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G. Pelosi



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    MINI 14 - Pre-Clinical Therapy (ID 119)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI14.11 - Establishment of a Lung Cancer Patient-Derived Xenografts Panel (ID 2607)

      10:45 - 12:15  |  Author(s): G. Pelosi

      • Abstract
      • Presentation
      • Slides

      Background:
      Studies based on cell lines were found to be poor predictors of clinical effects and therefore in many cases translation of the results into the clinics failed. A major determinant for the poor performance of cell lines is the observation that cell lines do not reflect the whole complexity and heterogeneity of primary tumors. A growing body of work suggests that Patient-Derived Xenografts (PDX) represent a more informative cancer model, providing a faithful representation of the patient’s original tumor.

      Methods:
      PDX were obtained by direct implants of small tumor fragments (30mm[3]) in previously anesthetized SCID mice, and were subsequently passaged as tissue explants. PDX metabolic in vivo imaging was performed using weekly [18F]FDG-PET and coronal and 3D-reconstruction at different days. Analysis of mutations and copy number alterations of PDX and human constitutive and tumoural DNA was performed by SALSA MLPA® probe mix X050-A1 Lung Cancer (MRC Holland).

      Results:
      Tumor samples from 95 lung cancer patients (66 AC, 16 SCC and 13 other lung cancer histotypes (OL)) have been implanted in the flanks of SCID mice. Overall, 36 samples (37,9%) successfully grafted and were propagated for at least 3 passages in immunocompromised mice. Take rate was 34,8 % (23/66) in AC, 43,8% (7/16) in SCC and 46.1% (6/13) in OL (2 large cell carcinomas, 1 sarcomatoid carcinoma and 3 small cell carcinomas). A detailed immunohistochemical analysis of 27 PDX, at different passage in mice, confirmed that tumor histology, expression of specific markers (TTF-1, p40, Vimentin, Ki64 and Synaptophysin) and the amount of specific tumor cell subpopulations (i.e. CD133[+] Cancer Initiating Cells) were generally maintained in PDX. In vivo animal PET imaging showed that also metabolic activity of PDX was strictly correlated with parental tumor’s features, especially for tumours with a SUV~max~ level higher than 8 (R[2]=0.67, p<0.05). Mutation and copy number analyses, performed on 29 biological samples belonging to 11 different engrafted models, showed that genetic changes were maintained in PDX that well recapitulated the frequency of the major changes involved in lung cancer development (66.7% TP53; 60% CDKN2A, 40% LKB1, 40% KEAP1, 38.4% KRAS, 20% SWI/SNF, 20% PTEN, 8% ERBB2). Furthermore, we developed a freeze/thawing procedure on samples derived from PDXs that allows for 100% successfully thawing and established a large collection of more than 200 frozen PDX samples for future preclinical studies.

      Conclusion:
      The deep characterization of our established PDX panel confirmed that these mouse models recapitulate the parental primary tumors in terms of tumor histology, cellular and mutation pattern, metabolic activity and expression of specific markers for several passages in mice. All these data support the use of these “human in mouse” models for functional studies, highlighting the relevance of our PDX panel as a valuable platform for preclinical studies.

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    P1.06 - Poster Session/ Screening and Early Detection (ID 218)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Screening and Early Detection
    • Presentations: 1
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      P1.06-017 - Small Cell Lung Cancer in Lung Cancer Screening: Frequency and Outcome (ID 2476)

      09:30 - 17:00  |  Author(s): G. Pelosi

      • Abstract
      • Slides

      Background:
      Only 30% of small cell lung cancers (SCLC) are diagnosed as limited stage (LS-SCLC), whereas the majority of cases show extensive stage disease (ES-SCLC). Specific frequency and outcome of SCLC within lung cancer screening trials have not been described. The purpose of this study was to describe the frequency and outcome of SCLC in lung cancer screening trials with annual or biennial LDCT controls.

      Methods:
      The population was selected from two lung cancer screening trials (one pilot study and one randomized controlled study) based on serial low-dose computed tomography (LDCT). Subjects with diagnosis of SCLC were selected and the stage of the disease was assessed at the time of diagnosis, as follows: a) TNM staging system; b) 2-stage staging system (e.g. LS-SCLC or ES-SCLC). Survival curves were estimated using Kaplan-Meier method and were compared by log-rank test.

      Results:
      5,134 subjects were recruited and, thereafter, followed up for a median time of 8.3 years, with 45,141 person-year of clinical follow up. Ten SCLC were reported with incidence of SCLC 22/100,000 person-year, notably, 8 in the LDCT arms with incidence of 24/100,000. SCLC was diagnosed in 3/1643 women and 7/3385 men, age at diagnosis 65 years (range 53-73), and cumulative tobacco consumption of 82 pack-years (range 30-113). The proportion of SCLC among all lung cancers diagnosed in the screening was 10/164. Six out of the 8 SCLC reported in LDCT arms were screen-detected, whereas 2 SCLC were non-screen-detected. Median standard uptake value (SUV) by [18]F-Fluorodeoxyglucose Positron Emission Tomography was 10 (range 5.5-14.4). According to TNM classification, all but 1 SCLC were advanced stage at the time of diagnosis, whereas according to the 2-stage system 5 LS-SCLC and 5 ES-SCLC were observed. The prevalence of LS-SCLC was 62.5% in LDCT arm, in particular, 66.7% among screen-detected and 50% non-screen-detected. The 2 SCLC reported in control group were both ES-SCLC. Six of the 10 subjects died from SCLC, with median overall survival of 21.2 months (95% CI 7.4 – nc months; Figure). Median overall survival was 12-month longer for LS-SCLC (p = 0.02). Survival at 5 years was 0%. Figure 1.



      Conclusion:
      SCLC was diagnosed with higher proportion of LS-SCLC in LDCT-based screening trials, as compared to data from the literature. Median overall survival of LS-SCLC was slightly longer than ES-SCLC, allegedly related to diagnosis anticipation. None of these patients was alive at 5 years.

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    PLEN 04 - Presidential Symposium Including Top 4 Abstracts (ID 86)

    • Event: WCLC 2015
    • Type: Plenary
    • Track: Plenary
    • Presentations: 1
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      PLEN04.07 - Stopping Smoking Reduces Mortality in Low-Dose Computed Tomography (LDCT) Screening Volunteers (ID 2458)

      10:45 - 12:15  |  Author(s): G. Pelosi

      • Abstract
      • Presentation
      • Slides

      Background:
      The National Lung Screening Trial (NLST) has achieved a 7% reduction in mortality from any cause with low-dose computed tomography (LDCT) screening, as compared with the chest radiography arm. Other randomized trials are under way, comparing LDCT screening with no intervention in heavy smokers populations. None of these studies is designed to investigate the impact of smoking habits on screening outcome. In the present study, we have tested the effect of stopping smoking on the overall mortality of volunteers undergoing LDCT screening.

      Methods:
      Between 2000 and 2010, 3381 heavy smokers aged more than 50 years were enrolled in two LDCT screening programmes. Sixty-nine percent were males with median age of 58 years and median smoking exposure of 40 pack-years. Based on the last follow-up information, subjects were divided in two groups: current smokers throughout the screening period, and former smokers. The latter group included ex-smokers at the time of baseline screening (early quitters), and those who stopped smoking during the screening period (late quitters).The effect of smoking on mortality was adjusted according to the following covariates: gender, age, body-mass index (BMI), lung function (FEV1 %) and pack years at baseline.

      Results:
      With a median follow-up time of 9.7 years, and a total of 32,857 person/years (P/Y) follow-up, a total of 151 deaths were observed in the group of 1797 current smokers (17,846 P/Y) and 109 in 1584 former smokers (15,011 P/Y). As compared to current smokers, the Relative Risk (RR) of death of former smokers was 0.77 (95% CI, 0.60 to 0.99, p = 0.0416), corresponding to a 23% reduction of total mortality. Excluding 239 subjects who had stopped smoking from less than 2 years from the end-point of follow-up, RR was 0.64 (95% CI, 0.48 to 0.84, p = 0.0016), with a 36% mortality reduction. A similar risk reduction was observed in the subset of 476 late quitters (27 deaths, 4,777 P/Y), with a RR of 0.60 (95% CI, 0.40 to 0.91, p = 0.0158).

      Conclusion:
      Stopping smoking is associated with a significant reduction of the overall mortality of heavy smokers enrolled in LDCT screening programs. The benefit of stopping smoking appears to be 3 to 5-fold greater than the one achieved by earlier detection in the NLST trial.

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