the plasma levels of TrxR1 were measured in 102 treatment-naïve NSCLC patients and 11 individuals with benign tumor-like pulmonary diseases. The random forest analysis identified that TrxR1, PET SUVmax, smoking and drinking history were potentially significant variables for NSCLC diagnosis and differentiation. After cross validation, the nomogram for the cohort was accurate and discriminating, with an area under the receiver operating characteristic (ROC) curve of 0.70. Figure 1



Conclusion:
Our data suggest that plasma TrxR1 activity is a useful non-invasive diagnostic marker for NSCLC. We developed a user-friendly nomogram that uses information commonly available to the clinician to easily and accurately calculate the likelihood of NSCLC.

Background:
Lung cancer is the leading cause of cancer-related deaths worldwide. Despite advances in systemic therapy and improvements in survival for advanced non-small cell lung carcinoma (NSCLC), brain metastasis (BM) remained an important etiology of morbidity and mortality. This study was designed to analyze the association between the epidermal growth factor receptor (EGFR) mutation status and the incidence of brain metastases (BM) and associated survival.

Method:
We retrospectively investigated the medical records of 491 patients diagnosed with NSCLC stage I to stage III from 2004 to 2015, who were tested for EGFR mutations. The time from the diagnosis of advanced NSCLC to the development of BM and the overall median survival after BM development were evaluated and compared by EGFR mutation status.

Result:
Seventy-eight of 491 patients developed BM. From 280 patients had EGFR mutations, 49 patients developed BM and 29 of 211 patients harboring wild-type EGFR developed BM. Comparing with wild-type EGFR group, the incidence of subsequent BM was statistically higher in patients with EGFR mutations [49 (17.5%) vs. 29 (13.7%), p=0.023]. Patients with EGFR mutations also demonstrated the trend with longer overall survival (OS) after BM diagnosis than patients with wild-type EGFR (17.8 v.s. 12.2 months, HR:0.79 , 95% CI: 0.45-1.40, p = 0.416) (Figure 1). Figure 1



Conclusion:
Our data suggested that EGFR mutation is a predictive risk factor for the development of brain metastasis. Though there is no statistical significance, NSCLC patients with EGFR mutation and brain metastasis tend to have longer survival than those with EGFR wild type.

Background:
The possibility of detection of tumor suppressor genes methylation in tumor DNA of NSCLC patients and the lack of methylation in healthy individuals makes this epigenetic alternation a potential diagnostic and prognostic marker of lung neoplastic processes. The aims of our study was to evaluate the promoter methylation of 7 genes in tumor DNA of NSCLC patients, matching nonmalignant lung tissue and blood samples to test weather these changes are lung cancer specific. We also wanted to investigate usefulness of this test for predicting the lung cancer course.

Method:
Genes methylation status was evaluated in DNA isolated from tumor, matching nonmalignant lung tissue and peripheral blood samples from 65 NSCLC patients treated with curative resectional surgery. Hypermethylation status was quantified at multiple CpG sites within each promoter in multiple genes - CDH13, MGMT, ESR1, SOX1, RASSF1A, HOXA9, and DAPK by pyrosequencing. Percent methylation for each CpG as well as average methylation across CpG’s was calculated for each promoter using PyroMark software (Qiagen).

Result:
Aberrant methylation in SOX1 and RASSF1A genes in tumor tissues were associated with inferior survival in surgically resected NSCLC patients. This effect was independent of TNM stage, which was also a predictor of survival. Methylation in tumors was significantly higher than in normal lung for SOX1, DAPK, RASSF1A, HOXA9 and CDH13. However, these changes could not be detected in patients’ blood samples, indicating a low feasibility of detecting lung cancer by analyzing these genes in a blood-based test.

Conclusion:
Hypermethylation of SOX1 and RASSF1A genes in NSCLC correlates with poor prognosis of patients. It may serve as novel epigenetic-based diagnostic biomarkers with further clinical impact for risk stratification of NSCLC patients. Our results also show that elevated methylation levels observed in genes SOX1, RASSF1A, HOXA9, CDH13 and DAPK in NSCLC were cancer-specific. We confirm that hypermethylation of these genes plays a role in NSCLC pathogenesis. However, the lack of reflection of these methylation changes in patients blood indicate their poorly suitability for a screening test.

Background:
Increasing molecular evidences have led to the development of molecular-targeted cancer therapies for non-small cell lung cancer (NSCLC). Especially, clinical implementation of EGFR- and ALK-targeted therapies has improved clinical outcomes in lung adenocarcinoma (LUAD). However, not all patients with LUAD benefit from these therapies. Moreover, molecular-targeted therapies for lung squamous cell carcinoma (LUSC) have not progressed much, because definitive drug targets have not been identified. To further expand the range of molecular-targeted therapeutics for NSCLC, this study explored novel therapeutic targets by integrated genomic characterization.

Method:
Surgically resected primary tumor specimens obtained between January 2014 and June 2016 from 372 patients with NSCLC (LUAD, 296; LUSC, 76) were subjected to whole-exome sequencing (WES) and gene-expression profiling (GEP). Corresponding peripheral blood samples were collected as controls to identify tumor-specific genetic alterations in WES. Written informed consent was obtained from all patients. WES was performed on an Ion Proton system. An Agilent SurePrint G3 Human Gene Expression 8×60K v2 Microarray was used to detect tumor-specific gene expression. Oncogenic fusions were detected by a targeted RNA-sequencing. Copy number alterations were detected by integrating copy numbers resulting from WES and GEP. Promising oncogenic genetic alterations were selected with OncodriveFML and Cancer Genome Interpreter.

Result:
Patient characteristics (LUAD; LUSC) were as follows: median age (70; 73), men (52%; 87%), smokers (59%; 99%), ratio of stage I/II/III/IV (70/16/13/1%; 57/32/12/0%). The median tumor mutational burden (TMB) in LUAD and LUSC was 1.59 mutations (mt)/Mb (0.06–65.6) and 5.63 mt/Mb (0.32–26.2), respectively. Eleven and two patients showed a hypermutator phenotype (TMB ≥ 20 mt/Mb) in LUAD and LUSC, respectively. In LUAD, hypermutator had significantly more truncating somatic mutations in DNA repair genes than others (73% vs. 5%, p < 0.0001). Oncogenic fusions of EML4-ALK, KIF5B-RET and EZR-ROS1, and FGFR3-TACC3 were observed in 2.7%, 0.3%, and 0.3% of LUAD, and 2.6% of LUSC, respectively. Promising oncogenic mutations were detected in EGFR, KRAS, SMARCA4, RBM10, BAP1 and PBRM1 in LUAD; in KEAP1, PIK3CA, NFE2L2, KMT2D, NF1, ATM, RASA1 and PTEN in LUSC; and in TP53 and CDKN2A in both tumor types. Promising amplified genes include FRS2, MDM2, CDK4, MET, AURKA, CCNE1 and ERBB2 in LUAD; in SOX2 and CDK6 in LUSC; and in EGFR and TERT in both tumor types.

Conclusion:
Theses promising oncogenic genetic alterations of the patients with NSCLC revealed in this study could contribute to the development of novel molecular-targeted therapies.

Background:
Tumor markers (TMs), cytokeratin 19 fragment (CYFRA 21-1) and carcinoembryonic antigen (CEA), which have demonstrated prognostic value in early-stage non-small cell lung cancer (NSCLC), may also predict which patients are suitable candidates for adjuvant chemotherapy (adCHT).

Method:
Presurgical serum samples collected during an observational study of patients with stage I-II NSCLC were analyzed for CYFRA 21-1 and CEA via electrochemiluminescence immunoassay (Elecsys[®]; Roche Diagnostics). Recurrence-free survival (RFS) was analyzed using Kaplan Meier methods and a Cox proportional hazards model. A TM-based risk score was generated with RFS as the endpoint and the log10 of CYFRA 21-1 and CEA values as independent risk predictors. RFS was compared for patients who received adCHT versus surgery alone, with patients stratified as high versus low risk based on pathological disease stage (I vs II), the TM-based risk score, and clinical characteristics (age, gender, smoking status, disease stage, Eastern Cooperative Oncology Group performance status).

Result:
227 patients were included (stage I: 69%; male: 67%; median age: 65 years; adenocarcinoma [ADC]: 47%, squamous-cell carcinoma [SCC]: 40%, mixed histology: 13%); 70 received adCHT (84% with a platinum-based regimen). Median follow-up was 58.8 months. Median RFS for all patients was 76.3 months (81.0 and 68.6 months for ADC and SCC, respectively). All high-risk patients, defined by TMs or clinical characteristics (but not stage alone), had a worse prognosis, irrespective of treatment received. A similar pattern was seen in patients with SCC, whereas stage and clinical characteristics (but not TMs) were prognostic in patients with ADC. All high-risk patients (defined by any method) derived an RFS benefit from adCHT versus surgery alone (stage HR 2.7, p = 0.002; TMs HR 2.1, p = 0.018; clinical characteristics HR 3.2, p = 0.001). However, in all low-risk patients, RFS was similar regardless of whether they received adCHT or not. High-risk SCC patients also derived an RFS benefit from adCHT versus surgery alone (stage HR 4.9, p = 0.004; TMs HR 9.4, p = 0.002; clinical characteristics HR 9.0, p = 0.003), whereas those with low-risk SCC did not. In patients with ADC, none of the methods used were able to predict which patients might benefit from adCHT.

Conclusion:
Baseline CYFRA 21‑1 and CEA levels may provide further information beyond clinical characteristics that could help clinicians to decide which patients with early-stage SCC should receive adCHT. Further evaluation of these biomarkers is warranted.

Background:
The Tumor markers (TMs) cytokeratin 19 fragment (CYFRA 21-1) and human epididymis protein 4 (HE4) have each been shown to be useful in diagnosis, prognosis and monitoring of NSCLC, but their combination has not been investigated. The objective of this analysis was to evaluate the ability of CYFRA 21-1 and HE4 to predict relapse in patients with adenocarcinoma (ADC).

Method:
In an observational study of adult patients with stage I-IIIA ADC, serum samples were prospectively collected prior to surgery and during follow-up at 3, 6, 12, 18 and 24 months and then every 6-12 months up to 5 years post-R0 resection. Patients could receive an adjuvant therapy of either radiotherapy or chemotherapy (not both) according to their clinical situation and local best practice. In a post hoc analysis, CYFRA 21-1 and HE4 levels from these samples were measured via electrochemiluminescence immunoassay (Elecsys[®]; Roche Diagnostics). All cases of disease recurrence were verified by imaging. The diagnostic performance of CYFRA 21-1, HE4 and their combination was assessed by the Receiver Operating Characteristic (ROC) and corresponding area under the curve (AUC). The combination of both TMs was based on the weighted sum of the logarithmized (base 10) markers. Weights were derived from a logistic regression model which included the log10 of CYFRA 21-1 and HE4 as independent variables and relapse (yes/no) as a dependent variable.

Result:
117 patients were included in the post hoc analysis (stage I/II/IIIA: 64%/21%/15%; male: 55%; median age: 63 years), providing a total of 623 TM measurements. All patients had received surgery for ADC; 34 patients (29%) also received adjuvant chemotherapy and 16 patients (14%) received radiation. Blood samples were collected for a median follow-up of 37 months. At this timepoint, 31 patients (26%) had experienced disease recurrence. Median recurrence-free survival was 80.2 months. Both CYFRA 21‑1 and HE4 were able to detect recurrence (AUC and corresponding 95% confidence interval [CI]): 76.6% [66.9–86.3%] and 73.7% [64.1–83.4%], respectively), but this increased with the combination (AUC 79.0%, 95% CI 69.4–88.6%). At a sensitivity of 80%, the respective specificities (95% CI) for CYFRA 21‑1, HE4 and the combination were 56.0% (51.9–60.1%), 49.1% (45.0–53.2%), and 70.1% (66.2–73.7%).

Conclusion:
Serial measurements of serum CYFRA 21‑1 and HE4 levels could provide a valuable alternative method for follow-up monitoring and recurrence detection in patients with early-stage ADC, which would trigger imaging if elevated.

Background:
Circular RNAs (circRNAs) are a special class of endogenous RNAs exhibiting stable structure and high tissue- and developmental-specific expression. Recent studies have found that aberrant expression of circular RNAs plays important roles in carcinogenesis and tumor progression. However, their value in the diagnosis of lung adenocarcinoma remains unknown. In this study, we focused on hsa_circ_0044013, which was found to be upregulated in lung adenocarcinoma tissues in our previous microarray analysis. The purpose of this study was to clarify the possible role of hsa_circ_0044013 and to define its diagnostic value in lung adenocarcinoma.

Method:
Expression levels of hsa_circ_0044013 in 30 paired lung adenocarcinoma tissues and adjacent non-tumor tissues were measured by real-time quantitative reverse transcription polymerase chain reaction（qRT-PCR）. We also measured expression levels of hsa_circ_0044013 in three NSCLC cell lines by qRT-PCR. Then, we detected expression levels of hsa_circ_0044013 in the plasma samples from 70 lung adenocarcinoma patients and 70 healthy individuals. Differences in expression levels of hsa_circ_0044013 were analyzed using the paired t-test. Then, the association between the expression level of hsa_circ_0044013 and the clinicopathological features of patients with lung adenocarcinoma was further analyzed. A receiver operating characteristic (ROC) curve was generated to evaluate the diagnostic value.

Result:
Hsa_circ_0044013 was significantly upregulated in lung adenocarcinoma tissues compared with adjacent non-tumor tissues (P = 0.0143). Its expression levels in two detected lung adenocarcinoma cell lines (A549, SPCA1) were upregulated than those in HBE and H1703. Moreover, Hsa_circ_0044013 was detected to be upregulated in plasma samples from lung adenocarcinoma patients (P = 0.0046). Its expression levels were significantly correlated with tumor diameter and TNM stage. The areas under the ROC curve (AUC) of hsa_circ_0044013 in plasma were up to 0.753. The sensitivity and specificity of the combination were 0.592 and 0.959.

Conclusion:
These results suggested that hsa_circ_0044013 may be a novel non-invasive biomarker for the diagnosis of lung adenocarcinoma.

Background:
Notch gene Encode 300kDa single-pass transmembrane receptors. It can variously serve as an oncogene or a tumor suppressor and a repressor or inducer of terminal differentiation. It also regulate cell division, differentiation and survival of stem and/or progenital cells in wide range tissues. We examined Notch 1 and 3 to study the correlation of Notch expression and prognosis for non-small cell lung cancer.

Method:
Paraffin-embedded tissue microarrays were constructed. We analyzed Notch 1 and 3 by immunohistochemical stain on surgical tumor specimens.

Result:
One hundred fifty-nine of 185 resected tissues for lung cancer (median age 62 years) were available for immunohistochemical stain. The types of tumor histology were adenocarcinoma;54, squamous cell carcinoma:79, others;26. 121 patients were taken lobectomy and 38 were done pneumonectomy. Notch 1 and 3 receptors were detected in 119 (74.8%) and 130 (81.7%) of total 159 (M:F=114:45) tumor tissues, respectively. Notch 1 receptors showed higher expressions on squamous cell carcinoma than non-squamous cell carcinoma (58.8% vs. 37.8%, p=0.03). However, it was not correlated with sex, smoking status or advanced stages. Five year-relapse free survival (RFS) and overall survival (OS) were 57.4 % and 59.3 % in 159 patients, respectively. Patients with any expression of Notch1 or 3 have correlated with neither RFS nor OS. 5 year OS for patients who showed Notch 3 expression were 62 % and the others were 47.8%, however, it was not statistically significant (p= 0.165). Both of their expressions were detected in 106 of 159 (66.7%) tumor tissues. Sixteen (10 %) had negative expressions in both of them. The patients with both positive expressions had the tendency of longer OS than all negative patients. Their 5 year OS were 60.8 % vs. 38.2% (p=0.068) and 5 year RFS were 56.5% vs. 49.7 % (p=0.35).

Conclusion:
Notch 1 showed higher expression on squamous cell carcinoma. Neither Notch 1 nor 3 have correlated with RFS or OS, but patients with both expressions had the tendency of longer overall survival.

Background:
Circulating tumor DNA (ctDNA)-based liquid biopsies have recently demonstrated substantial promise in the diagnosis and monitoring of advanced non-small cell lung cancer (NSCLC); however, data regarding utility in early-stage (operable) disease are very limited. The aim of this study is to define the clinical feasibility of ctDNA assessment in operable NSCLC.

Method:
We prospectively recruited 80 patients with clinical stage I-IIIa NSCLC undergoing cruative intent tumor resection. Pre-surgical plasma cell-free DNA (cfDNA) and matched tumor genomic DNA were collected and analyzed with a novel 21-gene Digital Sequencing NGS panel (Guardant Health, Inc.) with a theoretical genomic sensitivity of > 90% for NSCLC. Genomic results, including cfDNA yields, technical sequencing information, and identity and quantity of somatic variants, were correlated with various clinicopathological characteristics, including age, sex, smoking history, clinical and pathologic stage, histological tumor type, and preoperative treatment status.

Result:
[Cohort enrollment and sample collection is complete. Sequencing and analysis have been completed for the first 20 patients. The remaining patients will be completed within 1-2 months. Results from the complete cohort will be updated as directed by the Core Program Committee and will include the data elements described in the methods above. A preliminary review of the data is included below.] Of the 18 patients with somatic variants detected in tumor tissue (18/20, 90%), pre-operative ctDNA was detected in 12 (67%). Pre-operative ctDNA detection was high in squamous cell carcinoma (8/8), small cell lung cancer (1/1) and mixed histology (1/1) relative to adenocarcinoma (2/10, 20%). Clinical stage did not influence detection of small cell or squamous cell carcinoma; however, no ctDNA was detected in stage I or II adenocarcinoma samples (0/5). Detailed data from the complete cohort will be submitted as a late-breaking abstract.

Conclusion:
[Conclusion to be updated pending full cohort data.] ctDNA demonstrates sufficient pre-operative clinical sensitivity to be a feasible recurrence monitoring tool but appears to be influenced by tumor type.

Background:
Identifying patients at high risk for recurrence in non-small cell lung cancer (NSCLC) is the key to choose patients who can benefit from postoperative adjuvant therapy. In this study, recurrence related genes were analyzed using RNA-seq data of The Cancer Genomic Atlas (TCGA).

Method:
A regularized regression method called Elastic-Net was used to infer the genetic events associated with recurrence in patients with stage I to IIIA NSCLC from the RNA-seq data of TCGA. We used cross-validation to find the optimal value of regularization parameter λ with minimum mean square error (MSE). Multivariate Cox regression models were used to calculate the hazard ratio (HR) and p-value for recurrence of individual genes. Recurrence free survival (RFS) was compared between two groups which were dichotomized with median value of each genes using Kaplan-Meier analysis.

Result:
Among 670 NSCLC patients with stage I to IIIA, who underwent curative resection, 296 (44.2%) and 374 (55.8%) were diagnosed with adenocarcinoma and squamous cell carcinoma, respectively. The model is well fitted to the recurrence value with minimum MSE 0.65 and 30 recurrence-related genes were derived. Among them, ANKRB36, C19orf6, MAN2C1 and SFXN5 genes significantly affected the RFS in each stage I, II and IIIA and in all the stages. The RFS was significantly longer among the patients with low ANKRB36 than those with high ANKRB36 (HR, 15.07; P < 0.001). Low C19orf6, MAN2C1 and SFXN5 expression groups showed significantly longer RFS compared to high expression groups (HR, 5.4; P <0.001: HR, 12.8; P < 0.001: HR, 6.2; P <0.001, respectively).

Conclusion:
The expressions of ANKRD36, C19orf6, MAN2C1 and SFXN5 were prognostic for RFS in resected NSCLC patients in TCGA cohort. Further evaluation of the association between the expression of these genes and RFS and benefit from adjuvant chemotherapy are being tested in the clinical cohort of 126 patients.

Background:
India is one of the world’s largest producers of textile and garments. Kanchipuram is a city in Indian state of Tamil Nadu known for saree, which is traditionally made by weavers from kanchipuram popularly known as kanjivaram sari. The silk weavers are considered as the master weaver of Gods. The silk is also known for its quality and craftsmanship, which has helped earn its name globally. The people living around Kanchipuram take weaving as their main profession. Weaving being a sedentary work, tobacco has been used by this community as an entertainment factor to ward off boredom. Till date, there are no studies that have been conducted on the oral health status of silk weavers. Hence this study was contemplated with an aim to assess the tobacco use and its awareness among silk weavers.

Method:
A cross-sectional descriptive study was conducted to assess the tobacco use, its awareness and oral examination among 400 silk weavers at kanchipuram, India. Silk weavers aged 18 to 75 years who were involved in this occupation for more than 5years were included. Data was collected using a survey proforma which comprised of a questionnaire and WHO Oral Health Surveys – Basic Methods Proforma(1997).

Result:
.Results showed that among 400 study population, 57% had no formal education. Of those who had tobacco habit - 26% smoked beedi, 10.9% smoked cigarette, 65% chewed raw tobacco, 18% chewed Hans and 28% had a combination of smoking and smokeless tobacco usage. 34% of oral precancerous lesions were observed. The reason for practicing these habits were as a measure to combat boredom, relieving stress and body pain after work, and the lack of awareness of the hazards of the materials used.

Conclusion:
From the results of this study it may be concluded that the silk weavers were characterized by a lack of awareness about oral health, high prevalence of tobacco use and limited access to health services. Prevalence of oral mucosal lesions in the study population was due to tobacco usage and alcohol consumption and lack of awareness regarding the deleterious effects of the products used.

Background:
A sailor, seaman, mariner, or seafarer is a person who navigates waterborne vessels or assists as a crewmember in their operation and maintenance. Seafarers hold a variety of professions and ranks, each of which carries unique responsibilities which are integral to the successful operation of an ocean-going vessel. Seafarers are also frequently exposed to difficult working conditions and particular occupational risks. Seafaring is an exploratory profession with little research has been done to identify conditions that may lead to assess seafarer general health as well as oral health. Past research showed a prevalent use of tobacco and drug abuse among this population.

Method:
A cross-sectional descriptive study was conducted to assess the tobacco use, cancer awareness and oral health status among seafarers in VOC port, Tamilnadu, India. Data was collected using a pretested Questionnaire, which included Demographic data, tobacco habits, its frequency, form and oral examination was done The data collected was analysed using SPSS version15.

Result:
Total of 360 subjects participated in the survey. Adverse habits show the overall 72.3% prevalence among the study population. The percentage of oral mucosal lesions observed were as follows: 29% leukoplakia, 35% ulceration and 3% malignant tumor. 27% of the study populations had other abnormal conditions like candidiasis and OSMF. Prevalence of oral mucosal lesions in the study population was due to tobacco usage and alcohol consumption.

Conclusion:
Findings of the present study suggest that oral health condition of seafarer community was relatively poor, with high oral lesions and poor periodontal health. This epidemiological survey has provided baseline information to underpin the implementation of oral health programmes.

Background:
Despite a lot of reports on the harmful effects of smoking on health, according to DOXA (Italian Institute of Health survey, 2016), most of people smoke the first cigarette between age 15 and age 17 (56.8%). The aim of this study was to evaluate the attitudes and knowledge of school-age children about cigarette smoking

Method:
Within the national primary prevention campaign “Questa non me la fumo” supported and promoted by WALCE we asked to teachers to administer a dedicated questionnaire to pupils. 724 questionnaires were analyzed between September 2016 and May 2017: 365 from 9 years-old primary-school pupils and 359 from 10 years-old Primary-school pupils ( 357 male: 49.3%).

Result:
66% of pupils believes that a program of intervention might be useful as prevention action; however, the perception about smoke is that harms only those who smoke, improves sports performances and can help to lose weight in 28%, 1.8% and 5.1 % of cases, respectively. Among the smoking disadvantages, pupils describe bad breath (74.3%) and yellow teeth (70.1%), without reporting hair and muscle damage. 82.2% of students declare "I will never smoke", but 7.8% of them "the curiosity to try". Considering the living environment, it resulted that 44% of parents, 20% of grandparents, 21% of teachers, and 8% of peers smoke; however, most parents talk of smoking damage to their children (72%). Answers to “In your opinion, is it possible to quit smoking?” are encouraging: 76.2% responded “Yes” while “No” in 23.8% of cases. According to age, the reason "to be cool" why starting smoking was reported in 48.2% and 55%, in the fourth and firth grade of Primary school, respectively. Other reasons frequently reported were: “to imitate adults” and “to try”. When asked, “What do you think is more dangerous for you?”, “smoking a cigarette” was the most frequent (78%) among heterogeneous responses such as to travel by hitchhiking or skydiving .

Conclusion:
These results highlight the awareness of children about the deleterious effect of smoke on health, but areas of greatest vulnerability emerged, such as poor knowledge about the smoking effects on some parts of the body or the consequences of passive smoking. Notably, children live with adults (family and school educators) but also with peers who smoke and this is worrying if we consider that the main reason for adolescent to start smoking attitude is emulation. These data emphasize the need to implement specific prevention programs also in primary school.

Background:
Each day, nearly 6,000 children under 18 years of age start smoking; of these, nearly 2,000 will become regular smokers. In Nigeria, 25.9% students in Lagos Nigeria currently live in homes where others smoke in their presence, 43.1% are around others who smoke in places outside their home, 14.6% of the students currently use any tobacco product. Approximately one half of student’s exposed to cigarette smoking will also die prematurely from second hand or tobacco use; this is mostly after several years or more of excess disease and disability.

Method:
Experience has showed that adolescent and youths all over the world especially Nigeria are attracted to media of any form. Three (3) Role Models loved by adolescents were used to give a tobacco control sensitization talk and showed support towards implementation of the Nigeria Tobacco Control Bill for ten minutes each on a video that was televise in the targeted schools.

Result:
These methods creatively increased the awareness level of young people in Nigeria on the harmful effect of tobacco smoking and promote the campaign against tobacco smoking. The video reached about 12,200 students with over 721 success stories; the method reduced the rate of youth smoking among students in targeted schools by 27%.

Conclusion:
Evidence has showed that some of these role models are used as a campaign tool by the tobacco industry in Nigeria and other countries. It is therefore systemic and appropriate to use the same method to reduce the current upsurge in youth smoking and cancer related disease in Nigeria and Africa.

Background:
Newly diagnosed cancer patients are motivated to quit smoking and are more receptive to discussions on how to best accomplish this goal, but require support. However, little is known about the informational needs of cancer patients that would assist with their smoking cessation efforts. The purpose of this study is to determine the smoking cessation informational needs of cancer patients.

Method:
Patients at Princess Margaret Cancer Centre who are current smokers (smoking or quit within the last 6 months) completed a cross-sectional survey during their outpatient clinic appointments. The survey captured demographic data, details about smoking history and behaviors, and informational needs including: general information and support (8-items), health and disease (14-items), relationships (5-items), testimonials from patients who had quit (7-items) and smoking cessation interventions (3-items). Each item asked for information priority (not important, somewhat important or very important) and how much information is desired (none, a little bit or detailed). Data are summarized using descriptive statistics and Chi-square test was used to explore relationships between socio-demographic variables and smoking behaviour variables (perception of health, motivation to quit and readiness to quit).

Result:
44 current smokers were recruited. The mean age was 43 (23-76 years), 28 (64%) were male and 35 (80%) were Caucasian. 21 (48%) had college/university level education and 11 (25%) had completed high-school. 18 (41%) were married and 30 (68%) were working. 23 (52%) lived with a support person. 29 (66%) of patients currently use a tobacco product and 15 (34%) had quit within the last 6 months. 23 (52%) were motivated/very motivated to quit smoking and 12 (27%) were somewhat motivated. Only 7 (16%) reported a lack of cessation services as a reason for continued smoking and 26 (59%) reported smoking will have a negative impact on their health. Only employment status was found to be related to readiness to quit p=.028. The three most important information needs were: “Information about strategies to help you stay quit” (n=24, 54.5%),“Information about why patients continue to smoke even with the known health risks” (n= 23, 52.3%) and “Information about strategies to help you quit” (n= 22, 50%). The preferred modality for this information was pamphlets followed by one-on-one teaching.

Conclusion:
Patients are most interested in obtaining information about strategies to help them quit and to stay quit and exploring their motivations to quite may be critical to success. Pamphlets are the preferred modality for this information.

Background:
The government willingness to legislate tobacco control, as part of the Complex Tobacco Landscape developed by the Initiative on the Study and Implementation of Systems (ISIS), is directly related to tobacco taxes and antismoking legislation to make changes on individual behavior. According to the NCI (2007)[1], “The willingness of government to take actions against tobacco interests depends on the balance of forces created by the protobacco and antitobacco constituencies and the government’s perceptions of health risks associated with tobacco use”. In 2011, the Brazilian government established a new taxation system and a minimum price policy for cigarettes. In 1996, Brazil started promoting smoke-free places, banning the advertising, promotion and sponsorship that were finally regulated in 2014 by a federal decree. [1]National Cancer Institute. Greater Than the Sum: Systems Thinking in Tobacco Control. Tobacco Control Monograph No. 18. Bethesda, MD: U.S. Department of Health and Human Services, April 2007

Method:
Quantitative secondary data analysis confronting the prevalence rates found in Risk and Protective Factors Surveillance for Chronic Diseases Telephone Survey (VIGITEL).

Result:
The total adult prevalence rate decreased from 15.7% in 2006 to 10.2% in 2016 for both sexes; the prevalence of passive smokers at work decreased from 12.1% in 2009 to 7% in 2016 and daily smokers of 20 units or more also reduced from 4.6% in 2006 to 2.8% in 2016. Figure 1



Conclusion:
The present study shows a decline in prevalence as a positive result coming from smoke-free places, banning the advertising, promotion and sponsorship, and higher prices of cigarettes in Brazil between the years 2006 and 2016. In 2015, there were around 100,000 deaths of men and 55,000 deaths of women attributable to cigarettes. In 1990, an estimated 204,000 deaths were attributable to smoking. In absolute numbers, 55,000 lives have been saved[2]. [2] Department of Surveillance and Health-Ministry of Health

Background:
Lung cancer is one of the most common causes of cancer mortality among men in India and incidence is increasing, but actually, they are largely preventable diseases. In India, advanced stage at the time of presentation is responsible for high mortality and morbidity and early detection is the only way to reduce it. The purpose of this study is to know the level of awareness of various aspects of lung cancer among college students and impact of awareness programmes in its prevention and early detection.

Method:
This assessment was part of Pink Chain Campaign—a campaign on cancer awareness. During the cancer awareness events in 2013–2016 at various colleges in different parts in India, pre-test related to lung cancer was followed by awareness programme. Post-test using the same questionnaire was conducted at the end of interactive session, at 6 months and 1 year.

Result:
A total of 1644 out of 1970 students participated in the study (overall response rate was 88.5 %). Mean age of the study population was 18.2 years (range 16-21 years). There was a significant increase in the level of knowledge regarding lung cancer at 6 months, and this was sustained at 1 year. Among students who were just asked yes or no question, 542 students (33 %) were smokers and 711 students (43.2 %) were alcoholics. Internet and Newspapers were sources for knowledge in 70–80 % of students, whereas approximately 40 % of students were educated by TV and Magazines regarding various aspects of lung cancer. Post awareness at 6 months and 1 year, Pink Chain Campaign was the major source of knowledge related to lung cancer in more than 90 % of students by continuous and timely update on subject. Post awareness at 6 months and 1 year, there was a significant change in alcohol and smoking habits. Major reasons for not going for check-up were ignorance (83.1 %), fear (30.1 %) and lethargic attitude (29.3 %) initially, but over time, lack of time, lethargic attitude and hesitation became important factors after knowing various aspects of lung cancer.

Conclusion:
Knowledge of lung cancer due to smoking was known to most of the students. Overall awareness of risk factors, sign and symptoms, screening modalities of lung cancer has improved in a year along with practices related to smoking and alcohol, but there was not much improvement in people undergoing regular check-ups. To inculcate safe practices in the lifestyle of people, awareness programmes Such as the Pink Chain Campaign should be conducted more widely and frequently.

Background:
Pathways is a five-year program of targeted research to identify and implement those interventions that will have the greatest impact in reducing lung cancer incidence and mortality, and improving quality of life. It includes a sharply-focused research program to identify relevant interventions and health actions, a consultative phase with national and international experts to prioritise ‘best value’ interventions, whilst considering the broader political and economic issues around implementation and policy change. A final decision and investment stage will direct funding and research activities to implement the ‘best value’ interventions in lung cancer prevention, screening, early intervention, treatment and supportive care.

Method:
A microsimulation model (‘Policy1’) has been designed using a powerful, flexible platform that can be programmed with information about multiple aspects of lung cancer to formulate an evidence base for determining the ‘best value’ interventions by comparing the impact and costs of interventions. These aspects include the ‘natural history’ of the disease, prevention actions (including tobacco control and lifestyle interventions), individual risk factors and screening behaviours, and cancer treatment type and uptake in various population subgroups. Policy1 is informed by work programs in statistical projections of lung cancer mortality (based on available mortality data and Australian smoking survey data), systematic reviews, big data and epidemiological analysis, and implementation science, to address health behaviour change and contextual factors. A Scientific Advisory Committee (SAC) of key stakeholders provides content expertise and strategic advice about pursuing detailed analyses selected interventions.

Result:
The statistical projections program indicates that lung cancer mortality rates for males will continue to decline and plateau after 2035, while for females, the mortality rate is expected to decrease steadily after 2014. Data from over sixty years of Australian tobacco smoking surveys has been used to estimate smoking prevalence, tobacco consumption, quit rates and duration of smoking. Seven scoping reviews have been completed in the areas of preventative strategies, early diagnosis, treatment regimens and clinical practice guidelines, health services interventions, psychosocial and palliative care. Key questions have been formulated and presented to the SAC to guide selection of ‘best value’ interventions for detailed exploration.

Conclusion:
Pathways presents an innovative approach to addressing those interventions that are likely have the greatest impact on improving lung cancer outcomes. The program will make a significant contribution to reducing the burden of illness in the Australian population by engaging with key stakeholders, guiding future research priorities, and translating research evidence into action.

Background:
There is little evidence that lung cancer screening prompts smoking cessation in screened populations overall. However, a more complex relationship is emerging where abnormal screening results appear to promote abstinence and those smokers who attend screening seem more motivated to stop smoking than those who do not. There is a need to understand how screening programmes can best facilitate reductions in smoking prevalence in screening populations. We aimed to investigate in the context of lung cancer screening i) facilitators to smoking cessation and continued abstinence and ii) attitudes to cessation support.

Method:
A qualitative sub-study to the Early Cancer detection test Lung cancer Scotland (ECLS) trial was conducted. We examined responses to ECLS questionnaires completed pre- and post-screening to sample smokers who had made a successful attempt to stop smoking, an unsuccessful attempt to stop or no attempt to stop since screening. Participants with positive and negative screening test results were sampled. Thirty-one in-depth semi-structured face-to-face interviews were conducted to investigate wider experiences of smoking in the screening context. Audio recordings were transcribed verbatim and thematically analysed. We present here a subset of data relating to the specific aims above.

Result:
Participants reported receiving a 'fright' from positive test results and reassurance from negative results, both facilitating smoking cessation. Test results were seen as objective health feedback which could not be ignored. Recipients of positive test results were further motivated to remain abstinent by the prospect of future study-related CT scans. There was evidence that some had participated in screening with the intention of stopping smoking. Screening factors often acted in combination with other facilitators, including increasing smoking stigma, and life-stage changes such as becoming a grandparent. Attitudes to cessation support combined with a screening programme were mixed. Some felt they would be deterred from attending screening if they thought they would be targeted with cessation messages. Others were open to the idea of cessation support but doubted whether it could offer cessation strategies they had not already tried.

Conclusion:
Smoking cessation support targeted at lung cancer screening groups should take into account ways that test results can facilitate cessation attempts, and the contributing social and life stage factors of older smokers. Some smokers eligible for screening may be deterred by the prospect of associated cessation interventions. Others who want to quit may have exhausted available cessation strategies and may be seeking something novel to help them quit.

Background:
Lung cancer remains one of the most challenging conditions due to its poor prognosis. Extensive data regarding changes in cancer histology, sex-specific incidence and tumor localization are available for developed countries in Europe and the US. However, for countries where there is no unified and comprehensive cancer registry, these data are scarce. Additionally, data from elderly individuals, that represent a significant proportion of all lung cancer patients, are insufficient. The aim of the study was to provide an analysis of lung tumor characteristics in elderly patients from North-East Romania.

Method:
We retrospectively analyzed all lung cancer cases admitted to the Regional Institute of Oncology (a territorial unit responsible for the diagnosis and treatment of cancer patients in Moldova) from 2012 to 2017. We then selected the elderly patients (aged over 75 at the time of diagnosis) and collected several types of data, such as sex, age, histology, stage, EGFR status and localization (right versus left lung).

Result:
We identified 201 patients over 75 years old at the time of diagnosis. Average age was 77.1±2.1, with a median of 77 and a maximum of 90 years. The male to female ratio was 3.27:1. Regarding histology, most cancers were adenocarcinomas (32.8%), followed by squamous cell carcinomas (30.8%) and atypical/undetermined histology (25.4% - carcinoid tumor, adenosquamous tumor or large-cell carcinoma). Females were more likely to have adenocarcinoma, while males were more likely to have squamous cell carcinoma. Most patients were diagnosed in stage IV (53.7%), with more males being diagnosed in earlier stages when compared to females. We found that a very large proportion of the adenocarcinoma patients was not tested for the EGFR mutation (25.4% of the stage III or IV adenocarcinomas). Of those tested for EGFR, 33% had a mutation present, all female. Right lung tumors were more frequent than left lung tumors (62.2% vs 37.8%) in both sexes.

Conclusion:
Elderly patients represent an important segment of the individuals affected by lung cancer. Most likely due to their age, they are diagnosed in advanced or metastatic stages and additional Immunohistochemical staining and/or EGFR testing are sometimes omitted. Our data for Romanian patients is mainly in accordance with available literature, although we found an unusually high percent of tumors with atypical histology in elderly patients.

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.