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Harvey I Pass



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    MA 10 - Immunotherapy I (ID 664)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      MA 10.10 - Tumor Draining Lymph Node Immunophenotype Corresponds with Primary Tumor Characteristics in Patients with Non-Small Cell Lung Cancer (ID 10343)

      11:00 - 12:30  |  Author(s): Harvey I Pass

      • Abstract
      • Presentation
      • Slides

      Background:
      There is growing appreciation for the role of tumor-draining lymph nodes (TDLN) in the dynamic of immunoediting orchestrated by non-small cell lung cancers (NSCLC). By comparing T-cell subsets and gene expression in TDLN and non-draining lymph nodes (NDLN), we aim to determine whether there is tumor-regional variation in immunophenotype.

      Method:
      Patients undergoing endobronchial ultrasound-guided transbronchial needle aspiration for the diagnosis/staging of NSCLC were recruited. Aspirates were obtained from TDLN (N1/N2 nodes with increased fluorodeoxyglucose-F-18 (FDG) avidity and/or enlarged >1cm) and NDLN (non-enlarged/non-FDG-avid N2/N3 nodes) along with peripheral blood. Samples were stained with fluorophore-conjugated antibodies (CD4-FITC, CD8-V450, CD25-PECy7, CD127-APCR700, CD45RO-PECF594) and analyzed by flow cytometry. CD4+CD25- and CD8+ effector T-cells (Teff) were sorted. Gene expression profiling was performed on sorted Teff using the Nanostring™ platform to measure differential expression between TDLN and NDLNs.

      Result:
      We compared T-cell subpopulations in TDLN and paired NDLN from 16 subjects. There were significantly fewer CD4+ T-cells in TDLN vs NDLN (10.1% vs 28.9%, p=0.0039), with more Tregs (12.1% vs 7.3%, p=0.1563) suggesting a pattern of tumor-regional immunosuppression in the TDLN. This was more consistent when tumor histology was adenocarcinoma compared to squamous cell cancer with respect to both depletion of Teff and higher proportion of Tregs (Figure 1). A more immunosuppressive TDLN phenotype was also observed with high tumor PD-L1 expression (>50%), with 36% fewer CD4+ T-cells in TDLN relative to paired NDLN when PD-L1 expression was high relative to just 3.2% fewer CD4+ T-cells with low PD-L1 expression. Gene expression in Teff has preliminarily demonstrated upregulation of genes mediating T-cell exhaustion (CTLA-4, PD-1, TGF-β) and downregulation of co-stimulatory/recruitment factors (CD28, ICOS, ICAM2) in TDLN suggesting impaired activation of tumor-regional Teff. Figure 1



      Conclusion:
      Our findings suggest that TDLNs in patients with NSCLC display a tolerogenic phenotype, with more marked immunosuppression in the setting of adenocarcinoma and high tumor PD-L1 expression.

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    MS 03 - Best Practice for Small-Sized Early Stage Lung Cancer: Standard Surgery, Limited Resection, SBRT (ID 525)

    • Event: WCLC 2017
    • Type: Mini Symposium
    • Track: Early Stage NSCLC
    • Presentations: 1
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      MS 03.04 - Technical Aspects of Limited Resection (ID 7651)

      11:00 - 12:30  |  Presenting Author(s): Harvey I Pass

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Since its first report by Churchill and Belsey in 1939, and its evolution in lung cancer management described by Jensik in 1973 (Figure), pulmonary segmentectomy use for early lung cancer diagnosis and treatment has remained controversial. Definitive answers must wait regarding the results of the JCOG and Alliance randomized trials before true standards for surgical care for the lung cancer less than 2 cm are determined. Nevertheless, sublobar resections including wedge resection and segmentectomy are being adopted at an increasing rate compared to its use in previously published large databases (SEER, 5%; ACS NSQIP, 4%). Proper preoperative teaching and intraoperative performance of the technical aspects of sublobar resection are now becoming priorities for general thoracic resident and fellow training in an era where minimally invasive techniques are becoming increasingly the standard of care. General thoracic surgeons must have meticulous attention to detail in performing these resections in order to decrease the likelihood of collateral damage to neighboring segments as well as to minimize local recurrence whether there are performing the operation open, hybrid, standard VATS, uniportal VATS, or robotic. The technical aspects of sublobar resection begin before the patient goes to the operating room, and prime objectives in planning these resections include (1) expertise in the segmental anatomy for that particular patient (2) location and size of the nodule with relation to adjoining segmental bronchovascular components (3) careful study and possible supplementation of high resolution computerized tomography with newer 3-D methods to define the spatial relationships of the nodule and segments (4) pre- and intraoperative methods for locating the nodule if there is suspicion that parenchymal palpation will fail (5) whether to perform wedge resection first or proceed directly to anatomic segmentectomy (6) defining and managing the fissure between segments and recognizing when extended segmentectomy is possible or whether to convert to lobectomy and (7) to use other intraoperative strategies to avoid technique related complications. Preoperative planning includes careful examination of the CT scan in the axial, coronal and sagittal plans in order to get a first appreciation of the depth, size, segmental anatomy and relationship of the nodule bronchovascular elements. Three-dimensional reconstruction can be as simple as navigational bronchoscopy planning images, or newer techniques for total 3-D pulmonary reconstruction which are in development (1). When there is a question of whether up front segmentectomy is to be performed and a part solid or non-solid nodule may not be palpable, intraoperative localization techniques such as navigation bronchoscopy(2) or placement of fiducials/microcoils (3) can be very useful. When there is no preoperative histologic diagnosis, whether a wedge or segmentectomy is performed initially will depend on the location and depth of the lesion as well as the fitness of the patient. Segmentectomy for initial diagnosis with intraoperative frozen section of both the primary lesion and suspicious level 13 and 14 stations can be prudent, especially if wedge resection could compromise performing the segmentectomy(4). In order to avoid positive margins, meticulous attention to detail with compulsive dissection and skeletonizing of the bronchovascular elements must be performed. If it is difficult to preserve the margin in a single segment resection, an extended resection of the parenchyma of adjacent segments or bisegmentectomy can be performed(5). There is controversy regarding the chance for loco-regional recurrence for segmentectomy especially in cases of pure solid lesions or segmentectomies which involve portions of the basilar segments or right upper lobe (6-8). Defining the fissure and the method with which it is divided can be one of the most important yet challenging portions of the operation. A variety of methods to define the fissure have evolved including inflation of the residual lung after segment occlusion, selective inflation of the segment to be removed, or the use of indocyanine green to define the intersegmental vein (4, 5), and the fissure can be divided either with stapling alone or in combination with harmonic scalpel(9). A variety of fibrin sealants are available to decrease postoperative fistulae. With regard to the optimal approach, to date there have been no studies which show any superiority regarding conventional VATs or uniportal VATs for segmental resection, or any difference between the VATs approaches and robotic segmentectomy (10). A recent meta-analysis of over 7438 patients revealed a trend towards increased conversion to open with VATs, while postoperative complications, operation time, length of stay, chest tube duration, and number of lymph nodes were comparable(11). Figure 1 Reference List (1) Yao F, Wang J, Yao J, Hang F, Lei X, Cao Y. Three-dimensional image reconstruction with free open-source OsiriX software in video-assisted thoracoscopic lobectomy and segmentectomy. Int J Surg 2017;39:16-22. (2) Zhao ZR, Lau RW, Yu PS, Wong RH, Ng CS. Image-guided localization of small lung nodules in video-assisted thoracic surgery. J Thorac Dis 2016;8:S731-S737. (3) Donahoe LL, Nguyen ET, Chung TB, Kha LC, Cypel M, Darling GE, et al. CT-guided microcoil VATS resection of lung nodules: a single-centre experience and review of the literature. J Thorac Dis 2016;8:1986-94. (4) Landreneau RJ, D'Amico TA, Schuchert MJ, Swanson SJ. Segmentectomy and Lung Cancer: Why, When, How, and How Good? Semin Thorac Cardiovasc Surg 2017;29:119-28. (5) Oizumi H, Kato H, Endoh M, Inoue T, Watarai H, Sadahiro M. Techniques to define segmental anatomy during segmentectomy. Ann Cardiothorac Surg 2014;3:170-5. (6) Hattori A, Matsunaga T, Takamochi K, Oh S, Suzuki K. Locoregional recurrence after segmentectomy for clinical-T1aN0M0 radiologically solid non-small-cell lung carcinoma. Eur J Cardiothorac Surg 2017;51:518-25. (7) Hattori A, Matsunaga T, Takamochi K, Oh S, Suzuki K. The oncological outcomes of segmentectomy in clinical-T1b lung adenocarcinoma with a solid-dominant appearance on thin-section computed tomography. Surg Today 2016;46:914-21. (8) Ueda K, Tanaka T, Hayashi M, Tanaka N, Li TS, Hamano K. What proportion of lung cancers can be operated by segmentectomy? A computed-tomography-based simulation. Eur J Cardiothorac Surg 2012;41:341-5. (9) Kuroda H, Dejima H, Mizumo T, Sakakura N, Sakao Y. A new LigaSure technique for the formation of segmental plane by intravenous indocyanine green fluorescence during thoracoscopic anatomical segmentectomy. J Thorac Dis 2016;8:1210-6. (10) Veronesi G, Cerfolio R, Cingolani R, Rueckert JC, Soler L, Toker A, et al. Report on First International Workshop on Robotic Surgery in Thoracic Oncology. Front Oncol 2016;6:214. (11) Liang H, Liang W, Zhao L, Chen D, Zhang J, Zhang Y, et al. Robotic Versus Video-assisted Lobectomy/Segmentectomy for Lung Cancer: A Meta-analysis. Ann Surg 2017.



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    P1.09 - Mesothelioma (ID 695)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Mesothelioma
    • Presentations: 2
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      P1.09-001 - Multiplexed Biomarker Strategies Based on Targeted Proteomics for Detection of Malignant Pleural Mesothelioma in Blood (ID 8811)

      09:30 - 16:00  |  Author(s): Harvey I Pass

      • Abstract

      Background:
      Blood biomarkers are only infrequently used for the diagnosis of malignant pleural mesothelioma. Most of these biomarkers are single marker proteins relying on antibody assays and with limited accuracy for mesothelioma detection in the blood. In our study, we apply targeted proteomics technologies to investigate novel diagnostic strategies based on multiplexed protein biomarkers for mesothelioma detection in serum.

      Method:
      We studied more than 400 serum samples of early (I/II) and late stage (III/IV) mesothelioma and asbestos exposed donors collected in USA, Australia and Europe. For quantitative proteomics, 50 µl of serum were processed on 96-well plates over different days to enrich for N-linked glycoproteins based on hydrazide chemistry. After tryptic digestion, serum peptides were analyzed in replicates, separated by ultra-performance liquid chromatography followed by selected reaction monitoring on a triple quadrupole mass spectrometer (LC-SRM). Isotopically labeled peptides were spiked in each sample for quantification and to assess the performance of the LC-SRM platform. Two non-human N-linked glycoproteins were spiked in each serum sample before processing to monitor the performance of the targeted proteomics workflow across samples and plates. The software package MSstats was used for large scale quantitative data analysis.

      Result:
      We processed and quantified over 400 serum samples analyzed in LC-SRM replicates. We assessed the performance of the targeted proteomics platform for large scale quantification of a multiplexed six peptide signature (including peptides from the established mesothelin biomarker). The coefficient of variation (CV) for parallel peptide quantification on LC-SRM ranged from 2% to 11.4% with CVs below 8% for all peptides but for one. Based on quantification of the two non-human spiked-in glycoproteins, average standard deviation of the targeted proteomics workflow was 0.42 over all samples. We investigated the performance of the multiplexed six peptide signature in discriminating mesothelioma from asbestos exposed donors. For the signature we fit a multiple logistic regression model on a training set of 212 patients and a validation set of 193 mesothelioma and asbestos exposed donors. The multiplexed biomarker signature discriminated mesothelioma from asbestos exposed with AUC of 0.72 in the validation set. Here, compared with performance of the single marker mesothelin (assessed by LC-SRM), the multiplexed biomarker signature separated early stage mesothelioma from asbestos exposed with AUC of 0.74, with sensitivity of 37.8% at 90% specificity, whereas the single mesothelin peptide had AUC of 0.66 and sensitivity of 22.2%.

      Conclusion:
      Multiplexed biomarker strategies based on targeted proteomics technologies can improve mesothelioma diagnosis in blood samples.

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      P1.09-007 - Targeting MET/TAM Receptors in Mesothelioma: Are Multi-TKIs Superior to Specific TKI? (ID 9959)

      09:30 - 16:00  |  Author(s): Harvey I Pass

      • Abstract

      Background:
      Malignant pleural mesothelioma (MPM) is an aggressive inflammatory cancer associated with exposure to asbestos, and most patients die within 24 months of diagnosis. There is an urgent need to identify new therapies for treating MPM patients. Targeting “addicted” receptor tyrosine kinase (RTK) signalling networks has become a critical therapy option in cancer therapy. RTK hetero-dimerization may however, be a key element in the development of resistance to such therapy. As such Tyrosine kinase inhibitors (TKIs) with the ability to target multiple receptors may have superior efficacy to those targeting individual receptors. We and others have identified c-MET, MST1R (also known as RON), Axl and Tyro3 as RTKs frequently overexpressed and activated in MPM, making these attractive candidate targets. Several agents have been developed which target these. LCRF0004 specifically targets MST1R, whereas BMS-777607, RXDX-106 or Merestinib (LY2801653) are orally bioavailable small molecule inhibitors which inhibit c-MET, MST1R, Axl and Tyro3 at nM concentrations. These drugs may therefore have clinical utility in the treatment/management of MPM.

      Method:
      Expression of RON/MET/TAM and associated ligands were assessed in a cohort of patient samples and MPM cell lines comprising benign, epithelial, biphasic, and sarcomatoid histologies. In vitro and in vivo experiments were undertaken to determine the efficacy of single and multi RTK targeting agents (LCRF0004, RXDX-106, BMS-777607). The effects of LCRF0004 and BMS-777607 were subsequently examined in an in vivo SQ xenograft tumour model.

      Result:
      mRNA expression of the RON/MET/TAM family and associated ligands (MSP, GAS6) was detected in a large panel of normal pleural and MPM cell lines. In a cohort of patient samples, mRNA levels of c-MET, Axl, Tyro3 and various isoforms of MST1R (flRON, sfRON, t-ΔRON) and MSP but not Gas6 or MERTK were increased in tumours compared with benign pleural samples (p<0.05). No MET Exon 14 skipping mutations were detected. RTK targeting agents displayed in vitro efficacy in terms of reduced proliferation. In vivo, the multi-target TKI (BMS-777607) demonstrated superior anti-tumour activity compared with LCRF0004 (MST1R specific compound). IHC analysis of the xenograft tumours showed high cytoplasmic expression of Vimentin, Cytokeratin and Calretinin, with significant necrosis in many.

      Conclusion:
      Our data suggests that a multi-TKI, targeting the RON/MET/TAM signalling network, is superior to selective RTK inhibition as an interventional strategy in MPM.