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Marc De Perrot



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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: 3
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 10:30 - 12:00, Room 202 BD
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      MA12.04 - Discussant - MA 12.01, MA 12.02, MA 12.03 (Now Available) (ID 14623)

      10:45 - 11:00  |  Presenting Author(s): Marc De Perrot

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA12.09 - Preclinical Investigations of Folate Receptor Targeted Nanoparticles for Photodynamic Therapy of Malignant Pleural Mesothelioma (Now Available) (ID 11277)

      11:30 - 11:35  |  Author(s): Marc De Perrot

      • Abstract
      • Presentation
      • Slides

      Background

      Photodynamic therapy (PDT) following lung-sparing extended pleurectomy (EPD) for malignant pleural mesothelioma (MPM) has been investigated as a potential means to kill residual microscopic cells. High expression of folate receptor 1 (FOLR1) has been reported in MPM, and targeting the FOLR1 has been considered as a new potential strategy. We have developed FOLR1-targeting porphyrin-lipid nanoparticles (folate-porphysomes; FP) for PDT. The inhibition of survival pathways of activated epidermal growth factor (EGFR) also enhance the PDT efficacy. Here, we have combined these approaches by using FP based PDT together with an EGFR-tyrosine kinase inhibitor (EGFR-TKI).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The frequency of FOLR1 and EGFR expression in MPM was analyzed using tissue microarrays. Confocal microscopy and a cell viability assay were performed to confirm the specificity of FOLR1-targeting cellular uptake and photocytotoxicity in vitro. In vivo fluorescence activation and the therapeutic efficacy were then examined. The effect of EGFR-TKI was assessed in vitro. The in vivo combined anti-tumor effect of EGFR-TKI and FP-PDT was then evaluated.

      4c3880bb027f159e801041b1021e88e8 Result

      FOLR1 and EGFR were expressed in 79 % and 89 % of the MPM samples, respectively. The intracellular uptake of FP corresponded well with FOLR1 expression. When MPM cells were incubated in FP and then irradiated at 671 nm, there was significant in vitro cell kill, which was inhibited in the presence of free folic acid, suggesting the specificity of FPs. FOLR1 targeting resulted in disassembly of the porphysomes and subsequent fluorescence activation in intrathoracic disseminated MPM tumors, as demonstrated by ex vivo tissue imaging. FP-PDT resulted in significant cellular damage and apoptosis in vivo. Furthermore, the combination of pre-treatment with EGFR-TKI plus FP-PDT showed further marked improvement of treatment responses.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Folate-porphysome based PDT shows selective destruction of MPM cells based on FOLR1 targeting, and pre-treatment with EGFR-TKI further enhances the therapeutic response.

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      MA12.10 - Long-Term Impact of Radiotherapy Before Surgery for Mesothelioma on the Distribution of Memory T Cell Subsets (Now Available) (ID 12728)

      11:35 - 11:40  |  Author(s): Marc De Perrot

      • Abstract
      • Presentation
      • Slides

      Background

      Postoperative recurrence remains one of the critical issues in treatments for mesothelioma. We previously reported that non-ablative, hypo-fractionated radiation before surgery generated an antigen-specific activation of the immune system and could provide an in situ vaccination with long-term protection against mesothelioma in our murine model. An effective immunological protection depends on memory T cell subset diversification. However, limited work has been done to address the distribution of memory T cell subsets and its effects on the immune system after radiotherapy followed by surgery for mesothelioma.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      C57BL/6 mice bearing AE17-OVA tumor were treated with local radiotherapy (LRT). LRT 5Gy was delivered on days 10, 11 and 12. We performed radical tumor resection 7 days after LRT. The mice were re-challenged under the skin or into thoracic cavity with AE17-OVA 28 days after surgery and defined as immunological protective memory model if the tumors were completely rejected. Memory model received subcutaneous tumor inoculation once again (second rechallenge), samples were harvested on day 0, 3, 10. We investigated memory T cell subsets using flow cytometry. In addition, the harvested total splenocytes (effector) were co-cultured with CFSE-labeled AE17-OVA (target) for three days. Each of their cytotoxic potential was analyzed by evaluating a number of AE17-OVA and its early or late apoptosis.

      4c3880bb027f159e801041b1021e88e8 Result

      8 out of 10 mice completely rejected the subcutaneous tumor in mice treated with LRT and surgery after re-challenged. We observed significantly better survival in the memory model re-challenged into the thoracic cavity compared with no treatment mice. After subcutaneous tumor inoculation, central memory T cells (CD44[+]CD62L[+]KLRG1[-]) on day 0, effector memory T cells (CD44[+]CD62L[-]KLRG1[-]) and terminal effector T cells (CD44[+]CD62L[-]KLRG1[+]) on day 0, 3, 10 increased significantly in CD8[+] splenocytes of memory model compared with no treatment mice. This observation was also seen in draining and non-draining lymph nodes. The MFI of CFSE reflecting a number of AE17-OVA cells decreased, whereas the proportion of early (Annexin V[+]FVD[low]) or late (Annexin V[+]FVD[high]) apoptotic cells in CFSE[+] cells increased, depending on time passage and effector/target ratio after tumor inoculation in both memory model and naïve mice. However, during time passage, memory model always had a stronger cytotoxicity (even at Day 0) as compared to naïve mice.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our data raise an important possibility that non-ablative, hypo-fractionated radiotherapy followed by surgery for mesothelioma contributes to the development and long-term maintenance of memory T cell subsets, which could remain poised to rapidly recall effector functions upon antigen re-exposure.

      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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      MA22.06 - Preinvasive Multifocal Neuroendocrine Lesions with Primary Typical Carcinoid Lung Tumors: A Negative Prognostic Factor? (Now Available) (ID 12432)

      15:50 - 15:55  |  Author(s): Marc De Perrot

      • Abstract
      • Presentation
      • Slides

      Background

      Impact on survival in patients with surgically resected multifocal neuroendocrine lesions (MNET), such as diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) or tumorlets, along with primary typical lung carcinoid (TC) is unclear. Aim of this study is to analyze whether synchronous preinvasive multifocal neuroendocrine lesions of the lung with primary TC tumors (MTNET+TC) may represent a negative prognostic factor.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A retrospective study, prospectively collected, for TC from two institutional databases was evaluated with a lifelong follow-up from surgery. Patients who did not receive surgery, underwent bronchial resection or lung transplant were excluded. Pathology specimens were all reclassified according the 2015 WHO and the eight AJCC Staging system. Kaplan-Meier(KM) method and Log-rank test reports significance between TC and were MTNET+TC were used. Hence a 1:1 propensity score matching analyses was done by adjusting the imbalance and comparing the overall survival and progression free rate between matched groups with a Cox proportional hazards regression model. A p value of 0.05 or less was considered significant.

      4c3880bb027f159e801041b1021e88e8 Result

      From January 1983 to December 2013 a total of 234 patients was outlined from the databases (TABLE). A total of 41 patients (17.5%) with MNET+TC were identified. Overall KM progression free survival achieved at 5 and 10 years respectively MNET+TC 93.2% and 83.8% compare to TC 98.4% and 96.1% (p =0.00039). Thirty-six MNET+TC were matched pairs vs. TC alone. Univariate Cox proportional hazards model for matched patients MNET+TC compared to TC was 2.78 (95% CI=0.84-9.3, p=0.095). Difference in progression free rate between matched groups was p<0.001.

      table_net_daddi.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Synchronous multifocal neuroendocrine preinvasive lesions (MNET) with primary typical carcinoid (TC) lung tumors can be a negative prognostic factor. Careful search of MNET should be always performed in clinical and pathological staging of a suspected primary TC. The increased risk of progression of MNET+TC warrants an accurate and lifelong follow-up.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.01 - Advanced NSCLC (Not CME Accredited Session) (ID 950)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.01-76 - The Impact of Concordance with a Lung Cancer Diagnosis Pathway Guideline on Treatment Access in Patients with Stage IV Lung Cancer (Now Available) (ID 12628)

      16:45 - 18:00  |  Author(s): Marc De Perrot

      • Abstract
      • Slides

      Background

      Lung cancer is the leading cause of cancer mortality with the majority of cases diagnosed at an advanced stage. Timely access to treatment is dependent on efficient and appropriate patient assessment and early referral for diagnostic workup. This study aims to assess the impact of referral concordance with a new Lung Cancer Diagnostic Pathway Guideline (LCDPG) on access to treatment in patients with stage IV lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This is a retrospective cohort study of patients with clinical stage IV lung cancer referred to the Diagnostic Assessment Program (DAP) at a Canadian tertiary cancer centre between November 1, 2015 and May 31, 2017. Patient referrals were defined as concordant or discordant based on Cancer Care Ontario LCDPG. The primary outcome; time to treatment from initial healthcare presentation; was compared between the concordant and discordant referrals.

      4c3880bb027f159e801041b1021e88e8 Result

      Two hundred patients were referred for clinical stage IV lung cancer during the study period. Of these referrals, 151 (75.5%) were assessed and referred in concordance with LCDP guidelines. Guideline concordant referrals were associated with reduced time to treatment from first healthcare presentation compared with guideline discordant referrals (55.3 vs 108.8 days, p<0.001). Time to diagnostic procedure (32.2 vs 86.7 days, p<0.001) and decision to treat (38.5 vs 93.8 days, p<0.001) was also reduced with guideline concordance. The most common reason for discordant assessment and referral was delayed or inadequate investigation of symptoms in a high risk patient (32.7% of discordant referrals).

      The mean time from referral to diagnostic procedure (19.4 [SD 16.0] days), decision to treat (23.3 [SD 17.1] days), and treatment initiation (39.7 [SD 26.3] days) did not significantly differ between concordant and discordant groups. Time from referral to decision to treat was within 28 days in 71.5% of patients. The mean number of hospital visits from referral to treatment was 4.9 (SD 3.5). Diagnosis was achieved with a single diagnostic test in the majority of patients (91%). The most common method of diagnosis was EBUS-TBNA (33.5%). The most common treatment modalities initiated were radiation (60.5%) followed by chemotherapy (43%) and targeted therapy (21.5%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Guideline concordant assessment and referral of patients with stage IV lung cancer results in reduced time to diagnosis and treatment. The utilization of a LCDPG for lung cancer provides a streamlined and efficient framework to facilitate early diagnosis and treatment. Future research and education should focus on improving factors leading to a delay in DAP referral.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.06 - Mesothelioma (Not CME Accredited Session) (ID 955)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 3
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.06-06 - Role of GITRL-GITR System in Promoting Proliferation of Malignant Mesothelioma (ID 12852)

      16:45 - 18:00  |  Author(s): Marc De Perrot

      • Abstract

      Background

      Using microarray analysis to compare the gene expression profile of untreated murine mesothelioma cell line (RN5), RN5 treated with cisplatin, RN5 treated with radiation, and enriched mesothelioma stem cell (RN5-EOS-Puro2), we found 41 genes potentially linked to cell stemness. Among those 41 genes, Tnfsf18(GITRL) was one of the cell surface markers which is likely related to tumor proliferation. We therefore decided to analyze the role of this ligand and it’s receptor (GITRL-GITR system) in proliferation of human mesothelioma cancer cells.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Three human mesothelioma cell lines (CRL5820, CRL5915, CRL5946) were used in this study. They were treated with cisplatin and Cs-137 irradiator respectively. The rt-PCR and Western Blot were used to evaluate the GITRL and GITR expression level at different time points. To evaluate the effect of GITRL-GITR system in mesothelioma cell lines we design in vitro and in vivo model for it. A neutralizing monoclonal antibody (mAb) was used to break the GITRL-GITR system in vitro and in vivo. In the in vitro model, mesothelioma cells were seeded into 96 well plates and the MTT test was used to compare cell proliferating rate 4 days after seeding. In the in vivo model we injected the CRL5946 cells into the peritoneal cavity and implanted patient-derived xenograft subcutaneously of the NOD/SCID mice. We sacrificed mice 4 weeks later to evaluate tumor spheres formation number and draw tumor growing curve.

      4c3880bb027f159e801041b1021e88e8 Result

      All the three mesothelioma cell lines demonstrated increased expression of Tnfsf18 (GITRL) and Tnfrsf18(GITR) at an mRNA and protein levels after treatment with chemotherapy or radiothreapy. Breaking the GITRL-GITR system with neutralizing mAb decreased cell growth and survival rate in mesothelioma cell lines after chemotherapy or radiotherapy. In vitro cell viability test, the MTT test results showed in cisplatin-treated or radiation-treated cell lines with adding mAb to break GITRL-GITR system, the cell viability decreased. In vivo xenografting model of CRL5946 cell line which is treated in advance by chemotherapy or radiotherapy, the average tumor sphere number (>100um) also decreased after using mAb intraperitoneally. The inhibiting effect of GITR neutralizing monoclonal antibody could be demonstrated in vitro and in our in vivo model. In patient-derived xenografting subcutaneous model, the mAb could also delay cell growth.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The results of our study demonstrate that the GITRL-GITR system could play an important role in mesothelioma cells growth and survival especially after chemotherapy or radiotherapy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.06-23 - Association of Two BRM Promoter Polymorphisms and Tobacco Exposure with Malignant Pleural Mesothelioma (MPM) Risk and Survival (ID 12738)

      16:45 - 18:00  |  Author(s): Marc De Perrot

      • Abstract

      Background

      Brahma (BRM) is a critical ATPase subunit of the SWI/SNF chromatin remodeling complex. Homozygous 6-7bp insertion variants at two polymorphic promotor sites (BRM-741/BRM-1321) cause epigenetic suppression of BRM expression and they have been reported as susceptibility and/or prognostic markers in many malignancies, including non-small cell lung cancer. As epigenetic silencing of BRM can be reversed pharmacologically, targeting BRM polymorphisms has significant therapeutic potential. We evaluated BRM-741/BRM-1321 polymorphisms’ association with risk and prognosis of malignant pleural mesothelioma (MPM). While the effect of tobacco in MPM remains controversial, its interaction with genetic polymorphisms in MPM is largely unknown. We evaluated associations between BRM polymorphisms-tobacco exposure and MPM.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      MPM and age-distribution matched asbestos-exposed controls were recruited as part of an asbestos-exposure surveillance program. Participants were genotyped for BRM polymorphisms. Multivariable logistic regression assessed risk of MPM in case-control analyses. Association of BRM variants with overall survival (OS) was assessed by multivariable Cox regression. Secondary subset analyses were performed, stratified by smoking status.

      4c3880bb027f159e801041b1021e88e8 Result

      Of 265 MPM cases, 146 (55%) were ever-smokers; 51 (19%) were female; median age was 66 (range:21-84) years. Median OS was 18 months; median follow-up time was 15 months. Compared to 795 controls, there were no significant associations of BRM with risk (P>0.10, all comparisons). In contrast, compared to the wild-type genotype, the homozygous variant of BRM-741 and BRM-1321 were associated with lower OS, with adjusted hazard ratio (aHR)=2.56 [95%CI:1.7-3.8] and 2.07 [95%CI:1.4-3.1], respectively. Compared to patients carrying the double wild-type, patients homozygous at both loci had lower OS (aHR=2.70 [95%CI:1.7-4.4]).

      There was a significant differential effect of BRM polymorphisms on risk of MPM, by smoking status (interaction P<0.001): among ever-smokers, BRM homozygous variants in BRM-741, BRM-1321, or both conferred lower risks (adjusted odds ratios, aORs were between 0.18-0.28; each P<0.001), while for never-smokers, there was significantly greater risk conferred by carrying the homozygous variants (aORs between 2.7-4.4). Likewise, a similar differential effect by smoking status was seen in prognosis (interaction P<0.001): there was no association between BRM polymorphisms and OS in ever smokers (P>0.1, all comparisons), but in never-smokers, the aHR of carrying homozygous variants of BRM-741, BRM-1321 or both were 7.7 [95%CI:3.8-16], 4.0 [95%CI:2.1-7.7], and 8.6 [95%CI:3.7-20], respectively.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Never-smokers who develop malignant pleural mesothelioma have an increased chance of carrying BRM homozygous variants in their germline DNA, which results in substantially worse prognosis. In contrast, in smokers, there may be a protective effect, with no difference in overall survival.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.06-38 - Mesothelioma Stem Cells May Be the Critical Factor of Treatment Failure (ID 11344)

      16:45 - 18:00  |  Author(s): Marc De Perrot

      • Abstract

      Background

      Cancer cell repopulation during treatments of chemotherapy or radiotherapy is a major factor resulting in treatment failure. It has been indicated that cancer stem cells (CSC) may play critical roles during this process. The goal of our study is to characterise mesothelioma stem cells (MSC) and evaluate the prognostic values in those patients with malignant pleural mesothelioma (MPM). The eventual aim would be to design specific target therapy against MSC and develop novel approaches in clinical practice.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We have screened a group of genes that are most likely MSC-specific. Further characterization of the selected genes will be of critical importance in tumorigenesis, progression and prognosis. Murine mesothelioma AB12 and RN5 cells treated with either chemotherapy or γ-ray irradiation in culture, were used to compare gene expression profiles. The selected genes were confirmed by real-time PCR, flow cytometry and immunostaining. In vivo models, peritoneal lavage was collected at different time points after RN5 cell injection, to perform magnetic ranking cytometry with antibody-nanoparticle conjugates, and microarray assay. The expression of Tnfsf18 and Ngfr (CD271) genes associated with prognosis was evaluated in tumor tissues from MPM patients treated with SMART vs pre-SMART protocols, as SMART protocol has already shown significant clinical benefit. Image analysis was performed using Apero Imagescope program.

      4c3880bb027f159e801041b1021e88e8 Result

      The proportion of MSC significantly increased after RN5 parental cells were treated with either chemotherapy, or γ-ray irradiation, or in combination, while MSC showed more resistance to the above treatments, suggesting that chemoradiation resulted in MSC enrichment. Upregulation of genes Tnfsf18, Serpinb9b, Ly6a (Sca-1), Ngf, and Nppb were confirmed. CD271, the receptor of NGF, was shown to be upregulated after chemoradiation, especially after γ-ray radiation with a dose of 10Gy. Mesothelial precursors captured with magnetic nanoparticles conjugated to anti-Msln and trapped in the microfluidic device in the presence of a magnetic field showed an increase over time from 2-8weeks. Image analysis of human section slides indicated that total positive area of CD271 staining was significantly lower in those who were treated with SMART protocol than those with pre-SMART protocol (p<0.0025). Similar results were obtained in the high, medium and low positive areas from the SMART group, and p values are 0.0013, 0.0017 and 0.0035, respectively, when compared with the pre-SMART group.

      8eea62084ca7e541d918e823422bd82e Conclusion

      MSC-specific genes like CD271 and Tnfsf18 might be used as potential prognostic indicators and therapeutic targets.

      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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      WS02.04 - SMART, Where It Is Going (Now Available) (ID 14748)

      08:30 - 08:45  |  Presenting Author(s): Marc De Perrot

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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