Asbestos-related Malignant Pleural Mesothelioma Research Articles

ATG7 immunohistochemical expression in malignant pleural mesothelioma. A preliminary report.

Literature evidence has demonstrated a high incidence of asbestos-related malignant pleural mesothelioma (MPM) in a Sicilian town (Biancavilla, Italy), where fluoro-edenite (FE) fibers were discovered some decades ago. As ATG7 immunohistochemical analysis has been ascribed as a prognostic tool of improved survival, we decided to investigate, in MPM patients, exposed and not exposed to FE fibers, the immunohistochemical expression of this autophagy-related protein named ATG7. We analyzed the correlation between ATG7 immunohistochemical level and clinicopathological parameters. Twenty MPM tissue samples, from patients with available clinical and follow-up data, were included in paraffin and processed for immunohistochemistry. The immunohistochemical results confirmed activation of the autophagic process in MPM. Densitometric and morphometric expressions of ATG7 were significantly increased in MPMs when compared to the control tissues. A significant association of a high level of ATG7 with increased survival was demonstrated, with a mean overall survival (OS) of 12.5 months for patients with high expression vs. a mean OS of 4.5 months for patients with low ATG7 expression. In addition, a significant correlation between ATG7 expression and the survival time of MPM patients was observed. This study represents a starting point to hypothesize the prognostic role of ATG7 which could be a reliable prognostic indicator in MPM.

Upcoming epidemic of asbestos-related malignant pleural mesothelioma in Taiwan: A prediction of incidence in the next 30 years.

Globally, asbestos-related diseases (ARDs) keep rising over the coming decades. The epidemic of ARDs will be a burden on public health. We aimed to predict the malignant pleural mesothelioma (MPM) incidence in the next 30 years for Taiwan based on historical asbestos consumption. We collected annual data on local asbestos consumption during 1939-2015 and sex-specific incidence of pleural cancer as a proxy for MPM during 1979-2013. We applied Poisson log-linear models to predict future MPM numbers under the assumption that latency periods between asbestos exposure and MPM incidence were between 25 and 45 years. Asbestos consumption reached a peak in the 1980s, with a total of 668 thousand metric tons during 1939-2015. The observed number of MPM incidence increased by 9- and 6-fold in males and females during 1979-2013, with a cumulative number of 907. Given a latency period of 31 years, MPM incidences were expected to peak around 2012-2016 for males and 2016-2020 for females. In 2017-2046, the predicted total number of new MPM might reach 659 cases (95% confidence interval=579-749); and the male to female ratios ranged from 1.8 to 2.8. The MPM epidemic in Taiwan will likely peak in 2012-2020 as a result of local asbestos consumption. Approximately 659 new MPM cases in the next 30 years warrant an urgent need to implement a total asbestos ban and put more resources on a comprehensive surveillance, diagnosis, and follow-up health care system for ARDs.

Immunohistochemical Expression of Aquaporin-1 in Fluoro-Edenite-Induced Malignant Mesothelioma: A Preliminary Report.

Background: The immunohistochemical expression of aquaporin-1 (AQP1) in asbestos-related malignant pleural mesothelioma (MPM) is emerging as a useful prognostic indicator of improved survival. A significantly increased incidence of MPM in a small town in southern Italy was ascribed to exposure to fluoro-edenite (FE), a naturally occurring asbestos fiber. We investigated the immunohistochemical expression of AQP1 in patients affected by FE-related MPM; taking into consideration its suggested independent prognostic role, its possible correlation with clinicopathological parameters and patient outcome was also evaluated. Methods: Ten patients were selected for this study, as neoplastic tissue blocks, clinical and follow-up data were available. The immunohistochemical overexpression of AQP1 was defined as ≥50% of tumor cells showing membranous staining. Results: Six cases showed AQP1 expression in ≥50% of tumor cells; in this group, a significant association of AQP1 overexpression with an increased median overall survival (OS) of 26.3 months was observed. By contrast, four patients exhibited an AQP1 score of <50% of stained cells, with a shorter median OS of 8.9 months. Conclusions: The present study represents further confirmation of the hypothesized prognostic role of AQP1, which seems a reliable prognostic indicator.

Incidence and Survival of Malignant Pleural Mesothelioma in Norway: A Population-Based Study of 1686 Cases

Asbestos-related malignant pleural mesothelioma is one of the most lethal tumor types. The advent of antimetabolite treatment as pemetrexed, introduced in the early 2000s, may have increased survival on a population basis. In this study, we have analyzed population-based incidence and survival data over the last 40 years. Complete national data on 1686 patients from the Cancer Registry of Norway sampled from 1970 to 2009 are presented, with incidence rates in 5-year periods. Relative survival for 1 year and 3 years and median survival in 5-year intervals were calculated. The incidence of malignant pleural mesothelioma has been significantly and steadily increasing from 1970 until 2009, with 50 patients diagnosed in the period 1970-1974 and 377 diagnosed in 2005-2009. The incidence was highest among men in all time periods. A slight decline was observed in the last period. The 1-year survival rate increased from 20.7% to 44.0% during the period 1970-2009, whereas the 3-year survival rate remained below 10%. Median survival increased from 4.0 months in the first period to 9.3 months in the last period. The incidence of malignant pleural mesothelioma follows the curve of asbestos exposure with a 20- to 40-year lag. There has been a significant increase in survival, most likely because of earlier diagnosis and improvements in cytostatic treatment.

Biological effects of fibrous and particulate substances and related areas: foreword

Among the symposia organized by the various study groups of the Japanese Society for Hygiene (JSH), the Study Group on Fibrous and Particulate Substances (SGFPS) presented the symposium “Biological Effects of Fibrous and Particulate Substances and Related Areas”, chaired by Dr Seishiro Hirano (Environmental Health Sciences Division, National Institute for Environmental Studies, Tsukuba, Japan) and Professor Takemi Otsuki (Kawasaki Medical School, Japan), on 29 March, 2008 as part of the program of the 78th Annual Meeting of the Japanese Society for Hygiene (JSH). The SGFPS started its activity in 2006. Medical and social issues regarding asbestos-related malignant pleural mesothelioma (MPM) were raised previously in the summer of 2005. This issue has made people in Japan aware that asbestos causes malignant diseases, for example MPM, lung cancers, and asbestosis, through both industrial and environmental exposure. At the 76th Annual Meeting of the JSH held in 2006 at Ube, Yamaguchi, Japan, the SGFPS held a symposium entitled “Asbestos: Science and Society.” The SGFPS then had two special sessions at the 78th Annual Meeting of the JSH. One session involved a symposium entitled “Malignant Mesothelioma”, for which our study group invited mesothelioma specialists in Japan to improve recognition of this disease and develop preventive measures for this disease in the field of hygiene. The speakers were Professor Kouki Inai from Hiroshima University, Dr Yoshitaka Sekido from Aichi Cancer Center Research Institute, Professor Okio Hino from Juntendo University School of Medicine, and Professor Takashi Nakano from Hyogo College of Medicine. Reviews of speaker presentations were published in Vol. 13, No 2 of this journal as a special feature on malignant mesothelioma. The other session was a workshop, chaired by Professor Otsuki, in which five members of the SGFPS presented their research topics. Dr Ayako Takata (St Marianna University School of Medicine, Japan) presented “Hazard assessment of product materials of the innocuous process of asbestos” and Dr Yasumitsu Nishimura (Kawasaki Medical School) focused on the “Functional alteration of the NK cells upon the long-term exposure to asbestos”. In addition, Dr Akiyo Tanaka and Miyuki Hirata (Kyushu University, Graduate School of Medicine, Japan) lectured on “Pulmonary toxicity of dispersed carbon nanofiber instilled intratracheally in rats” and Dr Seishiro Hirano delivered a presentation on the “Cellular uptake and translocation of nanoparticles”. Furthermore, Professor Shuichi Adachi (Sagami Women’s University, Japan) made an additional presentation focusing on the “Prevention of mesothelioma by anti-oxidants”. Many people attended the symposium and workshop, and members of the JSH were encouraged to investigate the prevention and treatment of asbestos-related MPM. During the 78th Annual Meeting of the JSH, the SGFPS held a special symposium entitled “Biological Effects of Fibrous and Particulate Substances and Related Areas” chaired by Dr Hirano and Professor Otsuki. The purpose of this symposium was to recognize recent developments related to fibrous and particulate substances. The four members of the SGFPS introduced their research highlights that improved our understanding of recent scientific advances regarding fibrous and particulate substances. Dr Hirano summarized recent topics concerning nanoparticle research as “Worldwide trend for a safety evaluation of nanoparticles”. Dr Yuichiro Kudo (Kitasato University, School of Medicine, Japan) then presented results pertaining to “The evaluation of the safety of asbestos substitutes”. Professor Akira Ogami (Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Japan) then focused on “Inhalation and instillation studies of submicron and nano particles—importance of characterization of particles”. Finally, Professor Otsuki delivered a summarized presentation on “Cytokine alteration and speculated immunological pathophysiology in silicosis and asbestos-related diseases”. In this special feature of Environmental Health and Preventive Medicine, Dr Hirano, Dr Kudo and Prof. Otsuki provide a brief review of their specialties. All members of the JSH, irrespective of their attendance at the above-mentioned symposium, can enjoy this special feature and obtain detailed information concerning recent advances in studies of fibrous and particulate substances.

The Plexin-A1 Receptor Activates Vascular Endothelial Growth Factor-Receptor 2 and Nuclear Factor-κB to Mediate Survival and Anchorage-Independent Growth of Malignant Mesothelioma Cells

The semaphorins and their receptors, the neuropilins and the plexins, are constituents of a complex regulatory system that controls axonal guidance. Moreover, many types of tumor cells express various members of semaphorins and receptors, but the biological activities within tumor mass and the signal transduction mechanism(s) they use are largely unknown. Here, we show that in asbestos-related malignant pleural mesothelioma (MPM), Semaphorin-6D (Sema6D) and its receptor plexin-A1 are frequently expressed and trigger a prosurvival program that promotes anchorage-independent growth of MPM cells. Interestingly, the same response is also controlled by the tyrosine kinase receptors of vascular endothelial growth factor (VEGF) through a nuclear factor-kappaB (NF-kappaB)-dependent pathway. We found that in MPM cells, plexin-A1 and VEGF-receptor 2 (VEGF-R2) are associated in a complex. Moreover, the presence of Sema6D promotes the tyrosine phosphorylation of VEGF-R2 in a plexin-A1-dependent manner. This is necessary for basal and Sema6D-induced NF-kappaB transcriptional activity, and NF-kappaB mediates tumor cell survival. Expression of Sema6D and plexin-A1 is induced by asbestos fibers and overexpression of plexin-A1 in nonmalignant mesothelial cells inhibits cell death after asbestos exposure. This work identifies a new biological function of semaphorins in cancer cells and suggests the involvement of an undescribed survival pathway during MPM tumorigenesis.

Subarachnoid‐pleural fistula as a complication of malignant pleural mesothelioma

We report a 62-year-old male patient with asbestos-related malignant pleural mesothelioma who developed recurrent pleural effusions after surgical resection of paravertebral tumour masses. Pleural effusions were drained on several occasions with the patient suffering severe headaches and vascular dysregulation. Cytological studies of the pleural fluid showed no evidence of inflammatory or malignant cells. The fluid was interpreted as seroma despite its unusual transparency until magnetic resonance imaging was suggestive of a subarachnoid-pleural fistula; its presence was confirmed when beta-trace protein--a specific marker for cerebrospinal fluid--was added to the standard laboratory testing of the pleural effusion. A subarachnoid-pleural fistula has to be included in the differential diagnosis of patients with recurrent pleural effusions after surgical debulkment of malignant pleural mesothelioma. The beta-trace protein may help to establish this diagnosis especially in cases where important therapeutic consequences may need to be drawn.

Soluble mesothelin related peptides: A potential biomarker for malignant pleural mesothelioma

9532 Background: At this time there are no biomarkers that can monitor therapy or predict asbestos-related malignant pleural mesothelioma (MPM). Fujirebio Diagnostics, Inc. developed MESOMARK™ a quantitative dual-monoclonal ELISA for soluble members of a family of proteins expressed by mesothelial cells called soluble mesothelin related peptides (SMRP). We assessed whether (1) SMRP levels in sera and pleural effusions (PE) differed between MPM, non-MPM tumors, asbestos-exposed non-MPM individuals (ASB) and normal volunteers (NL), and (2) SMRP could predict recurrence of MPM after surgery. Methods: Archived frozen serum from 26 ASB, 50 NLs, 54 MPMs, and 14 non-MPMs, and PE from 30 NL, 20 non-MPM tumors, and 45 MPMs were analyzed by MESOMARK™. Blinded longitudinal serum samples (preoperative to 47 month range) from 16 patients having cytoreduction and identical adjuvant therapy were investigated for post surgery SMRP levels and correlation with computerized tomographic (CT) follow-up scans. One-way ANOVA with post-hoc Tamhane test was used for statistical analyses. ROC curves were constructed for the serum and PE groups. Results: Serum SMRP levels were equivalent between ASB (1.166, range 0.004–2.821 nM), and NL (1.222, range 0.216–3.430 nM), but were significantly different from MPM (17.275, range 0.219–278.356 nM, p = 0.003). Stage I MPMs had higher levels of serum SMRP than ASB (p=0.046). Comparing the ASB and NL combined to MPMs, ROC curve analysis revealed an AUC of 0.793 (95%CI: 0.705 to 0.880). No differences were seen in the PE SMRP levels between non-MPM tumors and NL (p=0.521), however, MPM PE SMRP (65.573 nM, range 0.421–255.166) was significantly increased compared to NL PE SMRP (18.997 nM, range 0.291–140.121, p=0.003). The AUC under the PE ROC curve was 0.742 (95%CI: 0.637 to 0.847). SMRP levels decreased in 13/16 patients immediately following surgery, and increased significantly and preceded detection by CT in 10/13 patients who subsequently displayed postoperative progression. Conclusions: These data establish SMRP as a promising marker for MPM, and studies to further refine and validate these data in larger cohorts should be initiated. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Fujirebio Diagnostics Fujirebio Diagnostics Fujirebio Diagnostics

Computed tomographic findings of environmental asbestos-related malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is not an infrequent fatal neoplasm. It is endemically present in some regions of Turkey due to its aetiological relationship to exposure to environmental fibrous minerals. The aim of this study was to determine the thorax computed tomographic (CT) features of environmental asbestos-related MPM. In this study, we examined retrospectively the CT scans of 46 untreated patients with pathological diagnosis of environmental asbestos-related MPM among 151 patients with malignant pleural mesothelioma in the Izmir Chest Disease and Surgery Hospital. The CT scans were interpreted by consultation of four observers. Malignant pleural mesothelioma was unilateral in 45 (97.2%) of the patients. Pleural effusions were found in 42 (91%) of the patients, pleural calcifications in 12 (26%), contracted hemithorax in 14 (30%), interlobar fissure involvement in 25 (54%) and mediastinal pleural involvement in 26 (57%). A contracted hemithorax was significantly correlated with pleural rind configuration. Pleural thickenings were found in 45 (99%) of the patients. Pleural thickenings were in the form of nodularity in 10 (22%) cases, regular in 12 (27%) cases, as a focal mass in 3 (7%) cases and as a pleural rind in 20 (44%) cases. Pleural thickening was greater than 1 cm in 32 (71%) cases. The most common CT findings in our series were unilateral circumferential pleural thickening, nodular pleural thickening, pleural thickening greater than 1 cm and mediastinal pleural involvement. Generally, pleural effusion was accompanied by this. There was interlobar fissure involvement in half of the patients. There was no pathognomonic CT finding in environmental asbestos-related MPM. But CT was useful in suggesting the diagnosis of malignant pleural disease in the cases with MPM.

CT Findings in Malignant Pleural Mesothelioma Related to Nonoccupational Exposure to Asbestos and Fibrous Zeolite (Erionite)

Endemic malignant pleural mesothelioma (MPM) in Turkey is related to two mineral fibers, tremolite asbestos and fibrous zeolite (erionite). Thirteen cases of MPM from the Cappadocian area, where the soil is rich in erionite, and 29 cases of MPM, from villages whose occupants have high asbestos exposure, were examined by CT. The CT findings of the two groups of MPM were compared with respect to the configuration of the pleural lesions, stage of disease, fissural involvement, pleural effusion, presence of calcified pleural plaques, and chronic fibrosing pleuritis. In erionite-related MPM the pleural lesions were flat and smooth in 69.1%; in asbestos-related MPM the lesions were nodular in 55.1%. Stage IV disease, calcified pleural plaques, and chronic fibrosing pleuritis were more common in the erionite-related MPM. The rest of the findings were similar in both groups. The early radiological diagnosis of erionite-related MPM may be even more difficult because of the similarity of the pleural lesions to chronic fibrosing pleuritis.

Asbestos-related malignant mesothelioma: growth, cytology, tumorigenicity and consistent chromosome findings in cell lines from five patients

Seven mesothelioma cell lines were established from clinical specimens from five patients with asbestos-related malignant pleural mesothelioma. The cells in culture show either epithelial or mixed epithelial/fibrosarcomatous growth with an average doubling time of 30 h. Giant multinucleated cells are common in all the cell lines, as well as long thin microvilli on the cell surfaces. All cell lines were cytokeratin positive and they stained negatively for monocyte-macrophage markers. All seven cell lines and one long-term tissue culture from a sixth mesothelioma patient were characterized cytogenetically. Karyotype analyses revealed complex structural and numerical abnormalities, primarily involving chromosome 1, 4, 5, 6, 7, 8, 9, 11, 12, 13 and 22. An excess of chromosome material of the short arm of chromosome 5 was seen consistently in six cell lines and in the long-term culture. In cell lines from four patients, changes in chromosome 13, mainly monosomy 13, were observed. The marker chromosomes observed in the early passages were conserved and few additional changes appeared in later passages. Six of the cell lines tested for tumorigenicity in athymic nude mice were weakly positive.