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Prasad S. Adusumilli



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    MA01 - Early Stage Lung Cancer: Questions and Controversies (ID 894)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 10:30 - 12:00, Room 202 BD
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      MA01.02 - Histologic Subtyping in Pathologic Stage I Lung Adenocarcinoma Provides Risk-Based Stratification for Surveillance (Now Available) (ID 13400)

      10:35 - 10:40  |  Author(s): Prasad S. Adusumilli

      • Abstract
      • Presentation
      • Slides

      Background

      Current national practice guidelines (NCCN, ACCP, ESMO) recommend a uniform follow-up protocol with intensive surveillance within the first two years following lung resection for stage I NSCLC. We hypothesize that the recurrence hazard following lung resection for stage I lung adenocarcinoma (ADC) varies according to histologic subtype.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A total of 1572 patients with resected pathologic stage I lung ADC were investigated. Two thoracic pathologists reviewed all tumor H&E slides (range 1-8, median 3) for histologic subtyping and percentage of each subtype. Recurrence hazard was estimated using the Kernel-Epanechnikov smoothing procedure. Association between recurrence hazard and high-grade histologic subtypes (micropapillary [MIP] and solid [SOL]) was assessed.

      4c3880bb027f159e801041b1021e88e8 Result

      Presence (≥5%) of these high-grade subtypes (MIP and/or SOL) was associated with significant increase of recurrence hazard compared to high-grade pattern negative (<5%) tumors (Figure): 1) patients with presence of either MIP or SOL had significant recurrence hazard peaks within two years after surgery; 2) SOL was associated with early hazard peak at the first year after surgery especially in distant recurrence hazard; 4) one-third of patients (515/1572, 33%) had no high-grade subtypes, in which the recurrence hazard was consistently very low (<2% risk each year) during the 10-year period after surgery without any hazard peak (red arrow).

      hazard fig 300.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our data suggest the utility of histologic subtyping for identifying patients with very low recurrence hazard, and provide foundation for establishing risk-based follow-up protocols. A potential option for low-risk patients may be omission of intensive follow-up during the first two years after surgery.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    MA05 - Improving Outcomes in Locoregional NSCLC II (ID 901)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 105
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      MA05.03 - Immune Microenvironment and its Association with Adjuvant Chemotherapy Benefit in Locoregionally Advanced Lung Adenocarcinoma (Now Available) (ID 12999)

      13:40 - 13:45  |  Author(s): Prasad S. Adusumilli

      • Abstract
      • Presentation
      • Slides

      Background

      The impact of the tumor immune microenvironment on the effectiveness of platinum-based adjuvant chemotherapy (ACT) in locoregionally advanced (stage II-III) lung adenocarcinoma (ADC) is unknown. We performed an analysis of the cellular components of the tumoral and tumor-associated stromal immune environment in stage II-III lung ADC and examined their association with ACT benefit.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Tissue microarrays (6 tumor and 3 stromal cores from each tumor) were constructed using resected tissue from patients with pT2-T4N1 lung ADC (n=500, 2000-2012) who did (n=225) and did not (n=214) receive ACT. Multiplex immunofluorescence was used to determine the quantity, localization, and colocalization of 21 types of immune cells and markers (including PD-1, PD-L1, CD3, CD20, CD68, CD163, MPO, and PanCK). The association between immune cell infiltration and recurrence free probability (RFP) was compared using Kaplan-Meier methods, and benefit from ACT by unsupervised hierarchical cluster modeling.

      4c3880bb027f159e801041b1021e88e8 Result

      Overall, increased tumoral infiltration of CD20+ B-cells and CD3+ and CD4+ T-cells was associated with an improvement in 5-yr RFP (CD20+ low vs high: 37% vs 49%, p=.03; CD3+: 39% vs 48%, p=.003; and CD4+: 39% vs 47%, p=.02, respectively) whereas increased stromal MPO+ neutrophil infiltration was associated with a worse 5-yr RFP (low vs high: 50% vs 38%, p=.003). Among patients who received ACT, cluster modeling revealed 5 risk groups (Groups A-E; Figure) with immune signatures including tumoral B-cells and CD163+PD-1+ macrophages as well as stromal CD57+ NK-cells and CD163+PD-L1+ macrophages that provided a progressive stratification of RFP following adjuvant treatment.

      vaghjiani.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Immune infiltration analysis can predict benefit from ACT and thereby provide a rationale to select patients for either chemotherapy, immunotherapy, or combination therapy following surgical resection.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    MA06 - PDL1, TMB and DNA Repair (ID 903)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 206 AC
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      MA06.06 - An Ex-Vivo Patient-Derived, Immunocompetent (PDI) Culture System to Evaluate Immunotherapeutic Agents’ Anti-Tumor Efficacy (Now Available) (ID 14299)

      14:05 - 14:10  |  Author(s): Prasad S. Adusumilli

      • Abstract
      • Presentation
      • Slides

      Background

      Anti-tumor efficacy of human immunotherapeutic agents, such as antibodies, chimeric antigen receptor (CAR) and T-cell receptor transduced T cells, are currently being investigated in immunodeficient mice prior to clinical translation. We developed and optimized an ex-vivo culture system utilizing malignant pleural effusions (MPEs) to compliment these investigations in a human, immunocompetent, tumor-like environment. We hypothesized that CAR T cells’ cytotoxicity will vary by the different immune compositions in each MPE, which are conditions unavailable in current efficacy assays.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Mesothelin-targeted CAR T cells from multiple donors were exposed to MPEs derived from non-small cell lung cancer patients (n=15) and RPMI culture medium. Influence of the MPEs on CAR T-cell efficacy was evaluated by viability and phenotype (flow cytometry), cytotoxicity (chromium release assay), and gene expression (NanoString). Group-based trajectory modeling was used to stratify the inhibitory effect of MPEs. MPE composition (ELISA and Luminex assays) was evaluated to interpret its influence on CAR T cells.

      4c3880bb027f159e801041b1021e88e8 Result

      With the incorporation of our optimized protocols, T cells retain their viability, phenotype (CD4/CD8), and percentage of CAR expression when cultured in MPEs. MPE soluble factor levels remained stable over multiple freeze/thaw cycles. CAR T cells co-cultured in MPE exhibited variable antigen-specific cytotoxicity (Fig. A). MPE-induced T-cell inhibition was stratified into groups of strong, mild, or no inhibition. (Fig. B). Compared to MPEs with either mild or no inhibition, MPEs with strong inhibition had significantly higher levels of TGFβ-2 (average TGFβ-2 level in strong vs. mild inhibition: 402 vs. 50 pg/mL, p<0.05) (Fig. C), IL-6, RANTES, and IL-5.

      pdi culture system.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      We present the first human immunocompetent culture system that can be used to evaluate immunotherapeutic agents’ efficacy prior to their clinical translation. Furthermore, analyses of the culture system’s soluble factors sheds light on their relative influence on T-cell efficacy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    MA09 - Lung Cancer Surgical and Molecular Pathology (ID 908)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 15:15 - 16:45, Room 202 BD
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      MA09.06 - The Newly Recognized Filigree Pattern of Micropapillary (MIP) Lung Adenocarcinoma (LADC) is as Clinically Important as the Classical Pattern (Now Available) (ID 11874)

      15:50 - 15:55  |  Author(s): Prasad S. Adusumilli

      • Abstract
      • Presentation
      • Slides

      Background

      Filigree pattern is a newly recognized addition to the morphological spectrum of the poor prognostic category of micropapillary (MIP) LADC. However, its morphologic features and clinical importance are not well understood. The aim of this study was to investigate the morphologic spectrum and clinical significance of filigree MIP pattern.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Filigree pattern was defined as tumor cells growing in delicate lace-like narrow stacks of cells (at least 3 piled-up nuclei) without fibrovascular cores, with frequently visible attachments to alveolar walls. This differs from the 2015 WHO description of classical MIP pattern as tumor cells growing in papillary tufts forming florets that lack fibrovascular cores. In order to assess for filigree vs classical MIP, we documented the frequency and extent of both patterns in 1325 Stage I LADC. These were correlated with recurrence free probability (RFP) and lung cancer-specific survival (LCSS) using Kaplan-Meier analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      In addition to 87 MIP predominant ADC previously diagnosed, we identified 57 more cases of MIP predominant LADC due to the new criteria of MIP filigree pattern. Of these 57 cases, 37, 16, and 4 cases were reclassified from papillary, acinar, and solid predominant LADCs, respectively. Survival curves of previously diagnosed MIP and newly diagnosed MIP for RFP showed a similar worse prognosis compared to other LADC histologic subtypes (previously diagnosed MIP vs newly diagnosed MIP, 5-year RFP 66% vs 68% [Figure]) as well as LCSS (previously diagnosed MIP vs newly diagnosed MIP, 5-year LCSS 82% vs 85%). When the MIP cases were divided into filigree or classical predominant MIP, no significant prognostic differences were observed between the two groups.

      figure filigree.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      The lack of significant prognostic difference between filigree vs classical predominant MIP LADC supports our proposal that the filigree pattern is an important addition to the morphologic spectrum of the MIP subtype.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    MA11 - Biomarkers of IO Response (ID 912)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Immunooncology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 10:30 - 12:00, Room 203 BD
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      MA11.01 - Comparative Efficacy of T-Cell Intrinsic Versus Extrinsic PD-1 Blockade to Overcome PD-L1+ Tumor-Mediated Exhaustion (Now Available) (ID 14194)

      10:30 - 10:35  |  Author(s): Prasad S. Adusumilli

      • Abstract
      • Presentation
      • Slides

      Background

      Anti-PD-1 agents are effective in overcoming PD-L1+ mediated T-cell exhaustion. Effective therapeutic regimens include multiple, long-term administration. We hypothesized that a single dose of T-cell intrinsic PD-1 blockade by expression of a dominant negative receptor (PD1-DNR) can be equally effective as multiple doses of anti-PD-1 agent administration in the treatment of PD-L1 overexpressing thoracic cancers.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Human T cells engineered to target the cancer-antigen mesothelin (MSLN) by expression of a chimeric antigen receptor (CAR) with or without co-transduction with a PD1-DNR underwent repeated antigen stress with cancer cells with constitutive overexpression of PD-L1. For comparative efficacy evaluation, anti-PD-1 antibody was co-administered with CAR T cells (CARs). In vitro efficacy was evaluated by cytotoxicity (chromium-51 release assay). In vivo, mice with established pleural tumor were treated with either a single dose of MSLN CARs (with and without anti-PD-1 agent) or MSLN PD1-DNR CARs. Tumor burden regression by bioluminescence imaging and median survival were evaluated.

      4c3880bb027f159e801041b1021e88e8 Result

      In vitro, constitutive PD-L1 overexpression (Fig. A) inhibits MSLN CAR effector function as evidenced by a decrease in cytotoxicity following repeated stimulation with MSLN+PD-L1hi tumor cells (Fig B). MSLN PD1-DNR CARs had increased cytotoxicity when compared to MSLN CARs with or without high frequency anti-PD-1 antibody supplementation. In vivo, mice treated with MSLN CAR (with or without anti-PD-1 antibody) or MSLN PD1-DNR CARs demonstrated enhanced tumor regression (Fig C) and prolonged median survival (Fig D) compared to MSLN CARs alone. Furthermore, a single low dose of MSLN PD1-DNR CARs shows equal anti-tumor efficacy compared to MSLN CARs with multiple doses of anti-PD-1 antibody.

      dozier_figure 1.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results demonstrate that CAR T cells engineered to express a cell-intrinsic PD-1 dominant negative receptor overcome PD-L1 mediated T-cell inhibition equally compared to multiple doses of anti-PD-1 antibody administration. A clinical trial with MSLN CAR PD1-DNR CAR T cells is being initiated.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    MA12 - Mesothelioma Surgery and Novel Targets for Prognosis and Therapy (ID 913)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Mesothelioma
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 10:30 - 12:00, Room 202 BD
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      MA12.07 - gC1qR Expression is Independently Prognostic for Survival Benefit Following Chemotherapy in Mesothelioma (Now Available) (ID 13284)

      11:10 - 11:15  |  Author(s): Prasad S. Adusumilli

      • Abstract
      • Presentation
      • Slides

      Background

      Overexpression of gC1qR, a multicompartmental and multifunctional cellular protein, has been shown to promote chemotherapy-induced apoptosis in cancer cells, but compromise CD4 T-cell proliferation in viral infections. The goal of this study was to investigate the overexpression of gC1qR, and its prognostic association with chemotherapy and CD4 T-cell infiltration in malignant pleural mesothelioma (MPM).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Tissue microarrays comprising 6 tumoral and 3 stromal cores from 265 patients with MPM (216 epitheloid, 26 biphasic, and 23sarcomatoid, 1989-2010) were investigated by immunohistochemistry for gC1qR expression (intensity and distribution by H-score, range 0-300), and CD4 T-cell infiltration. Overall survival (OS) was analyzed by the Kaplan-Meier method (high versus low gC1qR expression delineated by median score). Multi-variable analysis included clinical, pathological factors and stage (T, N).

      4c3880bb027f159e801041b1021e88e8 Result

      In comparison to benign and reactive mesothelial cells (median H-score 30), gC1qR is overexpressed (median H-score 155) in all histological types of MPMs (263/265, 99.2%). In epithelioid MPM patients – 1) among patients who received neoadjuvant chemotherapy (NAC), high gC1qR was associated with better median OS (25 vs.11 months, Fig1A), 2) among patients without NAC, high gC1qR was associated with better survival, survival benefit is pronounced in patients who received postoperative chemotherapy (median OS 38 vs.19 months, Fig1B), and 3) in multivariate analysis, high gC1qR was an independent factor for better OS. gC1qR expression did not correlate with CD4 T cell infiltration. However, among patients without NAC, high CD4+ T cell infiltration-high gC1qR expression was associated with better OS (26 vs 18,12, and11 months, Fig1C).

      gc1qr.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      gC1qR is overexpressed on MPM cells. MPM patients with high gC1qR expression have a significant survival benefit particularly following chemotherapy; or in the presence of high CD4 T-cell infiltration.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    MA22 - New Therapeutics, Pathology, and Brain Metastases for Small Cell and Neuroendocrine Tumour (ID 925)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 15:15 - 16:45, Room 206 BD
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      MA22.05 - Impact of Tumor Spread Through Air Spaces (STAS) in Lung Neuroendocrine Tumors (NETs) (Now Available) (ID 14221)

      15:45 - 15:50  |  Author(s): Prasad S. Adusumilli

      • Abstract
      • Presentation
      • Slides

      Background

      We have previously reported the prognostic significance of STAS in lung adenocarcinoma and squamous cell carcinoma. The aim of this study was to investigate the incidence and prognostic impact of STAS in lung NETs.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We evaluated all tumor slides (range 2-7, median 3) for presence of STAS from patients with p-Stage I-III primary lung NETs [n=628, typical carcinoid (TC, n=305), atypical carcinoid (AC, n=38), large cell neuroendocrine carcinoma (LCNEC, n=93) and small cell lung carcinoma (SCLC, n=57)]. Patients with combined NETs were excluded from this analysis (n=19). Cumulative incidence of recurrence (CIR) and lung cancer-specific cumulative incidence of death (LC-CID) were analyzed by competing risks approach.

      4c3880bb027f159e801041b1021e88e8 Result

      STAS was identified in 25% of NETs (15% in TC, 37% in AC, 43% in LCNEC, and 46% in SCLC). Prognostic analysis in TC cohort was not conducted due to the small number of events (<5 events). Patients with STAS positive tumors were associated with higher CIR than STAS negative tumors in the total (AC-LCNEC-SCLC) cohort as well as individual AC, LCNEC and SCLC cohorts (Figure 1, A-D). STAS was also associated with higher LC-CID in all cohorts except for AC (Figure 1, E-H). In multivariable analysis, STAS was a significant risk factor for recurrence and lung cancer specific-death, independent of stage and histologic subtype. Stratified by stage, STAS was an independent predictor of recurrence (subhazard ratio [SHR] 2.39, 95% CI 1.26-4.54, p= 0.007) and lung cancer-specific death (SHR 2.42, 95% CI 1.21- 4.84, p= 0.012) in LCNEC. In SCLC, STAS was also an independent risk factor of lung cancer-specific death (SHR 4.06, 95% CI 1.33- 12.35, p= 0.014).

      stas net figure abstract iaslc 2018 isa.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      STAS is a significant prognosticator in individual NET subtypes; AC, LCNEC, and SCLC. STAS is an independent poor prognostic factor in LCNEC and SCLC for lung cancer-specific death.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    MS10 - Part Solid Nodules, GGN and STAS (ID 789)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 15:15 - 16:45, Room 206 F
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      MS10.04 - Therapeutic Implications of Spread Through Air Spaces (STAS) (Now Available) (ID 11443)

      16:00 - 16:15  |  Author(s): Prasad S. Adusumilli

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MS31 - Clinical Science in Mesothelioma (ID 809)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track: Mesothelioma
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/26/2018, 13:30 - 15:00, Room 205 AC
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      MS31.04 - CAR-T and ADC's in MPM (Now Available) (ID 11538)

      14:15 - 14:30  |  Presenting Author(s): Prasad S. Adusumilli

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    OA03 - Advances in Lung Cancer Pathology (ID 897)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 10:30 - 12:00, Room 205 BD
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      OA03.07 - Three-Dimensional Immunofluorescence Analysis of Dynamic Vessel Co-Option of Spread Through Air Spaces (STAS) in Lung Cancer (Now Available) (ID 14318)

      11:35 - 11:45  |  Author(s): Prasad S. Adusumilli

      • Abstract
      • Presentation
      • Slides

      Background

      STAS was identified, by the 2015 WHO classification, as a new method of invasion in lung adenocarcinoma, with poor prognosis. Blood vessel co-option is a mechanism by which spreading intraalveolar tumor cells connect to the surrounding vasculature to survive. The aim of this study was to visualize the dynamic mechanism of blood vessel co-option using a high resolution and high-quality 3D reconstruction, and multiplex immunofluorescence (IF).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A 3D reconstruction image of a case of invasive lung adenocarcinoma with extensive STAS was performed on the formalin fixed paraffin-embedded (FFPE) block. 150 serial sections were obtained by the automated sectioning system AS410 (DNS. Ltd, Japan), and stained with H&E (100 slides), and multiplex IF (30 slides) for CD31, type IV collagen, TTF-1 and E-Cadherin to assess the relation between STAS and the surrounding lung parenchyma and vasculature. The IF stained sections were scanned with 0.33um/pixel by Panoramic P250 Flash (3D Histech Ltd, Hungary) Whole Slide Imaging Scanner (WSI). The WSIs were reconstructed into 3D exported to Imaris 8.0 (Bitplane, MA, US) for signal assessment.

      4c3880bb027f159e801041b1021e88e8 Result

      Serial 3D image analysis identifies the presence of STAS mainly in the form of micropapillary clusters. The multiplex IF staining highlighted the co-option which was determined by the spread and then attachment of STAS (TTF-1 and E-Cadherin positive) to distant alveolar wall capillaries (CD31 positive) with preservation of the alveolar wall (figure). This relation between STAS and the surrounding lung parenchyma was visualized in all serial sections of the whole FFPE block thickness. 01s1632681_ cd31a488_ecada594_col4a647_ttfa546_65.5x2.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      The survival of STAS, beyond the tumor edge, in lung adenocarcinoma is a viable mechanism for tumor recurrence. The combination of the high resolution and high-quality 3D reconstruction and multiplex immunofluorescence in our study, supports the concept that dynamic blood vessel co-option is a mechanism for STAS survival.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    WS02 - Mesothelioma Workshop (ID 996)

    • Event: WCLC 2018
    • Type: Workshop
    • Track: Mesothelioma
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/23/2018, 08:00 - 11:15, Room 205 AC
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      WS02.08 - The Microenvironment and Mesothelioma (Now Available) (ID 14751)

      09:05 - 09:20  |  Presenting Author(s): Prasad S. Adusumilli

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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