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M. Carbone



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    ED13 - Treatment of Malignant Pleural Mesothelioma (ID 282)

    • Event: WCLC 2016
    • Type: Education Session
    • Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
    • Presentations: 1
    • Now Available
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      ED13.06 - Mesothelioma in a Setting of Germline BAP1 Mutations (Now Available) (ID 6500)

      M. Carbone

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Individuals that are born with germline BAP1 mutations are affected by the BAP1 cancer syndrome. All individuals affected by this cancer syndrome have developed one or more malignancies in the course of their life. Mesothelioma, uveal and cutaneous melanomas –tumors often associated with exposure to environmental carcinogens-, are the most common malignancies, although almost any tumor type has been detected in carriers of this cancer syndrome. In addition, BAP1 mutant carriers develop multiple benign melanocytic tumors –histologically different from other SPITZ-like tumors- that we have called melanocytic BAP1 associated intradermal tumors (MBAITs) that can alert the physician that the patients is a carrier of the BAP1 cancer syndrome. Most malignancies develop after the 4[th] decade of life, although cancers in individuals as young as 19 years old have been detected. Because many of these malignancies, for example melanomas, can be cured by early detection, it is important to identify BAP1 mutant carriers that can be screened for early detection and curative resection. Moreover, carriers of germline BAP1 mutation may be at increased risk of developing mesothelioma and melanoma following exposure to low doses of asbestos, sunlight and X-Rays, thus cancer preventive measures can be implemented. When cancer develops in a setting of BAP1 germline mutations, these patients have a much better prognosis compared to patients with the same malignancies when they occur sporadically (i.e., not in carriers of BAP1 mutations). Familial mesotheliomas in these individuals occur in either the pleura or peritoneum (frequency ratio 1:1) at a median age of 56.3 years, have a male-to-female ratio of 0.73:1, and are associated with prolonged survival of 5 to 10 or more years, compared with a median age at diagnosis of 72, a pleural-to-peritoneal ratio of 86:14, a male-to-female ratio of 4:1, and a median survival of less than 1 year in sporadic mesothelioma. About 100 families with this mutated BAP1 cancer syndrome have been described in the United States, Europe, and New Zealand. Genetic studies demonstrated that these mutations are transmitted across multiple generations over the course of several centuries, and some US families carrying BAP1 mutations descend from a Swiss family that immigrated in the US in the early 1700s. An International Consensus Meeting sponsored by the IASLC supported medical screening for at-risk people who are carriers of BAP1 germline mutations as follows: (1) annual dermatological screening for early detection of melanoma at age 18 or younger; (2) annual eye examination/ophthalmoscopy for uveal melanoma at age 18 or younger; and (3) skin and eye examinations every 6 months after age of 30, when the frequency of cancer among carriers of germline BAP1 mutations starts to increase. It was also recommended that genetic counseling should be offered to all individuals tested for BAP1. Moreover, those with BAP1 germline mutations should be ncouraged to participate in studies to improve early detection of mesothelioma (Carbone M. et al., Journal of Thoracic Oncology 11, 1246-1262, 2016).

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    OA22 - Novel Trials and Biomarkers in Malignant Pleural Mesothelioma (ID 403)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
    • Presentations: 1
    • Now Available
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      OA22.03 - HMGB1, a Target for Mesothelioma Therapy and a Biomarker to Detect Asbestos Exposure and to Identify Mesothelioma Patients (Now Available) (ID 5211)

      M. Carbone

      • Abstract
      • Presentation
      • Slides

      Background:
      Millions of people have been potentially exposed to asbestos, the primary cause of malignant mesothelioma (MM). Presently, no reliable biomarkers are available to identify among potentially exposed people, those individuals who have actually been exposed and who are at high risk of MM. High Mobility Group Box Protein-1 (HMGB1) is a key mediator of asbestos-induced inflammation and MM pathogenesis. Recently, HMGB1 hyper-acetylation has been functionally associated to its active release by inflammatory cells. Here, we compared the serum levels of total and hyper-acetylated HMGB1 in individuals professionally exposed to asbestos, MM patients and healthy unexposed controls.

      Methods:
      We compared the serum levels of total and hyper-acetylated HMGB1 in individuals professionally exposed to asbestos, MM patients and healthy unexposed controls. Previously proposed MM biomarkers fibulin-3, osteopontin, and mesothelin were also blindly measured in blood collected from participants to the study.

      Results:
      HMGB1 serum levels reliably distinguished asbestos-exposed individuals and MM patients from unexposed controls. Moreover, the levels of total and hyper-acetylated HMGB1 were significantly higher in MM patients compared to asbestos-exposed individuals, and did not vary with tumor stage, suggesting that early lesions are also associated to increased HMGB1 levels. At a cutoff value of 2.00 ng/mL, the sensitivity and specificity of hyper-acetylated serum HMGB1 in differentiating MM patients from asbestos-exposed individuals was 100%, outperforming, in parallel experiments, other previously proposed biomarkers: osteopontin, fibulin-3, and mesothelin. When comparing MM patients to patients with other non-MM cytologically benign or malignant pleural effusion, the combination of two biomarkers, HMGB1 and fibulin-3, provided the highest sensitivity and specificity in differentiating these two groups. Moreover, we found that HMGB1 drives MM development and sustains MM progression, and we demonstrated that targeting HMGB1 inhibits MM cell growth and motility in vitro, reduced tumor growth in vivo and prolonged survival.

      Conclusion:
      Despite the relatively small size of our cohorts, our results are of exceptional significance and clinical relevance as they provide the first biomarker of asbestos exposure and indicate that hyper-acetylated HMGB1 is a very sensitive and specific biomarker to differentiate MM patients from individuals occupationally exposed to asbestos and unexposed controls. Moreover, our results on HMGB1 inhibitors indicate that HMGB1 targeting hampers the malignant phenotype of MM, offering a novel potential therapeutic approach to patients afflicted with this dismal disease.

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    PR01 - Press Conference (ID 495)

    • Event: WCLC 2016
    • Type: Press Conference
    • Track:
    • Presentations: 1
    • Now Available
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      PR01.04 - Mesothelioma Workshop (Now Available) (ID 7201)

      M. Carbone

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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