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Does the Amount of Asbestos Exposure Influence Prognosis?

      Two recent papers in the Journal of Thoracic Oncology propose two opposite hypotheses: that the amount of asbestos in the lungs may directly correlate with shorter survival in patients with mesothelioma
      • Laaksonen S.
      • Kettunen E.
      • Sutinen E.
      • et al.
      Pulmonary asbestos fiber burden is related to patient survival in malignant pleural mesothelioma.
      and, on the opposite, that the amount of asbestos in the lungs does not influence survival.
      • Barbieri P.G.
      • Consonni D.
      • Somigliana A.
      Asbestos lung burden does not predicts survival in malignant pleural mesothelioma. A necropsy-based study of 185 cases.
      Most pleural mesotheliomas continue to occur in patients who have been exposed to asbestos. “Asbestos” is a collective commercial and legal name given for regulatory purposes to six of approximately 400 mineral fibers present in nature.
      • Baumann F.
      • Ambrosi J.P.
      • Carbone M.
      Asbestos is not just asbestos: an unrecognised health hazard.
      These six fiber types were used by different industries, exposing millions of individuals worldwide to the risk of developing mesothelioma. Many mineral fibers are potentially carcinogenic, but only asbestos fibers are regulated: their use has been strictly reduced and regulated or entirely prohibited in the 80s and 90s in most of the Western world. Asbestos is inhaled and is trapped in the lungs where, by means of the lymphatic vessels, may reach the pleura.
      • Mutti L.
      • Peikert T.
      • Robinson B.W.S.
      • et al.
      Scientific advances and new frontiers in mesothelioma therapeutics.
      Asbestos causes inflammation in the lungs of patients exposed to high amounts of fibers, ensuing in diffuse bilateral lung fibrosis (asbestosis). In the pleura, asbestos-induced inflammation that results in scar tissue radiologically visible, the so-called pleural plaques. These markers of asbestos exposure are present in approximately 90% of patients with mesothelioma who were exposed to levels of asbestos above the background.
      • Dodson R.F.
      • O’Sullivan M.
      • Corn C.J.
      • McLarty J.W.
      • Hammar S.P.
      Analysis of asbestos fiber burden in lung tissue from mesothelioma patients.
      • Kato K.
      • Gemba K.
      • Ashizawa K.
      • et al.
      Low-dose chest computed tomography screening of subjects exposed to asbestos.
      • Carbone M.
      • Adusumilli P.S.
      • Alexander Jr., H.R.
      • et al.
      Mesothelioma: scientific clues for prevention, diagnosis, and therapy.
      In patients exposed to high amounts of asbestos, the fibers may also reach, by means of the lymphatic vessels, the abdominal lymph nodes, mesentery, and omentum, where they can cause peritoneal mesothelioma.
      • Carbone M.
      • Ly B.H.
      • Dodson R.F.
      • et al.
      Malignant mesothelioma: facts, myths, and hypotheses.
      ,
      • Dodson R.F.
      • O’Sullivan M.F.
      • Brooks D.R.
      • Bruce J.R.
      Asbestos content of omentum and mesentery in nonoccupationally exposed individuals.
      Thanks to the restrictions and regulatory measures taken since the 80s and 90s to reduce asbestos exposure, presently, heavy exposures are found almost exclusively among members of the older cohorts of patients with mesothelioma.
      • Baumann F.
      • Carbone M.
      Environmental risk of mesothelioma in the United States: an emerging concern-epidemiological issues.
      Accordingly, presently, peritoneal mesothelioma is rarely linked to asbestos exposure.
      • Lee M.
      • Alexander H.R.
      • Burke A.
      Diffuse mesothelioma of the peritoneum: a pathological study of 64 tumours treated with cytoreductive therapy.
      • Liu S.
      • Staats P.
      • Lee M.
      • Alexander H.R.
      • Burke A.P.
      Diffuse mesothelioma of the peritoneum: correlation between histological and clinical parameters and survival in 73 patients.
      • Greenbaum A.
      • Alexander H.R.
      Peritoneal mesothelioma.
      • Offin M.
      • Yang S.R.
      • Egger J.
      • et al.
      Molecular characterization of peritoneal mesotheliomas.
      Although imaging is helpful to identify asbestos exposure, lung content analyses are considered the most reliable test to measure exposure to asbestos and other carcinogenic mineral fibers.
      • Dodson R.F.
      • O’Sullivan M.
      • Corn C.J.
      • McLarty J.W.
      • Hammar S.P.
      Analysis of asbestos fiber burden in lung tissue from mesothelioma patients.
      ,
      • Carbone M.
      • Adusumilli P.S.
      • Alexander Jr., H.R.
      • et al.
      Mesothelioma: scientific clues for prevention, diagnosis, and therapy.
      • Carbone M.
      • Ly B.H.
      • Dodson R.F.
      • et al.
      Malignant mesothelioma: facts, myths, and hypotheses.
      • Dodson R.F.
      • O’Sullivan M.F.
      • Brooks D.R.
      • Bruce J.R.
      Asbestos content of omentum and mesentery in nonoccupationally exposed individuals.
      Moreover, this technique allows for identifying the types of fibers to which an individual has been exposed
      • Carbone M.
      • Ly B.H.
      • Dodson R.F.
      • et al.
      Malignant mesothelioma: facts, myths, and hypotheses.
      (Fig. 1). Nevertheless, because fibers have different biopersistence, lung content analyses underestimate exposure to chrysotile, a type of asbestos fiber that is rapidly degraded in tissues.
      • Dodson R.F.
      • O’Sullivan M.
      • Corn C.J.
      • McLarty J.W.
      • Hammar S.P.
      Analysis of asbestos fiber burden in lung tissue from mesothelioma patients.
      ,
      • Carbone M.
      • Adusumilli P.S.
      • Alexander Jr., H.R.
      • et al.
      Mesothelioma: scientific clues for prevention, diagnosis, and therapy.
      ,
      • Carbone M.
      • Ly B.H.
      • Dodson R.F.
      • et al.
      Malignant mesothelioma: facts, myths, and hypotheses.
      ,
      • Qi F.
      • Okimoto G.
      • Jube S.
      • et al.
      Continuous exposure to chrysotile asbestos can cause transformation of human mesothelial cells via HMGB1 and TNF-alpha signaling.
      Figure thumbnail gr1
      Figure 1The radiograph phase-contrast image of autoptic lung tissue from a former worker of an asbestos plant affected by grade 4 asbestosis, bilateral pleural plaques, and lung cancer. Asbestos bodies are clearly identifiable as the white elongated objects in the lung tissue matrix. The number of asbestos bodies per gram of dry weight was estimated to be approximately 12 million by SEM observations. The number of uncoated asbestos fibers (mainly crocidolite) was approximately 0.34 million per gram of dry weight. The dimension of the tissue fragment illustrated in the image is 845 × 845 × 713 μm3. The voxel size is 0.33 × 0.33 × 0.33 μm3 (data I13-2 beamline, Diamond Light Source, Didcot, United Kingdom).
      Asbestos fibers cause mesothelial cell death. The paradox of how a fiber that kills mesothelial cells could cause mesothelioma was addressed by the discovery that asbestos triggers the translocation of HMGB1 from the nucleus to the cytoplasm,
      • Yang H.
      • Rivera Z.
      • Jube S.
      • et al.
      Programmed necrosis induced by asbestos in human mesothelial cells causes high-mobility group box 1 protein release and resultant inflammation.
      where NFκB activation
      • Yang H.
      • Rivera Z.
      • Jube S.
      • et al.
      Programmed necrosis induced by asbestos in human mesothelial cells causes high-mobility group box 1 protein release and resultant inflammation.
      and autophagy
      • Xue J.
      • Patergnani S.
      • Giorgi C.
      • et al.
      Asbestos induces mesothelial cell transformation via HMGB1-driven autophagy.
      are induced. These two prosurvival mechanisms allow mesothelial cells to escape asbestos-induced cell death, and eventually over time genetically damaged mesothelial cells may become malignant.
      • Carbone M.
      • Adusumilli P.S.
      • Alexander Jr., H.R.
      • et al.
      Mesothelioma: scientific clues for prevention, diagnosis, and therapy.
      In parallel, asbestos-dependent cell necrosis causes the release of HMGB1 in the extracellular space, where HMGB1 kickstarts the inflammatory process that results in the production of mutagenic oxygen radicals and drives the growth of malignant cells.
      • Yang H.
      • Rivera Z.
      • Jube S.
      • et al.
      Programmed necrosis induced by asbestos in human mesothelial cells causes high-mobility group box 1 protein release and resultant inflammation.
      ,
      • Jube S.
      • Rivera Z.S.
      • Bianchi M.E.
      • et al.
      Cancer cell secretion of the DAMP protein HMGB1 supports progression in malignant mesothelioma.
      Moreover, chronic inflammation activates several cellular pathways that support malignant growth.
      • Ramos-Nino M.E.
      • Blumen S.R.
      • Sabo-Attwood T.
      • et al.
      HGF mediates cell proliferation of human mesothelioma cells through a PI3K/MEK5/Fra-1 pathway.
      • Altomare D.A.
      • Menges C.W.
      • Pei J.
      • et al.
      Activated TNF-alpha/NF-kappaB signaling via down-regulation of Fas-associated factor 1 in asbestos-induced mesotheliomas from Arf knockout mice.
      • Yang H.
      • Pellegrini L.
      • Napolitano A.
      • et al.
      Aspirin delays mesothelioma growth by inhibiting HMGB1-mediated tumor progression.
      Several therapeutic approaches have been and are being designed targeting these and other pathways activated on asbestos exposure.
      • Yang H.
      • Pellegrini L.
      • Napolitano A.
      • et al.
      Aspirin delays mesothelioma growth by inhibiting HMGB1-mediated tumor progression.
      • Pass H.I.
      • Mew D.J.
      • Carbone M.
      • et al.
      Inhibition of hamster mesothelioma tumorigenesis by an antisense expression plasmid to the insulin-like growth factor-1 receptor.
      • Nasu M.
      • Carbone M.
      • Gaudino G.
      • et al.
      Ranpirnase interferes with NF-κB pathway and MMP9 activity, inhibiting malignant mesothelioma cell invasiveness and xenograft growth.
      • Goparaju C.M.
      • Blasberg J.D.
      • Volinia S.
      • et al.
      Onconase mediated NFKβ downregulation in malignant pleural mesothelioma.
      Although effective in mice, their efficacy in preventing or reducing the growth of mesothelioma in humans remains to be revealed.
      • Tsao A.S.
      • Lindwasser O.W.
      • Adjei A.A.
      • et al.
      Current and future management of malignant mesothelioma: a consensus report from the National Cancer Institute Thoracic Malignancy Steering Committee, International Association for the Study of Lung Cancer, and Mesothelioma Applied Research Foundation.
      ,
      • McCambridge A.J.
      • Napolitano A.
      • Mansfield A.S.
      • et al.
      Progress in the management of malignant pleural mesothelioma in 2017.
      In synthesis, it is well established that asbestos exposure causes mesothelioma and key mechanisms by which asbestos causes mesothelioma have been elucidated.
      • Gaudino G.
      • Xue J.
      • Yang H.
      How asbestos and other fibers cause mesothelioma.
      Can the amount of asbestos present in the lungs influence tumor prognosis? If so, how? The two papers by Laaksonen et al.
      • Laaksonen S.
      • Kettunen E.
      • Sutinen E.
      • et al.
      Pulmonary asbestos fiber burden is related to patient survival in malignant pleural mesothelioma.
      and Barbieri et al.
      • Barbieri P.G.
      • Consonni D.
      • Somigliana A.
      Asbestos lung burden does not predicts survival in malignant pleural mesothelioma. A necropsy-based study of 185 cases.
      tried to address this question, but they reached opposite conclusions. Similarly, older studies discussed by the two publications reported conflicting results. The papers by Laaksonen et al.
      • Laaksonen S.
      • Kettunen E.
      • Sutinen E.
      • et al.
      Pulmonary asbestos fiber burden is related to patient survival in malignant pleural mesothelioma.
      and Barbieri et al.
      • Barbieri P.G.
      • Consonni D.
      • Somigliana A.
      Asbestos lung burden does not predicts survival in malignant pleural mesothelioma. A necropsy-based study of 185 cases.
      were submitted at about the same time, and they went through a strict peer-review process. Let us analyze some possible causes of these discordances.
      In both publications, germline mutations of BAP1 (or of other genes) were not included as selection criteria for patients’ analysis. It has been reported that in carriers of germline BAP1 or other pathogenic gene mutations, the risk of developing mesothelioma is increased.
      • Carbone M.
      • Harbour J.W.
      • Brugarolas J.
      • et al.
      Biological mechanisms and clinical significance of BAP1 mutations in human cancer.
      At the same time, these patients have a marked improved prognosis compared with the prognosis of patients affected by the more common and aggressive mesotheliomas caused by asbestos.
      • Pastorino S.
      • Yoshikawa Y.
      • Pass H.I.
      • et al.
      A subset of mesotheliomas with improved survival occurring in carriers of BAP1 and other germline mutations.
      • Carbone M.
      • Arron S.T.
      • Beutler B.
      • et al.
      Tumour predisposition and cancer syndromes as models to study gene-environment interactions.
      • Carbone M.
      • Pass H.I.
      • Ak G.
      • et al.
      Medical and surgical care of patients with mesothelioma and their relatives carrying germline BAP1 mutations.
      Therefore, the authors of both papers raise the hypothesis that the presence/absence and the number of patients carrying these mutations in their cohorts might have influenced the results.
      • Laaksonen S.
      • Kettunen E.
      • Sutinen E.
      • et al.
      Pulmonary asbestos fiber burden is related to patient survival in malignant pleural mesothelioma.
      ,
      • Barbieri P.G.
      • Consonni D.
      • Somigliana A.
      Asbestos lung burden does not predicts survival in malignant pleural mesothelioma. A necropsy-based study of 185 cases.
      This hypothesis is reasonable because several members of the same family carrying germline mutations are usually affected by mesothelioma, resulting in an aggregation of these patients in the same hospital.
      Another confounding factor, possibly contributing to the opposite results of the two publications, is the clinical setting of the patients before their death, when lung biopsy specimens taken during the autopsy were subjected to fiber content analysis. In both publications,
      • Laaksonen S.
      • Kettunen E.
      • Sutinen E.
      • et al.
      Pulmonary asbestos fiber burden is related to patient survival in malignant pleural mesothelioma.
      ,
      • Barbieri P.G.
      • Consonni D.
      • Somigliana A.
      Asbestos lung burden does not predicts survival in malignant pleural mesothelioma. A necropsy-based study of 185 cases.
      no data are provided about therapy. The most common therapy for mesotheliomas consists of a combination of cisplatin-pemetrexed,
      • Vogelzang N.J.
      • Rusthoven J.J.
      • Symanowski J.
      • et al.
      Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma.
      at times in combination with other drugs, surgery, and radiation. The median survival benefit of 2 to 3 months with the addition of chemotherapy (alone or as trimodality therapy together with surgical resection and radiation) is well established.
      • Mutti L.
      • Peikert T.
      • Robinson B.W.S.
      • et al.
      Scientific advances and new frontiers in mesothelioma therapeutics.
      Nevertheless, patients with sarcomatoid mesothelioma are resistant to therapy; therefore, many of them are treated only with supportive therapy. Very ill patients who cannot tolerate surgery or other types of aggressive therapies may also receive only supportive care. The type of therapy and the proportions of treated patients in these two papers,
      • Laaksonen S.
      • Kettunen E.
      • Sutinen E.
      • et al.
      Pulmonary asbestos fiber burden is related to patient survival in malignant pleural mesothelioma.
      ,
      • Barbieri P.G.
      • Consonni D.
      • Somigliana A.
      Asbestos lung burden does not predicts survival in malignant pleural mesothelioma. A necropsy-based study of 185 cases.
      although unknown, may vary. Moreover, recently, several immune-based approaches have been attempted in mouse models
      • Rivera Z.
      • Ferrone S.
      • Wang X.
      • et al.
      CSPG4 as a target of antibody-based immunotherapy for malignant mesothelioma.
      and patients with mesothelioma. Immunotherapy may benefit some patients with sarcomatoid mesothelioma, although the data are not conclusive.
      • Mutti L.
      • Peikert T.
      • Robinson B.W.S.
      • et al.
      Scientific advances and new frontiers in mesothelioma therapeutics.
      ,
      • Tsao A.S.
      • Lindwasser O.W.
      • Adjei A.A.
      • et al.
      Current and future management of malignant mesothelioma: a consensus report from the National Cancer Institute Thoracic Malignancy Steering Committee, International Association for the Study of Lung Cancer, and Mesothelioma Applied Research Foundation.
      ,
      • McCambridge A.J.
      • Napolitano A.
      • Mansfield A.S.
      • et al.
      Progress in the management of malignant pleural mesothelioma in 2017.
      We do not know whether any of the patients in these two studies
      • Laaksonen S.
      • Kettunen E.
      • Sutinen E.
      • et al.
      Pulmonary asbestos fiber burden is related to patient survival in malignant pleural mesothelioma.
      ,
      • Barbieri P.G.
      • Consonni D.
      • Somigliana A.
      Asbestos lung burden does not predicts survival in malignant pleural mesothelioma. A necropsy-based study of 185 cases.
      were treated with immunotherapy.
      In summary, because the conclusions drawn by both conflicting papers
      • Laaksonen S.
      • Kettunen E.
      • Sutinen E.
      • et al.
      Pulmonary asbestos fiber burden is related to patient survival in malignant pleural mesothelioma.
      ,
      • Barbieri P.G.
      • Consonni D.
      • Somigliana A.
      Asbestos lung burden does not predicts survival in malignant pleural mesothelioma. A necropsy-based study of 185 cases.
      are based on survival/all-cause mortality, possible differences in therapy might have influenced survival.
      The additional problem about a possible association between asbestos load and prognosis, as noted by both Laaksonen et al.
      • Laaksonen S.
      • Kettunen E.
      • Sutinen E.
      • et al.
      Pulmonary asbestos fiber burden is related to patient survival in malignant pleural mesothelioma.
      and Barbieri et al.,
      • Barbieri P.G.
      • Consonni D.
      • Somigliana A.
      Asbestos lung burden does not predicts survival in malignant pleural mesothelioma. A necropsy-based study of 185 cases.
      is the issue of the apparent lack of plausibility, which is one of the criteria used in cancer research to distinguish a mere association from a causative effect.
      • Carbone M.
      • Klein G.
      • Gruber J.
      • Wong M.
      Modern criteria to establish human cancer etiology.
      There are no known mechanisms by which the amount of asbestos in tissues might influence tumor aggressiveness per se, as noted by the authors.
      • Laaksonen S.
      • Kettunen E.
      • Sutinen E.
      • et al.
      Pulmonary asbestos fiber burden is related to patient survival in malignant pleural mesothelioma.
      ,
      • Barbieri P.G.
      • Consonni D.
      • Somigliana A.
      Asbestos lung burden does not predicts survival in malignant pleural mesothelioma. A necropsy-based study of 185 cases.
      Nevertheless, it seems possible that the deleterious effects on survival that Laaksonen et al.
      • Laaksonen S.
      • Kettunen E.
      • Sutinen E.
      • et al.
      Pulmonary asbestos fiber burden is related to patient survival in malignant pleural mesothelioma.
      observed might have been caused by a higher percentage of patients in their cohort with severe bilateral lung fibrosis (asbestosis) that often develops among those exposed to high amounts of asbestos. Asbestosis compromises gas exchanges and causes right ventricular hypertrophy, which in turn leads to right ventricular failure. Some of the patients with asbestosis may develop mesothelioma. These patients, owing to the compromised cardiopulmonary function caused by asbestosis, are often ineligible for surgery and other aggressive therapies, thus having shorter survival. In other words, the differences among the results observed by Laaksonen et al.
      • Laaksonen S.
      • Kettunen E.
      • Sutinen E.
      • et al.
      Pulmonary asbestos fiber burden is related to patient survival in malignant pleural mesothelioma.
      and Barbieri et al.
      • Barbieri P.G.
      • Consonni D.
      • Somigliana A.
      Asbestos lung burden does not predicts survival in malignant pleural mesothelioma. A necropsy-based study of 185 cases.
      might be related to a higher number of patients with severe asbestosis in the cohort studied by the former article.
      • Laaksonen S.
      • Kettunen E.
      • Sutinen E.
      • et al.
      Pulmonary asbestos fiber burden is related to patient survival in malignant pleural mesothelioma.
      An additional hypothesis is that mesothelioma, because of the field effects of asbestos, often occurs as a polyclonal malignancy.
      • Comertpay S.
      • Pastorino S.
      • Tanji M.
      • et al.
      Evaluation of clonal origin of malignant mesothelioma.
      Maybe exposure to a certain type of fibers or to a higher number of asbestos fibers may cause the development of more malignant clones, and this could affect prognosis. Nevertheless, no experimental evidence is available to support this hypothesis.
      A recent article by Visona et al.,
      • Visona S.D.
      • Capella S.
      • Bodini S.
      • et al.
      Evaluation of deposition and clearance of asbestos (detected by SEM-EDS) in lungs of deceased subjects environmentally and/or occupationally exposed in Broni (Pavia, Northern Italy).
      using a methodology similar to the one used by Laaksonen et al.
      • Laaksonen S.
      • Kettunen E.
      • Sutinen E.
      • et al.
      Pulmonary asbestos fiber burden is related to patient survival in malignant pleural mesothelioma.
      and Barbieri et al.,
      • Barbieri P.G.
      • Consonni D.
      • Somigliana A.
      Asbestos lung burden does not predicts survival in malignant pleural mesothelioma. A necropsy-based study of 185 cases.
      did not find any association between the amount of asbestos in the lungs and latency or survival; however, this article also lacks the clinical information and their cases were not screened for the possible presence of germline mutations.
      In summary, the missing clinical information in these two papers
      • Laaksonen S.
      • Kettunen E.
      • Sutinen E.
      • et al.
      Pulmonary asbestos fiber burden is related to patient survival in malignant pleural mesothelioma.
      ,
      • Barbieri P.G.
      • Consonni D.
      • Somigliana A.
      Asbestos lung burden does not predicts survival in malignant pleural mesothelioma. A necropsy-based study of 185 cases.
      prevents a conclusive assessment of the possible correlation between fiber burden and prognosis in mesothelioma. These two papers
      • Laaksonen S.
      • Kettunen E.
      • Sutinen E.
      • et al.
      Pulmonary asbestos fiber burden is related to patient survival in malignant pleural mesothelioma.
      ,
      • Barbieri P.G.
      • Consonni D.
      • Somigliana A.
      Asbestos lung burden does not predicts survival in malignant pleural mesothelioma. A necropsy-based study of 185 cases.
      have both determined with accuracy the fiber content in the lung of biopsy specimens from sizable cohorts of patients deceased with mesothelioma (590 and 185 biopsies, respectively), by using appropriate and sensitive methods (scanning transmission electron microscopy and transmission electron microscopy combined with radiograph spectroscopy, respectively). Nevertheless, the possible connection between fiber load and prognosis in pleural and peritoneal mesothelioma is probably influenced by a complex and multifactorial combination of factors. These factors, in addition to fiber exposure, may include germline mutations, the type of therapy, and the percentage of patients in each cohort with asbestosis with the consequent compromised cardiopulmonary function, which in turn will make them ineligible for several therapies. All these components should be considered in future studies that may try to address this issue.

      CRediT Authorship Contribution Statement

      Michele Carbone: Conceptualization, Writing and original draft preparation.
      Michele Carbone, Haining Yang, Giovanni Gaudino: Writing and original draft preparation.
      Fabrizio Bardelli: Contributing figure.
      Haining Yang, Giovanni Gaudino, Fabrizio Bardelli, and Michele Carbone: Reviewing and editing.

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