Virtual Library

Abstract not provided

Abstract not provided

Abstract:
Lobectomy with mediastinal lymph node dissection has been established as the most effective therapy for patients with resectable non-small cell lung cancer (NSCLC). Over the past 20 years, it has also been demonstrated that thoracoscopic (VATS) approaches are associated with better outcomes than open approaches. With the adoption of lung cancer screening protocols, more patients with early stage lung cancers (<2 cm) are going to be candidates for surgical resection, and some of these patients may benefit from anatomic sublobar resection (segmentectomy). The VATS approach to segmentectomy for stage I NSCLC has been shown to be feasible and safe and has found to be associated with decreased perioperative mortality and equivalent or improved overall survival when compared to segmentectomy via thoracotomy [1]. In addition, thoracoscopic segmentectomy may be particularly advantageous in patients with poor pulmonary function, with advantages in overall complication rates and other outcomes compared to open approaches. [2-6] Sublobar resection, as opposed to lobectomy, is appropriate for some patients with lung cancer: patients with ground glass opacities which are found to be adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), or minimally invasive adenocarcinoma (MIA). In addition, sublobar resection is considered an acceptable compromise procedure for patient with tumors less than 2 cm in diameter and co-morbidities that preclude lobectomy, although lobectomy is associated with superior outcomes in most patients [7-8]. Specific indications to consider anatomic sublobar resection in patients with tumors <2cm include: age >80, compromised pulmonary function (FEV1 or DLCO <30% predicted), and favorable tumor location. [1, 2, 5, 7, 8] While it is feasible to achieve sublobar resection of any of the 10 segments, some of the segments are more technically challenging to remove. The typical (commonly performed) sublobar resections include superior segmentectomy (S6), lingulectomy (L S4+5), lingula-sparing left upper trisegmentectomy (L S1-3), posterior segmentectomy of the right upper lobe (R S2), and basilar segmentectomy (S 7-10). [9]. Outcomes Much of the data comparing outcomes of segmentectomy to lobectomy has come from patients with GGOs. When comparing patients with solid nodules <2cm, lobectomy is associated with better outcomes in several studies. In one study of 39,403 patients from the National Cancer Database (NCDB), 29,736 (74%) underwent lobectomy. [7] Of the 26% sublobar resections, 85% were wedge resections. In addition, lymph node evaluation not performed in 29%. Sublobar resection associated with smaller T and low-volume institutions. 5-year survival for lobectomy was superior to sublobar resection: 66% vs. 51% (P < 0.001). Another study analyzed the outcomes of patients with stage I lung cancer over 80 years of age, also from the NCDB. [8] In this study, sublobar resection was associated with significant reductions in survival, even among patients with T1a tumors and patients >85 years. Sublobar resection was inferior in all patients except those >85 years of age and Charlson/Deyo comorbidity index >2. It has been demonstrated that superior oncologic outcomes are associated with lobectomy; however, anatomic sublobar resection or non-anatomic (wedge) resection may be appropriate in selected patients. One study of the Society of Thoracic Surgeons database compared the morbidity and mortality of wedge resections (n=3733) with that of anatomic lung resections (lobectomy and segmentectomy) (n=3733) for stage I and stage II NSCLC using propensity-matched analysis. [10] The operative mortality rate was 1.2% for wedge resections versus 1.9% for anatomic resection (p=0.01) while major morbidity occurred in 4.5% for wedge resections and 9.0% for anatomic resection (p<0.01). The authors noted the mortality benefit was most apparent in patients with FEV1 less than 80% predicted although the morbidity benefit was observed regardless of age, lung function or type of incision. [10] Another study from the NCDB reported by Rosen and colleagues found a higher perioperative mortality rate of 4.2% for wedge resections for NSCLC. [11] In comparison, the segmentectomy and lobectomy groups had a perioperative mortality rate of 3.6% and 2.6%, respectively. The difference in perioperative rates may be explained by a difference in baseline comorbidities between the groups; the wedge resection group was sicker than the other two groups. Summary Thoracoscopic segmentectomy is a sound option for lung-sparing, anatomic pulmonary resection in selected patients for experienced thoracoscopic surgeons and can be safely applied to the treatment of a variety of pulmonary disorders, including small primary lung cancers, metastatic pulmonary disease, and benign disorders. The minimally invasive approach appears to have distinct advantages compared with thoracotomy, including reduced hospital length of stay, less postoperative pain, and fewer overall complications. The decision to perform sublobar anatomic resection for NSCLC may be complex, and the best candidates appear to be those with clinical stage I disease and tumors <2cm in diameter and other significant co-morbidities precluding lobectomy, or in patients with AAH, AIS, or MIA. References 1. Yang CF, and D'Amico TA. Open, thoracoscopic and robotic segmentectomy for lung cancer. Annals of cardiothoracic surgery. 2014;3:142-52. 2. Atkins BZ, Harpole DH, Jr., Mangum JH, Toloza EM, D'Amico TA, and Burfeind WR, Jr. Pulmonary segmentectomy by thoracotomy or thoracoscopy: reduced hospital length of stay with a minimally-invasive approach. The Annals of thoracic surgery. 2007;84:1107-12 3. Gulack BC, Yang C-F, Yerokun B, Tong BC, et al. A risk score to assist selecting lobectomy versus sublobar resection for non-small cell lung cancer. Ann Thorac Surg 2016; 102: 1814-20 4. Smith CB, Kale M, Mhango G, Neugut AI, Hershman DL, Mandeli JP, and Wisnivesky JP. Comparative outcomes of elderly stage I lung cancer patients treated with segmentectomy via video-assisted thoracoscopic surgery versus open resection. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2014;9:383-9 5. Yang CF, and D'Amico TA. Thoracoscopic segmentectomy for lung cancer. The Annals of thoracic surgery. 2012;94(2):668-81 6. Zhong C, Fang W, Mao T, Yao F, Chen W, and Hu D. Comparison of thoracoscopic segmentectomy and thoracoscopic lobectomy for small-sized stage IA lung cancer. The Annals of thoracic surgery. 2012;94(2):362-7 7. Speicher PJ, Gu L, Gulack BC, Wang X, D'Amico TA, Hartwig MG, Berry MF. Sublobar resection for clinical stage IA non-small cell lung cancer in the United States. Clin Lung Cancer. 2016; 17: 47-55 8. Gulack BC, Yang CF, Speicher PJ, Kara HV, et al. Performing sublobar resection instead of lobectomy compromises the survival of stage I non-small cell lung cancer patients 80 years of age and older. (Under review) 9. Yerokun BA , Yang C-F, Gulack BC, Xuechan XL, Mulvihill MS, et al. A national analysis of wedge resection versus stereotactic body radiation therapy for clinical Stage IA non-small cell lung cancer. J Thorac Cardiovasc Surg 2017 Aug;154(2):675-686. Pham D, Balderson, S., and D’Amico, T.A. Technique of Thoracoscopic Segmentectomy. Operative Techniques in Thoracic and Cardiovascular Surgery. 2008;13: 188-203​. 10. Linden PA, D'Amico TA, Perry Y, Saha-Chaudhuri P, Sheng S, Kim S, and Onaitis M. Quantifying the safety benefits of wedge resection: a society of thoracic surgery database propensity-matched analysis. Ann Thorac Surg. 2014;98(5):1705-11; discussion 11-2. 11. Rosen JE, Hancock JG, Kim AW, Detterbeck FC, and Boffa DJ. Predictors of mortality after surgical management of lung cancer in the National Cancer Database. Ann Thorac Surg. 2014;98(6):1953-60.

Abstract not provided

Abstract:
The standard treatment of early stage non-small cell lung cancer (NSCLC) is lobectomy with systematic mediastinal lymph node evaluation. Unfortunately, up to 25% of patients with stage I NSCLC are not lobectomy candidates because of severe medical comorbidity including limited pulmonary reserve. During the past decade, stereotactic ablative radiotherapy (SABR) has resulted in local control in excess of 90% of tumours with medically inoperable and operable clinical stage I NSCLC. The local treatment including surgery and SABR is the stand of care for these patients . No definite evidence-based medicine data about the systemic therapy had been reported in this subgroup patients. A systemic therapy approach to the treatment of patients with medically inoperable, early stage NSCLC is not warranted. The management suggestions were unanimously agreed upon based on available literature. Systemic Therapy combined with local treatment could be a good option for these patients. 1. Chemotherapy+ local treatment: It seems that it is not recommended to add chemotherapy to local treatment for those medically inoperable, early stage NSCLC. It is reported that no evidence of an improvement in event-free survival was seen with the addition of weekly gemcitabine at this dose for patients with early stage NSCLC unfit for surgery, although the power of the study was low. 2. Targeted Therapy+ local treatment: No clear data about the targeted therapy for those medically inoperable, early stage NSCLC patients. For those driven gene positive patients, targeted therapy combined with local treatment seems to be a good choice. Some people worried about the combined therapy may increase the potential for pulmonary toxicity in patients with baseline pulmonary dysfunction, however, there is no cases of interstitial lung disease in early stage NSCLC as adjuvant therapy in 2017 ASCO (CTONG 1104). Further studies should be developed for these patients. 3. Immunotherapy + local treatment: The integration of radiation with immunotherapy is a conceptually promising strategy, as radiation has potent immune-modulatory effects and may contribute not only to local control but also augment systemic antitumor immune response. The advent of novel immunotherapy agents affords patients and clinicians therapeutic modalities to improve patient longevity and avenues to study innovative combinations of therapies. Preclinical data and case reports suggest the potential for robust clinical responses in metastatic NSCLC patients using this strategy, but prospective clinical trials evaluating the integration of radiation and immunotherapy are limited. The use of immunotherapy in non-metastatic settings is also intriguing but understudied. Summary: The assessment of treatment options for limited pulmonary reserve patients that requires uniform reporting of comorbidities and outcomes in clinical studies, which often is lacking. Systemic Therapy combined with local treatment could be a good option for these patients. Trials involving systemic therapy for patients with medically inoperable NSCLC should be developed.

Abstract not provided

Background:
T790M mutation of EGFR exon 20 is observed in approximately 50% of the non-small cell lung cancer (NSCLC) patients progressed on EGFR tyrosine kinase inhibitors (TKIs). Based on a preclinical study demonstrating that pharmacologic JAK1 inhibition increased the anti-tumor activity of afatinib in T790M-positive NSCLC cell lines, we conducted a phase Ib study to evaluate the safety and efficacy of the combination of afatinib and ruxolitinib, a selective JAK inhibitor, in NSCLC patients who had progressed on EGFR-TKIs.

Method:
We used the classical 3+3 design for dose-escalation cohort (DAC). Patients with histologically diagnosed, EGFR mutant stage IV NSCLC and documented disease progression on EGFR-TKIs were considered eligible. Afatinib was administered alone once daily from day 1 through day 8 (run-in period), then ruxolitinib was orally administered twice daily concomitantly with afatinib until progression. The primary endpoint was to determine RP2D and DLT. If DLT was not observed in 9 patients at the cohort of the highest level, we planned to decide RP2D and enroll 6 additional patients in the dose-expansion cohort (DEC).

Result:
As of June 14, 2017, 21 patients (12 with exon19 deletion, 9 with exon21 L858R) were enrolled in DAC, 8 of which had T790M mutations. All patients were previously treated with erlotinib (n=6) or gefitinib (n=15), and previously received a median of 2 (range, 1-4) lines of chemotherapy. Because no DLT was observed in the 9 patients at the highest dose level (afatinib 50 mg once daily plus ruxolitinib 25 mg twice daily), 6 patients with T790M mutation were enrolled in the DEC. Frequent AEs included paronychia (G1 in 11 cases, G2 in 2 cases), diarrhea (G1 in 14 cases, G2 in 2 cases, and G3 in 2 cases), acneiform rash (G1 in 13 cases), and oral mucositis (G1 in 7 cases, G2 in 3 cases). SAEs were reported in 6 patients, which were not related to the investigational products. Partial responses were observed in 7 patients (25.9%) with disease control rate (CR+PR+SD) of 96.3%. Median PFS was 5.7 months (95% CI, 4.2-7.2) and 3 patients remain on study.

Conclusion:
The combination of afatinib with ruxolitinib was well tolerated with clinical benefit of disease control in NSCLC with acquired resistance to EGFR-TKIs (NCT02145637).

Background:
S49076 is a potent ATP-competitive TKI that targets MET, AXL and FGFR1/2/3 at clinically relevant doses. Preclinical data showed that combination of S49076 with 1[st] generation EGFR-TKI can overcome acquired resistance to EGFR inhibition in a NSCLC EGFR-mutated MET-amplified cell model. Here we report interim phase I data from NSCLC patients treated with S49076 in combination with gefitinib to overcome acquired non-EGFR-T790M-mediated resistance to EGFR TKI (1[st]/2[nd] generation).

Method:
This is a phase I dose-finding study of S49076 combination with a standard dose of gefitinib using a modified Bayesian Continual Reassessment Method with S49076 doses of 500 and 600mg. Both agents are administered orally once daily. The primary objective is to determine the safety profile of the combination and the recommended phase 2 dose (RP2D) based on safety assessments. Patients are selected according to tumor status; they carried an activating-EGFR mutation without secondary T790M mutation and with at least one of the following dysregulations: MET IHC3+, MET FISH 2+/3+, or AXL IHC 2+/3+.

Result:
In June 2017, molecular screening was performed in 48 EGFR/T790M-negative tumor samples to assess MET and AXL dysregulation. 17/48 met the molecular eligibility criteria: 12/17 with MET overexpression/amplification; 4/17 with both MET overexpression/amplification and AXL overexpression; and 1/17 with AXL overexpression. As regards S49076 dose levels, 4 patients were included at 500 mg and 4 at 600 mg. Five patients discontinued treatment: 4 disease progression and 1 consent withdrawal. The most frequent related AEs (≥2 patients) were asthenia (n=5), diarrhea, nausea and paronychia (n=4 each), ASAT/ALAT increase, anemia, and yellow skin (n=3 each), peripheral edema, stomatitis, blood creatinine increase, vomiting, hypoalbuminemia, and decreased appetite (n=2 each); most were grade 1-2. A DLT occurred in 1 patient at 600mg (grade 3 stomatitis). The other severe related AEs included grade 3 ALAT increase, asthenia, and neutrophil count decrease. Concomitant intake of gefitinib did not appear to modify the S49076 PK profile as compared to previous data. The best overall response rate were partial response (PR, 1/8), stable disease (SD, 6/8), and progressive disease (1/8), including 3 patients with PR/SD ≥6 months.

Conclusion:
According to preliminary data, the frequency of MET and AXL dysregulations is consistent with the literature. Combination of S49076 and gefitinib is well tolerated and safety data are consistent with the overall safety profile of each drug. The phase II part of this study will start once the RP2D is defined to evaluate the anti-tumour activity of the combination.

Background:
Resistance invariably develops in EGFR-mutated NSCLC treated with EGFR tyrosine kinase inhibitors (TKI). In approximately 50% of cases, resistance is mediated by the EGFR T790M mutation; however, multiple other mechanisms of resistance have also been described, including case reports of acquired kinase fusions (PMIDs: 26187428, 28089157).

Method:
Hybrid-capture based genomic profiling (FoundationOne® or FoundationACT™) was performed prospectively on DNA isolated from tissue-based FFPE samples or blood-based circulating tumor (ctDNA) samples from NSCLC patients.

Result:
From a dataset of 3,014 unique EGFR-mutated (exon 19 deletion, L858R, G719X, L861Q, or S768I) TKI naïve or relapsed NSCLCs we identified 28 (0.9%) cases with co-occurring likely activating kinase rearrangements (BRAF [12], FGFR3 [5], RET [5], ALK [4], NTRK1 [1], EGFR [1]), including 24 confirmed fusions. Treatment histories were available for 21/28 cases, and prior evidence of EGFR mutation and treatment with an EGFR TKI was evident in 21/21 (100%) cases. In 25/28 cases no other known mechanisms of acquired resistance co-occurred with the primary EGFR mutation and the kinase fusion. The 3 cases with co-occurring known resistance mechanisms (T790M or MET amplification) were those with BRAF rearrangements for which no fusion partner was identified. Additionally, our dataset included 10 paired pre- and post-EGFR TKI treatment samples where the latter sample showed an acquired kinase fusion (4 FGFR3-TACC3, 2 EML4-ALK, 2 CCDC6-RET, 1 AGK-BRAF, 1 TPM3-NTRK1) in addition to the primary EGFR alteration. Notably, in 3/10 paired cases (2 FGFR3 and 1 BRAF) the fusion was acquired in the setting of dropout of an existing T790M mutation.

Conclusion:
Acquired kinase fusions are rare yet recurrent mechanisms of acquired resistance in EGFR-driven NSCLCs, and may be enriched in the setting of resistance to T790M-specific inhibitors. Genomic profiling capable of detecting all classes of genomic alterations, including base substitutions, indels, copy number alterations, and fusions, is warranted at the time of progression on EGFR TKIs, and often provides rationale for treatment in such cases.

Abstract not provided

Background:
The T790M mutation in the epidermal growth factor receptor (EGFR) gene altering the kinase domain is the most common mechanism of resistance to first or second-generation EGFR tyrosine kinase inhibitors (TKIs). Osimertinib is currently approved for treatment of metastatic EGFR T790M mutation positive non-small cell lung cancer (NSCLC). However, resistance to osimertinib is an emerging issue. Evaluation of the genomic profiles of patients with EGFR T790M mutated NSCLC treated with osimertinib is necessary to gain an understanding of the potential resistance mechanisms.

Method:
Between January 2014 and June 2017, we retrospectively reviewed DNA profiling data from blood and/or tissue (FoundationONE/ACT, Guardant 360, TruSight panel and/or Pyrosequencing) from patients with advanced NSCLC to identify those with an EGFR T790M mutation. For patients harboring the EGFR T790M mutation, electronic health records were reviewed to identify the clinical variables , outcomes and genotyping at the time of progression on osimertinib. Survival analysis was done using the Kaplan-Meier method (SPSS version 23).

Result:
We identified a total of 433 NSCLC patients who underwent genotypic profiling; EGFR T790M mutation was present in 29 (6.7%) patients. All patients received EGFR-TKIs prior to testing. Patient demographics included: Caucasian (76%), female (76%), adenocarcinoma (100%), never-smokers (52%) with a median age of 65 years and 3 median prior lines of treatment. At the time of identification of the T790M mutations, 27 (93%) patients retained their EGFR exon 19 deletion or exon 21 mutations and 24 (82%) patients received osimertinib. The median overall survival was 4.9 ± 3 months in patients not on osimertinib, and was not reachable in patients on osimertinib in the current follow up period. 7 of the 24 patients had repeat genotyping at the time of progression on osimertinib which revealed presence of acquired secondary mutations including EGFR C797S (43%, N=3), EGFR C797G (14%, N=1), amplifications in EGFR (43%, N=3), ERBB2 (HER2, 28%, N=2) and cell cycle genes (CD-K4, CCND1, CCND2, 28%, N=2), MAPK/ERK pathway alteration (KRAS amplification and Q61R mutation, 28%, N=2), PI3K/AKT/mTOR pathway alteration (ATK3 and PIK3C2B amplification, 14%, N=1) and RET fusion (NCOA4-RET, 14%, N=1).

Conclusion:
There is limited data regarding the mechanisms of resistance to osimertinib. In addition to the acquired mutations in C797S, our study identified several potential pathways for developing resistance to osimertinib including emergence of acquired amplification in EGFR and ERBB2, as well as MAP Kinase and PI3K/AKT pathway aberrations. Updated data will be presented at the meeting.

Background:
Acquired resistance to therapy occurs with both first- and newer-generation epidermal growth factor receptor (EGFR) inhibitors. One strategy to delay the emergence of resistance is to use the most active/least toxic inhibitor and replace the traditional daily dosing with a biologically-rational dosing approach. Osimertinib is a covalent mutation-specific EGFR tyrosine kinase inhibitor (TKI) with activity against common EGFR plus EGFR-T790M mutations and less activity against the wild-type receptor. This drug is poised to become a 1[st] line EGFR TKI for treatment-naïve EGFR mutated lung adenocarcinomas. Therefore, it is an ideal candidate to devise rationale dosing schemes to maximize its efficacy and minimize tumor adaptation.

Method:
We explored pulse dosing of osimertinib, to delay the emergence of acquired resistance. We applied population dynamics mathematical modeling to this question, using key parameters (“birth rate” and “death rate”), established through cellular assays. These parameters are presumed to be dose-dependent. First, we experimentally determined the “birth-rates” of PC9 lung cancer cells, PC9 cells bearing the T790M resistance mutation, and PC9 cells that were resistant to osimertinib, with increasing concentrations of osimertinib (0 - 10μM, total of eight doses at half log intervals) using cell viability assays (MTS assay). Next, we determined cellular “death-rates” using annexin V/propidium iodide (PI) fluorescence-activated cell sorting (FACS). We then applied those parameters to our population dynamics model and simulated various treatment conditions with different dosing strategies, to identify the most effective regimens at delaying or preventing the emergence of resistance to osimertinib.

Result:
Using our mathematical model, we predicted that high-dose weekly treatment of osimertinib with a low maintenance dose led to minimal cell proliferation in comparison to daily dosing. Following this in silico prediction of the superiority of pulse dose treatment, we experimentally compared the frequency of emergence of resistance with different treatment dosing regimens, using a long-term cell culture system. Indeed, weekly administration of 5uM osimertinib to PC9 cells, followed by a maintenance dose of 0.25uM, suppressed the emergence of resistance for up to 5-7 weeks in culture.

Conclusion:
We have established a population dynamics mathematical model to predict optimal dosing regimens for osimertinib in treatment-naïve EGFR mutated lung cancers. The model was experimentally validated using a long-term culture system. Future validation in additional preclinical models (cell lines, xenografts and genetically engineered mice) can lead to rationale development of pulse-maintenance clinical trials of osimertinib and eventually establish a novel paradigm for clinical use of EGFR TKIs.

Background:
Osimertinib was granted conditional marketing authorization from the EMA and accelerated approval by the FDA based on single-arm trial (SAT) data. Subsequent full FDA approval was supported by the RCT AURA3 (NCT02151981) and based on superior progression-free survival (PFS) of osimertinib versus platinum-based doublet chemotherapy (PDC) for patients with epidermal growth factor receptor (EGFRm) T790M-positive non-small-cell lung cancer (NSCLC). Accelerated and conditional approval coupled with a large treatment effect led to increased treatment switching post-progression from the control arm to the intervention arm in the RCT as clinicians and patients demanded the new treatment. This will confound analysis of overall survival (OS) benefit in the RCT. Adjusted indirect comparison from other sources can offer a robust analysis of OS without confounding owing to treatment switching and difference in subsequent therapies post-progression.

Method:
Recent SAT data (data cut-off, 1 November 2016) for osimertinib were provided by the AURA (NCT01802632) and AURA2 (NCT02094261) studies (N=405). Data for PDC were provided for a subgroup of the control arm of an RCT, IMPRESS (NCT01544179), which comprised patients with centrally confirmed EGFRm T790M-positive NSCLC whose prior treatment with an EGFRm TKI had failed and were subsequently treated with PDC (N=61). A propensity score (PS) approach was used to adjust for differences in baseline demographics and disease characteristics. Baseline characteristics of both groups were compared using statistical tests.

Result:
Following estimation of PS for each patient and adjustment for heterogeneity across the groups by matching, 288 patients from the osimertinib group and 53 patients from the PDC group were retained for analysis. Osimertinib demonstrated a statistically significant improvement in median PFS of 10.9 months versus 5.3 months for PDC (HR 0.28, 95% CI 0.19 to 0.41, P<0.0001), which was consistent with the gain in PFS from the RCT AURA3 (10.1 months versus 4.4 months; HR 0.30, 95% CI 0.23 to 0.41, P<0.001), and a statistically significant improvement in OS (HR 0.41, 95% CI 0.27 to 0.62, P<0.0001). Median OS for osimertinib was not reached and was 14.1 months for PDC.

Conclusion:
The indirect comparison estimated a statistically significant improvement in PFS and OS with osimertinib compared with PDC. The PFS benefit was consistent with that of the confirmatory RCT. The combined evidence from RCT data and indirect comparisons described may bridge the potential gap and confounding in evidence for OS produced by subsequent treatments after first progression in the RCT.

Abstract not provided

Background:
EGFR TKI therapy has improved lung adenocarcinoma patients’ prognosis tremendously, but almost all of the patients inevitably develop acquired resistance, and EGFR T790M mutation is the major contributors. T790M restores the EGFR tyrosine kinase domain affinity to ATP, and therefore gefitinib is displaced from the binding pocket, and the ‘driving’ signal for proliferation is switched on again. Previous work has shown that after TKI therapy, lung adenocarcinoma patients kept the sensitive mutation and acquired resistance mutation simultaneously by sequencing methods or in vitro cell line experiments. Whether the two different type mutations are in the same cell group or in two different cell groups is unknown. None of them has observed what was happening in the tumor cells after TKI therapy.

Method:
RNA in situ hybridization methods was employed to examined EGFR T790M and L858R mutation in lung adenocarcinoma cancer tissues which was obtained before and after TKI therapy. EGFR expression was examined by immunohistochemistry. EGFR mutation were detected by ARMS PCR methods.

Result:
Twenty five patients were enrolled in this study which were divided into 3 groups. Group 1: 5 patients who had concurrent primary T790M and sensitive EGFR mutation. Group 2: 14 patients who acquired T790M mutation after receiving TKI therapy. Among them, 6 patients had biopsy tissues before and after TKI therapy. 8 patients only own tissues after TKI therapy. Group 3: 6 patients who had sensitive EGFR mutation and received TKI therapy, but re-biopsy tissues didn’t had EGFR T790M. We found that the results of RNA ISH and ARMS PCR methods was identical in the majority of the examined tissues. Only one repeated biopsy tissue didn’t identify EGFR T790M after TKI therapy by PCR in group 3, while the RNA ISH method detected T790M in this tissue which contain only 150 tumor cells. In the serial cut slides, we observed that T790M and L858R mutations were in the same cell group, not only in the primary resistance cases, but also in the acquired resistance cases. For the two cases which had tissues available after receiving third generation TKI therapy, we observed that T790M disappeared in the repeated biopsy specimen, leaving the sensitive mutation which existed from the beginning.

Conclusion:
In the primary and acquired resistance tissues, EGFR sensitive mutation and T790M co-exist in the same cell groups. EGFR sensitive mutation is a trunk and drive mutation, while T790M is a passenger mutation during the treatment process by TKI therapy.

Background:
Circulating tumor DNA (ctDNA) has emerged as a specific and sensitive blood based biomarker for detection of several mutations in non–small cell lung cancer (NSCLC). Other clinical applications for ctDNA include molecular assessment of patients at diagnosis and serial (real-time) monitoring of biomarker status or the development of resistance mutations.

Method:
Eighty patients with advanced NSCLC who either (Group 1) had a new diagnosis or (Group 2) had developed acquired resistance to an EGFR kinase inhibitor were analyzed with highly sensitive Biocept, Inc. TargetSelector[TM] Real Time PCR based plasma assays genotyping for the detection of EGFR mutations L858R, Del19 and T790M. In addition, group 1 was analyzed for KRAS, BRAF, ROS1 and ALK and circulating tumor cells (CTCs) before and after TKI treatment.

Result:
Our results showed concordance rates of EGFR, KRAS and ALK mutations for up to 90% between the tissue and blood samples in newly diagnosed patients (Group 1). Paired analysis of mutations status monitoring in this group (P= 0.016) showed that the pattern of mutant ctDNA and CTCs changed in response to systemic therapy in 83% of the cases (Partial response or disease progression; R2=0.808). Plasma ctDNA analysis of multiple mutations showed that 40% of patients had at least one more mutation besides the one detected in tissue biopsy; 28% of EGFR tissue positive patients also had a KRAS mutation. In addition, 75% of KRAS positive patients had a BRAF mutation. These results demonstrate that plasma ctDNA analysis may even detect mutations missed by standard tissue genotyping due to tissue heterogeneity. Plasma EGFR T790M mutation was analyzed in patients with clinical progression to TKI inhibitors. Considering the RECIST criteria, 58% of progressive disease, 10% of stable disease and 16% of partial response patients were positive for T790M. According to metastatic disease type (locoregional, oligometastatic, polimetastatic), the T790M mutation was found on 64.3% of polimetastatic patients, 30.8% of oligometastatic patients and 17.6% of loco-regional patients.

Conclusion:
TargetSelector[TM] ctDNA assay is capable of rapidly detecting EGFR, KRAS and ALK mutations and is highly concordant with mutations present in tumor tissue with the robustness needed for real world testing to identify patients who progress on first line TKI therapy as well as for real-time monitoring of patients’ clinical status. Our findings highlight the importance of the RECIST criteria to define the progressive disease and determine the right moment to test for T790M mutation regardless the metastatic disease type.

Background:
Pre-treatment EGFR T790M mutation is more likely to coexist with L858R mutation than with exon 19 deletions (19del) in NSCLC. However, EGFR-TKIs might alter this status. We sought to compare the prevalence of T790M upon acquired resistance to EGFR-TKIs between 19del and L858R by assembling all existed data.

Method:
Electronic databases were comprehensively searched for eligible studies. The primary endpoint was the odds ratio (OR) of T790M mutation in NSCLC co-existing with L858R mutation and 19del upon resistance to first-generation EGFR-TKIs. A random effects model was used. Stratified analysis was performed based on study type (retrospective and prospective), race (Asians and Caucasians) and sample type (tissue and plasma).

Result:
A total of 25 studies involving 1,770 patients were included. The overall T790M existent rate was 45.25%. Post-resistance T790M was more frequent in 19del than in L858R mutated patients (53% vs. 36%; OR 1.87; p=0.00). All outcomes of subgroup and overall analyses were similar. In contrast, we re-analyzed the previous meta-analysis, finding that the pooled rate of pretreatment T790M was 14% and 22% in 19del and L858R respectively (OR 0.59; p<0.01). The increase of T790M rate was 2.79-fold in 19del and only 0.63-fold in L858R in the course of EGFR-TKIs therapy.

Conclusion:
Opposite to the situation of de novo T790M, it was observed that T790M was more frequent in exon 19del than in L858R among EGFR-TKI resistant acquired patients. The difference in T790M alteration between 19del and L858R encourages development of specific resistance mechanism detection or treatment strategies.

Abstract not provided

Background:
The objective of the study was to compare the program of early detection of lung cancer by low-dose computed tomography scan with other groups of lung cancer patients who live in the area where such a program is carried out. The study was based on the materials of one thoracic surgery clinic and the screening was carried out on the inhabitants of one district city. The objective of the study was implemented by analyzing selected factors that impact the activities of surgery ward. The study was retrospective.

Method:
The patients were divided into three groups. Group 1a - 52 patients operated due to primary lung cancer which were detected during the screening. Group 1b - 87 patients operated for primary lung cancer during the screening, but who did not participate in the screening program. Group 2 - 103 patients operated before the commencement of the screening. The analysis involved among others the factors described in the table below. For the statistics we utilised Statistica PL 2010 program. Non parametric Mann-Whitney U-test was used for not normally distributed data. Parametric t-Student test was used for normally distributed data and p<0.05 was considered significant.

Result:

Significant differences among the groups

		Group	Group	Group	Statistics	Statistics
	unit	1a	1b	2	p 1a/1b	p 1a/2
Patiens	n	52	87	103	-	-
Adenocarcinoma	%	58	34	38	0.01	0.03
G2 grading	%	44	28	24	0.03	0.02
Tumour volume	cm[3]	8	21	20	0.004	0.01
T1 factor	%	54	28	34	0.004	0.02
IA stage	%	50	24	32	0.003	0.02
Right side	%	73	63	59	ns	0.05
Lobectomy	%	75	53	56	0.02	0.04
Operation time	min	129	114	112	0.02	0.007

Conclusion:
In the screening 1a group adenocarcinoma was detected more frequently, as a smaller tumour, at an earlier stage, with the prevalent G2 factor and located mainly on the right side. In the group 1a lobectomy was performed more frequently, than the other groups. The duration of surgery of 1a group was longer than the other groups due to more often intraoperative assessment use. There were no differences according to postoperative complications and deaths among all groups. Our screening program detectes lung cancer at earlier stage and offers faster definitive surgical treatment, probably improving 5 year survival, what is being evaluated now.

Background:
Imaging screening programs are designed for specific eligibility criteria and technologies. Effectiveness of these programs is precisely known only after monitoring large populations over a long period. Ensuring generalizability of screening programs is required when targeting a population which is different from the original one tested or when modifying involved technologies. The NELSON screening program is a lung cancer triage process featuring four rounds of variable intervals (1, 2 and 2.5 years). Each screening round classifies the nodule’s malignancy according to the nodule’s volume, growth and volume doubling time, using CT. The aim of our study was to assess by simulation the influence of variable precision of measurement on the robustness of NELSON’s diagnostic algorithm.

Method:
We simulated 10[6] nodules using a Chi[2] distribution for nodule size [3mm; 20mm], an inverse Chi[ 2] distribution of growing. 2.1% of nodules were malignant (true positive). We tested several distributions of measurement error using a zero-mean Gaussian distribution and a standard deviation (SD) ranging [0%; 20%]. We reported positive and negative predictive values (PPV, NPV) at each round.

Result:
After round 4, we found that NPV decreased with increasing measurement error from 100% to 99.89%, PPV decreased from 100% to 29.6%. Figure 1 Figure 1: Detection performances of NELSON’s triage algorithm depending on measurement error. As shown in this graph, an increase of SD leads to a decrease of PPV (gray curve) and has almost no impact on NPV (yellow curve).



Conclusion:
Increasing measurement error of nodules significantly degrades the positive predictive value of NELSON’s diagnostic algorithm in identifying malignant pulmonary nodules, whereas the negative predictive value remained stable. We confirmed the efficacy of the successive rounds when measurement error is larger than 5%; however, the algorithm could be improved for larger measurement errors. Simulations could help us to assess better strategies lung in screening studies.

Background:
There is a need for more accurate and minimally invasive methods to screen high risk populations and diagnose lung cancer during its asymptomatic early stages. microRNAs (miRNAs) are small, non-coding strands of RNA that are shown to lead to carcinogenesis when dysregulated. miRNAs, expressed in a tissue specific manner, are stable and detectable in small quantities, thus are promising candidates for biomarkers. Through the use of previous miRNA profiling done in our group, we aim to validate this panel in a large sample size of non-small cell lung cancers (NSCLC) using miRNAs 21, 155, 210, and 223 in blood plasma to determine if this miRNA panel is able to differentiate lung cancer cases from controls.

Method:
A nested case-control study of 64 patients with stage I/II NSCLC and 110 healthy controls with similar age, gender, and smoking history was performed. Plasma was provided by Conservant Bio, Lung Cancer Biospecimen Resource Network, and Alberta’s Tomorrow Project. miRNA was isolated using the Qiagen miRNeasy serum/plasma kit. miR-21, 155, 210, and 223 were quantified via RT-PCR using C. elegans miR-39 as a spiked-in endogenous control. Binary logistic regression (SPSS version 15) was performed to develop a combined risk score of the patients’ risk of having lung cancer. Receiver operating curve (ROC) analysis was used to determine risk category cut-off values based on the sensitivity and specificity. Plasma samples were taken 4-7 months post resection and also analyzed and compared to pre-operative samples and controls.

Result:
The cases and controls showed similar age ranges (mean=61.97, SD=7.76; mean=61.38, SD=7.95) respectively. Smoking history was higher in the cases (mean=51.5, SD=29.46) than controls (mean=30.98, SD=10.84). The combined score was dichotomized at -0.4169 into high and low risk categories (sensitivity=81%, specificity=41%, AUC=72.3%), the cases pre-operative samples compared to healthy controls was significantly different (odds ratio=3, p-value=0.003, 95% C.I.=[1.440,6.249]). For the cases post-operative samples compared to healthy controls, the combined score was dichotomized at -0.3255 (sensitivity=77%, specificity=41%, AUC=67%), also showing a significant difference (odds ratio=2.3, p-value=0.023, 95% C.I.=[1.120,4.621]). There is no significant difference in the combined risk score when comparing the pre-operative and post-operative NSCLC samples.

Conclusion:
Through binary logistic regression miRNA profiling has the potential to assist in screening the high-risk population for lung cancer. Used in conjunction with radiologic screening, this approach could allow early detection and treatment of disease while sparing patients unnecessary investigations and biopsies.

Background:
Apatinib is a novel small molecular drug targeting vascular endothelial growth factor receptor-2 (VEGFR-2), which is currently being studied in multiple tumor types. The purpose of this study was to assess the treatment response in non-small cell lung cancer (NSCLC) patients enrolled in a clinical trial of apatinib according to the response evaluation criteria in solid tumors (RECIST) using non-contrast-enhanced computed tomography (CT) texture-based radiomics approach.

Method:
A total of 19 NSCLC patients from our single center participated in the currently undergoing multi-center phase III ANSWER study of apatinib (NCT 02332512). Patients were categorized as responders (CR and PR) and non-responders (SD and PD) according to RECIST criteria. Radiomic texture features were extracted from target lesions in post-therapy CT of NSCLC. Lasso regression was used to establish a model to discriminate between responders and non-responders. The performance of the model was assessed with ROC in both internal and independent validation cohorts.

Result:
Altogether, 108 CT scans were performed. Among them, 75 scans were randomly selected as internal validation group (70%), while the remaining 33 scans (30%) were identified as an independent validation group. Three hundred and eighty-four CT texture parameters were extracted and 21 out of 384 CT texture were finally selected for the model. The area under the curve (AUC) of ROC was 0.903 in the internal validation group, and that of the independent validation group was 0.714. Figure 1



Conclusion:
A radiomic discriminate model was built based on post-therapy CT texture features, which demonstrated a good performance in assessing the therapeutic response in NSCLC patients treated with apatinib.

Abstract not provided

Background:
In 1998, low-dose CT screening for lung cancer was introduced in Hitachi City, Japan. Based on time trend analysis, a significant reduction in lung cancer mortality was observed 4–8 years after introduction of CT screening.

Method:
To evaluate the effectiveness of lung cancer screening, we conducted a cohort study for CT screening participants and X-ray screening participants among Hitachi residents. Citizens aged 50 to 75 who underwent CT screening from 1998-2006 were defined as the CT group, and those who underwent X-ray screening during the same period, but did not receive CT screening throughout the follow-up period were defined as the X-ray group. We investigated lung cancer mortality and all-cause mortality of both groups from the first lung cancer screening of the subject to the end of 2012 using residence registry, the regional cancer registry, and national death statistics.

Result:
From the CT group (17,935 cases, 9,790 men and 8,145 women), 273 cases of lung cancer (1.5%), 72 cases of lung cancer death (0.4%), and 885 cases of all-cause mortality (4.9%) were observed. On the other hand, 164 cases (1.1%) of lung cancer, 80 cases (0.5%) of lung cancer death, and 1,188 cases (7.6%) of all-cause mortality were observed in the X-ray group (15,548 cases, 6,526 men and 9,022 women). The hazard ratios of the CT group to the X-ray group adjusted for sex, age, and smoking history were 0.49 for lung cancer mortality and 0.57 for all-cause mortality.

Conclusion:
Low dose CT screening participants exhibited a 51% reduction in lung cancer mortality during the observation period compared with the X-ray group. Although all-cause mortality also decreased by 43% in the CT group, the decrease in proportion of lung cancer deaths was greater.

Background:
The purpose of the present study was to investigate whether low-dose computed tomography (LDCT) screening is capable of enhancing the detection rate of early-stage lung cancer and reducing lung cancer mortality rate in China, thus determining the appropriate duration of screening and identifying additional risk factors for lung cancers in Chinese population.

Method:
A randomized lung cancer screening study was performed with participants aged 45 to 70 years old who had at least one high-risk factor as follows: 1) a history of cigarette smoking ≥20 pack-years; former smokers who had quit within the past 15 years; 2) cancer history in immediate family members; 3) personal cancer history; 4) professional exposure to carcinogens (asbestos, dust or radiation); 5) long history of passive smoking; or 6) long-term exposure to cooking oil fumes. Participants were randomly assigned to a screening group with alternating years of LDCT screening (R1, R2) or a control group with biennial questionnaire inquiries.

Result:
A total of 6657 eligible participants were enrolled, 3145 participants were assigned to the control group and 3512 were assigned to the baseline LDCT screening (R1) group. 1516 participants (43.2%) underwent the second round of LDCT screening (R2) in the alternate year. At R1 and R2 rounds, 19.6% and 24.0% participants showed non-calcified nodules ≥4 mm on LDCT images. Among these, lung cancer was diagnosed in 44 participants (1.3%) at R1, 12 (0.8%) at R2, and 10 (0.3%) in the control group through either biopsy or cytologic analysis. The proportions of early-stage (0 to I) lung cancer were 97.7% at R1, 91.7% at R2 and 20% in the control group, respectively. At R1, the sensitivity of LDCT for lung cancer screening was 97.7%, the specificity was 76.8%, the positive predictive value was 5.1%, and the negative predictive value (NPV) was 99.9%; at R2, both the sensitivity and the negative predictive value increased to 100%. Two cases of lung cancer-specific deaths occurred in the control group, but no death occurred in the LDCT group.

Conclusion:
Compared to usual care, the two biennial screenings with LDCT led to a 77.7% increase at R1 and 71.7% at R2 in detecting early-stage lung cancer and a 20% decrease in lung cancer mortality. Biennial screening may be at least as efficient as annual screening in terms of detecting rate, sensitivity and NPV. This study provides insights about the non-smoking related risk factors of lung cancer in the Chinese population.

Background:
Advances in cancer screening and therapeutics have led to an estimated 15.5 million US cancer survivors. A history of cancer is a known risk factor for lung cancer. Lung cancer screening (LCS) with low-dose CT (LDCT) and smoking cessation in high-risk populations are recommended standard-of-care practices for cancer survivors, yet knowledge and practice of these interventions is low among PCPs. Hematologists and oncologists commonly provide cancer survivorship care, and yet their practices of and attitudes toward LCS are unknown. Based on prior data, we hypothesized that very few providers (<25%) would report performing LDCT screening while most (>75%) would report providing tobacco cessation services in the last year, and that knowledge of LCS guidelines would be associated with LDCT screening.

Method:
We electronically surveyed all Hematology/Oncology providers (n = 104) at a large academic institution in the Mid-South and its affiliated VA from February to May 2017. The survey queried: LCS/tobacco cessation practices (LDCT screening as primary outcome), perceived cancer screening/tobacco cessation effectiveness, knowledge of USPSTF LCS guideline recommendations and CMS coverage, perceived barriers to LDCT screening, and interest in future provider/patient LCS education and reminder tools. Data were summarized using counts, proportions, means, and medians. We used logistic regression to evaluate the association of LCS guideline knowledge (primary predictor) with reported LDCT screening.

Result:
The overall survey response rate was 73%. Few providers (38%) reported performing LDCT screening in the past year, while almost all providers (95%) reported providing tobacco cessation services. In unadjusted analysis, providers who knew at least three LCS guideline components were more likely to perform LDCT screening (OR 5.96, CI 2.03-17.49; P = 0.001). Only 55% of providers knew at least three LCS guideline components. More providers rated Pap-smear (75%), colonoscopy (71%), smoking cessation (68%), and mammography (39%) as very effective at reducing cancer-specific mortality compared to LDCT (24%). Major perceived barriers included: lack of patient awareness (74%) and patient financial cost (51%). More VA providers (37%) rated lack of a multi-disciplinary screening program as a major screening barrier compared to academic providers (7%) (P = 0.002). Majority of providers (≥ 56%) reported interest in future provider/patient LCS education and reminders.

Conclusion:
LDCT screening is currently an uncommon practice among hematology/oncology providers. Future interventions aimed at the provider, patient, and health system levels are needed to ensure standard-of-care LCS practices in the cancer survivor population. Provider level interventions should incorporate education on screening/tobacco cessation effectiveness and screening guideline recommendations.

Background:
Lung cancer screening is only effective at reducing lung cancer deaths when the highest risk individuals are screened and followed. An individual’s risk of lung cancer, and therefore their screening eligibility, has not been shown to correlate with their perceived risk or intention to participate in screening. While previous studies have suggested many at-risk individuals are supportive of screening, no validated risk perception questionnaire has been used to compare perceived risk and worry with screening preference between eligible and ineligible individuals.

Method:
Participants were current or former smokers aged 55 to 80 years old who presented for medical outpatient specialist appointments at three Australian hospitals. The survey included 1) demographics and previous cancer screening participation 2) objective lung cancer risk measured by PLCOm2012 lung cancer risk prediction model 3) perceived lung cancer risk and worry about lung cancer measured by the questionnaire developed by Park et al and validated in sub-set of National Lung Screening Trial (NLST) participants and 4) preference for screening measured by a five point Likert scale. Eligibility for screening was PLCOm2012 risk >1.5%. Ordinal logistic regression identified factors associated with screening preference.

Result:
760 people 55-80 years old participated, of which 306 were ever-smokers. The participation rate was 26.9%. 23 did not complete either sufficient smoking details for PLCOm2012 risk or screening preference leaving 283 responses. Mean±SD age was 66.3±6.5, 60.4% (171/283) were male, median (IQR) PLCOm2012 risk was 1.28% (0.44-3.11) and 45.6% (129/283) were eligible for screening. Overall screening preference was high; 72.1% (204/283) either agreed or strongly agreed to having screening if offered. Objective lung cancer risk (PLCOm2012) was weakly correlated with both perceived lung cancer risk (r=0.28, p<0.0001) and worry (r=0.21, p<0.001). In univariate analysis, worry (OR 1.37, 95% CI [1.18-1.60], p<0.001), perceived risk (OR 1.10, 95% CI[1.04-1.16], p=0.002) and PLCOm2012 risk (OR 1.06, 95% CI[1.01-1.12], p=0.02) were associated with higher screening preference, but not associated with higher screening eligibility (OR 1.50, 95%CI[0.97-2.30], p=0.06). Age, gender, smoking status, family history of lung cancer and previous screening practice were not associated with screening preference. Only worry remained significantly associated with screening preference (adj-OR 1.33, [95%CI 1.10-1.60], p=0.003) with multivariate analysis.

Conclusion:
Worry about lung cancer appears to be a more important driver for screening preference than eligibility status. This presents a unique challenge when trying to engage with eligible individuals while minimizing screening demand from the ineligible majority.

Abstract not provided

Background:
Nodule size is an important parameter to determine malignancy risk. Semi-automated size measurements have the potential to replace manual measurements due to their higher accuracy and reproducibility, and less inter/intra-user variation. However, controversy exists regarding the relative accuracy of 2D diameter versus 3D volumetric measurement to predict malignancy risk. The objective of this study is to compare nodule malignancy prediction models based on 2D mean diameter versus volumetric measurement, both generated by a CAD Software.

Method:
We analyzed baseline LDCT reconstructed using high spatial frequency algorithm from 1746 participants (47% women, 53% men, age: 62.5 ± 5.8 yrs) in the Pan-Canadian Early Detection of Lung Cancer Study (PanCan), who had ≥1 non-calcified nodules ≥3mm in diameter. CAD software (CIRRUS Lung Screening, Radboud University Medical Center, Nijmegen, the Netherlands) performed an automatic nodule segmentation, which could be optimised manually, measurement of mean diameter and volume was generated. Malignant or benign nodule status was confirmed by pathology or prolonged follow-up (median follow-up 5.5 years). Logistic regression models predicting cancer were prepared with one including mean diameter and the other including volume. The discrimination, the ability to classify cancer versus benign nodules correctly, was evaluated by the area under the receiver operator characteristic cure (AUC). The calibration - do predicted probabilities match observed probabilities, was assessed using Spiegelhalter’s z-test and graphically by plotting the observed and predicted mean probabilities of cancer by deciles of model risk.

Result:
There were in total 5878 nodules, including 119 cancers in 115 individuals. Both models gave similar predictive performances. AUC was 0.947 (95% CI 0.922-0.964) in the mean diameter model and 0.946 (95% CI 0.921-0.966) in the volumetric model (p=0.83). The calibrations were similar between the two models (figure). Figure 1



Conclusion:
The predictive performances of nodule malignancy prediction models using mean 2D nodule diameter and 3D volumetric data were indistinguishable.

Background:
We tried a radiomics approach to build a random forest classifier for recognition of epidermal growth factor receptor (EGFR) mutation status in Chinese patients with lung adenocarcinomas using quantitative image features extracted from non-enhanced computed tomography (CT) images

Method:
From October 2008 to December 2015, 355 patients diagnosed with lung adenocarcinomas were included in this retrospective study. They all have complete clinical, pathological, and EGFR mutation status information, and their CT images were scanned before any invasive operation. Tumors with ground glass component or diameter smaller than 2 cm were not included. Their pathological phenotypes and EGFR mutation status were gained from surgical resections. Region of tumors on CT images were segmented semi-automatically first then manually modified by experienced clinicians. 440 quantitative image features were extracted from CT images and fall into four groups: first order statistics, shape and size based features, textural features, and wavelet features. Random forest was used to build the classification model which takes all the features into consideration and make an overall probability of mutation based on the vote of decision trees. The random forest classifier was validated using an independent set and its performance was evaluated using area under curve (AUC) values of the receiver operating characteristic

Result:
355 patients diagnosed with lung adenocarcinoma were enrolled in this study (170 male, 185 female; 54 smokers, 301 non-smokers). The patients all received surgery based treatment and their tumor stage varied from I to IV. EGFR mutations (mainly 19del and 21L858R) were found in 187/285(65.6%) and 48/70(68.6%) patients in training and validation sets respectively. The random forest model showed an AUC of 0.781 (95% confidence interval: 0.668-0.894, p<0.001) in the validation set. The sensitivity and specificity are 60.4% and 90.9% at best diagnostic decision point. These results were highest among published results of only using images to detect EGFR.

Conclusion:
The random forest classifier based on CT images showed potential ability to identify EGFR mutations in patients with lung adenocarcinomas and could be improved in future works.

Background:
Previously proposed risk models for the malignancy of Indeterminate Pulmonary Nodules (IPNs) detected on Computed Tomography (CT) typically incorporate a mixture of clinical factors, such as age and smoking history, and radiological factors such as nodule size and location. Of the latter, size is considered one of the most significant. Artificial Intelligence based risk stratification software has been previously proposed that uses Texture Analysis with Machine Learning to predict IPN malignancy and has been shown to achieve high classification performance. While it is assumed that such techniques can capture image texture patterns that separate benignity from malignancy, such methods also intrinsically measure nodule size. The contribution of texture to classifier performance beyond size has not been studied and we seek to quantify this. We show, for the first time, the relative contributions of texture and size on the performance of Artificial Intelligence risk stratification of solid nodules.

Method:
Two datasets were created from the US National Lung Screening Trial (NLST). The first (A), comprising 640 solid nodules, was built to remove size as a discriminatory factor between benign and malignant; all malignant solid nodules between 4 and 20 mm diameter were selected, and for each, a benign solid nodule was selected that most closely matched it in diameter. Any malignant nodule for which an equivalently sized benign could not be found within 0.8 mm was rejected. Sizes were measured using automated volumetric segmentation. The second dataset (B), also comprising 640 subjects, included all malignant nodules in A but benign nodules were randomly selected following the empirical size distribution of the whole NLST dataset. Therefore, nodule size cannot be a discriminative factor in A but would be in B. Two nodule stratification algorithms were developed using Texture Analysis combined with Machine Learning (Support Vector Regression) integrating 20 variables including 3D Haralick, Gabor and Shape features, from A and B respectively using five-fold cross validation and the performance compared measuring Area-Under-the-Curve (AUC).

Result:
The average AUC for the algorithm trained on dataset A was 0.70 whereas using size alone on the same dataset gave an AUC of 0.50. The AUC was 0.91 for the algorithm trained on B.

Conclusion:
On this data, Texture Analysis with Machine Learning contributes 0.20 AUC points to classfication performance. Artificial Intelligence based risk classification can identify radiological features that are predictive of solid nodule malignancy that are independent of nodule size.

Background:
An estimated 330,000 people in the province of Ontario are at high risk of developing lung cancer and eligible for screening with low-dose computed tomography (LDCT). On June 1 2017 Cancer Care Ontario launched the Lung Cancer Screening Pilot for People at High Risk with the purpose of informing the design and implementation of a province-wide organized screening program. Organized screening is available at 3 hospitals, and provider and public recruitment strategies are being implemented to engage the target population in regional catchment areas. Key aspects of pilot design include eligibility based on the PLCO~M2012noRace~ risk prediction model, navigation support, informed participation, embedded smoking cessation services, radiology quality assurance, LDCT findings categorized in accordance with Lung-RADS™, provision of same-visit screening results and seamless transition to a Diagnostic Assessment Program (DAP) for assessment of findings suspicious for lung cancer. Data collected for 3,000 participants over a 2-year period will inform a comprehensive evaluation of the pilot.

Method:
Indicators were selected to assess impacts of early recruitment efforts and outcomes of key screening processes related to eligibility assessment, the LDCT scan and smoking cessation. Data were collected by the pilot sites and submitted to Cancer Care Ontario. Participant feedback on the screening experience was collected by survey. Data were collected in June and July 2017; data from August 2017 will be available for presentation.

Result:
The majority (87%) of the 862 people recruited into the pilot were provider-referred. Of the 472 people who completed a risk assessment, 71% were found to be eligible for screening (PLCO~M2012noRace~ 6-year risk ≥2.0%). Baseline LDCT scans were conducted for 156 participants; approximately 8% of these participants were referred to a DAP for further assessment. Uptake of smoking cessation services by current smokers was high (data to be included in presentation). Feedback surveys were received from 78 of 156 participants screened. Overall experience with the screening visit was rated as ‘excellent’ by 91% of respondents, and 70% indicated a preference to receive results during the same visit as the LDCT.

Conclusion:
Provider-led recruitment supports the identification of screen-eligible individuals. Implementation of navigator-guided organized screening, following a detailed screening pathway that features provision of same-visit results, has contributed to high participant satisfaction to date. To our knowledge, this pilot involves the most detailed organized screening pathway and comprehensive evaluation plan developed to date. Learnings from this pilot will be highly relevant to jurisdictions around the world that are adopting screening.

Abstract not provided

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

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

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

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

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

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

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

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

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

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

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



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

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

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

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

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

Abstract not provided

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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



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

Abstract not provided

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Abstract not provided

Abstract not provided

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

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

Abstract not provided

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

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

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

Abstract:
A ground-glass nodule (GGN) is a morphologic description of pulmonary nodule category on thin-section chest computed tomography (CT). Pure GGNs are defined as focal nodular areas of increased pulmonary attenuation through which pulmonary parenchymal structures, such as pulmonary vessels or bronchial structures, can be observed. Part solid nodules present with ground-glass and solid components, in which the underlying pulmonary architecture cannot be visualized, whereas solid nodules are without ground-glass components. These nodules differ in pathological condition and natural history by type, and management corresponding to these differences is required. Transient GGNs, which disappear after 3 months in repeated CT, are likely due to inflammation or infection. If many small GGNs are present, these are more likely to represent atypical adenomatous hyperplasia (AAH), and follow-up with annual CT scans is advised. The majority of persistent solitary pure GGNs are pathologically atypical adenomatous hyperplasia, adenocarcinoma in situ (AIS), and minimally invasive adenocarcinoma (MIA); these nodules do not grow, or progress very slowly. Pure GGNs less than 15 mm in diameter are followed up after 3 months, 1 year, and 2 years with CT. In the meantime, when the GGN increases in size, or if solid components appear in the nodule, a definite diagnosis is made, although such cases are extremely rare. Even when a solid component appears inside the GGN, there are options for further follow-up as long as the diameter of the solid component remains less than 5 mm. A solitary pure GGN that is unchanged for 5 years could remain unchanged even after 10 years. Of solitary pure GGNs 5 mm or less in diameter, approximately 10% will grow, with 1% developing into invasive adenocarcinomas or MIAs. Therefore, it is recommended that solitary pure GGNs smaller than 5 mm be rescanned after 3 to 5 years, in order to look for development of a solid component. In cases of part solid nodules, which present with both ground-glass and solid components, the underlying pulmonary structures cannot be observed. These nodules are more suspicious than pure ground-glass nodules and thus require more aggressive management if they persist. Persistent part solid nodules usually represent lepidic predominant adenocarcinomas or MIAs. In particular, if the margin of a part solid nodule is well-defined on thin-section CT, it is often dianogsed as lepidic predominant adenocarcinoma or MIA. Some inflammatory lesions show part solid nodules on CT; if the nodules do not disappear or decrease in size on CT after 3 months, they are highly likely to be adenocarcinomas. Usually, a lung adenocarcinoma showing part solid nodules on CT does not grow rapidly in 3 months. Therefore, a 3-month CT follow-up is effective for diagnosing a partly solid nodule (which is difficult to diagnose). Small solid nodules are most commonly observed, although few are malignant. These nodules are easily detected on CT, but it is difficult to diagnose their malignancy. Nodules over 10 mm in diameter are suspicious for malignancy, and an attempt should be made to obtain a definitive diagnosis. Solid nodules with a maximum diameter of 5 to 10 mm in smokers should be followed up until after 3 months, 6 months, 1 year, and 2 years on CT. In non-smokers, however, intervals of follow-up could be longer. Solitary nodules less than 5 mm in diameter are very rarely malignant and only require annual follow-up if patients have risk factors such as smoking. The reasons why intervals of follow-up differ between smokers and non-smokers are because smokers have a higher risk of lung cancer, and the tumor doubling time is shorter in the case of lung cancer in smokers. If the size of a nodule increases during follow-up, a definitive diagnosis is needed. If the size of a solid nodule is unchanged for 2 years, the possibility of lung cancer is extremely low, and follow-up observation may be completed; however, in smokers, emphysema is often complicated, and the diagnosis is more difficult as the shape and margin of the nodule also vary. In the case of small cell carcinoma, hilar and mediastinal lymph node metastasis may occur 3 months after nodule detection, and the early diagnosis of small cell lung cancer is extremely difficult. In the present lecture, the outcomes of follow-up of these various small pulmonary nodules will be illustrated. Figure 1CT image at detection Figure 210 years later

Abstract:
Diagnostic procedures for lung cancer can broadly be defined as those that lead to the initial diagnosis, evaluation of extent of disease, and obtaining tissue for further characterization of molecular and genetic properties of the cancer. In each of these areas there have been tremendous technologic advances which ultimately lead to added complexity in terms of best utilization of tissue. Tissue can be obtained by the radiologist through either the use of fine needles (either single-needle or co-axial) or through the use of cutting needles which obtain cores of tissues) and through a variety of guidance techniques including fluoroscopy, CT guidance (including CT fluoroscopy), sonography, and MR. Most commonly, now for lung procedures is CT guidance. With the increasing use of CT imaging lung nodules are detected at smaller and smaller sizes and the diagnostic approach becomes increasingly challenging. In addition, since there is better chance for cure when treatment is performed earlier the desire to obtain early diagnosis is strong. The question that arises primarily relates to what level of confidence is needed before a definitive surgical procedure is performed. Factors to be balanced are the diagnostic accuracy of competing non-invasive tests such as growth analysis or PET-CT, compared to needle biopsy. All this must also be balanced with the type of surgical procedure that is being considered and the tremendous improvements that often allow patients to be discharged within 1-2 days post surgery. Evaluating extent of disease includes biopsy of either lymph nodes or other structures such as ribs, adrenal glands, liver etc. Within the chest, evaluation of lymph nodes pre-operatively has been greatly enhanced through the use of bronchoscopy with ultrasound. However, there are many nodal stations that remain difficult to reach using this approach that can be reached with CT guided needle biopsy, including all compartments of the mediastinum and hilum. Lesions outside the lung can also be evaluated including the soft tissues and the ribs. These lesions are often detected on PET-CT and are amenable to needle biopsy. Most rib lesions can easily be accessed with simple aspiration type needles. The need for further characterization of cancers through molecular or genetic testing is rapidly gaining in importance. As new therapeutic techniques become available the need for more complete characterization of tumors becomes increasingly important. Here the question relates to how much tissue is needed to perform the desired test. This is a continuously evolving area and depends on which particular tests are being requested, availability of the institution to perform the particular test, and the potential to obtain the appropriate amount of material given the particular characteristics of the lesion. Critical to these considerations is developing a close working relationship with the pathology department so as to make sure all of these considerations are taken into account prior to performing a procedure. Collaboration with the pathology department is critical on many levels and may need to vary depending on available resources. Best would be having rapid on-site evaluation (ROSE), although this is not always possible. For each situation, a plan as to how to best maximize yield needs to be developed. In this talk, I will outline the many considerations for how best to optimize the diagnostic yield of material obtained by interventional radiologist depending on the characteristics of the lesion and present various strategies to integrate these approaches into various scenarios where tissue is required.

Background:
Anetumab ravtansine (BAY 94-9343) is a novel fully human anti-mesothelin IgG1 antibody conjugated to the maytansinoid tubulin inhibitor DM4. We report the results of a randomized phase II trial of anetumab ravtansine compared to vinorelbine in patients with advanced malignant pleural mesothelioma (MPM) who have high mesothelin expression and have progressed on platinum/pemetrexed-based first-line chemotherapy (NCT02610140).

Method:
Patients (≥18 years) with locally advanced or metastatic MPM with progressive disease following first-line treatment with pemetrexed-based chemotherapy, with or without bevacizumab, were eligible. Patients were pre-screened based on obligatory tumor staining for mesothelin as determined by the Ventana MSLN (SP74) immunohistochemistry assay. The primary efficacy endpoint was progression-free survival (PFS) per central radiologic review using modified RECIST criteria for MPM. Secondary objectives included overall survival, tumor response, and safety. Patients were randomized in a 2:1 ratio to anetumab ravtansine 6.5 mg/kg Q3W IV or vinorelbine 30 mg/m[2] QW IV.

Result:
A total of 166 patients were randomized to anetumab ravtansine and 82 to vinorelbine; 3 and 10 patients, respectively, not receiving treatment were included for efficacy but not safety assessments. The treatment arms were evenly balanced, with 73% male, 64% ECOG performance status 1, 96% epithelioid histology, and a mean 2.5 (±2.4) months since last progression. The median duration of treatment (anetumab vs vinorelbine) was 12.6 weeks (range 3-61) vs 13.0 weeks (range 1-43). Treatment-emergent grade (G) ≥3 adverse events (AEs) were seen in 85 (52.1%) and 53 (73.6%) of patients, respectively. G3/G4 neutropenia (22.2%/16.7%) occurred in the vinorelbine arm whereas corneal epitheliopathy (39.3% all grade, 1.8% G3) was distinct for the anetumab ravtansine arm. Serious AEs (any grade) were similar; 52 (31.9%) vs 25 (34.7%). Treatment-emergent AEs leading to dose modification were 42.9% in the anetumab ravtansine arm and 80.6% in the vinorelbine arm. There was one treatment-related G5 event in each arm. Median PFS was 4.3 months (95% CI:4.1, 5.2) for anetumab ravtansine vs 4.5 months (4.1, 5.8) for vinorelbine; hazard ratio 1.22 (0.85, 1.74), p=0.859. Fourteen (8.4%) patients in the anetumab ravtansine arm had an objective response vs 5 (6.1%) in the vinorelbine arm, with no complete responses. Interim median overall survival was 10.1 mo (7.6, -) vs 11.6 mo (7.7, 12.5), respectively, p-value 0.721.

Conclusion:
In relapsed MPM, anetumab ravtansine was not superior to vinorelbine with respect to PFS.

Background:
There is an increasing interest in the use of IO therapy in Mesothelioma (MPM). We previously reported on the effect of nivolumab (s.a) in patients with recurrent MPM with a disease control rate of 50% at 12 weeks. We therefore decided to test the effect of the combination of nivolumab and ipilimumab in recurrent MPM.

Method:
Patients with previously treated MPM and a PS of 0-1 are consented in this single arm prospective study. Pleural lesions must be available for biopsy before and after 6 weeks of treatment.Nivolumab is administered at a fixed dose of 240 mg (q2w) until progression and combined with ipilimumab (1mg/kg) on week 1, 7, 13 and 19. CT scans are performed every 6 weeks for analysis and duration of response. The primary endpoint is disease controle rate at 12 weeks. Translational research is performed on paired biopsies. A Simon’s minimax two-stage design is used to identify a DCR of >50%. Therefore 33 patients will be included.

Result:
From October 2016 until August 2017 38 patients gave informed consent. Three patients did not start due to progression or impossibility to biopsy. Two stopped after 1 cycle (due to progression or withdrawn consent). At time of analysis (August 29) 25 patients could be evaluated for response. At 12 weeks a DCR of 72% (18/25) and ORR of 28% (7/25) is observed. Two patients continued treatment after progression at 6 weeks; 1 achieved a PR after 4 months , and the other one is stable. Of the first 11 patients that have been in study for 6 months, 5 have PR, 1 SD and 4 PD. Toxicity is mild. SAE’s reported in the 38 patients occurred in 11 patients with grade 3 or 4 toxicity. No grade 5 toxicity was observed.

Conclusion:
In this interim analysis nivolumab plus ipilimumab meets the primary endpoint for patients with recurrent malignant mesothelioma. Toxicity is mild. The full data set will be presented at the WCLC.

Background:
It has been widespread practice across Europe to irradiate diagnostic or therapeutic chest wall (CW) intervention sites in patients with malignant pleural mesothelioma (MPM) post-procedure - a practice known as prophylactic irradiation of tracts (PIT). This study aims to determine the efficacy of PIT in reducing the incidence of CW metastases following a chest wall procedure in MPM.

Method:
In this multicentre phase III randomised controlled trial, MPM patients following a chest wall procedure were randomised 1: 1 to receive PIT (within 42-days of procedure) or no PIT. Large thoracotomies, needle biopsy sites and indwelling pleural catheters were excluded. PIT was delivered at a dose of 21Gy in 3 fractions over 3 consecutive weekdays using a single electron field adapted to maximise coverage of the tract from skin surface to pleura. The primary outcome was the incidence of CW metastases within 6 months from randomisation, assessed in the intention-to-treat population. Stratification factors included epitheloid histology and intention to give chemotherapy. Trial registration number NCT01604005.

Result:
375 patients (186 PIT and 189 no PIT) were randomised between 06/2012-12/2015 from 54 UK centres. Comparing PIT vs no PIT, %male patients was 89.8/88.4%, median age 72.8/74.6 years, %ECOG PS (0,1,2) 32.2,56.5,11.3/23.8,56.1,20.1%, %confirmed epithelioid histology 79.6/74.1%, and %with intention to give chemotherapy 71.5/71.4%. The chest wall procedures were VATS (58.1/51.3%), open surgical biopsy (2.7/5.3%), local-anaesthetic-thoracoscopy (26.9/27.0%), chest drain (5.9/8.5%) and others (6.5/7.9%) for the PIT vs no PIT arm respectively. Radiotherapy was received as intended by 181/186 patients in the PIT arm. The proportion of CW metastases by 6 months was 6/186 (3.2%) vs 10/189 (5.3%) for the PIT vs no PIT arm respectively (odds ratio 0.60 [95% CI 0.17-1.86]; p=0.44) and by 12 months 15/186 (8.1%) versus 19/189 (10.1%) respectively (OR=0.79 [95% CI 0.36-1.69];p=0.59). Cumulative incidence of CW metastases at 6months/12 months/24 months was 3.3/8.5/10.0% in the PIT arm vs 5.6/10.9/18.7% in the no PIT arm. Evaluable patients who developed CW metastases reported a mean increase in visual analogue scale pain score of 13.3 (p<0.01) compared to baseline. Skin toxicity was the most common radiotherapy-related adverse event in the PIT arm with 96(51.6%) grade 1, 19(10.2%) grade 2, and 1(0.5%) grade 3 radiation dermatitis (CTCAE V4.0). There were no other grade 3 or higher radiotherapy-related adverse events.

Conclusion:
There is no role for the routine use of PIT following diagnostic or therapeutic CW procedures in patients with MPM.

Abstract not provided

Background:
Malignant pleural mesothelioma (MPM) has a high symptom burden and early specialist palliative care (SPC) may have a beneficial role for these patients. We examined the effect of early SPC in patients with MPM.

Method:
Participants with newly diagnosed MPM (within the last 6 weeks) were randomised to early SPC integrated with standard care, or standard care alone, in a 1:1 ratio. SPC visits were 4 weekly throughout the study period. Quality of life (QoL) and mood were assessed at baseline and every 4 weeks for up to 24 weeks with the EORTC QLQ–C30 questionnaire for QoL and General Health Questionnaire (GHQ-12) for anxiety/depression. The primary outcome was the change in EORTC C30 Global Health Status (GHS) QoL 12 weeks after randomisation.

Result:
174 participants underwent randomisation with 148 (85.1%) completing the primary outcome. The two groups were well matched after randomisation. Median (IQR) age was 72.6 (68.5-78.3) years and 139 (79.9%) were male. Epithelioid was the most common MPM subtype in 136 (78.2%) cases, ECOG PS was 0 in 66 (37.9%) and 1 in 108 (62.1%) participants. At randomisation, 134 (77.0%) participants reported dyspnoea and 100 (57.4%) had chest pain. At least 1 cycle of chemotherapy was completed in 103 (59.2%) participants. At 24 weeks 30 (17.2%) participants had died. Table 1 presents the primary and secondary outcome data. 68 (78.2%) participants in the intervention arm completed all scheduled monthly SPC visits at 12 weeks, and 46 (52.9%) at 24 weeks. 15 (17.2%) participants in the control arm were referred to SPC within 12 weeks, and 30 (34.5%) by 24 weeks.

Table 1. Primary and secondary outcomes

	Control	SPC	Mean difference*	p=
Mean (SD) GHS QoL 12 weeks	59.5 (SD 21.2)	60.2 (23.6)	1.8 (95% CI -4.0 to 8.5)	0.60
Mean (SD) GHS QoL 24 weeks	63.7 (SD 19.8)	61.3 (20.8)	-2.0 (-8.8 to 4.6)	0.55
Mean (SD) GHQ-12 anxiety / depression scores 12 weeks	2.6 (3.2)	2.2 (3.0)	-0.6 (-1.5 to 0.4)	0.24
Mean (SD) GHQ-12 anxiety / depression scores 24 weeks	2.1 (2.55)	1.75 (2.5)	-0.4 (-1.2 to 0.4)	0.28
Median (95% CI) survival (months)	12.6 (10.7-19.7)	11.5 (9.8-15.9)	-	0.51
Mean (SD) GHS QoL alive after 6 months of randomisation	60.9 (20.9) (n=66)	64.3 (19.9) (n=63)	-	-
Mean (SD) GHS QoL in those who died within 6 months of randomisation	46.4 (21.4) (n=7)	38.9 (30.6) (n=12)	3.9 (-2.8 to 10.7)**	0.25
* adjusted for baseline score; ** post hoc analysis SPC = specialist palliative care; SD = standard deviation; CI = confidence interval; GHS = Global Health Status (from EORTC QLQ–C30; higher score – better QoL); GHQ = General Health Questionnaire (higher score - higher depression/anxiety)

Conclusion:
Provision of early palliative care for all patients with recently diagnosed MPM is not associated with beneficial changes in quality of life as compared to palliative care review based on symptom burden.

Background:
Our group has developed a new approach focusing on Surgery for Mesothelioma After Radiation Therapy (SMART), with encouraging results in a phase I/II clinical trial. The impact on the immune system of high-dose hypofractionated radiation therapy is expected to open the door for new combination therapy of immunotherapy and radiation to optimize their synergism on the immune system. The aim of this study is to investigate the antitumor effect of non-ablative hypofractionated radiation combined with anti-CTLA-4 antibody (a-CTLA-4) or low-dose cyclophosphamide (LD-CTX) in murine malignant mesothelioma model.

Method:
Balb/c mice were subcutaneously injected with murine mesothelioma AB12 cells into the left flank on day 0 (primary tumor) and into the right flank on day 7 (secondary tumor). Local radiotherapy (LRT) 5 Gy was delivered to primary tumor once daily for 3 consecutive days (total dose: 15 Gy). Mice were randomized into six groups: (1) No treatment, (2) LRT, (3) a-CTLA-4, (4) LRT+a-CTLA-4, (5) LD-CTX, (6) LRT+LD-CTX. We assessed local and abscopal effects by measuring primary and secondary tumor growth. Furthermore, CD4+ and CD8+ T cell proportion in tumor, spleen and peripheral blood were determined by flow cytometry.

Result:
Mice treated with LRT+a-CTLA-4 and LRT+LD-CTX showed the most significant deceleration in primary tumor growth compared to the other 4 groups. Both combination groups showed similar antitumor effects on the primary tumor. The secondary tumor growth tested the abscopal effect tended to be decreased in mice treated with LRT and LRT+a-CTLA-4 or LRT+LD-CTX compared to untreated mice, but the difference was not significant. Quantification of tumor-infiltrating T cells by flow cytometry showed that the percentages of total T cells, and CD4+ and CD8+ T cells in the primary tumor were increased in the combination groups.

Conclusion:
Combination of LRT and immunotherapy showed synergistic antitumor effects in controlling irradiated-tumor growth. CTLA-4 blockade and LD-CTX might be good candidates in combination with radiotherapy.

Background:
Encouraging survival has been reported with pleurectomy decortication (PD) for malignant pleural mesothelioma (MPM) in several surgical case series. However, doubts remain over the degree of selection bias that constitutes the final composition of these series which therefore lead to questions surrounding the validity of the reported outcomes. We have reviewed our initial experience in the MARS 2 study to analyse this surgical selection process in more detail.

Method:
The MARS 2 pilot is randomised trial of RCT of 14 UK centres recruiting into a cisplatin/pemetrexed with or without the addition of PD for meseothelioma in those who remain suitable after an induction two cycle regime. We completed the pilot to analyse screening, eligibility, consent and randomisation data to estimate the eventual pool of patients considered suitable for surgery.

Result:
From 19 Jun 2015 to 5 Dec 2016, 331 patients were screened from the participating centres. In total, 254 patients were excluded, 176 for failed screening and 78 who declined participation. Of the 176, who failed screening the reasons were non resectable disease (74), poor performance status (24), not fit for surgery (4), not mesothelioma (6), death (5) and other (63). From the 331 screened participants, 77 were enrolled to and received the initial two cycles of chemotherapy and a further 21 withdrew. The reasons for withdrawal were declining randomisation (5), progressive disease (10) and other reasons (6), leaving 56 participants randomised into the trial.

Conclusion:
Screening data of a prospective randomised trial (MARS 2) has provided a unique insight into the detailed selection process for PD for MPM. Exclusions occurred at multiple points in the pathway but these have identified potential points for intervention in patient education, staging and fitness assessment and the proportion of tumour progression which will inform the forthcoming phase III study. The clear extent of possible selection bias underscores the importance of evaluating the efficacy of surgery within the context of this randomised trial to be able derive robust estimates of treatment effect.

Abstract not provided