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M. Carbone
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MINI 24 - Epidemiology, Early Detection, Biology (ID 140)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 15
- Moderators:J. Creaney, M. Carbone
- Coordinates: 9/08/2015, 16:45 - 18:15, 102+104+106
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MINI24.01 - Pleural and Peritoneal Malignant Mesothelioma in Women Correlated to Occupational, Domestic and Environmental Asbestos Exposure (ID 1361)
16:45 - 16:50 | Author(s): V. Panou, Ø. Omland, C. Meristoudis, L. Hoffmann, O.D. Røe
- Abstract
- Presentation
Background:
Malignant Mesothelioma (MM) is an aggressive neoplasm affecting the pleura and more rarely the peritoneum. Occupational exposure to asbestos is the most common cause, but domestic exposure through cohabitation with an asbestos worker and environmental exposure by living in proximity to an asbestos emitting industry are acknowledged risk factors. The Region of North Jutland in Denmark hosted two large shipyards and the only Danish asbestos cement factory in the period 1928-1986, using mainly chrysotile asbestos and resulting in high MM incidence (5/100,000 in 2011). In our patient cohort the proportion of MM cases in peritoneum (MAM) is larger for females than males, also noted by others. We examined whether this could be related to the source of asbestos exposure
Methods:
A retrospective investigation of medical records (Departments of Pathology and Medicine, Aalborg University Hospital) was performed, concerning females diagnosed with pleural MM (MPM) and MAM between January 1992 and February 2015. We focused on the correlation between the source of asbestos exposure and the development of either pleural or peritoneal disease. The asbestos exposure source was divided in two categories; primary, representing occupational asbestos exposure and secondary, including domestic and environmental exposure. Patients with unknown asbestos exposure or habitation history were excluded. We hypothesized that the site of MM development, pleura or peritoneum, is independent from primary or secondary asbestos exposure. Fischer´s exact test was applied to test the hypothesis.
Results:
Out of 67 women with MM, 27 were excluded due to insufficient information about asbestos exposure or habitation (data not shown). Of the remaining 40 females, 33 were diagnosed with MPM (83%) and 7 with MAM (17%). The median age for MAM and MPM diagnosis was 60 and 72 years respectively. Among the 40 MM patients, 25% (n=10) had a history of occupational asbestos exposure, 57.5% (n=23) had domestic and 17.5% (n=7) had environmental exposure. Importantly, secondary asbestos exposure was documented for 85% of the MPM patients (n=28) while primary in only 15% of them (n=5). On the contrary for the MAM patients, secondary asbestos exposure was reported for 29% (n=2) and 71% of them had primary exposure (n=5). The correlation between the source of asbestos exposure and the MM site was significant (p= 0.006, OR= 0.078).
Conclusion:
The majority of female MM patients have a non-occupational asbestos exposure, with a considerable rate of environmental exposure. Furthermore, the source of asbestos exposure seems to play an important role in determining the site of MM development. Primary asbestos exposure, inferring more intense exposure through occupation, may predispose to peritoneal while secondary, lighter asbestos exposure to pleural disease. This may also be indicated by younger age at MAM diagnosis and is in line with previous reports. Anatomical, biological or other genetical differences related to the site of MM cannot be excluded, as some studies indicate that asbestos exposed women develop MAM more often than men. Our study of large Danish population cohorts is in progress and aims to elucidate these questions (updates will be presented at the conference).
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MINI24.02 - Mesothelioma Risk in Turkey (ID 462)
16:50 - 16:55 | Author(s): M. Metintas
- Abstract
- Presentation
Background:
Turkish Mesothelioma Working Group; Drs. Abdurrahman Abakay, Sedat Altın, Güntülü Ak, Şule Akçay, Hasan Bayram, Mehmet Bayram, Hasan Fevzi Batırel, Serdar Berk, Mehmet Bilgin, Nilgün Yılmaz Demirci, Figen Deveci, Levent Elbeyli, Ahmet Erbaycu, Dilek Ernam, Sebahat Genç, Murat Gültekin, Ezgi Hacikamiloğlu, Hüseyin İlter, Selahattin Kadir, Hasan Kahraman, Mehmet Karadağ, Özkan Kaan Karadağ, Talat Kılıç, Gamze Kırkıl, Berna Kömürcüoğlu, Muzaffer Metintaş, Selma Metintaş, Arzu Mirici, Tevfik Pınar, Ömer Özbudak, Sibel Özkurt, Önder Öztürk, Mutafa Taşdemir, Dursun Tatar, Engin Tutkun, Umran Toru, Toros Selçuk, Zehra Seyfikli, Nazan Şen, Abdurrahman Şenyiğit, Gaye Ulubay, Ülkü Yılmaz, Adil Zamani In this study, we aimed to detect the current and future mesothelioma risk for Turkey to guide the studies for the elimination of asbestos exposure in the rural areas.
Methods:
Thirty-eight faculty members who were members of the Turkish Mesothelioma Working Group and and 4 foreign consultants took part in this study. In hospitals of 30 provinces where mesothelioma cases were most diagnosed, the patients diagnosed with "mesothelioma" under the code of C45 between 2008 and 2012 (for five years) were identified. The cases were checked one by one according to their identity, name, age, birth place, register and address information with their national identification numbers from the Central Register System (MERNIS). The deceased cases were identified; their dates of death and age were determined and these were also verified by the national registers. Following the identification of all deceased cases, the median survival was determined according to their diagnoses dates. After obtaining the final records of the cases with mesothelioma, the cases born in villages/rural areas were determined. Finally, "population exposed to asbestos in rural areas for a risky period of time" was determined. The number of mesothelioma to develop in the risky populations for the next 20 years was estimated based on those findings.
Results:
7,789 cases with C45 code between 2008 and 2012 in Turkey was collected and the demographic information was collected from 5,617 mesothelioma cases whose data were reliable. Out of these cases, 3,718 were born/lived in villages. 3,495 of the 5,617 mesothelioma cases had died until July 2014. The median survival was 8 months. 1,879 cases were not born and/or lived in a village with known asbestos exposure. These cases were most possibly related with occupational exposure. Between 2013 and 2033, it was projected that 15,450 mesothelioma will emerge in the population exposed to asbestos in the above mentioned rural areas. Moreover, it was projected that 2,511 new mesothelioma cases will emerge in the population who are still being exposed to environmental asbestos after 2013.
Conclusion:
We determined that mesothelioma caused by environmental and occupational asbestos exposure in Turkey is a more serious problem than previously anticipated. This is a unique epidemiological study that has determined the magnitude of an environmental/occupational carcinogen induced cancer problem through data collection from patients. Country wide measures are being implemented by the Public Health Institute of Turkey and Turkish Mesothelioma Working Group.
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MINI24.03 - Asbestos Knowledge and Awareness Level (ID 2610)
16:55 - 17:00 | Author(s): S. Metintas, G. Ak, F. Bogar, M. Metintas
- Abstract
- Presentation
Background:
Asbestos is an important carcinogen and people can be exposed to asbestos either occupationally or environmentally. There is naturally occurring asbestos in some regions of Turkey. The soil including asbestos was commonly used for plastering, whitewashing and roofing to build village house in these regions. The aim of this study is to determine knowledge and awareness level of people about asbestos in a region of Turkey where asbestos related diseases is endemic due to environmental exposure to asbestos in the rural area.
Methods:
The study is a questionnaire-based cross-sectional study included patients and their relatives admitted to a tertiary hospital in Eskisehir located central part of Turkey, in 2015. The questionnaire was applied by face-to-face interview after verbal consent from each participant. The questionnaire included 19 questions. The data was determined by percent and confidence interval. Chi-square test was used to compare the groups and multiple logistic regression analysis was used to determinate variables affecting knowledge level of asbestos.
Results:
A total number of 505 participants were included in this study. The mean age of them was 52.6±15.2 years (15-89) and 51.9% of them were male. About 41.2% of participants were born in the rural area and 14.5% of them still live in the villages. The educational status: 8.3% never, 55.7% elementary school; 19.0% secondary school; 17% university. About 4.4% of the participants were unemployed, 13.5% official, 20.8% worker, 2.8% farmer, 34.5% housewife and 24.2% others including retired, barber etc. About 76.4% of the participants who live in the villages had history of asbestos-contaminated soil in their villages. Only 20.5% of the group knew that white soil included asbestos. About 3.5% of the group mentioned that asbestos was useful, 44.1% harmful, 3.5% ineffective and the rest of them had no idea. Regarding the knowledge about asbestos related diseases among them, 34.9% stated that asbestos can cause lung cancer, 18.3% benign pleural or lung diseases and 23.1% mesothelioma. Most of the participants who never live in the village or moved to the city (62.9%) stated that asbestos was harmful and 30.9% had no idea. About 53.1% of them mentioned that asbestos can cause lung cancer, 26.9% benign pleural or lung diseases and 33.5% mesothelioma. In this group, the rate of true answers regarding usage of asbestos at workplace was 12.9% (8%-20%). Their knowledge about environmental usage of asbestos was low (16.6%) in this group. More than half of the participants (53.5%) pointed out that it is necessary to avoid from asbestos. The factors affecting knowledge level of asbestos were found to be young (p=0.016), live in the city (p=0.016) and high education level (p<0.001) by multiple logistic regression analysis.
Conclusion:
Although approximately 30 years passed after the first scientific report about hazards of environmental asbestos exposure on the respiratory system in this region, knowledge and awareness level of asbestos was quite low by sampling of this population. Health and environment authorities should inform the people as quickly and intensely about asbestos.
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MINI24.04 - Cluster Analysis of Malignant Mesothelioma Incidence in Louisiana (ID 1568)
17:00 - 17:05 | Author(s): E.G. Levitzky, E. Trapido
- Abstract
- Presentation
Background:
Exposure to asbestos fibers is the predominant causal factor in malignant mesothelioma (MM). The higher than expected incidence of MM in Louisiana, particularly among males, has been attributed to occupational exposure at facilities engaged in the shipping, ship construction and manufacturing industries that utilized substantial quantities of materials containing asbestos fibers. The primary aim of this study was to investigate the locations and demographic characteristics of spatial clusters of malignant mesothelioma (MM) cases reported in Louisiana between 1992 and 2011.
Methods:
Incident case data reported to the SEER Louisiana Tumor Registry (LTR) were geocoded by census tract and stratified into four categories based on gender and age at diagnosis - Males under 60 years, Males 60 years and over, Females under 60 years and Females 60 years and over. Investigation of probable spatial clusters for each gender/age group combination was conducted using a Poisson-based model for the LTR incidence data. The ratio of male to female cases in the probable clusters was utilized to assess environmental versus occupational exposure. Locations of possible spatial clusters and locations of facilities processing, manufacturing and utilizing asbestos materials were illustrated graphically using geographic information system software.
Results:
The most likely clusters of MM for each age/gender group were located in the Greater New Orleans area and were statistically significant. There was substantial overlap of the boundaries for the four clusters located in Jefferson Parish with 15 census tracts included in all four clusters. The overall ratio of male to female cases in the most likely clusters was 1.35:1. A statistically significant secondary cluster was identified for males under 60 years of age northwest of Baton Rouge, LA. A pair of spatial clusters was identified for Males under 60 years and Females 60 years and older south of Lafayette.
Conclusion:
Our results of a most likely cluster of MM for males 60 years and older in Jefferson Parish was expected given the presence of large business enterprises known to have processed, manufactured and used asbestos materials since the 1930s. The presence of probable spatial clusters of MM cases of females in both age groups and males under 60 years of age was unexpected. The spatial clusters reported for Males under 60 years and Females 60 years and older near Lafayette and no cluster for Males 60 years and older in the area also suggested possible environmental exposure in the area. These results, along with the ratio of male to female cases among the four combined spatial clusters in the Greater New Orleans area suggested that exposure to asbestos was likely a combination of occupational and environmental exposure. Spatial analysis of MM incidence is an effective approach for investigating geographic areas with elevated rates of the disease, especially where exposure to asbestos has not been investigated. Further research is needed to evaluate occupational and environmental exposure sources in these populations by gathering detailed asbestos exposure measurements, demographic and health data among cases by gender and age group.
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MINI24.05 - Discussant for MINI24.01, MINI24.02, MINI24.03, MINI24.04 (ID 3427)
17:05 - 17:15 | Author(s): M.G. Zauderer
- Abstract
- Presentation
Abstract not provided
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MINI24.06 - Mesothelioma in Finland: 10 Year Population-Based Cohort Between 2000-2009 (ID 1048)
17:15 - 17:20 | Author(s): I. Ilonen, S. Laaksonen, J.A. Salo
- Abstract
Background:
Malignant pleural mesothelioma (MPM) is associated with high morbidity and poor prognosis. We evaluated in population-based analysis the impact of enhanced diagnostics like positrone emission tomography (PET) and thoracoscopy. Also introduction of new medical therapy, Pemetrexed in 2004 could also benefit overall survival.
Methods:
Complete national data on 763 patients from the Finnish Cancer Registry sampled from 2000 to 2009 are presented. Survival for 1 year and 2 years and median survival were calculated. Survival data was acquired in February 2013.
Results:
During study period the incidence of MPM has been significantly and steadily increasing. The incidence was highest among men in all time periods (fig 1). Median age at the diagnosis was 68 years (range: 25-94 years). Reported histology was epitheloid in 211 (27.7%), sarcomatoid in 79 (10.4%), biphasic 33 (4.3%) and non-specified in 437 patients (57.3%). Median survival was 10 months (range 0 - 150 months), Fig 2. Between two 5-year cohorts (2000-2004 and 2005-2009) no significant difference in overallsurvival was observed (0.537). One year survival was 43.1% and two year 18.7%, with no differences were noted in the 5-year cohorts (0.826 and 0.402 respectively). Primary diagnosis was made in autopsy in 50 (6.6%) patients. A total of 27 patients (3.7% of deceaced) died for other reasons than MPM. 34 patients (4.5%) lived over 5 years and 16 (2.1%) of these are still alive. Figure 1Figure 2
Conclusion:
Despite significantly increased availability of new diagnostic tools like thoracoscopy, PET, and pemetrexed therapy during this cohort, no significant difference in overall survival was noted in this population based analysis. In order to facilitate better outcomes nationaly, new means are needed to coordinate both diagnostic and therapy of MPM.
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MINI24.07 - Infrared Spectroscopy as a Novel Approach in Differential Diagnosis of Malignant Pleural Mesothelioma from Lung Cancer Using Pleural Fluid (ID 2601)
17:20 - 17:25 | Author(s): S. Abbas, N.S. Ozek, D. Koksal, M. Severcan, S.A. Emri, F. Severcan
- Abstract
Background:
Malignant pleural mesothelioma (MPM) is an aggressive and rare form of cancer which arises from mesothelial cells lining pleural cavity. Since it is difficult to differentiate the benign pleural thickenings from carcinomas, MPM can only be diagnosed in the advanced stage. To decrease the mortality rate of this disease highly sensitive and specific diagnostic methods are required. In the current study we propose Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) spectroscopy coupled with chemometrics as a novel approach in diagnosis of MPM from pleural fluids with better sensitivity and specificity values than the other biomarker analysis methods that are currently used.
Methods:
The pleural fluid samples from MPM (n=24), lung cancer (LC, n=20) and benign transudate (BT, n=20) patients were collected to perform FTIR spectroscopic experiments. Recording and analysis of the spectral data were performed by using Spectrum One software. Unsupervised chemometric analysis methods including hierarchical cluster (HCA) and principal component analysis (PCA) were applied to discriminate MPM from BT and LC groups. To develop a diagnostic method, SIMCA, a supervised chemometric method was also performed.
Results:
Quantitative spectral analysis indicated that lipid, triglyceride, cholesterol ester, protein and nucleic acid contents of MPM group differ from BT and LC groups. The score plots obtained from PCA analysis of pleural fluid at whole (4000-650 cm[-1]), lipid (3000-2800 cm[-1]) and fingerprint (1800-650 cm[-1]) spectral regions showed that BT, LC and MPM groups are successfully discriminated from each other (fig 1.).Figure 1 Figure 1. PCA scatter plots for all BT, LC and MPM pleural fluid samples in the 4000–650 cm-1 spectral region. Moreover, the loading plots obtained from these spectral regions supported the differences in molecular content of all three groups. SIMCA results performed at whole and fingerprint regions also revealed high accuracy values for the diagnosis of MPM and LC.
Conclusion:
The results demonstrated that ATR-FTIR spectroscopy together with chemometric tools can be used for successful and rapid differential diagnosis of MPM from LC and BT groups . *This work was supported by the Scientific and Technical Research Council of Turkey (TUBITAK), SBAG-113S294 Research Fund.
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MINI24.08 - Breath Analysis by Ion Mobility Spectrometry Allows Discrimination of Pleural Mesothelioma Patients From Controls (ID 1508)
17:25 - 17:30 | Author(s): K. Lamote, M. Vynck, J. Van Cleemput, O. Thas, K. Nackaerts, J.P. Van Meerbeeck
- Abstract
Background:
Despite the use of asbestos has been banned in many countries, 125 million people worldwide are still exposed to asbestos and at risk for developing malignant pleural mesothelioma (MPM). Since MPM is a lethal tumor, with diagnosis mainly at advanced stage due to non-specific symptoms and investigations, it is thought that only an early diagnosis will improve patient’s outcome (van Meerbeeck et al., 2011). Breathomics has emerged as a new research field, allowing to detect volatile organic compounds (VOCs) in breath which can be used as non-invasive markers for disease (Lamote et al., 2014). We investigated if asbestos induces VOCs and how breath VOCs could help discriminating MPM patients from occupational asbestos-exposed and non-exposed controls.
Methods:
Twenty-three MPM patients, ten healthy asbestos-exposed (AEx) individuals and twelve healthy non-exposed (HC) persons were included. After a fasting period of 2 hours before the breath sampling, participants breathed tidally for 3 minutes through a mouthpiece connected to a bacteria filter. Subsequently, ten ml alveolar air was sampled via a CO~2~-controlled ultrasonic sensor and analyzed using the BioScout Multicapillary Column/Ion Mobility Spectrometer (MCC/IMS, B&S Analytik, Dortmund, Germany). Per subject a background sample was taken. VOCs were visually selected and their intensity (V) was calculated via on-board VisualNow 3.7 software. After calculating the alveolar gradient, we performed a lasso regression in R to search for peaks that have the most discriminative power to distinguish MPM patients from controls. Predictions were made by leave-one-out cross-validation. The use of breath VOCs on the diagnostic performance was investigated by ROC-analysis.
Results:
Eighty-nine VOCs were selected in breath and background samples. The VOCs P25, P8 and P7 were able to discriminate HC from AEx controls with 91% accuracy (AUC~ROC~=0.95), yielding a sensitivity, specificity and positive (PPV) and negative predictive value (NPV) of respectively 90%, 92%, 90% and 92%. MPM patients were discriminated from AEx by the VOCs P5, P3, P30, P1 and P54 with 82% accuracy (AUC~ROC~=0.73), yielding a sensitivity, specificity and PPV and NPV of respectively 91%, 60%, 84% and 75%. When discriminating MPM patients from pooled HC and AEx controls, the VOCs P5, P3 and P1 were found to be important, yielding 73% accuracy (AUC~ROC~=0.71) and a sensitivity, specificity and PPV and NPV of respectively 70%, 77%, 76% and 71%.
Conclusion:
Breath analysis can discriminate MPM patients from healthy asbestos-exposed persons with 82% accuracy and from combined asbestos-exposed and non-exposed controls with 73% accuracy while healthy asbestos-exposed persons can be discriminated from non-exposed persons with 91% accuracy. The VOCs P25, P8 and P7 seem markers for asbestos-exposure while VOCs P5, P1 and P3 seem linked to MPM pathogenesis after exposure. For screening and to rule out diagnosis, a high sensitivity and NPV are mandatory and to rule in diagnosis, a high specificity and PPV are mandatory, which can enrich a population at risk for follow-up with (annual) CT scans or chest radiography. Hence, our results hold promise to use the breath test for screening of asbestos-exposed healthy seniors.
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MINI24.09 - Cell-Free MicroRNA miR-625-3p Is Elevated in the Blood of Patients with Thoracic Malignancies (ID 1282)
17:30 - 17:35 | Author(s): M.B. Kirschner, M. Williams, S. Burgers, M.A. Hoda, C.M. Korse, D. Van Den Broek, T. Klikovits, B. Hegedus, B. Dome, M. Grusch, W. Klepetko, N. Van Zandwijk, G. Reid
- Abstract
Background:
In most instances definitive diagnosis of malignant pleural mesothelioma (MPM) requires a tissue biopsy of sufficient size. As a biopsy is not always feasible, the identification of an accurate biomarker easily measured in blood would represent an important step forward. A recent study indicated that microRNA miR-625-3p was present in elevated concentration in plasma or serum of MPM patients compared to healthy controls and asbestosis patients. (Kirschner et al, JTO; 7:1184). In this study, we have further investigated the diagnostic potential of miR-625-3p.
Methods:
MiR-625-3p and other microRNAs were measured by RT-qPCR in two independent series of MPM patients and controls. After exclusion of haemolysed samples and those yielding RNA of insufficient quality, series 1 consisted of serum samples from 73 MPM patients, 69 healthy volunteers and 64 patients with non-small cell lung cancer (NSCLC) collected at the Netherlands Cancer Institute (NKI) between 1994 and 2013. The second series consisted of plasma samples from 29 MPM patients and 35 healthy volunteers collected in Vienna and Hungary (V/H) between 2011 and 2013. Additionally levels of soluble mesothelin-related protein (SMRP) were assessed (ELISA) in the NKI series.
Results:
Analyses of samples from patients and controls in the NKI series revealed that serum miR-625-3p concentrations were on average 5.35-fold higher (p=0.0054) in MPM, and 3.47-fold (p=0.003) in NSCLC than in control samples. Levels in MPM patients were 1.54-fold higher than in NSCLC patients but this did not reach statistical significance (p=0.273). Compared to healthy controls, the areas under the ROC curve (AUC) were 0.82 (95% CI: 0.75-0.89) for MPM and 0.75 (95% CI: 0.67-0.84) for NSCLC. In the samples of the V/H series, plasma miR-625-3p concentrations were on average 1.98-fold (p<0.001) higher in MPM patients than in healthy volunteers, with an AUC of 0.80 (95% CI: 0.69-0.91). Assessment of SMRP in the NKI series revealed AUCs of 0.69 (95% CI: 0.59-0.78) differentiating MPM from healthy individuals and 0.65 (95% CI: 0.54-0.75) separating MPM from NSCLC, comparable to AUC values reported earlier.
Conclusion:
Data from two independent validation series confirms the previously observed increased abundance of miR-625-3p in blood from MPM patients. However, the miR-625-3p levels observed in NSCLC patients show that elevation of the level of this microRNA in plasma/serum is not restricted to MPM. Further studies into combinations of microRNAs and SMRP (diagnostic signature) in MPM are warranted.
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MINI24.10 - Discussant for MINI24.06, MINI24.07, MINI24.08, MINI24.09 (ID 3428)
17:35 - 17:45 | Author(s): T. Nakano
- Abstract
- Presentation
Abstract not provided
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MINI24.11 - Expression of PD-1 and Its Ligands in Human Malignant Pleural Mesothelioma (ID 1676)
17:45 - 17:50 | Author(s): E. Marcq, J. De Waele, J. Van Audenaerde, K. Zwaenepoel, P. Baas, P. Pauwels, E.L.J. Smits, J.P. Van Meerbeeck
- Abstract
- Presentation
Background:
The discovery of immune checkpoint receptors as cytotoxic T lymphocyte antigen-4 (CTLA-4) and more recently programmed death-1 (PD-1) introduced a new era in cancer immunotherapy. Immune checkpoints are responsible for controlling and inactivating the immune system in order to avoid autoimmunity and prevent tissue damage. PD-1 is expressed primarily on activated effector T lymphocytes. Its natural ligands are programmed death ligand-1 (PD-L1) and programmed death ligand-2 (PD-L2). Expression of PD-L1/PD-L2 on tumor cells or in stroma impairs effector T lymphocyte activity within the tumor microenvironment. Trials with antibodies that block the ligand-immune checkpoint interaction have shown promising results in several cancer types.Data on few mesothelioma patients suggest that blocking immune checkpoints could offer new opportunities for treatment of this very aggressive tumor.. We investigated PD-1, PD-L1 and PD-L2 expression in MPM. Furthermore the effect of interferon-gamma (IFNg), an important cytokine for immune-mediated tumor control, on their expression pattern was analyzed.
Methods:
Flow cytometry and immunohistochemistry (IHC) were used for the expression of PD-1, PD-L1 and PD-L2 on human primary MPM and T cells and on MPM cell lines that cover the three major histological subtypes of of MPM, i.e. epitheloid (M28, H2795, H2818), sarcomatoid (VAMT-1, H2731, H-Meso-1) and mixed (NKI04, MSTO-211H) mesothelioma cells. The effect of stimulation with IFNg on expression of PD-1 and its ligands was measured.
Results:
PD-1 surface expression was found on T cells and not on MPM tumor cells, corresponding to literature showing that PD-1 is only expressed on T cells, B cells and macrophages. Different expression patterns were observed regarding PD-L1 and PD-L2. Flow cytometry showed significant PD-L1 expression on all the epitheloid and sarcomatoid mesothelioma cell lines. Two out of three cell lines tested positive for PD-L2, both for the epitheloid and the sarcomatoid subtype. The mixed cell lines were negative for PD-1 and its ligands. Following IFNg stimulation, PD-L1 and PD-L2 expression was induced or upregulated on all cell lines. Primary MPM cells showed variable expression of PD-L1. IHC data for PD-1 and PD-L1 expression correspond to the flow cytometry results.
Conclusion:
Taken together, these data on PD-1, PD-L1 and PD-L2 expression on human MPM cells and T cells support further investigation of the expression profile of the immune checkpoint PD-1 and its ligands in MPM patients samples. We are currently performing this using multicolor flow cytometry and IHC.
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- Abstract
- Presentation
Background:
“Avoiding immune destruction” is one of the emerging hallmarks of cancer, as proposed by Weinburg and Hanahan. High expressions of immunosuppresive proteins strongly links to prognosis and cancer treatment. This study aimed to exam the expressions of immunosuppressors programmed death receptor ligand-1 (PD-L1) and transforming growth factor –β (TGF-β), and CD8+ tumor-infiltrating lymphocytes (TILs) in pre-treatment specimens from patients with advanced thymic epithelial tumors (TETs) including advanced thymic carcinoma and advanced invasive thymoma. To our knowledge, this is the first report to demonstrate the expression of PD-L1, TGF-β and CD8 and their clinical relevance in advanced TETs in Chinese population.
Methods:
Retrospective analysis was performed using tumor specimens from 20 patients with stage IV thymic carcinoma and 13 patients with stage III/IV invasive thymoma. Tissue biopsies were obtained before the first-line chemotherapy with (or without radiotherapy). The expression level of PD-L1, TGF-β and the prevalence of CD8+ TILs were assessed using immunohistochemistry (IHC). Their prognostic value for predicting overall survival (OS) and progression-free survival (PFS) were statistically analyzed using the SPSS software.
Results:
Higher expression levels of PD-L1 and TGF-β were detected in advanced thymic carcinoma than in advanced invasive thymoma (65.0% vs. 46.2%, 65.0% vs. 15.4%, respectively). Low level of CD8+ TILs was presented in 45.0% cases with advanced thymic carcinoma. In advanced thymic carcinoma, higher TGF-β expression was strongly associated with worse OS, with a p-value almost reaching statistical significance (p = 0.052). Median OS of patients with TGF-β high and low expression was 29.5 ms (95%CI: 18.6-40.4) and 62.9 ms (95%CI: 15.6-110.1), respectively. Higher PD-L1 expressions significantly predicted worse PFS after firs-line chemotherapy with (or without) radiotherapy (p =0.043). Median PFS was not estimable in PD-L1 low expression group. Mean PFS of patients with PD-L1 high and low expression was 13.3ms (95%CI: 8.0-18.6) and 23.5ms (95%CI: 13.9-33.2), respectively. An additional radiation treatment was particularly needed for CD8 low expression patients, in which first-line treatment with “chemotherapy + radiotherapy” significantly prolonged PFS compared to “chemotherapy-alone” (median PFS = 6.8ms, 95%CI: 0.0-2.7 vs. 3.5ms, 95%CI: NE, p = 0.015).
Conclusion:
Our results documented the clinical relevance of PD-L1, TGF-β, and CD8 in advanced TETs, with the prognostic value of predicting OS and PFS, as well as a potential association of immune conditions with therapeutic benefits.
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MINI24.13 - Molecular and Pathological Features of Different Malignant Pleural Mesothelioma (MPM) Histologic Subtypes (ID 2121)
17:55 - 18:00 | Author(s): G. Pasello, L. Urso, M. Mencoboni, F. Grosso, G.L. Ceresoli, F. Lunardi, R. Bertorelle, V. Ciminale, F. Rea, A.G. Favaretto, P. Conte, F. Calabrese
- Abstract
- Presentation
Background:
Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis and limited treatment options. Sarcomatoid/biphasic mesotheliomas are characterized by more aggressive behaviour, characterized by a higher resistance to systemic treatments, more frequent distant spread and a poorer prognosis compared with the epithelioid subtype. To date prognostic and tailored therapeutic biomarkers are lacking
Methods:
The present study analyzed the expression levels of MDM2 and HIF1alpha and the presence of inflammation, necrosis and proliferation in different histologic subtypes from chemonaive MPM patients. Diagnostic biopsies of MPM patients from four Italian cancer centers were centrally collected and analyzed. MDM2, and HIF1alpha expression levels were investigated through immunohistochemistry and RT-qPCR. A pathological assessment of necrosis, inflammation and proliferation index (through Ki67 immunostaining) was also performed. Molecular markers, pathological features and clinical characteristics were related to overall (OS) and progression free survival (PFS).
Results:
Sixty MPM patients were included in the study (32 epithelioid and 28 non-epithelioid). Higher levels of MDM2 (p<0.001), HIFalpha (p=0.013), necrosis (p=0.013) and proliferation index (p<0.001) were significantly associated with sarcomatoid/biphasic subtypes, while higher levels of inflammation were significantly associated with epithelioid subtype (p=0.044). MDM2 expression levels were correlated with HIF1alpha (p=0.0001), necrosis (p=0.008) and Ki67 (p=0.009). Univariate analysis showed a significant correlation of non-epithelioid histology (p=0.04), high levels of necrosis (p=0.037) and proliferation index (p=0.0002) with shorter PFS. This finding, however, was not confirmed by the multivariate analysis.
Conclusion:
Sarcomatoid/biphasic and epithelioid mesotheliomas show different MDM2 and HIF1alpha expression levels and are characterized by different levels of necrosis, proliferation and inflammation. Further studies are warranted in order to confirm a prognostic and predictive role of such markers and features.
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MINI24.14 - Use of Next Generation Sequencing to Improve Lung Tumor Immunotherapy (ID 1749)
18:00 - 18:05 | Author(s): B.W.S. Robinson, S. Ma, S. Sneddon, M.R. Tourigny, I. Dick, J.S. Leon, A. Khong, S.A. Fisher, R.A. Lake, W.J. Lesterhuis, A.K. Nowak, S. Leary, M.W. Watson, J. Creaney
- Abstract
- Presentation
Background:
Immunotherapy of pulmonary tumors is now a clinical reality, however most patients do not respond. To convert non-responders into responders one potential approach is to identify the tumor‐specific ‘neo‐antigens’ that arise from DNA mutations in order to follow tumor-specific responses and to design therapeutic vaccines to try to ‘enforce’ a response against these resistant tumors.
Methods:
First, in order to identify tumor neo-antigens we performed RNAseq and exome analysis to identify single nucleotide variants (SNV) in murine pulmonary tumors. An average of 485 SNVs was found. We focused on AB1 and AB1-HA (asbestos-induced mesotheliomas, which mimic human mesothelioma) and Line 1 (lung cancer). We used the NetMHCpan 2.8 algorithm to identify candidate mutation‐carrying peptides and screened them in an interferon‐γ ELISPOT assay. Second, to determine if more neo-antigens could be ‘unmasked’ by therapy, we tested three candidate therapies in our murine model then reanalyzed neo-antigen responses a) Treg depletion using Foxp3-DTR mice, b) gemcitabine, an immunogenic cytotoxic chemotherapy commonly used for pulmonary malignancies, and c) antiCTLA4 (a checkpoint blockade therapy).
Results:
We identified 20 candidate mutation‐carrying peptides in the ELISPOT assay. A strong spontaneous endogenous pre-treatment immune response was demonstrated to DUqcrc2, a component of the respiratory chain protein ubiquinol cytochrome complex. It was found to stimulate a strong response at a similar magnitude to the model neo-antigen viral haemagglutinin (HA). The DUqcrc2 peptide sequence (amino acid 405-413) is predicted to bind the H-2Kd, and the mutant has a proline to alanine substitution mutation at position 408. Treg depletion unmasked a second neo-antigen, DGANAB. GANAB is an alpha glucosidase which cleaves the 2 innermost alpha-1,3-linked glucose residues from the Glc-2-Man-9-GlcNAc-2 oligosaccharide precursor of immature glycoproteins. There is an arginine to glutamine substitution mutation at position 969 of DGANAB (965-972) sequence. This observation supports the theory that removing Treg cells may broaden the immune response to a greater number of neo-antigens, a response presumably otherwise restrained by Treg suppression. Gemcitabine and antiCTLA4 checkpoint blockade did not unmask any additional neo-antigens.
Conclusion:
Thus, removing some immune restraints may expose a greater number of neo-antigens as potential clinical targets. The results from these approaches suggest novel ways to improve the immunotherapy of lung tumor and are the basis for planning current clinical trials.
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MINI24.15 - Discussant for MINI24.11, MINI24.12, MINI24.13, MINI24.14 (ID 3429)
18:05 - 18:15 | Author(s): E. Felip
- Abstract
- Presentation
Abstract not provided
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Author of
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MS 08 - BAP1 Cancer Syndrome and Mesothelioma (ID 26)
- Event: WCLC 2015
- Type: Mini Symposium
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:L.M. Krug, N. van Zandwijk
- Coordinates: 9/07/2015, 14:15 - 15:45, 702+704+706
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MS08.01 - Mesothelioma and BAP1 Germline Mutations (ID 1877)
14:20 - 14:40 | Author(s): M. Carbone
- Abstract
- Presentation
Abstract not provided
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ORAL 23 - Prevention and Cancer Risk (ID 121)
- Event: WCLC 2015
- Type: Oral Session
- Track: Prevention and Tobacco Control
- Presentations: 2
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ORAL23.05 - Increased Proportion of Female and Young Mesothelioma Cases Are Indicators of Environmental Exposure to Carcinogenic Mineral Fibers in Nevada (ID 959)
11:28 - 11:39 | Author(s): M. Carbone
- Abstract
- Presentation
Background:
Inhalation of asbestos and other carcinogenic mineral fibers cause malignant mesothelioma (MM) and lung cancer. Occupational exposure leads to a MM male to female (M:F) sex-ratio of 4-8:1, with a mean age of diagnosis of 74 years old because of the 30-50 years latency between initial exposure and MM development. In places where people are only environmentally exposed to carcinogenic fibers, the M:F sex-ratio is about 1:1 and the mean age of diagnosis is 50-60 years. In places where both types of exposure exist, the M:F sex ratio decreases and the proportion of young (<55 years old) cases increases, compared to places with occupational exposure only. Therefore, incidence rates cannot distinguish between occupationally- and environmentally-caused mesotheliomas.
Methods:
In order to detect areas with possible environmental exposure to carcinogenic fibers, we studied the geology of Nevada. We compiled and integrated known presence of fibrous minerals in Nevada from published sources. We used the CDC 2006-2010 cancer data to study MM incidence and death rates by state and by gender. We also analyzed MM mortality data from the CDC in different Nevada Counties, per sex and age group, for the 1999-2010 period.
Results:
Several fibrous minerals were identified in Nevada, including actinolite asbestos, other amphiboles such as magnesioriebeckite, winchite and richterite that caused an epidemic of asbestos-related disease in Libby, Montana, and the highly carcinogenic erionite. For the 2006-2010 period, Nevada has a global MM age-standardized incidence rate of 10 cases per million inhabitants-year (95% confidence interval (CI): 8-12), similar to the average MM rate in the US (10 per million; 95% CI: 10-10). We discovered that Clark and Nye counties in southern Nevada had higher proportion of young (<55 years) MM cases (11.28%) and lower M:F sex-ratio (2.69:1), compared with other Nevada counties (M:F sex-ratio=6.33:1, p=0.04; proportion of young MMs=9.09%, p=0.80) and with the US (M:F sex-ratio=4.97:1, p=0.04; proportion of young MMs=6.21%, p=0.02).
Conclusion:
The significant decrease of MM M:F sex-ratio and increase of young cases are indicators of possible environmental exposure to carcinogenic fibers in southern Nevada. In this arid region, naturally occurring asbestos minerals are present in urban and rural areas where people use to enjoy outdoor activities including horseback riding, running, hiking, bicycling, and off-road vehicle (ORV) recreation. Airborne dust is common due to wind erosion. Asbestos fibers have been found in air and dust samples in Clark County. Further research should be conducted in this area to help identify sources of environmental exposure to these mineral fibers, activities that lead to the release of these carcinogenic fibers into the air, and measures to reduce the consequent risk of MM and other cancers.
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ORAL23.08 - Discussant for ORAL23.05, ORAL23.06, ORAL23.07 (ID 3563)
12:01 - 12:11 | Author(s): M. Carbone
- Abstract
- Presentation
Abstract not provided
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P1.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 224)
- Event: WCLC 2015
- Type: Poster
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.08-003 - Minimal Asbestos Exposure in Germline BAP1 Heterozygous Mice Is Associated with Deregulated Inflammatory Response and Increased Risk of MM (ID 1483)
09:30 - 09:30 | Author(s): M. Carbone
- Abstract
Background:
Germline BAP1 mutations predispose to several cancers, in particular malignant mesothelioma. Mesothelioma is an aggressive malignancy generally associated to professional exposure to asbestos. However, to date we found that none of the mesothelioma patients carrying germline BAP1 mutations were professionally exposed to asbestos. We hypothesized that germline BAP1 mutations might influence the asbestos-induced inflammatory response that is linked to asbestos carcinogenesis, thereby increasing the risk of developing mesothelioma after even minimal exposure.
Methods:
We experimentally tested in a BAP1[+/-] murine model whether germline BAP1 heterozygosity would result in alterations of the asbestos-induced inflammatory response, and whether low doses of asbestos might be sufficient to cause MM.
Results:
Germline BAP1 heterozygosity is associated with a significantly altered peritoneal inflammatory response upon exposure to asbestos fibers and to an increased risk of MM following exposure to even minimal amounts of asbestos that rarely cause MM in wild type animals.
Conclusion:
Our findings support our hypothesis that germline BAP1 heterozygosity increases susceptibility to the carcinogenic effects of low doses of asbestos. Based on these results, we suggest that prevention programs of MM in individuals carrying germline BAP1 mutations should focus on reducing exposure to even minimal indoor and/or naturally occurring outdoor sources of carcinogenic fibers, levels that are within the acceptable “safe” limits for the population at large.
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P2.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 225)
- Event: WCLC 2015
- Type: Poster
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.08-002 - Germline BAP1 Mutation Is Associated with a Significant Increased Survival and Multiple Cancer in Mesothelioma Patients (ID 961)
09:30 - 09:30 | Author(s): M. Carbone
- Abstract
Background:
Because the diagnosis is often made at a late stage, malignant mesothelioma (MM) prognosis is very poor, with a median survival of 6-12 months and a five-year survival of less than 5%. We found that germline BAP1 mutation is associated with a new cancer syndrome, including rare malignancies such as MM and uveal carcinoma (UV), and other cancers. We noted that some MM cases that we followed from BAP1 mutated families had prolonged survival. We carried out a pooled analysis of BAP1 mutated MM patients to test the hypothesis that they had a better survival compared to sporadic MM.
Methods:
: We included all published BAP1 germline mutated MMs with available data on BAP1 status, site of MM, age at diagnosis, gender, and age at death or status at end of follow-up, in addition to the BAP1 mutated MM cases from families that we are following. Twenty-three BAP1 MM patients were included. Using the Kaplan-Meier method and Wilcoxon test, we compared survival among BAP1 mutated MM patients with that of all MMs (N = 10 556) recorded in the US SEER data from 1973 to 2010.
Results:
In our BAP1 cohort, ten patients had peritoneal MM, ten pleural MM, and three MM in both locations. Thirteen patients had one or more malignancies in addition to MM. Actuarial median survival for the MM patients with germline BAP1 mutations was five years, as compared with less than one year in the SEER MM control group. Five-year survival was 47%, 95%CI [24-67%], as compared with 6.7% [6.2-7.3%] in the SEER MM control group. The small size of our BAP1 cohort did not allow for significant statistical comparisons. However, patients with peritoneal MM (median survival of 10 years, P=0.0571), or with a second malignancy in addition to MM (median survival of 10 years, P=0.0716), survived for a longer time compared to patients who only had pleural MM, or MM patients without a second malignancy, respectively. Figure 1
Conclusion:
MM patients with germline BAP1 mutations have an overall seven-fold increased survival, independently of sex and age. This better prognosis was associated with multiple cancer and/or peritoneal MM. Appropriate genetic counseling and clinical management should be considered for MM patients who are also BAP1 mutation carriers.
