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  1. Malignant mesothelioma

    PubMed Central

    Ahmed, Ishtiaq; Ahmed Tipu, Salman; Ishtiaq, Sundas

    2013-01-01

    Malignant Mesothelioma (MM) is a rare but rapidly fatal and aggressive tumor of the pleura and peritoneum with limited knowledge of its natural history. The incidence has increased in the past two decades but still it is a rare tumor. Etiology of all forms of mesothelioma is strongly associated with industrial pollutants, of which asbestos is the principal carcinogen. Mesothelioma is an insidious neoplasm arising from mesothelial surfaces i.e., pleura (65%-70%), peritoneum (30%), tunica vaginalis testis, and pericardium (1%-2%). The diagnosis of peritoneal and Pleural mesothelioma is often delayed, due to a long latent period between onset and symptoms and the common and nonspecific clinical presentation. The definite diagnosis can only be established by diagnostic laparoscopy or open surgery along with biopsy to obtain histological examination and immunocytochemical analysis. Different treatment options are available but Surgery can achieve a complete or incomplete resection and Radical resection is the preferred treatment. Chemotherapy has an important role in palliative treatment. Photodynamic therapy is also an option under trial. Patients who successfully underwent surgical resection had a considerably longer median survival as well as a significantly higher 5-year survival. Source of Data/Study Selection: The data were collected from case reports, cross-sectional studies, Open-label studies and phase –II trials between 1973-2012. Data Extraction: Web sites and other online resources of American college of surgeons, Medline, NCBI and Medscape resource centers were used to extract data. Conclusion: Malignant Mesothelioma (MM) is a rare but rapidly fatal and aggressive tumor with limited knowledge of its natural history. The diagnosis of peritoneal and Pleural mesothelioma is often delayed, so level of index of suspicion must be kept high. PMID:24550969

  2. Drugs Approved for Malignant Mesothelioma

    MedlinePlus

    ... Professionals Questions to Ask about Your Treatment Research Drugs Approved for Malignant Mesothelioma This page lists cancer ... in malignant mesothelioma that are not listed here. Drugs Approved for Malignant Mesothelioma Alimta (Pemetrexed Disodium) Pemetrexed ...

  3. Mesothelioma - malignant

    MedlinePlus

    ... abdomen (peritoneum). It is due to long-term asbestos exposure. ... Long-term exposure to asbestos -- a fire-resistant material -- is the biggest risk factor. Asbestos was once commonly found in insulation, ceiling and roofing vinyls, ...

  4. [Malignant mesothelioma and asbestos].

    PubMed

    Rüttner, J R

    1983-03-12

    Malignant mesothelioma is a rare neoplasm of rapidly lethal course arising primarily in the pleura and less often in the peritoneum. In the majority of cases the disease is closely related to occupational exposure to asbestos. The latency period, calculated from the first contact with asbestos to the appearance of mesothelioma, is generally in the order of 20 years or more irrespective of the duration of exposure. A causal relationship can be established with certainty only by a careful history and positive tissue analysis for the presence of asbestos. The author's own series of 48 pleural mesotheliomas comprises 39 cases involving occupational exposure to asbestos, 6 others with asbestos demonstrable in pulmonary tissue but no discernible source in the history, and 3 where no relation to asbestos could be established at all. Although a dose-response relation may be assumed for asbestos as for all other carcinogens, the lack of data on asbestos dust concentrations at former places of work rendered determination of the minimal noxious dose difficult or impossible. It also remains unclear whether the various asbestos types, such as chrysotile and amphiboles, differ in pathogenic effect. It is hoped that careful registration and continuing study of mesotheliomas will shed further light on their relationship to asbestos and on the possible hazards of the mineral to the general population.

  5. Malignant mesothelioma in Eastern Asia.

    PubMed

    Bianchi, Claudio; Bianchi, Tommaso

    2012-01-01

    Relatively low numbers of malignant mesotheliomas have been reported from Eastern Asia. In order to explore the causes of this fact, the available data on mesothelioma incidence/mortality in five countries (Japan, South Korea, Taiwan, Hong Kong, and Singapore) were reviewed. Data on the industrial histories of the above countries were also examined. Mesothelioma incidence was low, despite a history of high shipbuilding and port activities, in which heavy exposure to asbestos generally has occurred. Underestimation of mesothelioma could partly explain the above discrepancy. Moreover, in some areas a sufficient latency period for mesothelioma development may have not yet elapsed, due to recent industrialization. However, other possibilities have to be considered. The cancer epidemiology in Eastern Asia differs deeply from that seen in Western countries, an indication of differences in etiologic factors of cancer as well as in co-factors. In addition, the oncogenic spectrum of asbestos is wide, and not completely defined. In a very different milieu from that of Western countries, asbestos could preferentially hit targets other than serosal membranes.

  6. Pleural malignancies including mesothelioma.

    PubMed

    Hillerdal, G

    1995-07-01

    Malignant mesothelioma is caused almost exclusively by occupational exposure to asbestos. During the past few years, however, increasing evidence has mounted that background exposure to asbestos could be sufficient to cause mesothelioma. Treatment of malignant mesothelioma remains a big problem. Some new approaches are on their way, and the most exciting ones are local immunotherapy in very early cases. Some success has been reported with local interferon treatment. As for treatment of metastatic pleural disease, the main purpose is symptomatic relief of dyspnea caused by fluid accumulation. The best way to achieve a lasting palliation is pleurodesis, and the most common way to do this, is by chemical means. The drug of choice in the United States has for many years been tetracycline, but since injectable tetracycline is no longer available, some substitute must be found. The substance that will "win" is not yet clear, but the two leading contestants are talc and doxycycline. Bleomycin also has its supporters, and a dark horse is quinacrine, which although not easily available in the United States, has been used in many European centers for decades. PMID:9363074

  7. Drugs Approved for Malignant Mesothelioma

    Cancer.gov

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for malignant mesothelioma. The list includes generic names and brand names. The drug names link to NCI's Cancer Drug Information summaries.

  8. Malignant pleural mesothelioma.

    PubMed

    Ho, L; Sugarbaker, D J; Skarin, A T

    2001-01-01

    Malignant pleural mesothelioma remains a difficult tumor to treat, much less cure. Currently, the best chance for long-term survival lies with early diagnosis and aggressive surgical extirpation, but given the typically long delay between the onset of symptoms and diagnosis, this is only possible with a high index of suspicion and an aggressive diagnosis workup. Early referral to a tertiary center experienced in the treatment of MPM may be important for several reasons: (1) decreased risk of tumor spread along multiple thoracenesis/biopsy tracts, (2) the availability of specialized pathologic assays for definitive diagnosis, (3) the availability of critical staging modalities (aggressive mediastinoscopy +/- thoracoscopy, MRI scans performed according to specific mesothelioma protocols, and perhaps PET scans), (4) surgical experience with pleurectomy/decortication and/or extrapleural pneumonectomy, that may decrease morbidity and mortality, and (5) the availability of novel adjuvant protocols. Single-modality therapy is unlikely to result in long-term survival. Aggressive surgery is required for optimal debulking, and extrapleural pneumonectomy may offer better local control compared with pleurectomy/ecortication. Delivery of optimal radiation schedules, which may involve large fractions as well as large total doses, is limited by the presence of nearby dose-limiting structures. Current chemotherapy is severely lacking in producing objective responses and improved survival although gemcitabine and IL-2 may be active agents to be combined with radiation and/or other agents. Hyperthermia, photodynamic therapy, intracavitary therapy, and gene therapy are all relatively new techniques under active investigation that should be supported by enrollment in on-going protocols. Predictably, many of these techniques provide greater benefit when used in the setting of adjuvant protocols or minimal residual disease, emphasizing the importance of multimodality therapy.

  9. Malignant pleural mesothelioma.

    PubMed

    Boutin, C; Schlesser, M; Frenay, C; Astoul, P

    1998-10-01

    The incidence of malignant pleural mesothelioma (MPM) has risen for some decades and is expected to peak between 2010 and 2020. Up to now, no single treatment has been proven to be effective and death usually occurs within about 12-17 months after diagnosis. Perhaps because of this poor prognosis, early screening has incited little interest. However, certain forms may have a better prognosis when diagnosed early and treated by multimodal therapy or intrapleural immunotherapy. Diagnosis depends foremost on histological analysis of samples obtained by thoracoscopy. This procedure allows the best staging of the pleural cavity with an attempt to detect visceral pleural involvement, which is one of the most important prognostic factors. Although radiotherapy seems necessary and is efficient in preventing the malignant seeding after diagnostic procedures in patients, there has been no randomized phase III study showing the superiority of any treatment compared with another. However, for the early-stage disease (stage I) a logical therapeutic approach seems to be neoadjuvant intrapleural treatment using cytokines. For more advanced disease (stages II and III) resectability should be discussed with the thoracic surgeons and a multimodal treatment combining surgery, radiotherapy and chemotherapy should be proposed for a randomized controlled study. Palliative treatment is indicated for stage IV. In any case, each patient should be enrolled in a clinical trial.

  10. Malignant mesothelioma in Hong Kong.

    PubMed

    Chang, Kwok C; Leung, Chi C; Tam, Cheuk M; Yu, Wai C; Hui, David S; Lam, Wah K

    2006-01-01

    Malignant mesothelioma (mesothelioma) is rare. We conducted the first systematic study of the epidemiology of mesothelioma in Hong Kong from 1988 to May 2002 by reviewing medical records. Mesothelioma patients were identified from the database of 12 out of 20 hospitals that would have admitted mesothelioma patients territory-wide. These 12 hospitals served 73% of the total hospital bed-years of the 20 hospitals. We identified 67 mesothelioma patients. The estimated annual incidence was one per million, which was similar to the background incidence of one to two per million among Caucasians. Occupational history was available in 43 subjects. Three quarters of mesothelioma patients with available occupational history had occupational asbestos exposure. Restricting analysis to 48 patients with accessible medical records and using 67 occupational asbestosis patients for comparison, the epidemiology of mesothelioma in Hong Kong shares similarities with the literature: mean age of 63 years upon diagnosis, mean latency of 46 years, median survival of 9.5 months, male predominance, selective presentation among women, high prevalence among workers in ships and dockyards, predominantly epithelioid type, lower prevalence of asbestos bodies, and negative association with pleural plaques. Asbestos consumption in Hong Kong rose in the 1970s and peaked in early 1980s and late 1990s. Hong Kong may encounter an epidemic of mesothelioma in the 2010s if effective occupational asbestos control measures are not in place.

  11. Malignant pleural mesothelioma due to environmental mineral fiber exposure in Turkey. Analysis of 135 cases.

    PubMed

    Selçuk, Z T; Cöplü, L; Emri, S; Kalyoncu, A F; Sahin, A A; Bariş, Y I

    1992-09-01

    We reviewed data from 135 patients with environment-associated malignant pleural mesothelioma (MPM) from the Central Anatolian region of Turkey. The most significant factors suggesting the diagnosis of MPM were the village where the patient resided and the typical presenting symptoms and signs of unilateral exudative pleural effusion associated with nonpleuritic chest pain. Computed tomography and ultrasonography were very useful for evaluating the extension of the tumor in the thoracic and abdominal cavities and chest wall. The tissue diagnosis was established by either thoracoscopy (39 percent) or pleural biopsy (39 percent) in the majority of the cases. The median survival after diagnosis was 13.52 months for erionite-associated MPM and 21.56 months for asbestos-associated MPM. The actuarial survival curves for the fibrous minerals were significantly different for survival computed both from onset of the symptoms and after diagnosis. Medical or surgical treatment or both did not change the outcome of the disease.

  12. Malignant pleural mesothelioma due to environmental mineral fiber exposure in Turkey. Analysis of 135 cases

    SciTech Connect

    Selcuk, Z.T.; Coeplue, L.Em.; Emri, S.; Kalyoncu, A.F.; Sahin, A.A.; Baris, Y.I. )

    1992-09-01

    We reviewed data from 135 patients with environment-associated malignant pleural mesothelioma (MPM) from the Central Anatolian region of Turkey. The most significant factors suggesting the diagnosis of MPM were the village where the patient resided and the typical presenting symptoms and signs of unilateral exudative pleural effusion associated with nonpleuritic chest pain. Computed tomography and ultrasonography were very useful for evaluating the extension of the tumor in the thoracic and abdominal cavities and chest wall. The tissue diagnosis was established by either thoracoscopy (39 percent) or pleural biopsy (39 percent) in the majority of the cases. The median survival after diagnosis was 13.52 months for erionite-associated MPM and 21.56 months for asbestos-associated MPM. The actuarial survival curves for the fibrous minerals were significantly different for survival computed both from onset of the symptoms and after diagnosis. Medical or surgical treatment or both did not change the outcome of the disease.

  13. [Malignant Pleural Mesotheliomas].

    PubMed

    Biancosino, C; Redwan, B; Krüger, M; Eberlein, M; Bölükbas, S

    2016-09-01

    Malignant pleural mesotheliomas (MPM) are very aggressive tumors, which originate from the mesothelial cells of the pleural surface. The main risk factor associated with MPM is exposure to asbestos. The latency period between asbestos exposure and MPM can be 30-60 years. Clinical symptoms and signs are often nonspecifc. The diagnosis of MPM requires an adequate tissue specimen for pathological examination, and video assisted thoracoscopic surgey (VATS) is associated with the highest diagnostic yield. MPM are histologically classified into epitheloid, sacromatoid and biphasic (mixed) sub-types. Accurate staging with invasive tests, if needed, is an important step before an interdisciplinary team can decide on an optimal (multi-modal) treatment approach. A multi-modal treatment approach (surgery, radiation oncology and chemotherapy) is superior to all approaches relying only on a single modality, if the patient qualifies for it from an oncological and functional standpoint. The goal of the surgical therapy is to achieve macroscopic complete resection. There are two competing surgical approaches and philosophies: extrapleural pneumonectomy (EPP) and radical pleurectomy (RP). Over the last years a paradigm shift from EPP to RP occurred and RP is now often the preferred surgical option. PMID:27612329

  14. Asbestos exposure and malignant mesothelioma in Korea.

    PubMed

    Lee, Kyoung-Ho; Yoon, Hyung-Suk; Choi, Sang-Jun; Kang, Daehee

    2009-01-01

    Although importation of asbestos to Korea has decreased, there are growing concerns of its hazardous effects. This paper describes the use and occupational exposure to asbestos, and the incidence and mortality of malignant mesotheliomas in Korea. Asbestos raw material imports from other countries peaked between 1990 and 1995, but importation of asbestos-containing and -processed materials has steadily increased until now. A comprehensive exposure survey was conducted in Korea between 1995 and 2006. The average airborne asbestos concentration was lower than from other countries and steadily decreased during the study period. The number of malignant mesothelioma cases in Korea was 48 in 1998, 39 in 1999, 45 in 2000, 38 in 2001, and 46 in 2002. There were 334 deaths due to malignant mesothelioma and an average of 30.4 deaths per year between 1996 and 2006. The number of deaths attributed to malignant mesothelioma ranged from 16 cases in 1999 to 57 cases in 2006. The magnitude of asbestos-related health problems in Korea has been underestimated due to under-diagnosis, incomplete reports, and shorter duration of exposure. A nationwide surveillance system for asbestos exposure and malignant mesothelioma should therefore be implemented.

  15. Diffuse Malignant Mesothelioma: A Review

    PubMed Central

    Rom, William N.; Lockey, James E.

    1982-01-01

    Diffuse malignant mesothelioma is a signal tumor of asbestos exposure. Mesothelioma incidence has been steadily rising during the past two decades, reflecting the increases in asbestos use during and following World War II. The onset of the disease follows exposure by 25 to 40 years. The dose-response relationship appears to be much lower than that for asbestosis or lung cancer—it is not known whether current levels of exposure will entail a risk for disease 30 years hence. There is no synergistic or additive interaction with smoking for this tumor. Current knowledge indicates that pleural plaques, per se, do not increase the risk for this tumor beyond that of the previous asbestos exposure alone. Durable fibers with high aspect ratios, especially amphiboles, are associated with experimental tumor induction. Treatment modalities including surgical procedures and chemotherapy with doxorubicin and 5-azacytidine offer prospects for palliation. ImagesFigure 1.Figure 2. PMID:6761970

  16. Malignant pleural mesothelioma: a problematic review.

    PubMed

    Moskal, T L; Urschel, J D; Anderson, T M; Antkowiak, J G; Takita, H

    1998-01-01

    Malignant pleural mesothelioma is a rare tumor that has been difficult to study. Because of disappointing treatment results, malignant pleural mesothelioma has remained an area of active research and development. A clinicopathologic review is performed in light of several problematic issues involving diagnosis, staging, natural history, and treatment. Multimodality treatment with surgery followed by adjuvant local and systemic therapy remains the most optimal therapy. Many controversial issues still exist in the treatment of malignant pleural mesothelioma. In the ensuing years newer staging systems, better preoperative staging, newer experimental therapies, and the localization of patients at expert centers will undoubtedly have an impact on disease management.

  17. What's New in Malignant Mesothelioma Research and Treatment?

    MedlinePlus

    ... Next Topic Additional resources for malignant mesothelioma What’s new in malignant mesothelioma research and treatment? There is ... that has shown promise in some studies. Other new drugs have different targets. For example, some new ...

  18. Epithelial-mesenchymal transition in malignant mesothelioma.

    PubMed

    Fassina, Ambrogio; Cappellesso, Rocco; Guzzardo, Vincenza; Dalla Via, Lisa; Piccolo, Stefano; Ventura, Laura; Fassan, Matteo

    2012-01-01

    Epithelial-mesenchymal transition is a physiopathological process by which epithelial cells acquire mesenchymal shape and properties. Malignant mesothelioma is histologically characterized by the concomitant presence of epithelioid and sarcomatoid features, the latter being associated to worse prognosis, thus suggesting a role of epithelial-mesenchymal transition in this dual phenotype. We studied 109 malignant mesotheliomas (58 epithelioid, 26 sarcomatoid, and 25 biphasic) by immunohistochemistry and qRT-PCR analysis, and demonstrated a substantial switch from epithelial markers (E-cadherin, β-catenin, and cytokeratins 5/6) to mesenchymal markers (N-cadherin, vimentin, α-smooth muscle actin, Snail, Slug, Twist, ZEB1, ZEB2, S100A4, MMP2, and MMP9) through epithelioid to biphasic and sarcomatoid histotypes. In agreement with these findings, the ectopic expression of miR-205 (a repressor of ZEB1 and ZEB2 expression) in MeT-5A (mesothelial cell line), H2452 (an epithelioid malignant mesothelioma cell line) and MSTO-211H (a biphasic malignant mesothelioma cell line) not only induced a significant reduction of ZEB1 and ZEB2 and a consequent up-regulation of E-cadherin gene expression, but also inhibited migration and invasion. Moreover, miR-205 was significantly down-regulated in biphasic and sarcomatoid histotypes (qRT-PCR and in situ hybridization analyses). Collectively, our findings indicate that epithelial-mesenchymal transition has a significant part in the morphological features of malignant mesothelioma. In particular, miR-205 down-regulation correlated significantly with both a mesenchymal phenotype and a more aggressive behavior.

  19. [Asbestos and malignant pleural mesothelioma: molecular, cellular and physiopathological aspects].

    PubMed

    Mohr, Steve; Keith, Gérard; Rihn, Bertrand

    2005-11-01

    Asbestos is known as mutagenic and carcinogenic for human and is responsible for many pulmonary diseases including asbestosis, bronchogenic carcinoma and malignant pleural mesothelioma. Occupational exposure to asbestos is involved in 70-80% of all malignant pleural mesothelioma. The later presents a growing challenge for both researcher and clinician. The diagnosis of malignant pleural mesothelioma is difficult and the current treatments did not show significant improvement of the survival. The increasing incidence of malignant pleural mesothelioma, its gravity and its human, social and financial consequences are of high concern in public health. In this paper we summarize the so far knowledge on cellular, molecular and pathophysiological events involved in genesis and development of malignant pleural mesothelioma. Finally, the paper also report recent data sourced from the study of malignant pleural mesothelioma transcriptome using high-throughput technologies such as gene expression array. These data should improve the accuracy of mesothelioma diagnosis and therapy.

  20. Pleurodesis outcome in malignant pleural mesothelioma.

    PubMed

    Fysh, Edward Thomas Hamilton; Tan, Sze Khen; Read, Catherine Ann; Lee, Felicity; McKenzie, Kate; Olsen, Nola; Weerasena, Indunil; Threlfall, Timothy; de Klerk, Nicholas; Musk, A William; Lee, Y C Gary

    2013-06-01

    Few data exist on the pleurodesis outcome in patients with malignant pleural mesothelioma (MPM). A retrospective review of the Western Australian Mesothelioma Registry over 5 years revealed 390 evaluable patients. Only a subset of patients (42.3%) underwent pleurodesis, surgically (n=78) or by bedside instillation of sclerosants (n=87). Surgical pleurodesis showed no advantages over bedside pleurodesis in efficacy (32% vs 31% failures requiring further drainage, p=0.98), patient survival (p=0.52) or total time spent in hospital from procedure till death (p=0.36). No clinical, biochemical or radiographic parameters tested adequately predict pleurodesis outcome.

  1. Malignant Mesothelioma: Facts, Myths and Hypotheses

    PubMed Central

    Carbone, Michele; Ly, Bevan H.; Dodson, Ronald F.; Pagano, Ian; Morris, Paul T.; Dogan, Umran A.; Gazdar, Adi F.; Pass, Harvey I.; Yang, Haining

    2011-01-01

    Malignant mesothelioma (MM) is a neoplasm arising from mesothelial cells lining the pleural, peritoneal, and pericardial cavities. Over 20 million people in the US are at risk of developing MM due to asbestos exposure. MM mortality rates are estimated to increase by 5-10% per year in most industrialized countries until about 2020. The incidence of MM in men has continued to rise during the past 50 years, while the incidence in women appears largely unchanged. It is estimated that about 50-80% of pleural MM in men and 20-30% in women developed in individuals whose history indicates asbestos exposure(s) above that expected from most background settings. While rare for women, about 30% of peritoneal mesothelioma in men has been associated with exposure to asbestos. Erionite is a potent carcinogenic mineral fiber capable of causing both pleural and peritoneal MM. Since erionite is considerably less widespread than asbestos, the number of MM cases associated with erionite exposure is smaller. Asbestos induces DNA alterations mostly by inducing mesothelial cells and reactive macrophages to secrete mutagenic oxygen and nitrogen species. In addition, asbestos carcinogenesis is linked to the chronic inflammatory process caused by the deposition of a sufficient number of asbestos fibers and the consequent release of pro-inflammatory molecules, especially HMGB-1, the master switch that starts the inflammatory process, and TNF-alpha by macrophages and mesothelial cells. Genetic predisposition, radiation exposure and viral infection are co-factors that can alone or together with asbestos and erionite cause MM. PMID:21412769

  2. [Development in the treatment of malignant mesothelioma].

    PubMed

    Bass, P; Burgers, J A

    2005-04-01

    For many years there has been a search for an effective treatment of malignant pleural mesothelioma. Surgery is of limited applicability and is reserved for special cases, in which it is combined with radiation therapy. In the previous century, many cytostatic agents have been tested, alone or in combination, but the response was limited, the median survival time was unchanged and the toxicity was high. New drugs, including the new antifolates, are being used much more often in the treatment of malignant pleural mesothelioma in combination with a platinum derivative. Cytostatics such as pemetrexed, an antifolate, and to a lesser extent raltitrexed, have shown good response rates and increased survival in phase III studies, but the survival benefit evaporates within 2 years. Inhibitors of angiogenesis and of epidermal growth factor are being tested, but they have shown only limited activity until now. The current studies focus on the use of chemotherapy and biological agents as part of a more complex treatment schedule.

  3. Clinical aspects of malignant mesothelioma in Australia.

    PubMed

    Driscoll, T R; Baker, G J; Daniels, S; Lee, J; Thompson, R; Ferguson, D A; Leigh, J

    1993-02-01

    Australia is currently experiencing an epidemic of malignant mesothelioma. The clinical aspects of malignant mesothelioma were investigated in 295 Australian patients as part of a national study of the disease. Most patients were male (91%), with the mean age at diagnosis being 64 years. The predominant cell type was epithelial (38%) and the majority of primary tumours arose from the pleura (94%). Mean survival was poor (17.6 months from first symptom; 11.8 months from diagnosis). Patients with a pleural primary tumour were more likely to present with dyspnoea, chest pain and cough; to have a pleural effusion diagnosed radiologically; and to have metastatic spread. Patients with a peritoneal primary tumour were more likely to present with weight loss, loss of appetite, abdominal pain and ascites; to have radiologic evidence of asbestos exposure; and to have spread along a needle track created during a diagnostic tap. A minority of patients had past thoracic conditions, or radiologic findings, specifically related to previous asbestos exposure. About one fifth of patients had no known asbestos exposure. Forty-one per cent of subjects received some form of chemotherapy, radiotherapy and/or surgery, but no formal disease staging had been documented for any patient. Proper controlled trials of secondary and tertiary treatments in malignant mesothelioma are now needed.

  4. Cigarette smoking, asbestos exposure, and malignant mesothelioma.

    PubMed

    Muscat, J E; Wynder, E L

    1991-05-01

    In a hospital-based case-control study of 124 (105 male and 19 female) histologically confirmed malignant mesothelioma cases and age- and sex-matched controls, the role of cigarette smoking and the risk of asbestos exposure was investigated. Exposure to asbestos for at least 1 year was likely for 78% of male cases and 16% of female cases, and 90% of males were possibly exposed. Male cases worked predominantly in the ship-building industry, construction, or insulation trades. Elevated risks were found for males employed in asbestos-related industries [odds ratio (OR) 8.1; 95% confidence interval (CI) 4.9-13.5], e.g., shipyards (OR 82.9, 95% CI 25.5-269.1), construction/maintenance (OR 8.3, 95% CI 4.6-14.8), and other asbestos-related jobs (OR 3.2, 95% CI 1.4-7.2), and for males who self-reported exposure to asbestos or insulation (OR 50.9, 95% CI 21.7-119.8). A statistically significant trend was found for the risk of mesothelioma with increasing years employed in non-shipyard asbestos-related occupations. Among women, only one case worked in an asbestos-related industry and two reported domestic contact with asbestos. No association between cigarette smoking and mesothelioma was found for either men or women. We also report the occurrence of mesothelioma in occupations which have not been previously reported.

  5. [Malignant pleural mesothelioma after radiation treatment for Hodgkin lymphoma].

    PubMed

    Vandenbos, F; Figueredo, M; Dumon-Gubeno, M-C; Nicolle, I; Tarhini, A; Butori, C; Mouroux, J

    2013-10-01

    Malignant mesothelioma is a relatively uncommon malignancy. Although the pathogenesis is primarily related to asbestos, the role of ionizing radiation is more controversial. We report the case of a 41-year-old male who developed pleural mesothelioma. He had both, a prior short asbestos exposure and a thoracic radiotherapy for Hodgkin's disease 26years before. The evidence for radiotherapy as cause for mesothelioma is expanding and the diagnosis of mesothelioma in patients who had previous irradiation should be kept in mind. PMID:23796498

  6. Biphasic Malignant Pleural Mesothelioma Masquerading as a Primary Skeletal Tumor

    PubMed Central

    Diacovo, Maria Julia

    2016-01-01

    Biphasic malignant pleural mesothelioma is a rare malignant tumor, usually presenting as a pleural-based mass in a patient with history of chronic asbestos exposure. We herein report a case of a 41-year-old man who presented with chest pain and had a chest computed tomography (CT) scan suggestive of a primary skeletal tumor originating from the ribs (chondrosarcoma or osteosarcoma), with no history of asbestos exposure. CT-guided core needle biopsies were diagnosed as malignant sarcomatoid mesothelioma. Surgical resection and chest wall reconstruction were performed, confirming the diagnosis and revealing a secondary histologic component (epithelioid), supporting the diagnosis of biphasic malignant mesothelioma. PMID:27660729

  7. Biphasic Malignant Pleural Mesothelioma Masquerading as a Primary Skeletal Tumor

    PubMed Central

    Diacovo, Maria Julia

    2016-01-01

    Biphasic malignant pleural mesothelioma is a rare malignant tumor, usually presenting as a pleural-based mass in a patient with history of chronic asbestos exposure. We herein report a case of a 41-year-old man who presented with chest pain and had a chest computed tomography (CT) scan suggestive of a primary skeletal tumor originating from the ribs (chondrosarcoma or osteosarcoma), with no history of asbestos exposure. CT-guided core needle biopsies were diagnosed as malignant sarcomatoid mesothelioma. Surgical resection and chest wall reconstruction were performed, confirming the diagnosis and revealing a secondary histologic component (epithelioid), supporting the diagnosis of biphasic malignant mesothelioma.

  8. Biphasic Malignant Pleural Mesothelioma Masquerading as a Primary Skeletal Tumor.

    PubMed

    Gleason, James Benjamin; Tashtoush, Basheer; Diacovo, Maria Julia

    2016-01-01

    Biphasic malignant pleural mesothelioma is a rare malignant tumor, usually presenting as a pleural-based mass in a patient with history of chronic asbestos exposure. We herein report a case of a 41-year-old man who presented with chest pain and had a chest computed tomography (CT) scan suggestive of a primary skeletal tumor originating from the ribs (chondrosarcoma or osteosarcoma), with no history of asbestos exposure. CT-guided core needle biopsies were diagnosed as malignant sarcomatoid mesothelioma. Surgical resection and chest wall reconstruction were performed, confirming the diagnosis and revealing a secondary histologic component (epithelioid), supporting the diagnosis of biphasic malignant mesothelioma. PMID:27660729

  9. Ultrastructure of human malignant diffuse mesothelioma.

    PubMed Central

    Suzuki, Y.; Kannerstein, M.

    1976-01-01

    Eleven cases of malignant diffuse mesotheliomas, histologically classified into two groups, epithelial (5 pleural and 3 peritoneal) and biphasic or mixed (2 pleural and 1 peritoneal) forms, were stuied by electron microscopy to elucidate their ultrastructural characteristics. The neoplastic cells of the epithelial forms were varied in ultrastructure, from well differentiated (marked by polarity, micovilli, glycogen granules, junctional structures, tonofilaments, intracellular vacuoles, and a basement membrane) to poorly differentiated (which lacked some of these epithelial characteristics). In four of eight instances in epithelial type tumors, nonepithelial or mesenchymal neoplastic cells were recognized. The biphasic or mixed cases included three major cell types: epithelial, atypical epithelial, and mesenchymal. It appeared that there were transitional forms among the three cell types. The observations support the concept that the neoplastic cell of malignant mesothelioma can differentiate into a number of cell lines. Images Figures 20 and 21 Figure 22 Figure 23 Figures 24 and 25 Figure 26 Figure 27A Figure 27B and C Figure 28 Figure 29 Figure 30 Figure 31 Figures 32 and 33 Figure 34 Figure 35 Figure 36 Figures 1-4 Figures 5 and 6 Figure 37 Figures 7-10 Figure 11 Figure 12 Figure 13 Figure 14 Figure 15 Figure 16 Figures 17 and 18 Figure 19 PMID:998721

  10. Malignant mesothelioma after radiation treatment for Hodgkin lymphoma.

    PubMed

    De Bruin, Marie L; Burgers, Jacobus A; Baas, Paul; van 't Veer, Mars B; Noordijk, Evert M; Louwman, Marieke W J; Zijlstra, Josée M; van den Berg, Hendrik; Aleman, Berthe M P; van Leeuwen, Flora E

    2009-04-16

    Malignant mesothelioma is a relatively uncommon malignancy. Although the pathogenesis is primarily related to asbestos, the disease may be associated with radiation exposure. Recently, increased risks for second primary mesothelioma after radiation for lymphoma have been reported. Because these findings are based on small numbers of patients, they need to be confirmed. We examined mesothelioma risk in 2567 5-year survivors of Hodgkin lymphoma. The risk was almost 30-fold increased in Hodgkin lymphoma patients treated with irradiation compared with the general population. Although histology and survival of the mesothelioma cases were comparable with cases from the general population, asbestos exposure and the proportion of males were lower than expected. The evidence for radiotherapy as cause for mesothelioma independent of exposure to asbestos is expanding, and the diagnosis of mesothelioma should be kept in mind whenever related symptoms arise in patients who had previous irradiation.

  11. Intercellular communication in malignant pleural mesothelioma: properties of tunneling nanotubes

    PubMed Central

    Ady, Justin W.; Desir, Snider; Thayanithy, Venugopal; Vogel, Rachel I.; Moreira, André L.; Downey, Robert J.; Fong, Yuman; Manova-Todorova, Katia; Moore, Malcolm A. S.; Lou, Emil

    2014-01-01

    Malignant pleural mesothelioma is a particularly aggressive and locally invasive malignancy with a poor prognosis despite advances in understanding of cancer cell biology and development of new therapies. At the cellular level, cultured mesothelioma cells present a mesenchymal appearance and a strong capacity for local cellular invasion. One important but underexplored area of mesothelioma cell biology is intercellular communication. Our group has previously characterized in multiple histological subtypes of mesothelioma a unique cellular protrusion known as tunneling nanotubes (TnTs). TnTs are long, actin filament-based, narrow cytoplasmic extensions that are non-adherent when cultured in vitro and are capable of shuttling cellular cargo between connected cells. Our prior work confirmed the presence of nanotube structures in tumors resected from patients with human mesothelioma. In our current study, we quantified the number of TnTs/cell among various mesothelioma subtypes and normal mesothelial cells using confocal microscopic techniques. We also examined changes in TnT length over time in comparison to cell proliferation. We further examined potential approaches to the in vivo study of TnTs in animal models of cancer. We have developed novel approaches to study TnTs in aggressive solid tumor malignancies and define fundamental characteristics of TnTs in malignant mesothelioma. There is mounting evidence that TnTs play an important role in intercellular communication in mesothelioma and thus merit further investigation of their role in vivo. PMID:25400582

  12. Malignant mesothelioma in British Columbia in 1982.

    PubMed

    Churg, A

    1985-02-01

    All cases newly diagnosed by a pathologist in 1982 in British Columbia as a malignant mesothelioma of the pleura or peritoneum were reviewed. In men there were 17 cases (incidence rate, 17.0/million/year), and in women 2 cases (1.9/million/year). A history of asbestos exposure (largely in shipyards, construction, or insulation work) was obtained for 14 of 15 men, and 0 of 1 woman. Mineralogic analysis of lung on 6 of the men confirmed that the tumor was associated in every instance with exposure to amosite and crocidolite asbestos; some patients also had elevated levels of tremolite asbestos, presumably reflecting exposure to a chrysotile asbestos product. No unusual levels of asbestos were found in the lungs of the one woman studied. These data show that the incidence rate of mesothelioma in British Columbia has increased nearly six times for men compared to the period 1969 to 1975, but has remained roughly unchanged for women. Almost all of the cases in men in this series could be linked to asbestos exposure.

  13. Malignant pleural mesothelioma: a clinicopathological study.

    PubMed

    Qua, J C; Rao, U N; Takita, H

    1993-09-01

    In this paper the results of a retrospective review of 58 patients with malignant pleural mesothelioma treated at our Institute are reported. There were 50 males and 8 females; the mean age was 56.3 years (range: 13-77). History of asbestos exposure was ascertained in 25 patients (43%). The most common finding in chest X-ray was pleural effusion which was seen in 47/58 patients on presentation. The cytological examination of pleural effusion was most of the time nondiagnostic. Pleural biopsy was needed for the correct diagnosis. Pathologically, 26 patients (44.8%) had epithelial type, 24 patients (41.4%) had mixed type, and 8 patients (13.8%) had fibrous or sarcomatous type of pleural mesothelioma. Most of the patients on presentation had Stage I disease by Butchart's classification. The overall survival time ranged from 1 month to as long as 17 years with a median of 12.5 months. The mean survival of patients who received nonsurgical therapies was 7-13.4 months. Thirteen patients were treated surgically: three patients survived over 5 years, but the median survival was 15 months. Six patients received no treatment, and the median survival was seven months.

  14. Epidemiology of malignant mesothelioma--an outline.

    PubMed

    McDonald, J Corbett

    2010-11-01

    In the 1960s and 1970s, well designed case-referent studies put beyond doubt that exposure to airborne asbestos fibres was a cause of malignant mesothelioma. Some 35 cohort mortality studies in a large variety of industries during the 20-year period, 1974-1994, showed a wide range of outcomes, but in general that the risk was higher in exposures which included amphiboles rather than chrysotile alone. Real progress began, however, with discoveries along several lines: the link between pleural changes and mineralogy, the concept and importance of biopersistence, the developments in counting and typing mineral fibres in lung tissue, and data on amphibole mining in South Africa and Australia for comparison with that on chrysotile in Canada and Italy. This led to the recognition of the potential contamination in North America of chrysotile with tremolite. A survey in Canada in 1980-1988 and other surveys demonstrated that crocidolite, amosite, and tremolite could explain almost all cases of mesothelioma. Effective confirmation of this was finally achieved with data on vermiculite miners in Libby, Montana, in the years 1983-1999, where exposure was to tremolite-actinolite and/or other amphibole fibres alone.

  15. Malignant pleural mesothelioma: a survival study.

    PubMed

    Harvey, J C; Fleischman, E H; Kagan, A R; Streeter, O E

    1990-09-01

    Ninety-four patients with malignant pleural mesothelioma were treated at Southern California Permanente Medical Group Facilities between 1965 and 1988. This retrospective analysis of survival in these patients is compared according to surgical and/or supportive management. Group I patients received supportive care only, including pleurodesis as needed. This group included the majority of patients. Group II patients were managed largely with debulking procedures including decortication and pleurectomy. Group III patients received extrapleural pneumonectomy. This group included the two long-term survivors of the entire group. This study of survival points out the need for a cooperative protocol as well as the consistent use of proper modern preoperative staging in an attempt to select patients who benefit from extrapleural pneumonectomy.

  16. CD30 is a potential therapeutic target in malignant mesothelioma.

    PubMed

    Dabir, Snehal; Kresak, Adam; Yang, Michael; Fu, Pingfu; Wildey, Gary; Dowlati, Afshin

    2015-03-01

    CD30 is a cytokine receptor belonging to the TNF superfamily (TNFRSF8) that acts as a regulator of apoptosis. The presence of CD30 antigen is important in the diagnosis of Hodgkin disease and anaplastic large cell lymphoma. There have been sporadic reports of CD30 expression in nonlymphoid tumors, including malignant mesothelioma. Given the remarkable success of brentuximab vedotin, an antibody-drug conjugate directed against CD30 antigen, in lymphoid malignancies, we undertook a study to examine the incidence of CD30 in mesothelioma and to investigate the ability to target CD30 antigen in mesothelioma. Mesothelioma tumor specimens (N = 83) were examined for CD30 expression by IHC. Positive CD30 expression was noted in 13 mesothelioma specimens, primarily those of epithelial histology. There was no significant correlation of CD30 positivity with tumor grade, stage, or survival. Examination of four mesothelioma cell lines (H28, H2052, H2452, and 211H) for CD30 expression by both FACS analysis and confocal microscopy showed that CD30 antigen localized to the cell membrane. Brentuximab vedotin treatment of cultured mesothelioma cells produced a dose-dependent decrease in cell growth and viability at clinically relevant concentrations. Our studies validate the presence of CD30 antigen in a subgroup of epithelial-type mesothelioma tumors and indicate that selected mesothelioma patients may derive benefit from brentuximab vedotin treatment.

  17. CD30 is a potential therapeutic target in malignant mesothelioma

    PubMed Central

    Dabir, Snehal; Kresak, Adam; Yang, Michael; Fu, Pingfu; Wildey, Gary; Dowlati, Afshin

    2015-01-01

    CD30 is a cytokine receptor belonging to the tumor necrosis factor superfamily (TNFRSF8) that acts as a regulator of apoptosis. The presence of CD30 antigen is important in the diagnosis of Hodgkin’s disease and anaplastic large cell lymphoma. There have been sporadic reports of CD30 expression in non-lymphoid tumors, including malignant mesothelioma. Given the remarkable success of brentuximab vedotin, an antibody-drug conjugate directed against CD30 antigen, in lymphoid malignancies, we undertook a study to examine the incidence of CD30 in mesothelioma and to investigate the ability to target CD30 antigen in mesothelioma. Mesothelioma tumor specimens (N = 83) were examined for CD30 expression by immunohistochemistry. Positive CD30 expression was noted in 13 mesothelioma specimens, primarily those of epithelial histology. There was no significant correlation of CD30 positivity with either tumor grade, stage or survival. Examination of four mesothelioma cell lines (H28, H2052, H2452, and 211H) for CD30 expression by both FACS analysis and confocal microscopy showed that CD30 antigen localized to the cell membrane. Brentuximab vedotin treatment of cultured mesothelioma cells produced a dose-dependent decrease in cell growth and viability at clinically relevant concentrations. Our studies validate the presence of CD30 antigen in a subgroup of epithelial-type mesothelioma tumors and indicate that selected mesothelioma patients may derive benefit from brentuximab vedotin treatment. PMID:25589494

  18. Oncolytic virotherapy for human malignant mesothelioma: recent advances

    PubMed Central

    Boisgerault, Nicolas; Achard, Carole; Delaunay, Tiphaine; Cellerin, Laurent; Tangy, Frédéric; Grégoire, Marc; Fonteneau, Jean-François

    2015-01-01

    Cancer virotherapy is an attractive alternative to conventional treatments because it offers a wide range of antitumor effects due to 1) the diversity of the oncolytic viruses that are now available and 2) their multifaceted activities against both tumor cells and tumor vessels, in addition to their ability to induce antitumor immune responses. In this review, we summarize preclinical and clinical data regarding the targeting of malignant mesothelioma (MM) by oncolytic viruses. We also discuss the potential of other oncolytic viruses that have already shown antitumor effects against several malignancies in advanced clinical trials but are yet to be tested against MM cells. Finally, we review how the activation of the immune system and combinations with other types of anticancer treatments could support the development of oncolytic virotherapy for the treatment of MM. PMID:27512676

  19. HLA antigen expression and malignant mesothelioma.

    PubMed

    Christmas, T I; Manning, L S; Davis, M R; Robinson, B W; Garlepp, M J

    1991-09-01

    The expression of HLA antigens by a tumor may determine its progression and metastatic potential by influencing the immune response to that tumor. The upregulation of HLA antigen expression on some cell types by interferons (IFNs) may contribute to their antitumor activity. Malignant mesothelioma (MM) is a tumor that has a poor prognosis and is unaffected by conventional therapy, although immunotherapy has not been adequately assessed. In this study, we have examined the constitutive and IFN-inducible expression of class I and class II HLA antigens on MM cell lines using indirect immunofluorescence and Northern blotting. All MM cell lines constitutively expressed class I, but not class II, surface antigen, and all three class I loci (HLA-A, HLA-B, and HLA-C) were expressed. The MM cell lines were heterogeneous in their response to the IFNs. Treatment with IFN-alpha marginally increased class I surface expression, but not class II. Class I mRNA was, however, clearly increased in all cell lines after IFN-alpha treatment, suggesting that class I surface antigen was already maximally expressed. IFN-gamma increased class I mRNA expression in all but one cell line and induced DR expression on three of the cell lines. DQ-beta, but not DQ-alpha, mRNA was inducible in the same three cell lines, but DQ surface antigen was never demonstrable.(ABSTRACT TRUNCATED AT 250 WORDS)

  20. Soluble Mesothelin Related Peptide (SMRP) and Osteopontin (OPN) as Early Detection Markers for Malignant Mesothelioma (MM) — EDRN Public Portal

    Cancer.gov

    Phase I: - Identification and assemblage of representative cohorts of individuals with MM, no malignancies but increased risk for MM due to asbestos exposure, and (optionally) lung malignancies other than MM Phase II (A) - Determine the sensitivity and specificity of SMRP and OPN in distinguishing individuals with a clinical diagnosis of malignant mesothelioma from individuals who are asbestos-exposed but without a clinical diagnosis of malignant mesothelioma. Phase II (B) – Determine the comparability of analyte values across contributing centers and determine covariates that influence analyte levels Phase II (C) – Determine the sensitivity and specificity of SMRP and OPN, alone and in combination, in distinguishing individuals with MM from those without. Phase III. Determine the sensitivity and specificity of SMRP and OPN in distinguishing individuals who would subsequently develop malignant mesothelioma from matched individuals who did not subsequently develop malignant mesothelioma. Phase IV. Determine the sensitivity and specificity of SMRP and OPN in other populations of interest.

  1. [Malignant mesothelioma in the industrial area of Colleferro].

    PubMed

    Ascoli, V; Fantini, F; Carnovale Scalzo, C; Blasetti, F; Bruno, C; Di Domenicantonio, R; Lo Presti, E; Pasetto, R; Nardi, F; Comba, P

    2000-01-01

    The study describes the occurrence of pleural and peritoneal malignant mesothelioma in the Colleferro industrial area (Province of Rome, 9 municipalities, population 63,000, period 1993-98) which is the site of a large chemical plant (BPD) producing organic chemicals, acid mixtures, insecticides, explosives and dynamite, and was involved in manufacturing/maintenance of railroad rolling stock. Asbestos was extensively used in these plants in the past. Mesothelioma cases were actively searched from data in files of pathology archives, hospital admission and discharge (records), and death certificates recorded at local health authority register. 23 potential cases were identified for whom clinical charts and pathological slides were reviewed. A multidisciplinary evaluation of all collected information confirmed 18 cases of cyto-histologically proven malignant mesothelioma (pleural/peritoneal ratio of 2.75:1) among residents and/or workers at BPD. The remaining 5 cases were defined as not mesothelioma; however, two were cases of lung cancer (both occupationally exposed to asbestos). All subjects with malignant mesothelioma had been occupationally exposed to asbestos (14 males and 3 females), except one (1 female with domestic exposure). No mesothelioma case was attributable to environmental exposure. Of the 17 cases with occupational asbestos exposure, 15 occurred in BPD workers employed in manufacturing/maintenance of railroad rolling stock (3 cases), general maintenance services (5 cases), or in the armaments sector (7 cases) and 2 in residents but not BPD workers (1 baker, 1 pipefitter). The incidence rate in residents of the 9 municipalities was 5.5 in males and 1.3 in females (standardized on the Italian population x100,000, census 1981). For Colleferro municipality only, the incidence was 10.1 in males and 4.1 in females, which are the highest rates reported so far in Italy. Besides confirming the risk of mesothelioma risk in railroad rolling stock manufacturing

  2. Non-malignant chest x ray changes in patients with mesothelioma in a large cohort of asbestos insulation workers.

    PubMed Central

    Lilis, R; Ribak, J; Suzuki, Y; Penner, L; Bernstein, N; Selikoff, I J

    1987-01-01

    To assess the prevalence of non-malignant chest x ray abnormalities in cases of mesothelioma 184 cases of mesothelioma (72 pleural and 112 peritoneal) which had occurred in a cohort of asbestos insulation workers followed up since 1967 were studied. Chest x ray films of satisfactory quality, on which the presence or absence of non-malignant radiological changes indicating interstitial pulmonary fibrosis or pleural fibrosis or both, could be assessed with a high degree of certainty were available. In some cases (20% for pleural mesothelioma, 11.6% for peritoneal mesothelioma) non-malignant radiological changes were not radiologically detectable. Parenchymal interstitial fibrosis (small irregular opacities) only was found in a proportion of cases (25.4% of pleural mesotheliomas, 12.5% of peritoneal mesotheliomas). Pleural fibrosis only was detected in 17% of cases of pleural mesothelioma and 27% of cases of peritoneal mesothelioma. Most patients had both parenchymal and pleural fibrosis. Although these results tend to indicate that in peritoneal mesothelioma the proportion of pleural fibrosis is significantly higher, these findings might have been due to the fact that in most cases of pleural mesothelioma non-malignant changes were interpreted in one hemithorax only. In 46 cases (21 pleural, 25 peritoneal) in which sufficient lung tissue was available histopathology of lung parenchyma indicated the presence of interstitial fibrosis; in 20 (43.5%) of these the chest x ray film had been read as negative. Thus the absence of radiologically detectable small opacities on the chest x ray film does not exclude the existence of interstitial pulmonary fibrosis in cases of mesothelioma among insulation workers. With lower levels of exposure (such as in family contacts of asbestos workers) it is conceivable that mesothelioma might occur in the absence of interstitial pulmonary fibrosis. PMID:3606969

  3. Membranous nephropathy associated with malignant pleural mesothelioma in an adult patient: A case report

    PubMed Central

    Pu, Xinyu; Dou, Yanna; Liu, Dong; Lu, Shan; Quan, Songxia; Zhang, Xiaoxue; Ma, Shuang; Zhao, Zhanzheng

    2016-01-01

    A 23-year-old man presented to our hospital with membranous nephropathy and received a detailed examination, including pleural biopsy, due to a feeling of chest oppression. The result of the pleural biopsy was malignant pleural mesothelioma. However, the patient did not have a history of asbestos or tobacco exposure. A review of the English literature identified only 7 reported cases of concomitant malignant mesothelioma and nephrotic syndrome. Furthermore, among the 7 cases reviewed, 6 had a history of asbestos exposure, 1 had a history of prolonged tobacco exposure and in only 1 case the renal pathology results revealed the presence of membranous nephropathy. PMID:27699035

  4. Membranous nephropathy associated with malignant pleural mesothelioma in an adult patient: A case report

    PubMed Central

    Pu, Xinyu; Dou, Yanna; Liu, Dong; Lu, Shan; Quan, Songxia; Zhang, Xiaoxue; Ma, Shuang; Zhao, Zhanzheng

    2016-01-01

    A 23-year-old man presented to our hospital with membranous nephropathy and received a detailed examination, including pleural biopsy, due to a feeling of chest oppression. The result of the pleural biopsy was malignant pleural mesothelioma. However, the patient did not have a history of asbestos or tobacco exposure. A review of the English literature identified only 7 reported cases of concomitant malignant mesothelioma and nephrotic syndrome. Furthermore, among the 7 cases reviewed, 6 had a history of asbestos exposure, 1 had a history of prolonged tobacco exposure and in only 1 case the renal pathology results revealed the presence of membranous nephropathy.

  5. Dietary intake and the risk of malignant mesothelioma.

    PubMed

    Muscat, J E; Huncharek, M

    1996-05-01

    A high consumption of fruit and vegetables reduces the risk of several types of cancer. There is little information on the association between dietary intake and mesothelioma. A hospital-based case-control study of 94 men and women with malignant mesothelioma and 64 control patients without cancer was conducted to determine the odds associated with consumption of carotenoid-containing fruits and vegetables. After statistical adjustment for occupational asbestos exposure, the odds ratio was 0.2 [95% confidence interval (CI) 0.1-0.8] for carrot consumption and 0.5 (95% CI 0.2-1.4) for tomato consumption. However, the frequency of consuming other foods that have a high vitamin A or carotenoid content was not associated with a decreased risk of cancer. These results provide some justification for the hypothesis that provitamin A or beta-carotene may decrease the risk of mesothelioma. The body mass index was unrelated to the risk of mesothelioma.

  6. Recurrent hydropneumothorax: An unusual presentation for malignant pleural mesothelioma.

    PubMed

    DeLapp, David; Chan, Christopher; Nystrom, Perry

    2016-01-01

    Mesothelioma is a rare pulmonary malignancy commonly associated with asbestos exposure. Its presentation is insidious and non-specific, with complaints of chest pain, dyspnea and cough. Chest X-ray may demonstrate unilateral pleural effusion. CT and PET scans may highlight nodular pleural plaques. Diagnosis often times is difficult with negative imaging and negative pleural fluid studies. In rare cases, hydropneumothoraces may be seen. We report a case of malignant pleural mesothelioma presenting as recurrent hydropneumothorax with negative CT scan of the chest for pleural abnormalities and negative pleural fluid studies. PMID:27489758

  7. Cul4A is an oncogene in malignant pleural mesothelioma.

    PubMed

    Hung, Ming-Szu; Mao, Jian-Hua; Xu, Zhidong; Yang, Cheng-Ta; Yu, Jau-Song; Harvard, Chansonette; Lin, Yu-Ching; Bravo, Dawn Therese; Jablons, David M; You, Liang

    2011-02-01

    Cullin 4A (Cul4A) is important in cell survival, development, growth and the cell cycle, but its role in mesothelioma has not been studied. For the first time, we identified amplification of the Cul4A gene in four of five mesothelioma cell lines. Consistent with increased Cul4A gene copy number, we found that Cul4A protein was overexpressed in mesothelioma cells as well. Cul4A protein was also overexpressed in 64% of primary malignant pleural mesothelioma (MPM) tumours. Furthermore, knockdown of Cul4A with shRNA in mesothelioma cells resulted in up-regulation of p21 and p27 tumour suppressor proteins in a p53-independent manner in H290, H28 and MS-1 mesothelioma cell lines. Knockdown of Cul4A also resulted in G0/G1 cell cycle arrest and decreased colony formation in H290, H28 and MS-1 mesothelioma cell lines. Moreover, G0/G1 cell cycle arrest was partially reversed by siRNA down-regulation of p21 and/or p27 in Cul4A knockdown H290 cell line. In the contrary, overexpression of Cul4A resulted in down-regulation of p21 and p27 proteins and increased colony formation in H28 mesothelioma cell line. Both p21 and p27 showed faster degradation rates in Cul4A overexpressed H28 cell line and slower degradation rates in Cul4A knockdown H28 cell line. Our study indicates that Cul4A amplification and overexpression play an oncogenic role in the pathogenesis of mesothelioma. Thus, Cul4A may be a potential therapeutic target for MPM.

  8. A molecular epidemiology case control study on pleural malignant mesothelioma.

    PubMed

    Bolognesi, Claudia; Martini, Fernanda; Tognon, Mauro; Filiberti, Rosa; Neri, Monica; Perrone, Emanuela; Landini, Eleonora; Canessa, Paolo A; Ivaldi, Gian Paolo; Betta, Pietro; Mutti, Luciano; Puntoni, Riccardo

    2005-07-01

    Pleural malignant mesothelioma is an uncommon neoplasm usually associated with asbestos exposure. The increasing incidence of malignant mesothelioma cases involving individuals with low levels of asbestos exposure suggests a complex carcinogenetic process with the involvement of other cofactors. Cytogenetic studies revealed the complexity of the genetic changes involved in this neoplasm reflecting the accumulation of genomic damage. One of the most used methodologies for assessing genomic damage is the cytokinesis-blocked micronucleus test applied in peripheral blood lymphocytes (PBL). This approach allows the detection of chromosomal alterations expressed in binucleated cells after nuclear division in vitro. This marker could provide a tool for assessing genetically determined constitutional differences in chromosomal instability. A biomonitoring study was carried out to evaluate the micronuclei frequency in PBLs of patients with pleural malignant mesothelioma with respect to lung cancer, healthy, and risk controls as a marker of cancer susceptibility in correlation with the presence of SV40. A significant increased micronuclei frequency was observed in patients with malignant mesothelioma in comparison with all the other groups, the mean micronuclei frequency was double in patients with malignant mesothelioma compared with healthy controls, risk controls, and patients with lung adenocarcinoma (median 11.4 binucleated cells with micronuclei/1,000 binucleated cells versus 6.2, 6.1, and 5.1, respectively). Our data indicate that human T lymphocyte samples carry DNA sequences coding for SV40 large T antigen at low prevalence, both in cancer cases and controls. Evidence of cytogenetic damage revealed as micronuclei frequency in mesothelioma cancer patients could be related to exogenous and endogenous cofactors besides asbestos exposure.

  9. Malignant mesothelioma in non-asbestos textile workers in Florence

    SciTech Connect

    Paci, E.; Dini, S.; Buiatti, E.; Seniori Costantini, A.; Lenzi, S.; Zappa, M.

    1987-01-01

    By means of a review of histological diagnosis in the Pathology Department of the University of Florence, suspected cases of malignant mesothelioma, diagnosed in the period 1979-1984, were identified. Study of histological specimens permitted the selection of 13 cases of malignant mesothelioma resident in the Province of Florence. To these cases, referents were matched for age, sex, and year of hospital admission, with residence weighted for the general population of the Province. Both cases and referents (or their next of kin) completed an occupational questionnaire detailing possible occupational exposures. Out of the 13 cases of mesothelioma, 6 were textile workers and 5 of these were rag-sorters. There were only 5 textile workers among the 52 controls. No asbestos cloth production plants have been in operation in the area from which the cases and referents are derived. Possible sources of exposure to asbestos in the textile industry of this area are discussed.

  10. Peritoneal malignant mesothelioma in a patient with recurrent peritonitis

    SciTech Connect

    Riddell, R.H.; Goodman, M.J.; Moossa, A.R.

    1981-07-01

    A patient is presented who developed a peritoneal malignant mesothelioma in association with severe persistent and recurrent diverticulitis. The case is unusual in that a spectrum of mesothelial proliferation was documented beginning initially as benign foci of mesothelial proliferation and passing through a stage of atypical proliferation before terminating as a malignant process. The possible role of the diverticular disease in the pathogenesis of the tumor is discussed.

  11. Malignant mesothelioma: a clinical study of 238 cases.

    PubMed

    Haber, Steven E; Haber, Jason M

    2011-01-01

    Malignant mesothelioma is a diffuse tumor arising in the pleura, peritoneum, or other serosal surface and is closely associated with asbestos exposure. An estimated 2,500 to 3,000 cases are diagnosed each year in the United States. Although there are individual case reports and small series detailing the clinical aspects of mesothelioma, few studies examine a large series of patients with malignant mesothelioma from the clinical perspective. This study reports on the findings of 238 cases of malignant mesothelioma from a private consultative medical practice. Most cases had a history of occupational asbestos exposure. The mean latency was 48.5 yr, with women having a longer latency than men. The mean age at diagnosis was 70. Survival overall was poor (mean 8.8 months), but treatment was beneficial (mean 11.3 versus 6.4 months). Epithelioid histology conferred a survival advantage over sarcomatoid and responded better to treatment. Our data support an inverse relationship between asbestos dose and latency.

  12. Non-coding RNA repertoires in malignant pleural mesothelioma.

    PubMed

    Quinn, Leah; Finn, Stephen P; Cuffe, Sinead; Gray, Steven G

    2015-12-01

    Malignant pleural mesothelioma (MPM) is a rare malignancy, with extremely poor survival rates. There are limited treatment options, with no second line standard of care for those who fail first line chemotherapy. Recent advances have been made to characterise the underlying molecular mechanisms of mesothelioma, in the hope of providing new targets for therapy. With the discovery that non-coding regions of our DNA are more than mere junk, the field of research into non-coding RNAs (ncRNAs) has exploded in recent years. Non-coding RNAs have diverse and important roles in a variety of cellular processes, but are also implicated in malignancy. In the following review, we discuss two types of non-coding RNAs, long non-coding RNAs and microRNAs, in terms of their role in the pathogenesis of MPM and their potential as both biomarkers and as therapeutic targets in this disease. PMID:26791801

  13. Non-coding RNA repertoires in malignant pleural mesothelioma.

    PubMed

    Quinn, Leah; Finn, Stephen P; Cuffe, Sinead; Gray, Steven G

    2015-12-01

    Malignant pleural mesothelioma (MPM) is a rare malignancy, with extremely poor survival rates. There are limited treatment options, with no second line standard of care for those who fail first line chemotherapy. Recent advances have been made to characterise the underlying molecular mechanisms of mesothelioma, in the hope of providing new targets for therapy. With the discovery that non-coding regions of our DNA are more than mere junk, the field of research into non-coding RNAs (ncRNAs) has exploded in recent years. Non-coding RNAs have diverse and important roles in a variety of cellular processes, but are also implicated in malignancy. In the following review, we discuss two types of non-coding RNAs, long non-coding RNAs and microRNAs, in terms of their role in the pathogenesis of MPM and their potential as both biomarkers and as therapeutic targets in this disease.

  14. Peritoneal malignant mesothelioma metastatic to supraclavicular lymph nodes.

    PubMed

    Zannella, Stefano; Testi, Maria Adele; Cattoretti, Giorgio; Pelosi, Giuseppe; Zucchini, Nicola

    2014-09-01

    Distinguishing between malignant mesothelioma and reactive mesothelial hyperplasia is often inestimable, but may be a challenging gauntlet for pathologists. A 62-year-old man underwent appendectomy after the identification of a peritoneal mass and the histological examination showed mesothelial proliferation along the appendix surface with no clear images of infiltration. After a few months the patient developed mediastinal and supraclavicular lymphadenopathies, and a nodal biopsy showed mesothelial cell proliferation invading lymphatic sinuses, consistent with the cells seen in the abdominal cavity. Since overt morphologic criteria for malignancy were lacking and reactive mesothelial cell deposits have been documented in lymph nodes, a molecular investigation of the CDKN2A (henceforth simply p16) gene status via fluorescence in situ hybridization was performed, which showed homozygous deletion in 100% tumor cells. These data ruled out the hypothesis of reactive mesothelial cells inclusion in lymph nodes, thus confirming the diagnosis of epithelioid malignant mesothelioma.

  15. [A case of sarcomatoid malignant peritoneal mesothelioma responding to combination chemotherapy of cyclophosphamide, vincristine, adriamycin and dacarbazine(CYVADIC)].

    PubMed

    Kusama, Toshiyuki; Kodaka, Taiichi; Tsunemine, Hiroko; Akasaka, Hiroshi; Koizumi, Naoki; Fujimoto, Koji; Sakano, Shigeru; Ito, Rieko; Kondo, Takeshi; Kitazawa, Sohei; Yamamura, Hisako; Takahashi, Katsuhito

    2009-03-01

    A 66-year-old woman was seen at our hospital because of abdominal fullness. A computed tomography(CT)revealed massive tumors in abdominal cavity. The patient underwent surgery consisting of tumorectomy, segmental gastrectomy, partial resection of small intestin, transverse colectomy, left oophorectomy and gastrostomy. By using immunohistochemical staining, the patient was diagnosed as sarcomatoid malignant peritoneal mesothelioma. Rapidly abdominal fullness occurred as of 22 days after the operation, and an abdominal CT revealed the massive recurrent tumors. We started a combination chemotherapy of cyclophosphamide, vincristine, adriamycin and dacarbazine (CYVADIC). The recurrent tumors showed remarkable reduction after the two courses of CYVADIC chemotherapy. Although we next started carboplatin and paclitaxel combination chemotherapy, she died due to rapidly progression of the disease with disseminated intravascular coagulation after 132 days of the operation. Malignant mesothelioma, especially sarcomatoid mesothelioma, is known to have a poor prognosis. However, our case suggests that we could improve the prognosis of sarcomatoid malignant mesothelioma by aggressive chemotherapy.

  16. Secreted primary human malignant mesothelioma exosome signature reflects oncogenic cargo.

    PubMed

    Greening, David W; Ji, Hong; Chen, Maoshan; Robinson, Bruce W S; Dick, Ian M; Creaney, Jenette; Simpson, Richard J

    2016-01-01

    Malignant mesothelioma (MM) is a highly-aggressive heterogeneous malignancy, typically diagnosed at advanced stage. An important area of mesothelioma biology and progression is understanding intercellular communication and the contribution of the secretome. Exosomes are secreted extracellular vesicles shown to shuttle cellular cargo and direct intercellular communication in the tumour microenvironment, facilitate immunoregulation and metastasis. In this study, quantitative proteomics was used to investigate MM-derived exosomes from distinct human models and identify select cargo protein networks associated with angiogenesis, metastasis, and immunoregulation. Utilising bioinformatics pathway/network analyses, and correlation with previous studies on tumour exosomes, we defined a select mesothelioma exosomal signature (mEXOS, 570 proteins) enriched in tumour antigens and various cancer-specific signalling (HPGD/ENO1/OSMR) and secreted modulators (FN1/ITLN1/MAMDC2/PDGFD/GBP1). Notably, such circulating cargo offers unique insights into mesothelioma progression and tumour microenvironment reprogramming. Functionally, we demonstrate that oncogenic exosomes facilitate the migratory capacity of fibroblast/endothelial cells, supporting the systematic model of MM progression associated with vascular remodelling and angiogenesis. We provide biophysical and proteomic characterisation of exosomes, define a unique oncogenic signature (mEXOS), and demonstrate the regulatory capacity of exosomes in cell migration/tube formation assays. These findings contribute to understanding tumour-stromal crosstalk in the context of MM, and potential new diagnostic and therapeutic extracellular targets.

  17. Secreted primary human malignant mesothelioma exosome signature reflects oncogenic cargo

    NASA Astrophysics Data System (ADS)

    Greening, David W.; Ji, Hong; Chen, Maoshan; Robinson, Bruce W. S.; Dick, Ian M.; Creaney, Jenette; Simpson, Richard J.

    2016-09-01

    Malignant mesothelioma (MM) is a highly-aggressive heterogeneous malignancy, typically diagnosed at advanced stage. An important area of mesothelioma biology and progression is understanding intercellular communication and the contribution of the secretome. Exosomes are secreted extracellular vesicles shown to shuttle cellular cargo and direct intercellular communication in the tumour microenvironment, facilitate immunoregulation and metastasis. In this study, quantitative proteomics was used to investigate MM-derived exosomes from distinct human models and identify select cargo protein networks associated with angiogenesis, metastasis, and immunoregulation. Utilising bioinformatics pathway/network analyses, and correlation with previous studies on tumour exosomes, we defined a select mesothelioma exosomal signature (mEXOS, 570 proteins) enriched in tumour antigens and various cancer-specific signalling (HPGD/ENO1/OSMR) and secreted modulators (FN1/ITLN1/MAMDC2/PDGFD/GBP1). Notably, such circulating cargo offers unique insights into mesothelioma progression and tumour microenvironment reprogramming. Functionally, we demonstrate that oncogenic exosomes facilitate the migratory capacity of fibroblast/endothelial cells, supporting the systematic model of MM progression associated with vascular remodelling and angiogenesis. We provide biophysical and proteomic characterisation of exosomes, define a unique oncogenic signature (mEXOS), and demonstrate the regulatory capacity of exosomes in cell migration/tube formation assays. These findings contribute to understanding tumour-stromal crosstalk in the context of MM, and potential new diagnostic and therapeutic extracellular targets.

  18. Secreted primary human malignant mesothelioma exosome signature reflects oncogenic cargo

    PubMed Central

    Greening, David W.; Ji, Hong; Chen, Maoshan; Robinson, Bruce W. S.; Dick, Ian M.; Creaney, Jenette; Simpson, Richard J.

    2016-01-01

    Malignant mesothelioma (MM) is a highly-aggressive heterogeneous malignancy, typically diagnosed at advanced stage. An important area of mesothelioma biology and progression is understanding intercellular communication and the contribution of the secretome. Exosomes are secreted extracellular vesicles shown to shuttle cellular cargo and direct intercellular communication in the tumour microenvironment, facilitate immunoregulation and metastasis. In this study, quantitative proteomics was used to investigate MM-derived exosomes from distinct human models and identify select cargo protein networks associated with angiogenesis, metastasis, and immunoregulation. Utilising bioinformatics pathway/network analyses, and correlation with previous studies on tumour exosomes, we defined a select mesothelioma exosomal signature (mEXOS, 570 proteins) enriched in tumour antigens and various cancer-specific signalling (HPGD/ENO1/OSMR) and secreted modulators (FN1/ITLN1/MAMDC2/PDGFD/GBP1). Notably, such circulating cargo offers unique insights into mesothelioma progression and tumour microenvironment reprogramming. Functionally, we demonstrate that oncogenic exosomes facilitate the migratory capacity of fibroblast/endothelial cells, supporting the systematic model of MM progression associated with vascular remodelling and angiogenesis. We provide biophysical and proteomic characterisation of exosomes, define a unique oncogenic signature (mEXOS), and demonstrate the regulatory capacity of exosomes in cell migration/tube formation assays. These findings contribute to understanding tumour-stromal crosstalk in the context of MM, and potential new diagnostic and therapeutic extracellular targets. PMID:27605433

  19. Secreted primary human malignant mesothelioma exosome signature reflects oncogenic cargo.

    PubMed

    Greening, David W; Ji, Hong; Chen, Maoshan; Robinson, Bruce W S; Dick, Ian M; Creaney, Jenette; Simpson, Richard J

    2016-01-01

    Malignant mesothelioma (MM) is a highly-aggressive heterogeneous malignancy, typically diagnosed at advanced stage. An important area of mesothelioma biology and progression is understanding intercellular communication and the contribution of the secretome. Exosomes are secreted extracellular vesicles shown to shuttle cellular cargo and direct intercellular communication in the tumour microenvironment, facilitate immunoregulation and metastasis. In this study, quantitative proteomics was used to investigate MM-derived exosomes from distinct human models and identify select cargo protein networks associated with angiogenesis, metastasis, and immunoregulation. Utilising bioinformatics pathway/network analyses, and correlation with previous studies on tumour exosomes, we defined a select mesothelioma exosomal signature (mEXOS, 570 proteins) enriched in tumour antigens and various cancer-specific signalling (HPGD/ENO1/OSMR) and secreted modulators (FN1/ITLN1/MAMDC2/PDGFD/GBP1). Notably, such circulating cargo offers unique insights into mesothelioma progression and tumour microenvironment reprogramming. Functionally, we demonstrate that oncogenic exosomes facilitate the migratory capacity of fibroblast/endothelial cells, supporting the systematic model of MM progression associated with vascular remodelling and angiogenesis. We provide biophysical and proteomic characterisation of exosomes, define a unique oncogenic signature (mEXOS), and demonstrate the regulatory capacity of exosomes in cell migration/tube formation assays. These findings contribute to understanding tumour-stromal crosstalk in the context of MM, and potential new diagnostic and therapeutic extracellular targets. PMID:27605433

  20. [Localized Malignant Mesothelioma of the Pleura with Hemothorax].

    PubMed

    Mega, Seiji

    2016-03-01

    Localized malignant mesothelioma of the pleura (LMM) is an extremely rare tumor. The biologic association between LMM and diffuse malignant mesothelioma of the pleura (DMM) remains unclear, and the standard treatment for LMM has not been established to date. We experienced a rare case of LMM. A 49-year-old male was admitted to our hospital because of dyspnea on effort and an abnormal shadow on the chest X-ray. He had a 7 cm pleural tumor with right hemothorax. The tumor was surgically removed completely and the diagnosis of LMM was established pathologically. After surgery, he underwent radio-chemotherapy. The patient has been followed up for 6 years with no evidence of reccurence. PMID:27075290

  1. [Horner's syndrome in a patient with diffuse malignant pleural mesothelioma].

    PubMed

    Minami, T; Matsumoto, K; Aizawa, H; Nakano, H; Sugio, K; Nakashima, Y; Hara, N

    1999-04-01

    A 63-year-old man was admitted to our hospital because of left back pain and dysesthesia in his left arm. On physical examination, the patient had ptosis, myosis, and anhydrosis on the left side, suggesting Horner's syndrome. A chest computed tomographic scan disclosed a mass lesion adjoining to the left posterior mediastinum. Although the mass lesion showed a slight decrease in size after the systemic administration of corticosteroids, no further improvement was obtained. Open chest examination revealed extended thickening of the parietal pleura with massive involvement of the upper thoracic sympathetic trunk. The diagnosis was malignant mesothelioma of sarcomatous type. Horner's syndrome is a rare but possible complication in the clinical course of malignant pleural mesothelioma. PMID:10390966

  2. The incidence of malignant mesothelioma in Australia, 1947-1980.

    PubMed

    Musk, A W; Dolin, P J; Armstrong, B K; Ford, J M; de Klerk, N H; Hobbs, M S

    1989-03-01

    Details of patients with malignant mesothelioma that was diagnosed in Australia before 1981 were obtained by searching all possible sources throughout Australia as far into the past as possible and up to and including 1980. The earliest patient with mesothelioma who was identified was diagnosed in Victoria in 1947. By 1980, 535 (81%) men and 123 (19%) women had been diagnosed with the disease; only 14 persons were aged less than 35 years at the time of diagnosis (the youngest person was 15 years of age). The incidence rate in subjects who were 35 years or older at diagnosis was less than 1.0 cases per million person-years until 1964-1968, and then it rose progressively to 15.5 cases per million person-years in 1979-1980. The highest rate (69.7 cases per million person-years) was observed in 65- to 74-year-old men in 1979-1980. The incidence rate in Western Australia was greater than were the rates in other states of Australia after the mid 1960s. Pleural mesotheliomas accounted for 88% of cases in which the site of the tumour was known; peritoneal mesotheliomas accounted for 10% of such cases and "other" sites for 2% of such cases. In 6% of cases the site was not specified. The exposure to asbestos was stated as "definite" in 59% of the cases with a recorded history of exposure: 8% of all the cases in the study had been exposed to crocidolite (blue asbestos) from Wittenoom Gorge in Western Australia. The age at diagnosis of patients with known exposure to asbestos was similar to that in those without known exposure. The increases in the incidence of malignant mesothelioma in Australia follow the published trends in the production and use of the amphibole varieties of asbestos in this country after a lag period of between 20 and 30 years.

  3. Cynara scolymus affects malignant pleural mesothelioma by promoting apoptosis and restraining invasion.

    PubMed

    Pulito, Claudio; Mori, Federica; Sacconi, Andrea; Casadei, Luca; Ferraiuolo, Maria; Valerio, Maria Cristina; Santoro, Raffaela; Goeman, Frauke; Maidecchi, Anna; Mattoli, Luisa; Manetti, Cesare; Di Agostino, Silvia; Muti, Paola; Blandino, Giovanni; Strano, Sabrina

    2015-07-20

    Malignant pleural mesothelioma is a poorly treated neoplasia arising from the pleural mesothelial lining. Here we document that the leaf extract of Cynara scolymus exerts broad antitumoral effects both in vitro and in vivo on mesothelioma cell lines. We found that Cynara scolymus treatment affects strongly cell growth, migration and tumor engraftment of mesothelioma cell lines. Strikingly, dietary feeding with Cynara scolymus leaf extract reduces the growth of mesothelioma xenografted tumors similarly to pemetrexed, a commonly employed drug in the treatment of mesothelioma. In aggregate our findings suggest that leaf extract of Cynara scolymus holds therapeutic potential for the treatment of mesothelioma. PMID:26136339

  4. Cynara scolymus affects malignant pleural mesothelioma by promoting apoptosis and restraining invasion

    PubMed Central

    Pulito, Claudio; Mori, Federica; Sacconi, Andrea; Casadei, Luca; Ferraiuolo, Maria; Valerio, Maria Cristina; Santoro, Raffaela; Goeman, Frauke; Maidecchi, Anna; Mattoli, Luisa; Manetti, Cesare; Di Agostino, Silvia; Muti, Paola; Blandino, Giovanni; Strano, Sabrina

    2015-01-01

    Malignant pleural mesothelioma is a poorly treated neoplasia arising from the pleural mesothelial lining. Here we document that the leaf extract of Cynara scolymus exerts broad antitumoral effects both in vitro and in vivo on mesothelioma cell lines. We found that Cynara scolymus treatment affects strongly cell growth, migration and tumor engraftment of mesothelioma cell lines. Strikingly, dietary feeding with Cynara scolymus leaf extract reduces the growth of mesothelioma xenografted tumors similarly to pemetrexed, a commonly employed drug in the treatment of mesothelioma. In aggregate our findings suggest that leaf extract of Cynara scolymus holds therapeutic potential for the treatment of mesothelioma. PMID:26136339

  5. Cynara scolymus affects malignant pleural mesothelioma by promoting apoptosis and restraining invasion.

    PubMed

    Pulito, Claudio; Mori, Federica; Sacconi, Andrea; Casadei, Luca; Ferraiuolo, Maria; Valerio, Maria Cristina; Santoro, Raffaela; Goeman, Frauke; Maidecchi, Anna; Mattoli, Luisa; Manetti, Cesare; Di Agostino, Silvia; Muti, Paola; Blandino, Giovanni; Strano, Sabrina

    2015-07-20

    Malignant pleural mesothelioma is a poorly treated neoplasia arising from the pleural mesothelial lining. Here we document that the leaf extract of Cynara scolymus exerts broad antitumoral effects both in vitro and in vivo on mesothelioma cell lines. We found that Cynara scolymus treatment affects strongly cell growth, migration and tumor engraftment of mesothelioma cell lines. Strikingly, dietary feeding with Cynara scolymus leaf extract reduces the growth of mesothelioma xenografted tumors similarly to pemetrexed, a commonly employed drug in the treatment of mesothelioma. In aggregate our findings suggest that leaf extract of Cynara scolymus holds therapeutic potential for the treatment of mesothelioma.

  6. Gene-asbestos interaction in malignant pleural mesothelioma susceptibility.

    PubMed

    Tunesi, Sara; Ferrante, Daniela; Mirabelli, Dario; Andorno, Silvano; Betti, Marta; Fiorito, Giovanni; Guarrera, Simonetta; Casalone, Elisabetta; Neri, Monica; Ugolini, Donatella; Bonassi, Stefano; Matullo, Giuseppe; Dianzani, Irma; Magnani, Corrado

    2015-10-01

    Asbestos exposure is the main risk factor for malignant pleural mesothelioma (MPM), a rare aggressive tumor. Nevertheless, on average less than 10% of subjects highly exposed to asbestos develop MPM, suggesting the possible involvement of other risk factors. To identify the genetic factors that may modulate the risk of MPM, we conducted a gene-environment interaction analysis including asbestos exposure and 15 single nucleotide polymorphisms (SNPs) previously identified through a genome-wide association study on Italian subjects. In the present study, we assessed gene-asbestos interaction on MPM risk using relative excess risk due to interaction and synergy index for additive interaction and V index for multiplicative interaction. Generalized multifactor dimensionality reduction (GMDR) analyses were also performed. Positive deviation from additivity was found for six SNPs (rs1508805, rs2501618, rs4701085, rs4290865, rs10519201, rs763271), and four of them (rs1508805, rs2501618, rs4701085, rs10519201) deviated also from multiplicative models. However, after Bonferroni correction, deviation from multiplicative model was still significant for rs1508805 and rs4701085 only. GMDR analysis showed a strong MPM risk due to asbestos exposure and suggested a possible synergistic effect between asbestos exposure and rs1508805, rs2501618 and rs5756444. Our results suggested that gene-asbestos interaction may play an additional role on MPM susceptibility, given that asbestos exposure appears as the main risk factor.

  7. [Case studies on the malignant mesothelioma in Pellezzano (SA)].

    PubMed

    Menegozzo, S; Izzo, F; Canfora, M L; Petronzio, M F; Santoro, M; Menegozzo, M

    2007-01-01

    41 malignant mesothelioma cases were reported between January 2000 and April 2007 in the province of Salerno. The small town of Pellezzano, near Salerno, has more cases than any other urban centre in the province; five mesothelioma cases (three male and two female) in Pellezzano (population 9,171 in 1991) means a standardized incidence rate of 32.7 males and 21.8 females per 100.000 inhabitants. That's very alarming, considering that in Italy mesothelioma standardized incidence rate per 100.000 inhabitants is 2,98 for males and 0,98 for females. Campania Mesothelioma Register aims to investigate which kind of exposure caused this abnormal incidence rate. All five patients answered the questionnaire and a team of doctors performed an on-the-spot investigation. The studies verified the existence of two kind of asbestos exposure, professional (Cotton Manufacture, Construction, Foundry) and environmental (cement-asbestos pre-fabricated since 1980 earthquake), that have to be analyzed further. PMID:18409885

  8. Current Issues in Malignant Pleural Mesothelioma Evaluation and Management

    PubMed Central

    Ai, Jing

    2014-01-01

    Malignant pleural mesothelioma (MPM) is an uncommon disease most often associated with occupational asbestos exposure and is steadily increasing in worldwide incidence. Patients typically present at an older age, with advanced clinical stage and other medical comorbidities, making management quite challenging. Despite great efforts, the prognosis of MPM remains poor, especially at progression after initial treatment. Macroscopic complete resection of MPM can be achieved through extrapleural pneumonectomy (EPP) or extended (ie, radical) pleurectomy (e-P/D) in selected patients and can result in prolonged survival when incorporated into a multimodality approach. Given the morbidity associated with surgical resection of MPM, optimizing identification of appropriate patients is essential. Unfortunately, most patients are not candidates for EPP or e-P/D due to advanced stage, age, and/or medical comorbidity. Pemetrexed and platinum combination chemotherapy has become the cornerstone of therapy for patients with unresectable disease because the combination is associated with improved survival and quality of life in treated patients. However, MPM eventually becomes resistant to initial therapy, and benefit to further lines of therapy has not been substantiated in randomized clinical trials. Translational research has provided exciting insights into tumorigenesis, biomarkers, and immune response in MPM, leading to the development of multiple novel therapeutic agents that are currently in clinical trials. These advances hold the promise of a new era in the treatment of MPM and suggest that this disease will not be left behind in the war on cancer. PMID:25061089

  9. Diagnosis and management of patients with malignant peritoneal mesothelioma

    PubMed Central

    Burke, Allen P.

    2016-01-01

    Malignant peritoneal mesothelioma (MPM) is a rare neoplastic condition that arises, usually diffusely, from the serosal membranes of the abdominal cavity. MPM represents about 7% to 10% of all mesothelioma diagnoses and this translates into approximately 800 cases per year in the United States. The disease has variable tumor biology but progression, when it occurs, is almost always within the abdominal cavity. Although many patients can be successfully treated at initial presentation, the disease is almost always fatal in time. It afflicts men and women almost equally and the median age at presentation is 50 years. The diagnosis is made when a diffuse malignant process within the abdominal cavity is observed and a tissue sample reveals the characteristic histopathology and immunohistochemical profile of mesothelioma. Initial staging is usually via a cross sectional imaging study of the abdomen and pelvis making sure that the lower thorax is also assessed. If the disease burden and distribution is favorable then operative exploration, cytoreduction, and hyperthermic intraperitoneal chemotherapy (HIPEC) are considered first line treatment in selected patients. Systemic pemetrexed and cisplatin (or gemcitabine) have modest response rates that are of limited duration. Research advances with novel systemic or intraperitoneal agents hold promise. PMID:26941986

  10. Simian virus 40 transformation, malignant mesothelioma and brain tumors

    PubMed Central

    Qi, Fang; Carbone, Michele; Yang, Haining; Gaudino, Giovanni

    2011-01-01

    Simian virus 40 (SV40) is a DNA virus isolated in 1960 from contaminated polio vaccines, that induces mesotheliomas, lymphomas, brain and bone tumors, and sarcomas, including osteosarcomas, in hamsters. These same tumor types have been found to contain SV40 DNA and proteins in humans. Mesotheliomas and brain tumors are the two tumor types that have been most consistently associated with SV40, and the range of positivity has varied about from 6 to 60%, although a few reported 100% of positivity and a few reported 0%. It appears unlikely that SV40 infection alone is sufficient to cause human malignancy, as we did not observe an epidemic of cancers following the administration of SV40-contaminated vaccines. However, it seems possible that SV40 may act as a cofactor in the pathogenesis of some tumors. In vitro and animal experiments showing cocarcinogenicity between SV40 and asbestos support this hypothesis. PMID:21955238

  11. The role of interleukin-6 in malignant mesothelioma

    PubMed Central

    Abdul Rahim, Siti N.; Ho, Gwo Y.

    2015-01-01

    Malignant mesothelioma (MM) still remains a dismal disease with a median overall survival between 9-12 months. During the past decade since the introduction of the multi-folate antagonist, pemetrexed, there have been no significant advances in its systemic treatment, particularly with novel therapeutics that have exhibited varying degrees of success in other solid tumours. In recent years, the pleiotropic proinflammatory cytokine, interleukin-6 (IL-6) has emerged as a mediator of pivotal processes such as cell proliferation and chemoresistance within the mesothelioma tumour microenvironment in addition to clinical symptoms commonly witnessed in this disease. This manuscript provides a brief summary on the pathophysiology and clinical management of MM, followed by the role of IL-6 in its tumourigenesis and the rationale for utilising anti-IL-6 therapeutics alongside standard chemotherapy and targeted agents in an attempt to prolong survival. PMID:25806346

  12. Oleuropein-Enriched Olive Leaf Extract Affects Calcium Dynamics and Impairs Viability of Malignant Mesothelioma Cells

    PubMed Central

    Marchetti, Carla; Clericuzio, Marco; Borghesi, Barbara; Cornara, Laura; Ribulla, Stefania; Gosetti, Fabio; Marengo, Emilio; Burlando, Bruno

    2015-01-01

    Malignant mesothelioma is a poor prognosis cancer in urgent need of alternative therapies. Oleuropein, the major phenolic of olive tree (Olea europaea L.), is believed to have therapeutic potentials for various diseases, including tumors. We obtained an oleuropein-enriched fraction, consisting of 60% w/w oleuropein, from olive leaves, and assessed its effects on intracellular Ca2+ and cell viability in mesothelioma cells. Effects of the oleuropein-enriched fraction on Ca2+ dynamics and cell viability were studied in the REN mesothelioma cell line, using fura-2 microspectrofluorimetry and MTT assay, respectively. Fura-2-loaded cells, transiently exposed to the oleuropein-enriched fraction, showed dose-dependent transient elevations of cytosolic Ca2+ concentration ([Ca2+]i). Application of standard oleuropein and hydroxytyrosol, and of the inhibitor of low-voltage T-type Ca2+ channels NNC-55-0396, suggested that the effect is mainly due to oleuropein acting through its hydroxytyrosol moiety on T-type Ca2+ channels. The oleuropein-enriched fraction and standard oleuropein displayed a significant antiproliferative effect, as measured on REN cells by MTT cell viability assay, with IC50 of 22 μg/mL oleuropein. Data suggest that our oleuropein-enriched fraction from olive leaf extract could have pharmacological application in malignant mesothelioma anticancer therapy, possibly by targeting T-type Ca2+ channels and thereby dysregulating intracellular Ca2+ dynamics. PMID:26693247

  13. [Development of New Therapy for Malignant Mesothelioma Based on CD26 Molecule].

    PubMed

    Morimoto, Chikao; Ohnuma, Kei

    2016-07-01

    CD26 is a 110 kDa, type II transmembrane glycoprotein with dipeptidyl peptidase IV activity and is capable of cleaving Nterminal dipeptides with either L-proline or L-alanine at the penultimate position. Malignant mesothelioma(MM)is an aggressive malignancy arising from the mesothelial cells. It is generally associated with a history of asbestos exposure and has a very poor prognosis. Due to lack of efficacy of conventional treatments, novel therapeutic strategies are urgently needed to improve outcomes. Recently we showed that CD26 is preferentially expressed on epithelial type of MM cells but not on normal mesothelial cells. We have developed a highly biological active humanized anti-CD26 monoclonal antibody(mAb)and have published previously extensive in vivo data demonstrating the anti-tumor activity of humanized anti-CD26 mAb(YS110)in mouse xenograft models. The use of a humanized anti-CD26 mAb may therefore be a rational therapy for patients with MM. The first-in-human(FIH)phase I study performed in France demonstrates that humanized anti-CD26 therapy is generally well-tolerated with preliminary evidence of activity in patients with advanced/refractory CD26-expressing cancers, particularly refractory malignant mesothelioma. From the above results, the phase I clinical trial for malignant mesothelioma in Japan is to be started in the very near future. PMID:27431629

  14. Gender-related differences in the distribution of thoracic versus abdominal malignant mesothelioma.

    PubMed

    Delfino, R J; Anton-Culver, H; Saltzstein, S L

    1995-01-01

    The relationship between malignant mesothelioma (MM) and asbestos is well established, but the determinants of host factor susceptibility of MM are not. This study probes susceptibility issues by examining gender-related differences in the distribution of 417 thoracic and 42 abdominal cases of MM from 1988-1989 California Cancer Registry databases. The age-adjusted incidence rate ratio (IRR) for male/female thoracic MM was 6.9 (95% confidence interval [CI]; 5.0-9.6) consistent with greater occupational exposure among men. However, the IRR for male/female abdominal MM was 1.5 (95% CI: 0.6-3.6). Also, average age of onset for thoracic MM was greater than for abdominal MM. Thus, some abdominal MMs may be due to nonoccupational asbestos exposure, occurring over a lifetime, interacting with host factor susceptibility. This study gives impetus to research regarding the importance of host factors and nonoccupational asbestos exposure in the etiology of malignant mesothelioma.

  15. Cancer cell secretion of the DAMP protein HMGB1 supports progression in malignant mesothelioma.

    PubMed

    Jube, Sandro; Rivera, Zeyana S; Bianchi, Marco E; Powers, Amy; Wang, Ena; Pagano, Ian; Pass, Harvey I; Gaudino, Giovanni; Carbone, Michele; Yang, Haining

    2012-07-01

    Human malignant mesothelioma is an aggressive and highly lethal cancer that is believed to be caused by chronic exposure to asbestos and erionite. Prognosis for this cancer is generally poor because of late-stage diagnosis and resistance to current conventional therapies. The damage-associated molecular pattern protein HMGB1 has been implicated previously in transformation of mesothelial cells. Here we show that HMGB1 establishes an autocrine circuit in malignant mesothelioma cells that influences their proliferation and survival. Malignant mesothelioma cells strongly expressed HMGB1 and secreted it at high levels in vitro. Accordingly, HMGB1 levels in malignant mesothelioma patient sera were higher than that found in healthy individuals. The motility, survival, and anchorage-independent growth of HMGB1-secreting malignant mesothelioma cells was inhibited in vitro by treatment with monoclonal antibodies directed against HMGB1 or against the receptor for advanced glycation end products, a putative HMGB1 receptor. HMGB1 inhibition in vivo reduced the growth of malignant mesothelioma xenografts in severe-combined immunodeficient mice and extended host survival. Taken together, our findings indicate that malignant mesothelioma cells rely on HMGB1, and they offer a preclinical proof-of-principle that antibody-mediated ablation of HMBG1 is sufficient to elicit therapeutic activity, suggesting a novel therapeutic approach for malignant mesothelioma treatment.

  16. [The computed tomographic diagnosis of malignant pleural mesothelioma. A multicenter study].

    PubMed

    Falaschi, F; Boraschi, P; Musante, F; Volpini, F; D'Alessandro, F; Torri, T; Barbieri, L

    1992-01-01

    CT features are described and accuracy of the method is discussed in the diagnosis of malignant pleural mesothelioma. Ninety-eight patients suffering from pleural disease mimicking mesothelioma were examined by means of III-generation CT scanners; according to the final diagnosis, 37 patients suffered from malignant pleural mesothelioma, 27 from other malignant pleural diseases and 34 from various benign diseases. In all patients a series of CT signs was evaluated: pleural thickening patterns, lesion spread and possible associated characters. In the diagnosis of mesothelioma CT showed 72.5% sensitivity, 63.8% specificity, 68.3% diagnostic accuracy, 68.5% positive predictive value and 68.2% negative predictive value. Some significant CT patterns in distinguishing malignant from benign pleural disease were identified, while the characterization of malignant disease (mesothelioma versus other neoplastic conditions) proved to be unreliable.

  17. Malignant pleural mesothelioma in parts of Japan in relationship to asbestos exposure.

    PubMed

    Kishimoto, Takumi; Ozaki, Shinji; Kato, Katsuya; Nishi, Hideyuki; Genba, Kenichi

    2004-10-01

    Malignant pleural mesothelioma is induced by asbestos exposure. Many reports have described this situation in America and European countries, but a few have been published in Japan. In this study malignant pleural mesothelioma cases in hospitals located in an area facing the Seto Inland Sea were evaluated. A total of 106 patients were examined with 100 patients having had occupational exposure to asbestos and 6 patients without such histories of asbestos exposure. Ninety seven were male and 9 were female. Ages ranged from 41 to 87 yr with mean of 64.8+/-5.3 yr. Thirty seven cases showed epithelial type of tumor, 25 biphasic type and 15 showed sarcomatous. The remaining 23 cases had insufficient evidence for typing the tumor. The mean survival rate for all cases was 9.2+/-11.6 months. Fifty-one patients had occupational histories of shipyard work, 16 patients worked in asbestos cement piping, and the remainder were employed in miscellaneous jobs related asbestos exposure. The duration of asbestos exposure ranged up to 20 yr or longer with the mean of 17.2+/-8.9 yr and the average latent period for the occurrence of malignant pleural mesothelioma was more than 31 yr with the mean of 37.0+/-13.3 yr. Quantification of asbestos bodies in the lungs indicated a high concentration in most patients and the major types of asbestos fibers were crocidolite and amosite. Six cases appeared after exposure to chrysotile. These results indicated that ninety four percent of malignant pleural mesothelioma appeared due to the exposure to asbestos including crocidolite and amosite. The remainder may be blamed on exposure to chrysotile.

  18. National survey of malignant mesothelioma and asbestos exposure in Japan.

    PubMed

    Gemba, Kenichi; Fujimoto, Nobukazu; Kato, Katsuya; Aoe, Keisuke; Takeshima, Yukio; Inai, Kouki; Kishimoto, Takumi

    2012-03-01

    In the present study, malignant mesothelioma (MM) cases in Japan were investigated retrospectively. We extracted records for 6030 cases of death due to MM between 2003 and 2008 to clarify the clinical features of MM, including its association with asbestos exposure (AE). Of all these cases, a clinical diagnosis of MM was confirmed for 929. The origin of MM included the pleura in 794 cases (85.5%), the peritoneum in 123 cases (13.2%), the pericardium in seven cases (0.8%), and the testicular tunica vaginalis in five cases (0.5%). The histological subtypes of MM included 396 epithelioid (55.9%), 154 sarcomatoid (21.7%), 126 biphasic (17.8%), and 33 cases (4.7%) classified as "other types". Of all the MM cases, AE was indicated in 76.8% and pleural plaques were detected in 34.2%. The number of asbestos particles was determined in 103 cases of MM. More than 1000 asbestos particles per gram dried lung tissue were detected in 74.8% of cases and more than 5000 particles were detected in 43.7% of cases. We compared patient characteristics and the diagnostic procedures for MM before and after the "Kubota shock". Compared with the early phase of this study (2003-2005), the median age at diagnosis of MM was higher, the number of cases without definite diagnosis of MM was lower, the proportion of cases diagnosed by thoracoscopy was higher, and the percentage of cases in which the occupational history was described in the medical records was significantly higher in the later phase (2006-2008). Our study confirmed that more than 70% of MM cases in Japan are associated with AE. The "Kubota shock" may affect some features pertaining to MM.

  19. Zoledronic acid overcomes chemoresistance and immunosuppression of malignant mesothelioma.

    PubMed

    Salaroglio, Iris Chiara; Campia, Ivana; Kopecka, Joanna; Gazzano, Elena; Orecchia, Sara; Ghigo, Dario; Riganti, Chiara

    2015-01-20

    The human malignant mesothelioma (HMM) is characterized by a chemoresistant and immunosuppressive phenotype. An effective strategy to restore chemosensitivity and immune reactivity against HMM is lacking. We investigated whether the use of zoledronic acid is an effective chemo-immunosensitizing strategy. We compared primary HMM samples with non-transformed mesothelial cells. HMM cells had higher rate of cholesterol and isoprenoid synthesis, constitutive activation of Ras/extracellular signal-regulated kinase1/2 (ERK1/2)/hypoxia inducible factor-1α (HIF-1α) pathway and up-regulation of the drug efflux transporter P-glycoprotein (Pgp). By decreasing the isoprenoid supply, zoledronic acid down-regulated the Ras/ERK1/2/HIF-1α/Pgp axis and chemosensitized the HMM cells to Pgp substrates. The HMM cells also produced higher amounts of kynurenine, decreased the proliferation of T-lymphocytes and expanded the number of T-regulatory (Treg) cells. Kynurenine synthesis was due to the transcription of the indoleamine 1,2 dioxygenase (IDO) enzyme, consequent to the activation of the signal transducer and activator of transcription-3 (STAT3). By reducing the activity of the Ras/ERK1/2/STAT3/IDO axis, zoledronic acid lowered the kyurenine synthesis and the expansion of Treg cells, and increased the proliferation of T-lymphocytes. Thanks to its ability to decrease Ras/ERK1/2 activity, which is responsible for both Pgp-mediated chemoresistance and IDO-mediated immunosuppression, zoledronic acid is an effective chemo-immunosensitizing agent in HMM cells. PMID:25544757

  20. Zoledronic acid overcomes chemoresistance and immunosuppression of malignant mesothelioma

    PubMed Central

    Kopecka, Joanna; Gazzano, Elena; Sara, Orecchia; Ghigo, Dario; Riganti, Chiara

    2015-01-01

    The human malignant mesothelioma (HMM) is characterized by a chemoresistant and immunosuppressive phenotype. An effective strategy to restore chemosensitivity and immune reactivity against HMM is lacking. We investigated whether the use of zoledronic acid is an effective chemo-immunosensitizing strategy. We compared primary HMM samples with non-transformed mesothelial cells. HMM cells had higher rate of cholesterol and isoprenoid synthesis, constitutive activation of Ras/extracellular signal-regulated kinase1/2 (ERK1/2)/hypoxia inducible factor-1α (HIF-1α) pathway and up-regulation of the drug efflux transporter P-glycoprotein (Pgp). By decreasing the isoprenoid supply, zoledronic acid down-regulated the Ras/ERK1/2/HIF-1α/Pgp axis and chemosensitized the HMM cells to Pgp substrates. The HMM cells also produced higher amounts of kynurenine, decreased the proliferation of T-lymphocytes and expanded the number of T-regulatory (Treg) cells. Kynurenine synthesis was due to the transcription of the indoleamine 1,2 dioxygenase (IDO) enzyme, consequent to the activation of the signal transducer and activator of transcription-3 (STAT3). By reducing the activity of the Ras/ERK1/2/STAT3/IDO axis, zoledronic acid lowered the kyurenine synthesis and the expansion of Treg cells, and increased the proliferation of T-lymphocytes. Thanks to its ability to decrease Ras/ERK1/2 activity, which is responsible for both Pgp-mediated chemoresistance and IDO-mediated immunosuppression, zoledronic acid is an effective chemo-immunosensitizing agent in HMM cells. PMID:25544757

  1. Diffuse malignant pleural mesothelioma in an urban hospital: clinical spectrum and trend in incidence over time.

    PubMed

    Shepherd, K E; Oliver, L C; Kazemi, H

    1989-01-01

    This retrospective analysis reviews the clinical experience of a major urban referral hospital with diffuse malignant pleural mesothelioma during the 14-year period from 1973 through 1986. Seventy-five cases of definite or equivocal mesothelioma were identified. There were four cases of primary malignant peritoneal mesothelioma, seven cases of benign fibrous mesothelioma, and 64 cases of diffuse malignant pleural mesothelioma. In 43 cases (67%) of diffuse malignant pleural mesothelioma, there was historic evidence of asbestos exposure. In 21 cases (33%), there was no known history of asbestos exposure. An increase in annual incidence of diffuse malignant pleural mesothelioma was observed over the study period, from three cases in 1973 to ten cases in 1986. Despite greater awareness of this disease, the diagnosis remains a difficult one to establish given the nonspecific symptoms, signs and radiographic appearance, variable histologic appearance, and poor diagnostic sensitivity and specificity of thoracentesis and closed pleural biopsy. Thoracotomy, thoracoscopy, and CT-guided needle biopsies gave higher yields and are the diagnostic measures of choice when diffuse malignant pleural mesothelioma is suspected.

  2. Clinical and Prognostic Features of Erionite-Induced Malignant Mesothelioma

    PubMed Central

    Demirer, Ersin; Ghattas, Christian F.; Radwan, Mohamed O.

    2015-01-01

    This review analytically examines the published data for erionite-related malignant pleural mesothelioma (E-MPM) and any data to support a genetically predisposed mechanism to erionite fiber carcinogenesis. Adult patients of age ≥18 years with erionite-related pleural diseases and genetically predisposed mechanisms to erionite carcinogenesis were included, while exclusion criteria included asbestos- or tremolite-related pleural diseases. The search was limited to human studies though not limited to a specific timeframe. A total of 33 studies (31042 patients) including 22 retrospective studies, 6 prospective studies, and 5 case reports were reviewed. E-MPM developed in some subjects with high exposures to erionite, though not all. Chest CT was more reliable in detecting various pleural changes in E-MPM than chest X-ray, and pleural effusion was the most common finding in E-MPM cases, by both tests. Bronchoalveolar lavage remains a reliable and relatively less invasive technique. Chemotherapy with cisplatin and mitomycin can be administered either alone or following surgery. Erionite has been the culprit of numerous malignant mesothelioma cases in Europe and even in North America. Erionite has a higher degree of carcinogenicity with possible genetic transmission of erionite susceptibility in an autosomal dominant fashion. Therapeutic management for E-MPM remains very limited, and cure of the disease is extremely rare. PMID:25683976

  3. Overview of the biochemical and genetic processes in malignant mesothelioma.

    PubMed

    Assis, Leonardo Vinícius Monteiro de; Isoldi, Mauro César

    2014-01-01

    Malignant mesothelioma (MM) is a highly aggressive form of cancer, has a long latency period, and is resistant to chemotherapy. It is extremely fatal, with a mean survival of less than one year. The development of MM is strongly correlated with exposure to asbestos and with other factors, such as erionite and simian virus 40 [corrected]. Although various countries have banned the use of asbestos, MM has proven to be difficult to control and there appears to be a trend toward an increase in its incidence in the years to come. In Brazil, MM has not been widely studied from a genetic or biochemical standpoint. In addition, there have been few epidemiological studies of the disease, and the profile of its incidence has yet to be well established in the Brazilian population. The objective of this study was to review the literature regarding the processes of malignant transformation, as well as the respective mechanisms of tumorigenesis, in MM.

  4. Overview of the biochemical and genetic processes in malignant mesothelioma*

    PubMed Central

    de Assis, Leonardo Vinícius Monteiro; Isoldi, Mauro César

    2014-01-01

    Malignant mesothelioma (MM) is a highly aggressive form of cancer, has a long latency period, and is resistant to chemotherapy. It is extremely fatal, with a mean survival of less than one year. The development of MM is strongly correlated with exposure to asbestos and erionite, as well as to simian virus 40. Although various countries have banned the use of asbestos, MM has proven to be difficult to control and there appears to be a trend toward an increase in its incidence in the years to come. In Brazil, MM has not been widely studied from a genetic or biochemical standpoint. In addition, there have been few epidemiological studies of the disease, and the profile of its incidence has yet to be well established in the Brazilian population. The objective of this study was to review the literature regarding the processes of malignant transformation, as well as the respective mechanisms of tumorigenesis, in MM. PMID:25210967

  5. Detection of malignant mesothelioma using nuclear structure of mesothelial cells in effusion cytology specimens.

    PubMed

    Tosun, Akif Burak; Yergiyev, Oleksandr; Kolouri, Soheil; Silverman, Jan F; Rohde, Gustavo K

    2015-04-01

    Mesothelioma is a form of cancer generally caused from previous exposure to asbestos. Although it was considered a rare neoplasm in the past, its incidence is increasing worldwide due to extensive use of asbestos. In the current practice of medicine, the gold standard for diagnosing mesothelioma is through a pleural biopsy with subsequent histologic examination of the tissue. The diagnostic tissue should demonstrate the invasion by the tumor and is obtained through thoracoscopy or open thoracotomy, both being highly invasive surgical operations. On the other hand, thoracocentesis, which is removal of effusion fluid from the pleural space, is a far less invasive procedure that can provide material for cytological examination. In this study, we aim at detecting and classifying malignant mesothelioma based on the nuclear chromatin distribution from digital images of mesothelial cells in effusion cytology specimens. Accordingly, a computerized method is developed to determine whether a set of nuclei belonging to a patient is benign or malignant. The quantification of chromatin distribution is performed by using the optimal transport-based linear embedding for segmented nuclei in combination with the modified Fisher discriminant analysis. Classification is then performed through a k-nearest neighborhood approach and a basic voting strategy. Our experiments on 34 different human cases result in 100% accurate predictions computed with blind cross validation. Experimental comparisons also show that the new method can significantly outperform standard numerical feature-type methods in terms of agreement with the clinical diagnosis gold standard. According to our results, we conclude that nuclear structure of mesothelial cells alone may contain enough information to separate malignant mesothelioma from benign mesothelial proliferations. PMID:25598227

  6. A case of malignant pleural mesothelioma following exposure to atomic radiation in Nagasaki.

    PubMed

    Mizuki, M; Yukishige, K; Abe, Y; Tsuda, T

    1997-09-01

    We report the case of a 75-year-old Japanese man who developed malignant mesothelioma in the left hemithorax 50 years after the dropping of the atomic bomb on Nagasaki in 1945. This may be the first reported case of malignant mesothelioma following exposure to atomic radiation. Asbestos is the leading cause of malignant mesothelioma, but radiation therapy is the primary non-asbestos-related cause. In the case of radiation therapy, the interval between exposure and the occurrence of malignant mesothelioma tends to be many years. This patient was at a high risk of malignant mesothelioma as he had been exposed to radiation from the atomic bomb and may also have had a history of asbestos exposure at the munitions factory where he was employed as a shipbuilder for 2 years. It has been suggested that combined exposure to atomic radiation and asbestos is associated with an increased incidence of malignant mesothelioma. If thickening of the pleura or pleural effusion is found in atomic bomb survivors, malignant mesothelioma should be considered as one of the options in the differential diagnosis, even although the atomic bomb attacks occurred several decades ago.

  7. Disabling Mitochondrial Peroxide Metabolism via Combinatorial Targeting of Peroxiredoxin 3 as an Effective Therapeutic Approach for Malignant Mesothelioma

    PubMed Central

    Wozniak, Alexandra N.; Beuschel, Stacie; Leavitt, Bruce; Bhave, Anant; Butnor, Kelly; Koenig, Andreas; Chouchani, Edward T.; James, Andrew M.; Haynes, Alexina C.; Lowther, W. Todd; Murphy, Michael P.; Shukla, Arti; Heintz, Nicholas H.

    2015-01-01

    Dysregulation of signaling pathways and energy metabolism in cancer cells enhances production of mitochondrial hydrogen peroxide that supports tumorigenesis through multiple mechanisms. To counteract the adverse effects of mitochondrial peroxide many solid tumor types up-regulate the mitochondrial thioredoxin reductase 2 - thioredoxin 2 (TRX2) - peroxiredoxin 3 (PRX3) antioxidant network. Using malignant mesothelioma cells as a model, we show that thiostrepton (TS) irreversibly disables PRX3 via covalent crosslinking of peroxidatic and resolving cysteine residues in homodimers, and that targeting the oxidoreductase TRX2 with the triphenylmethane gentian violet (GV) potentiates adduction by increasing levels of disulfide-bonded PRX3 dimers. Due to the fact that activity of the PRX3 catalytic cycle dictates the rate of adduction by TS, immortalized and primary human mesothelial cells are significantly less sensitive to both compounds. Moreover, stable knockdown of PRX3 reduces mesothelioma cell proliferation and sensitivity to TS. Expression of catalase in shPRX3 mesothelioma cells restores defects in cell proliferation but not sensitivity to TS. In a SCID mouse xenograft model of human mesothelioma, administration of TS and GV together reduced tumor burden more effectively than either agent alone. Because increased production of mitochondrial hydrogen peroxide is a common phenotype of malignant cells, and TS and GV are well tolerated in mammals, we propose that targeting PRX3 is a feasible redox-dependent strategy for managing mesothelioma and other intractable human malignancies. PMID:26011724

  8. Disabling Mitochondrial Peroxide Metabolism via Combinatorial Targeting of Peroxiredoxin 3 as an Effective Therapeutic Approach for Malignant Mesothelioma.

    PubMed

    Cunniff, Brian; Newick, Kheng; Nelson, Kimberly J; Wozniak, Alexandra N; Beuschel, Stacie; Leavitt, Bruce; Bhave, Anant; Butnor, Kelly; Koenig, Andreas; Chouchani, Edward T; James, Andrew M; Haynes, Alexina C; Lowther, W Todd; Murphy, Michael P; Shukla, Arti; Heintz, Nicholas H

    2015-01-01

    Dysregulation of signaling pathways and energy metabolism in cancer cells enhances production of mitochondrial hydrogen peroxide that supports tumorigenesis through multiple mechanisms. To counteract the adverse effects of mitochondrial peroxide many solid tumor types up-regulate the mitochondrial thioredoxin reductase 2--thioredoxin 2 (TRX2)--peroxiredoxin 3 (PRX3) antioxidant network. Using malignant mesothelioma cells as a model, we show that thiostrepton (TS) irreversibly disables PRX3 via covalent crosslinking of peroxidatic and resolving cysteine residues in homodimers, and that targeting the oxidoreductase TRX2 with the triphenylmethane gentian violet (GV) potentiates adduction by increasing levels of disulfide-bonded PRX3 dimers. Due to the fact that activity of the PRX3 catalytic cycle dictates the rate of adduction by TS, immortalized and primary human mesothelial cells are significantly less sensitive to both compounds. Moreover, stable knockdown of PRX3 reduces mesothelioma cell proliferation and sensitivity to TS. Expression of catalase in shPRX3 mesothelioma cells restores defects in cell proliferation but not sensitivity to TS. In a SCID mouse xenograft model of human mesothelioma, administration of TS and GV together reduced tumor burden more effectively than either agent alone. Because increased production of mitochondrial hydrogen peroxide is a common phenotype of malignant cells, and TS and GV are well tolerated in mammals, we propose that targeting PRX3 is a feasible redox-dependent strategy for managing mesothelioma and other intractable human malignancies.

  9. Cul4A overexpression associated with Gli1 expression in malignant pleural mesothelioma

    SciTech Connect

    Yang, Yi -Lin; Ni, Jian; Hsu, Ping -Chih; Mao, Jian -Hua; Hsieh, David; Xu, Angela; Chan, Geraldine; Au, Alfred; Xu, Zhidong; Jablons, David M.; You, Liang

    2015-07-27

    Malignant pleural mesothelioma (mesothelioma) is a highly aggressive cancer without an effective treatment. Cul4A, a scaffold protein that recruits substrates for degradation, is amplified in several human cancers, including mesothelioma. We have recently shown that Cul4A plays an oncogenic role in vitro and in a mouse model. In this study, we analysed clinical mesothelioma tumours and found moderate to strong expression of Cul4A in 70.9% (51/72) of these tumours, as shown by immunohistochemistry. In 72.2% mesothelioma tumours with increased Cul4A copy number identified by fluorescence in situ hybridization analysis, Cul4A protein expression was moderate to strong. Similarly, Cul4A was overexpressed and Cul4A copy number was increased in human mesothelioma cell lines. Because Gli1 is highly expressed in human mesothelioma cells, we compared Cul4A and Gli1 expression in mesothelioma tumours and found their expression associated (P < 0.05, chi-square). In mesothelioma cell lines, inhibiting Cul4A by siRNA decreased Gli1 expression, suggesting that Gli1 expression is, at least in part, regulated by Cul4A in mesothelioma cells. Our results suggest a linkage between Cul4A and Gli1 expression in human mesothelioma.

  10. Cul4A overexpression associated with Gli1 expression in malignant pleural mesothelioma.

    PubMed

    Yang, Yi-Lin; Ni, Jian; Hsu, Ping-Chih; Mao, Jian-Hua; Hsieh, David; Xu, Angela; Chan, Geraldine; Au, Alfred; Xu, Zhidong; Jablons, David M; You, Liang

    2015-10-01

    Malignant pleural mesothelioma (mesothelioma) is a highly aggressive cancer without an effective treatment. Cul4A, a scaffold protein that recruits substrates for degradation, is amplified in several human cancers, including mesothelioma. We have recently shown that Cul4A plays an oncogenic role in vitro and in a mouse model. In this study, we analysed clinical mesothelioma tumours and found moderate to strong expression of Cul4A in 70.9% (51/72) of these tumours, as shown by immunohistochemistry. In 72.2% mesothelioma tumours with increased Cul4A copy number identified by fluorescence in situ hybridization analysis, Cul4A protein expression was moderate to strong. Similarly, Cul4A was overexpressed and Cul4A copy number was increased in human mesothelioma cell lines. Because Gli1 is highly expressed in human mesothelioma cells, we compared Cul4A and Gli1 expression in mesothelioma tumours and found their expression associated (P < 0.05, chi-square). In mesothelioma cell lines, inhibiting Cul4A by siRNA decreased Gli1 expression, suggesting that Gli1 expression is, at least in part, regulated by Cul4A in mesothelioma cells. Our results suggest a linkage between Cul4A and Gli1 expression in human mesothelioma. PMID:26218750

  11. Cul4A overexpression associated with Gli1 expression in malignant pleural mesothelioma

    DOE PAGES

    Yang, Yi -Lin; Ni, Jian; Hsu, Ping -Chih; Mao, Jian -Hua; Hsieh, David; Xu, Angela; Chan, Geraldine; Au, Alfred; Xu, Zhidong; Jablons, David M.; et al

    2015-07-27

    Malignant pleural mesothelioma (mesothelioma) is a highly aggressive cancer without an effective treatment. Cul4A, a scaffold protein that recruits substrates for degradation, is amplified in several human cancers, including mesothelioma. We have recently shown that Cul4A plays an oncogenic role in vitro and in a mouse model. In this study, we analysed clinical mesothelioma tumours and found moderate to strong expression of Cul4A in 70.9% (51/72) of these tumours, as shown by immunohistochemistry. In 72.2% mesothelioma tumours with increased Cul4A copy number identified by fluorescence in situ hybridization analysis, Cul4A protein expression was moderate to strong. Similarly, Cul4A was overexpressedmore » and Cul4A copy number was increased in human mesothelioma cell lines. Because Gli1 is highly expressed in human mesothelioma cells, we compared Cul4A and Gli1 expression in mesothelioma tumours and found their expression associated (P < 0.05, chi-square). In mesothelioma cell lines, inhibiting Cul4A by siRNA decreased Gli1 expression, suggesting that Gli1 expression is, at least in part, regulated by Cul4A in mesothelioma cells. Our results suggest a linkage between Cul4A and Gli1 expression in human mesothelioma.« less

  12. BAP1 protein is a progression factor in malignant pleural mesothelioma.

    PubMed

    Arzt, Lisa; Quehenberger, Franz; Halbwedl, Iris; Mairinger, Thomas; Popper, Helmut H

    2014-01-01

    Human malignant pleural mesothelioma (MPM) is an aggressive cancer due to former asbestos exposure with little knowledge about prognostic factors of outcome and resistance to conventional therapy. BRCA1-associated protein 1 (BAP1) is a tumor suppressor gene that is frequently lost in MPM. Germline mutations of BAP1 predispose to several different tumors including malignant mesothelioma. Our study aimed to clarify if asbestos exposure has an influence on BAP1 expression and if BAP1 expression could be used as a prognostic factor of outcome. An immunohistochemical staining for BAP1 was performed on 123 MPM tissue samples and the expression levels have been correlated with asbestos exposure and overall survival time. BAP1 expression was not associated with asbestos exposure but we detected a significant effect of BAP1 expression on overall survival time--the higher the BAP1 expression (non-mutated BAP1), the shorter the overall survival. BAP1 mutation has been linked to non-asbestos induced familial mesotheliomas, which usually belong to the long survivor group and BAP1 is most probably functioning differently than in sporadic cases. Further investigations need to be performed to characterize the BAP1 mutations and to identify the BAP1 downstream targets in MPM.

  13. [Malignant pleuric mesothelioma in Sicily. Epidemiologic observations during the time 1998-2005].

    PubMed

    Venuti, V; De Pasquale, D; Abbate, A; Brecciaroli, R; Giorgianni, C

    2007-01-01

    Pleural malign mesothelioma is the only one to which we can straight attribute to an exposition, in professional and ambient ambit, to a good identified agent and, precisely, to the fibres of asbestos. Objective of our work has been to verify the incidence of the pleural malign mesothelioma in Sicily and in particular in the Messina's area, during the period 1988-2005. We have examined the epidemiologic data of the period 1988-1997 and 1998-2005 through the consultation of the Mesothelioma Sicilian Register; Mesothelioma Italian Register and of the available documentation in the Health Superior Institute. The study showed that the pleural malign mesothelioma in sicily and in Messina's area is reduced for the elimination of the asbestos and for the low use of asbestos in the sicilian industry.

  14. Malignant mesothelioma in a cohort of asbestos insulation workers: clinical presentation, diagnosis, and causes of death.

    PubMed

    Ribak, J; Lilis, R; Suzuki, Y; Penner, L; Selikoff, I J

    1988-03-01

    Malignant mesothelioma has been rare in the general population. In recent decades its incidence has risen dramatically, parallel to the increasing use of asbestos in industry since 1930. Altogether 17,800 asbestos insulation workers, members of the International Association of Heat and Frost Insulators and Asbestos Workers (AFL-CIO-CLC) in the United States and Canada, were enrolled for prospective study on 1 January 1967 and followed up to the present. Every death that occurs is investigated by our laboratory. One hundred and seventy five deaths from mesothelioma occurred among the 2221 men who died in 1967-76 and 181 more such deaths in the next eight years. Altogether, 356 workers had died of malignant mesothelioma (pleural or peritoneal) by 1984. Diagnosis of mesothelioma was accepted only after all available clinical, radiological, and pathological material was reviewed by our laboratory and histopathological confirmation by the pathology unit made in each case. One hundred and thirty four workers died of pleural and 222 of peritoneal mesothelioma. Age at onset of exposure, age at onset of the disease, and age at death were similar in both groups of patients. Significant difference was noted only in the time elapsed from onset of exposure to the development of first symptoms, which was longer in the group with peritoneal mesothelioma. Shortness of breath, either new or recently increased, and chest pain were the most frequent presenting symptoms in the group with pleural mesothelioma; abdominal pain and distension were frequent in the patients with peritoneal mesothelioma. Pleural effusion or ascites were found in most patients. The most effective approach to the diagnosis of malignant pleural mesothelioma in these cases was by open lung biopsy; exploratory laparotomy was best for diagnosing peritoneal mesothelioma. Patients with pleural mesothelioma died principally from pulmonary insufficiency whereas those with peritoneal mesothelioma succumbed after a

  15. Malignant mesothelioma in a cohort of asbestos insulation workers: clinical presentation, diagnosis, and causes of death.

    PubMed Central

    Ribak, J; Lilis, R; Suzuki, Y; Penner, L; Selikoff, I J

    1988-01-01

    Malignant mesothelioma has been rare in the general population. In recent decades its incidence has risen dramatically, parallel to the increasing use of asbestos in industry since 1930. Altogether 17,800 asbestos insulation workers, members of the International Association of Heat and Frost Insulators and Asbestos Workers (AFL-CIO-CLC) in the United States and Canada, were enrolled for prospective study on 1 January 1967 and followed up to the present. Every death that occurs is investigated by our laboratory. One hundred and seventy five deaths from mesothelioma occurred among the 2221 men who died in 1967-76 and 181 more such deaths in the next eight years. Altogether, 356 workers had died of malignant mesothelioma (pleural or peritoneal) by 1984. Diagnosis of mesothelioma was accepted only after all available clinical, radiological, and pathological material was reviewed by our laboratory and histopathological confirmation by the pathology unit made in each case. One hundred and thirty four workers died of pleural and 222 of peritoneal mesothelioma. Age at onset of exposure, age at onset of the disease, and age at death were similar in both groups of patients. Significant difference was noted only in the time elapsed from onset of exposure to the development of first symptoms, which was longer in the group with peritoneal mesothelioma. Shortness of breath, either new or recently increased, and chest pain were the most frequent presenting symptoms in the group with pleural mesothelioma; abdominal pain and distension were frequent in the patients with peritoneal mesothelioma. Pleural effusion or ascites were found in most patients. The most effective approach to the diagnosis of malignant pleural mesothelioma in these cases was by open lung biopsy; exploratory laparotomy was best for diagnosing peritoneal mesothelioma. Patients with pleural mesothelioma died principally from pulmonary insufficiency whereas those with peritoneal mesothelioma succumbed after a

  16. Malignant mesothelioma: incidence, asbestos exposure, and reclassification of histopathology.

    PubMed

    Wright, W E; Sherwin, R P; Dickson, E A; Bernstein, L; Fromm, J B; Henderson, B E

    1984-02-01

    The Los Angeles County Cancer Surveillance Program abstracts records on almost all cases of cancer occurring in the county. In a study of those cases of pleural and peritoneal malignant mesothelioma (MM) that occurred from 1972 to 1979 occupational histories were obtained during interviews, and histopathology of the tumours was reviewed and classified by a member of a mesothelioma reference panel who was unaware of the exposure histories. About half the cases reviewed had likely exposure to asbestos at work. The greatest proportion of cases designated as MM by the pathologist occurred among individuals likely to have had the heaviest exposure of asbestos (42%). No upward trend of incidence over time was apparent among cases designated as MM. The age adjusted incidence rates for designated MM were lower than in other studies. The well recognised interobserver variability in diagnosing MM apparently produces raised estimates of incidence and an overestimate of trends of incidence. The interobserver variability may result from different awareness of MM occurrence, a lack of precise histopathological criteria for the diagnosis, or the influence of a history of exposure to asbestos on the interpretation. A history of exposure to asbestos may bias interpretation of histopathology and should not be used to make the histological diagnosis.

  17. [Malignant pleural mesothelioma in housewives in the province of Catania].

    PubMed

    Proietti, Lidia; Migliore, Marcello; Polosa, Riccardo; Comba, Pietro; Circo, Cristina; Di Maria, Giuseppe U

    2004-01-01

    Our study reports pleural malignant mesothelioma (PMM) in seven female patients. All patients were resident in Catania area (Sicily), the median age was 69.2 years and ranged from 59 to 81 years. They were housewife. Their anamnesis was negative for both direct and indirect previous exposure to asbestos; the partners of all patients were also not exposed to asbestos. The exposure to X-rays was also excluded for these patients. Different pathogenetic mechanisms for the appearance of PMM in these patients can be hypothesized, for example, SV40 infection and genetic susceptibility; a minimal domestic exposure to asbestos can be not excluded. Therefore, further studies in a more large number of subjects are necessary to determine whether one or all of these hypothetic pathogenetic mechanisms are more significant for the develop of PMM.

  18. Malignant mesothelioma, airborne asbestos, and the need for accuracy in chrysotile risk assessments.

    PubMed

    Meisenkothen, Christopher

    2013-01-01

    A man diagnosed with pleural mesothelioma sought legal representation with the author's law firm. He worked 33 years in a wire and cable factory in the northeastern United States (Connecticut) that exclusively used chrysotile asbestos in its manufacturing process. This is the first report of mesothelioma arising from employees of this factory. This report provides additional support for the proposition that chrysotile asbestos can cause malignant mesothelioma in humans. If chrysotile risk assessments are to be accurate, then the literature should contain an accurate accounting of all mesotheliomas alleged to be caused by chrysotile asbestos. This is important not just for public health professionals but also for individuals and companies involved in litigation over asbestos-related diseases. If reports such as these remain unknown, it is probable that cases of mesothelioma among chrysotile-exposed cohorts would go unrecognized and chrysotile-using factories would be incorrectly cited as having no mesotheliomas among their employees.

  19. Familial malignant mesothelioma: a population-based study in central Italy (1980-2012).

    PubMed

    Ascoli, Valeria; Romeo, Elisa; Carnovale Scalzo, Caterina; Cozzi, Ilaria; Ancona, Laura; Cavariani, Fulvio; Balestri, Anna; Gasperini, Letizia; Forastiere, Francesco

    2014-06-01

    Malignant mesothelioma is a sporadic cancer linked to asbestos exposure. Its occurrence among blood relatives (familial mesothelioma) may point to genetic susceptibility or shared exposures. The burden of the familial disease is unknown. The aims of the study were to assess at population level the proportion of familial mesotheliomas among all mesotheliomas and to investigate the family history of cancer among relatives of mesothelioma cases. We actively searched familial clusters based on a mesothelioma registry from central Italy (5.5 million people, 10% of the Italian population) of the National Mesothelioma Register network (ReNaM) as well as a pathology-based archive. Among 997 incident mesotheliomas recorded in a 32-year-period (1980-2012), we detected 13 clusters and 34 familial cases, accounting for 3.4% of all mesotheliomas. The most common clusters where those with affected siblings and unaffected parents. Asbestos exposure was occupational (n=7 clusters), household (n=2), environmental (n=1), or not attributable for insufficient information (n=3). There were 25 additional cancers in nine families. Some were cancer sites for which there is sufficient evidence (lung and larynx) or limited evidence (stomach and colon) of causal association with asbestos. The results suggest potential genetic recessive effects in mesothelioma that interact with asbestos exposure, but it is not possible to estimate the specific proportion attributable to each of these components.

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

    PubMed

    Yilmaz, U M; Utkaner, G; Yalniz, E; Kumcuoglu, Z

    1998-03-01

    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.

  1. The "missing cases" of pleural malignant mesothelioma in Minnesota, 1979-81: preliminary report.

    PubMed

    Lilienfeld, D E; Gunderson, P D

    1986-01-01

    Malignant mesothelioma is a sentinel neoplasm for population exposure to asbestiform fibers. Public health officials may be alerted to temporal or spatial clustering of malignant mesothelioma through analyses of vital records, such as death certificates. Hence, the maintenance of the integrity of the vital statistics system, particularly the cause of death statement on the death certificate, is very important. The report by a northeastern Minnesota radiologist in January 1985 of an elevated prevalence of pleural plaques (related to asbestiform fiber exposure) to the Minnesota Department of Health resulted in an investigation of pleural malignant mesothelioma mortality trends in that area and in three other similar areas in the State. In that study, we noted that in several instances malignant mesothelioma (either intrathoracic or unspecified site) was listed on the death certificate in such a manner as to imply that the neoplasm was either a lung cancer or a malignancy of an unspecified site. The effect of this misclassification is to underestimate the mortality from malignant mesothelioma by fourfold to eightfold. Given the importance of malignant mesothelioma as a proxy for past asbestos exposure, it is necessary to determine the extent of such misclassification for all deaths in the United States.

  2. A Case of Encapsulating Peritoneal Sclerosis Complicated by Malignant Peritoneal Mesothelioma.

    PubMed

    Kanai, Genta; Kakuta, Takatoshi; Hirukawa, Takashi; Okamatsu, Chizuko; Fukagawa, Masafumi

    2016-01-01

    We report a case of peritoneal mesothelioma discovered in a patient during peritoneal dialysis. The patient was a 55-year-old woman who had no history of asbestos exposure. Owing to end-stage kidney failure, she had been undergoing peritoneal dialysis for over 8 years, and she had been diagnosed with encapsulating peritoneal sclerosis. She was admitted to the hospital for intestinal obstruction. Three months later, she noticed an enlarging mass in the epigastric region. Computed tomography showed a 10-cm mass originating in the abdominal wall that had invaded the liver. It was diagnosed as malignant mesothelioma via biopsy. Cases of sarcoma-like mass-forming peritoneal mesothelioma are rare, and there are no prior reports of encapsulating peritoneal sclerosis complicated by malignant peritoneal mesothelioma. Thus, this unique case of peritoneal mesothelioma can provide us with important knowledge about this rare entity. PMID:27628605

  3. Electron microscopy remains the gold standard for the diagnosis of epithelial malignant mesothelioma: A case study

    PubMed Central

    Oczypok, Elizabeth A.; Oury, Tim D.

    2014-01-01

    This is a case of idiopathic epithelial malignant mesothelioma in a 47-year-old mechanic. The advent of a large battery of immunochemical markers has provided new tools for the diagnosis of mesothelioma in recent years, however, immunostaining can often be misleading or inconsistent, as demonstrated in the current case. This report highlights the lasting utility of electron microscopy in the diagnosis of mesothelioma. Ultrastructural features of epithelial mesothelioma were discernable using electron microscopy even on somewhat poorly preserved chest wall biopsy specimens from paraffin blocks. These images, combined with immunostains and a fiber analysis from the lungs, allowed for a final diagnosis of a non-asbestos related malignant epithelial mesothelioma in this patient. PMID:25268063

  4. Increasing of malignant pleural mesothelioma: burning issue in Split-Dalmatian County, Croatia.

    PubMed

    Mise, Kornelija; Jurcev-Savicević, Anamarija; Bradarić, Anteo; Perić, Irena; Barisić, Igor; Puntarić, Dinko; Mise, Josko; Ilić, Nenad

    2009-12-01

    Asbestos-related diseases are one of the burning public health issues worldwide. The incidence and the epidemiological patterns of malignant pleural mesothelioma in Split-Dalmatian County, where a large part of Croatian industry related to asbestos processing and use have been situated were assessed in this study. The history of asbestos-related issues and development of current legislation in Croatia was also discussed briefly. Data on the incidence were collected retrospectively from the medical records of patients with malignant pleural mesothelioma treated at Department of Pulmonary Diseases University Hospital Split during the 2000-2007 period. A total of 137 new cases was recorded with the mean incidence of 3.55/100,000 and the trend was increasing over years compared with 1992-1995 period in the same county when the mean incidence was 1.7/100,000. Men accounted for 85.4% of all cases. The mean age of patients was 64.9 +/- 15.4 years. The majority of patients were occupationally exposed to asbestos (85.4%), 8.8% had environmental exposure, and 2.2% had domestic exposure. The type of household exposition was in 5.8% of patients. More than half of the cases were exposed to asbestos 31-40 years. The mean length of exposure was 28.87 +/- 15.63 years. The incidence of malignant pleural mesothelioma in Split-Dalmatian County has been obviously increasing due to the predominantly occupational exposure and it is reasonable to assume that it will remain high in the next two-three decades and to be a reason for concern and fear among the general population.

  5. A molecular targeting against nuclear factor-κB, as a chemotherapeutic approach for human malignant mesothelioma.

    PubMed

    Nishikawa, Sho; Tanaka, Akane; Matsuda, Akira; Oida, Kumiko; Jang, Hyosun; Jung, Kyungsook; Amagai, Yosuke; Ahn, Ginae; Okamoto, Noriko; Ishizaka, Saori; Matsuda, Hiroshi

    2014-04-01

    Chronic inflammation due to the absorption of asbestos is an important cause of mesothelioma. Although the increased prevalence of mesothelioma is a serious problem, the development of effective chemotherapeutic agents remains incomplete. As the nuclear factor-κB (NF-κB) pathway contributes to malignant transformation of various types of cells, we explored NF-κB activity in three different pathological types of malignant mesothelioma cells, and evaluated the therapeutic potential of a recently reported NF-κB inhibitor, IMD-0354. NF-κB was constantly activated in MSTO-211H, NCI-H28, and NCI-H2052 cells, and the proliferation of these cell lines was inhibited by IMD-0354. D-type cyclins were effectively suppressed in mixed tissue type MSTO-211H, leading to cell cycle arrest at sub G1 /G1 phase. IMD-0354 reduced cyclin D3 in both epithelial tissue type NCI-H28 and sarcomatoid tissue type NCI-H2052. In a sphere formation assay, IMD-0354 effectively decreased the number and diameter of MSTO-211H spheres. Preincubation of MSTO-211H cells with IMD-0354 delayed tumor formation in transplanted immunodeficient mice. Furthermore, administration of IMD-0354 markedly rescued the survival rate of mice that received intrathoracic injections of MSTO-211H cells. These results indicate that a targeted drug against NF-κB might have therapeutic efficacy in the treatment of human malignant mesothelioma.

  6. Malignant mesothelioma: global incidence and relationship with asbestos.

    PubMed

    Bianchi, Claudio; Bianchi, Tommaso

    2007-06-01

    Mesothelioma incidence varies markedly from one country to another. The highest annual crude incidence rates (about 30 cases per million) are observed in Australia, Belgium, and Great Britain. A lot of data indicate a relationship between mesothelioma and asbestos. The hot areas for mesothelioma exactly correspond to the sites of industries with high asbestos use, such as shipbuilding and asbestos-cement industry. However, in many countries with high asbestos consumption, mesothelioma incidence is low. The reasons for this fact are not clear. The latency periods elapsing between first exposure to asbestos and development of mesothelioma are mostly longer than 40 yr. An inverse relationship exists between intensity of asbestos exposure and length of the latency period. Mesothelioma generally develops after long-time exposures to asbestos. Some recent studies show that the risk increases with the duration of exposure. Possible co-factors in the pathogenesis of asbestos-related mesothelioma include genetic predisposition, diets poor in fruit and vegetables, viruses, immune impairment, recurrent serosal inflammation. The study of co-morbidity in mesothelioma could give an insight into the pathogenesis of the tumor. While a levelling-off in mesothelioma incidence has been registered in some countries, a worsening of the epidemic is predictable in large parts of the world.

  7. Lung carcinoma and malignant mesothelioma in patients exposed to Thorotrast: incidence, histology and p53 status.

    PubMed

    Andersson, M; Wallin, H; Jönsson, M; Nielsen, L L; Visfeldt, J; Vyberg, M; Bennett, W P; De Benedetti, V M; Travis, L B; Storm, H H

    1995-11-01

    In a previous registry-based survey of 999 patients injected with alpha-emitting 232ThO2 (Thorotrast), we identified elevated risks for lung carcinoma and malignant mesothelioma. Since injected Thorotrast is retained lifelong mostly in liver, spleen and lymph nodes, the mesothelial surfaces of these organs are constantly irradiated. Thorotrast-administered patients also perpetually exhale 220Rn, a 232Th-daughter. Study of Thorotrast-exposed patients may, therefore, provide data with regard to carcinogenicity of radon exposure, a current public health concern, as well as the pathogenesis of malignant mesothelioma. The incidence and histologic types of lung carcinoma and malignant mesothelioma within the cohort were examined by review of available histopathologic material and medical records. Further, mutations of the p53 gene were analyzed whenever possible as it has previously been suggested that radon-associated lung carcinomas exhibit specific mutational patterns. The cumulative risk for lung carcinoma reached 11.0% based on 20 confirmed cases. Nine were small cell lung cancer (SCLC), whereas the expected frequency was 18%. The risk for malignant mesothelioma reached 2.5% based on 7 cases. The actuarial risk of malignant mesothelioma for patients given more than 20 ml Thorotrast was 7.8% compared to 1.4% for patients administered smaller amounts. Seven lung carcinomas and 5 malignant mesotheliomas were analyzed for p53 mutations; only 1 (in a lung adenocarcinoma) was detected. A possible association between Thorotrast and SCLC is suggested. In addition, a possible dose-response gradient exists for Thorotrast and malignant mesothelioma.

  8. Fowlpox-based survivin vaccination for malignant mesothelioma therapy

    PubMed Central

    Bertino, Pietro; Panigada, Maddalena; Soprana, Elisa; Bianchi, Valentina; Bertilaccio, Sabrina; Sanvito, Francesca; Rose, Aaron H.; Yang, Haining; Gaudino, Giovanni; Hoffmann, Peter R.; Siccardi, Antonio; Carbone, Michele

    2013-01-01

    Survivin protein is an attractive candidate for cancer immunotherapy since it is abundantly expressed in most common human cancers and mostly absent in normal adult tissues. Malignant mesothelioma (MM) is a deadly cancer associated with asbestos or erionite exposure for which no successful therapies are currently available. In this study, we evaluated the therapeutic efficacy of a novel survivin-based vaccine by subcutaneous or intraperitoneum injection of BALB/c mice with murine fiber-induced MM tumor cells followed by vaccination with recombinant Fowlpox virus replicons encoding survivin. Vaccination generated significant immune responses in both models, leading to delayed tumor growth and improved animal survival. Flow cytometry and immunofluorescence analyses of tumors from vaccinated mice showed CD8+ T cell infiltration, and real-time PCR demonstrated increased mRNA and protein levels of immunostimulatory cytokines. Analyses of survivin peptide-pulsed spleen and lymph node cells from vaccinated mice using ELISPOT and intracellular cytokine staining confirmed antigen-specific, interferon-γ-producing CD8+ T cell responses. In addition pentamer-based flow cytometry showed that vaccination generated survivin-specific CD8+ T cells. Importantly, vaccination did not affect fertility or induce autoimmune abnormalities in mice. Our results demonstrate that vaccination with recombinant Fowlpox expressing survivin improves T cell responses against aggressive MM tumors and may form the basis for promising clinical applications. PMID:23335100

  9. Malignant mesothelioma of the pleura in Trieste, Italy.

    PubMed

    Giarelli, L; Bianchi, C; Grandi, G

    1992-01-01

    One hundred and seventy malignant pleural mesotheliomas seen at necropsy at the Institute of Pathological Anatomy of the Trieste University during the period 1968-1987 were reviewed. The series included 153 men and 17 women, aged between 33 and 92 years (median 70 years). Lifetime work histories were obtained from the patients' relatives by personal or telephone interviews in 162 cases. A majority of the male subjects had been employed in "naval" work, 99 people having worked in the ship-building industry, 19 in the navy and merchant marine, and 7 in docks. A variety of trades appeared in the remaining histories. Work histories were indicative of occupational exposure to asbestos in 150 cases. A further 5 patients with negative or insufficient data showed asbestos bodies in routine lung sections and 5 women had a history of domestic exposure. A majority of the patients had had their first exposure before 1950. The intervals between first exposure and death ranged from 14 to 71 years (median 48 years). PMID:1442787

  10. Effect of interferon-alpha 2a on malignant mesothelioma.

    PubMed

    Christmas, T I; Manning, L S; Garlepp, M J; Musk, A W; Robinson, B W

    1993-02-01

    Malignant mesothelioma (MM) is a tumor that is resistant to conventional therapy. Interferon-alpha (IFN-alpha) has been used in the treatment of some human tumors, and we have previously demonstrated an in vitro anti-proliferative effect of IFN against MM cell lines. Therefore, the effect of recombinant human IFN-alpha (IFN-alpha 2a) (Roferon-A, Hoffmann-La Roche) on previously untreated patients with MM has been studied. Twenty-five patients (24 male and 1 female), with a mean age of 59 +/- 9.9 years, were treated for 3 months with IFN-alpha 2a. The starting dose was 3 x 10(6) IU daily increasing to a maximum of 18 x 10(6) IU daily or as tolerated. All patients had measurable tumor on thoracic CT prior to commencement. CT scans were performed at 6 and 12 weeks to determine tumor response. Twenty patients completed 3 months of treatment. Five patients were withdrawn because of disease progression. Side effects were predictable and dose related. Dose reductions were necessary in 12 patients for grade 2 toxicity. One patient had a complete response (CR), 2 patients had partial responses (PR) (response rate = 12%), 13 (52%) patients remained stable, 1 of whom exhibited a delayed PR, and 9 (36%) had progressive disease. These data suggest that IFN-alpha 2a is well tolerated in patients with MM and is active against MM in a proportion of patients.

  11. Survival of malignant pleural mesothelioma cases in the Tuscan Mesothelioma Register, 1988-2000: a population-based study.

    PubMed

    Gorini, G; De Gregorio, G; Silvestri, S; Chellini, E; Cupelli, V; Seniori Costantini, A

    2005-06-01

    This study analyses survival of Tuscan residents (Italy, 3.5 million population) diagnosed by histological examination with malignant pleural mesothelioma (MPM) during the period 1988-2000, and recorded in the Tuscan Malignant Mesothelioma Register. The aim was to establish the prognostic role of demographic, diagnostic and asbestos exposure variables. During 1988-2000, 381 MPM cases were recorded (318 men; 63 women). Vital status was ascertained up to 31 December 2002. No cases were lost to follow-up. Median survival of certain MPM was 324 days (11 months; 95% CI 297-366); 45.7% (95% CI 40.6-50.6%) survived more than 1 year; 24.2% (95% CI 20.0-28.5%) more than 2 years. In univariate and multivariate analyses survival was associated with histological subtype (epithelioid subtype had the longest survival). Gender, age, period of diagnosis, hospital of diagnosis and asbestos exposure did not show significant effects. Therapeutic information was available for patients of the period 1997-2000. There was no significant difference in survival between treated versus untreated patients. In conclusion, no advance in prognosis at the population level in the most recent period can be suggested on the basis of the data available to the Tuscan Malignant Mesothelioma Register.

  12. Distinctive clinical characteristics of malignant mesothelioma in young patients.

    PubMed

    Thomas, Anish; Chen, Yuanbin; Yu, Tinghui; Gill, Ammara; Prasad, Vinay

    2015-06-30

    Although considered a disease of the elderly, a subset of patients with mesothelioma are young (<40 years). The goal of this study was to understand their characteristics and outcomes. The Surveillance, Epidemiology, and End Results (SEER) database was used to extract mesothelioma cases (1990-2010). We modeled Kaplan-Meyer survival curves stratified by site of disease, and age of presentation. 2% (207 of 12345) of mesothelioma patients are young. Sex distribution is comparable among the young (51% males, 49% females); males predominated (78%, 22%) in the older cohort. Frequency of pleural and peritoneal mesothelioma are similar in the young (47%, 48% respectively); pleural disease predominated in the old (90%, 9%). Cancer-directed surgeries are more frequent in the young. Regardless of histologic subtype, young patients with pleural (11 vs. 8 months) and peritoneal (not reached vs. 10 months) mesothelioma had significantly improved overall survival. In multivariate analysis, younger age was an independent prognostic factor. Although rare, mesothelioma do occur in the young; their characteristics are distinct from those of older patients. Further studies are needed to understand the interplay between genetic susceptibility and mineral fiber carcinogenesis in the pathogenesis of mesothelioma in the young.

  13. Thrombomodulin expression in malignant pleural mesothelioma and pulmonary adenocarcinoma.

    PubMed

    Collins, C L; Ordonez, N G; Schaefer, R; Cook, C D; Xie, S S; Granger, J; Hsu, P L; Fink, L; Hsu, S M

    1992-10-01

    Thrombomodulin (TM) is a glycoprotein of molecular weight 75,000 kd that is normally present in restricted numbers of cells, including endothelial and mesothelial cells. In this study, the authors tested the possibility of using anti-TM to facilitate the diagnosis of mesothelioma. All of the 31 mesotheliomas and the two mesothelioma cell lines (MS-1 and MS-2) tested were stained positively with anti-TM. The specificity of anti-TM staining in mesothelioma cells was further confirmed by in situ hybridization of MS-1 cells with a TM-specific probe. The expression of TM in MS-1 cells was increased markedly when these cells were induced by 12-0-tetradecanyl phorbol 13-acetate (TPA) to differentiate. The expression of TM in mesothelioma cells, however, did not correlate with any particular phase of the cell cycle. In an attempt to differentiate pleural mesothelioma from pulmonary adenocarcinoma, the authors compared the expression of TM, carcinoembryonic antigen (CEA), and Leu M1 in these two types of tumors. Only four of 48 (8%) pulmonary adenocarcinomas were stained positively by antibodies to TM. Therefore, immunohistochemical staining with antibodies to TM yielded 100% sensitivity and 92% specificity for diagnosis of mesothelioma. All of the mesotheliomas stained negatively for CEA and Leu M1, except for one, which showed minimal focal positivity for Leu M1. In contrast, 79% and 60% of adenocarcinomas stained positively for CEA and Leu M1, respectively. These findings suggest that immunocytochemical staining with anti-TM should be added to the battery of tests to increase the diagnostic sensitivity and specificity for differentiating mesothelioma from pulmonary adenocarcinoma.

  14. Localized malignant pleural sarcomatoid mesothelioma misdiagnosed as benign localized fibrous tumor

    PubMed Central

    Vo, Hong-Phuc

    2016-01-01

    Localized malignant pleural mesothelioma (LMPM) is a rare tumor with good prognosis by surgical resection. We report an atypical case of malignant pleural sarcomatoid mesothelioma (SM) in an asymptomatic 65-year-old woman, who had no history of exposure to asbestos. She presented with a small pleural mass without pleural effusion and was misdiagnosed as a benign localized fibrous tumor (BLFT) on pathologic examination through a surgical tumor specimen. However, seven months later, the patient returned with serious cancerous symptoms. A large recurrent tumor mass was found within the chest wall invading at the old surgical resection site. SM, a subtype of LMPM, was confirmed with histopathogy and immunohistochemisty. In conclusion, malignant pleural mesothelioma (MPM) can present with typical radiologic finding similar to a BLFT, and has a wide histopathologic presentation in biopsy specimen. A thorough pathologic investigation should be attempted even when a pleural mass resembles benign, localized, and small on radiologic studies. PMID:27293862

  15. Localized malignant pleural sarcomatoid mesothelioma misdiagnosed as benign localized fibrous tumor.

    PubMed

    Kim, Kwan-Chang; Vo, Hong-Phuc

    2016-06-01

    Localized malignant pleural mesothelioma (LMPM) is a rare tumor with good prognosis by surgical resection. We report an atypical case of malignant pleural sarcomatoid mesothelioma (SM) in an asymptomatic 65-year-old woman, who had no history of exposure to asbestos. She presented with a small pleural mass without pleural effusion and was misdiagnosed as a benign localized fibrous tumor (BLFT) on pathologic examination through a surgical tumor specimen. However, seven months later, the patient returned with serious cancerous symptoms. A large recurrent tumor mass was found within the chest wall invading at the old surgical resection site. SM, a subtype of LMPM, was confirmed with histopathogy and immunohistochemisty. In conclusion, malignant pleural mesothelioma (MPM) can present with typical radiologic finding similar to a BLFT, and has a wide histopathologic presentation in biopsy specimen. A thorough pathologic investigation should be attempted even when a pleural mass resembles benign, localized, and small on radiologic studies. PMID:27293862

  16. The established and future biomarkers of malignant pleural mesothelioma.

    PubMed

    Panou, V; Vyberg, M; Weinreich, U M; Meristoudis, C; Falkmer, U G; Røe, O D

    2015-06-01

    Malignant pleural mesothelioma (MPM) is an asbestos-related cancer with a median survival of 12months. The MPM incidence is 1-6/100,000 and is increasing as a result of historic asbestos exposure in industrialized countries and continued use of asbestos in developing countries. Lack of accurate biomarkers makes diagnosis, prognostication and treatment prediction of MPM challenging. The aim of this review is to identify the front line of MPM biomarkers with current or potential clinical impact. Literature search using the PubMed and PLoS One databases, the related-articles function of PubMed and the reference lists of associated publications until April 26th 2015 revealed a plethora of candidate biomarkers. The current gold standard of MPM diagnosis is a combination of two positive and two negative immunohistochemical markers in the epithelioid and biphasic type, but sarcomatous type do not have specific markers, making diagnosis more difficult. Mesothelin in serum and pleural fluid may serve as adjuvant diagnostic with high specificity but low sensitivity. Circulating proteomic and microRNA signatures, fibulin-3, tumor cell gene-ratio test, transcriptomic, lncRNA, glycopeptides, pleural fluid FISH assay, hyaluronate/N-ERC mesothelin and deformability cytometry may be important future markers. Putative predictive markers for pemetrexed-platinum are tumor TS and TYMS, for vinorelbine the ERCC1, beta-tubuline class III and BRCA1. Mutations of the BAP1 gene are potential markers of MPM susceptibility. In conclusion, the current status of MPM biomarkers is not satisfactory but encouraging as more sensitive and specific non-invasive markers are emerging. However, prospective validation is needed before clinical application. PMID:25979846

  17. Diarachidonoylphosphoethanolamine induces necrosis/necroptosis of malignant pleural mesothelioma cells.

    PubMed

    Kaku, Yoshiko; Tsuchiya, Ayako; Kanno, Takeshi; Nakano, Takashi; Nishizaki, Tomoyuki

    2015-09-01

    The present study investigated 1,2-diarachidonoyl-sn-glycero-3-phosphoethanolamine (DAPE)-induced cell death in malignant pleural mesothelioma (MPM) cells. DAPE reduced cell viability in NCI-H28, NCI-H2052, NCI-H2452, and MSTO-211H MPM cell lines in a concentration (1-100μM)-dependent manner. In the flow cytometry using propidium iodide (PI) and annexin V (AV), DAPE significantly increased the population of PI-positive and AV-negative cells, corresponding to primary necrosis, and that of PI-positive and AV-positive cells, corresponding to late apoptosis/secondary necrosis, in NCI-H28 cells. DAPE-induced reduction of NCI-H28 cell viability was partially inhibited by necrostatin-1, an inhibitor of RIP1 kinase to induce necroptosis, or knocking-down RIP1. DAPE generated reactive oxygen species (ROS) followed by disruption of mitochondrial membrane potentials in NCI-H28 cells. DAPE-induced mitochondrial damage was attenuated by cyclosporin A, an inhibitor of cyclophilin D (CypD). DAPE did not affect expression and mitochondrial localization of p53 protein in NCI-H28 cells. DAPE significantly decreased intracellular ATP concentrations in NCI-H28 cells. Overall, the results of the present study indicate that DAPE induces necroptosis and necrosis of MPM cells; the former is mediated by RIP1 kinase and the latter is caused by generating ROS and opening CypD-dependent mitochondrial permeability transition pore, to reduce intracellular ATP concentrations.

  18. Proton Therapy for Malignant Pleural Mesothelioma After Extrapleural Pleuropneumonectomy

    SciTech Connect

    Krayenbuehl, Jerome; Hartmann, Matthias; Lomax, Anthony J.

    2010-10-01

    Purpose: To perform comparative planning for intensity-modulated radiotherapy (IMRT) and proton therapy (PT) for malignant pleural mesothelioma after radical surgery. Methods and Materials: Eight patients treated with IMRT after extrapleural pleuropneumonectomy (EPP) were replanned for PT, comparing dose homogeneity, target volume coverage, and mean and maximal dose to organs at risk. Feasibility of PT was evaluated regarding the dose distribution with respect to air cavities after EPP. Results: Dose coverage and dose homogeneity of the planning target volume (PTV) were significantly better for PT than for IMRT regarding the volume covered by >95% (V95) for the high-dose PTV. The mean dose to the contralateral kidney, ipsilateral kidney, contralateral lung, liver, and heart and spinal cord dose were significantly reduced with PT compared with IMRT. After EPP, air cavities were common (range, 0-850 cm{sup 3}), decreasing from 0 to 18.5 cm{sup 3}/day. In 2 patients, air cavity changes during RT decreased the generalized equivalent uniform dose (gEUD) in the case of using an a value of < - 10 to the PTV2 to <2 Gy in the presence of changing cavities for PT, and to 40 Gy for IMRT. Small changes were observed for gEUD of PTV1 because PTV1 was reached by the beams before air. Conclusion: Both PT and IMRT achieved good target coverage and dose homogeneity. Proton therapy accomplished additional dose sparing of most organs at risk compared with IMRT. Proton therapy dose distributions were more susceptible to changing air cavities, emphasizing the need for adaptive RT and replanning.

  19. Capacity of tumor necrosis factor to augment lymphocyte-mediated tumor cell lysis of malignant mesothelioma

    SciTech Connect

    Bowman, R.V.; Manning, L.S.; Davis, M.R.; Robinson, B.W. )

    1991-01-01

    Recombinant human tumor necrosis factor (rHuTNF) was evaluated both for direct anti-tumor action against human malignant mesothelioma and for its capacity to augment the generation and lytic phases of lymphocyte-mediated cytotoxicity against this tumor. rHuTNF was directly toxic by MTT assay to one of two mesothelioma cell lines evaluated, but had no effect on susceptibility to subsequent lymphocyte-mediated lysis of either line. TNF alone was incapable of generating anti-mesothelioma lymphokine-activated killer cell (LAK) activity. Furthermore, it did not augment the degree or LAK activity produced by submaximal interleukin-2 (IL-2) concentrations nor did it augment lysis of mesothelioma cells by natural killer (NK) or LAK effector cells during the 4-hr 51chromium release cytolytic reaction. The studies also suggest that mesothelioma targets are less responsive to TNF plus submaximal IL-2 concentrations than the standard LAK sensitive target Daudi, raising the possibility that intermediate LAK sensitive tumors such as mesothelioma may require separate and specific evaluation in immunomodulation studies. This in vitro study indicates that use of low-dose rHuTNF and IL-2 is unlikely to be an effective substitute for high-dose IL-2 in generation and maintenance of LAK activity in adoptive immunotherapy for mesothelioma.

  20. Endemic malignant mesothelioma: exposure to erionite is more important than genetic factors.

    PubMed

    Metintas, Muzaffer; Hillerdal, Gunnar; Metintas, Selma; Dumortier, Pascal

    2010-01-01

    The village of Karain, Turkey, has the world's highest prevalence rate of malignant mesothelioma (MM). Environmental exposure to erionite is thought to cause the disease. However, it has also been suggested that the disease is mainly genetic. Residents in Karain village were traced from 1990 to 2006. Mineral samples were obtained from stones used in construction of their houses and any fibers present were identified. All women who had moved to the village as brides were traced and their cause of death determined. MM was the cause of death in 52 of 322 villagers, representing 50.5% of all deaths. Only 2 of 8 types of stones used in construction contained erionite, and these stones had been used almost exclusively in the mid-sections of the village, where MM was common. In houses not containing erionite, no cases of MM were observed. Sixty-four women came as brides to Karain from villages where erionite or asbestos is not found. Of the 16 women who have died, 11 (69%) died from MM. The extreme risk of MM in Karain is due to indoor exposure to erionite. The effect of genetic factors on mesothelioma development cannot be evaluated in this study, but is likely to be minor.

  1. [Epidemiology, molecular biology, diagnostic and therapeutic strategy of malignant pleural mesothelioma in 2007 - an update].

    PubMed

    Porret, E; Madelaine, J; Galateau-Sallé, F; Bergot, E; Zalcman, G

    2007-10-01

    Malignant pleural mesothelioma (MPM) is a rare tumour due to occupational asbestos exposure. The incidence of MPM will continue to increase until 2020-2030. The incidence reaches 100 cases/million/year in occupationally exposed populations as opposed to 1 case/million/year in the general population, leading to 800 to 1,000 cases per year in France. The molecular carcinogenesis of MPM is incompletely understood but alterations to genes NF2, c-met, WT1 RASSF and p16 have been described. These genes are involved in cell invasion and motility, cell division and apoptosis control. Histological diagnosis remains difficult and depends on immunohistochemical analysis as described by the French Mesopath group. Clinical diagnosis relies on thoracoscopy and large pleural biopsies, with increasing use of CT-PET for the evaluation of disease extent. Therapeutic strategy includes prophylactic irradiation following drainage or thoracoscopy to prevent tumour nodule development along drainage channels and puncture sites. In selected patients, extensive extra-pleural pneumonectomy can be performed with curative intent. First line chemotherapy is based on a combination of pemetrexed and cisplatin that has demonstrated an improvement in overall survival and quality of life in phase 3 trials. Antiangiogenic agents such as bevacizumab (Avastatin) may be of interest but need to be tested in phase 3 trials. The Mesothelioma Avastatin Pemetrexed Study (MAPS) is ongoing, coordinated by the French Thoracic Cancer Intergroup (IFCT).

  2. Spontaneous peritoneal malignant mesothelioma in a geriatric japanese macaque (Macaca fuscata).

    PubMed

    Yamate, Jyoji; Tomita, Akitada; Kuwamura, Mitsuru; Mitsunaga, Fusako; Nakamura, Shin

    2007-04-01

    A 28.5-year-old female Japanese macaque (Macaca fuscata) was euthanatized because of abdominal distension due to severe ascites. Nodular lesions of varying sizes up to 5 mm in diameter were distributed diffusely on the surface of the omentum, mesentery and parietal peritoneum. No neoplastic masses were detected in any visceral organ. The nodules were composed of proliferation of mono- or multi-layered epithelial-like cells occasionally showing papillary growth and sheets of small round or polygonal cells. Signet ring-like cells and tubular structures were occasionally present. Neoplastic cells were strongly positive to cytokeratin, and occasionally to vimentin. Based on gross and histopathological findings, this tumor was diagnosed as an epithelial type of peritoneal malignant mesothelioma, the first reported case in the non-human primates.

  3. Mesotheliomas due to asbestos used in railroads in Italy.

    PubMed

    Maltoni, C; Pinto, C; Mobiglia, A

    1991-12-31

    The available knowledge of the oncogenic risks of asbestos, the presentation of some data on the uses of asbestos in railroads, with particular regard to the Italian State Railroads (Ferrovie dello Stato = FS), and the identification of groups at risk because of exposure to asbestos used in railroads are briefly reviewed. The available data in the literature on the pathologic effects of such exposure, and in particular on the onset of mesotheliomas among machinists and other railroad workers, are also summarized. Eighty-three cases, in various Italian regions, of mesothelioma (78 pleural, 4, peritoneal, and 1 pericardial) are reported that are related to the exposure to asbestos used in railroads. Twenty-six of these cases (among which 25 were reported in the Emilia-Romagna region) were submitted to a detailed study at the Bologna Institute of Oncology. Forty-nine cases of mesothelioma occurred among FS workers, in particular machinists; 29 cases occurred among machinists of rolling-stock workshops not belonging to the FS; 3 cases occurred among travelling workers of rolling-stock not belonging to the FS; 2 cases were found in members of the family (a daughter and a wife) of FS workers. This series of cases, together with similar data from the literature, proves the existence and gravity of an actual health risk due to asbestos used in the railroads. On the basis of the available data, the following steps are considered necessary: the adoption of preventive measures, the performance of medical oncological surveillance, the promotion of systematic epidemiologic investigations, and, finally, the placement of greater emphasis on basic research, aimed at generating information on the biological events taking place during the incubation period of the tumors. This information, hopefully, could be used to reduce the biological effect of exposure, and therefore for controlling the neoplastic process before onset of the disease in those who, having been exposed, although

  4. Pleural malignant mesothelioma, genetic susceptibility and asbestos exposure.

    PubMed

    Neri, Monica; Filiberti, Rosangela; Taioli, Emanuela; Garte, Seymour; Paracchini, Valentina; Bolognesi, Claudia; Canessa, Pier Aldo; Fontana, Vincenzo; Ivaldi, Giovanni Paolo; Verna, Anna; Bonassi, Stefano; Puntoni, Riccardo

    2005-12-30

    Pleural malignant mesothelioma (MM) is a rare but extremely aggressive cancer. The limited impact of standard therapeutic treatments on survival rates makes the identification of factors that increase the individual risk a leading priority. The high proportion of cases explained by exposure to asbestos has guided intervention policies to an effective ban of this compound from our environment. However, MM cannot be solely attributed to this agent, and the role of predisposing factors and their interaction with asbestos exposure is increasingly studied. The role of mEH, GSTM1, GSTT1, NAT2, and CYP1A1 genotypes in modulating susceptibility to MM was examined in a case-control study of 80 subjects with a confirmed diagnosis of MM and 255 controls. Subjects with low mEH activity showed a significantly increased risk of MM (OR, 2.51; 95% CI, 1.11-5.68). The association was stronger in the group with low asbestos exposure (OR, 7.83; 95% CI, 0.98-62.60). A significant increased risk of MM was also found in NAT2 fast acetylators (OR, 1.74; 95% CI, 1.02-2.96). The presence of synergisms between genotypes, i.e., mEH and NAT2 (LRT for heterogeneity p<0.023), mEH and GSTM1 (LRT p<0.061), and NAT2 and GSTM1 (LRT p<0.049), combined with the interaction observed with exposure to asbestos, suggests the presence of gene-environment and gene-gene interactions in the development of MM, although the size of the study group does not allow to draw clearcut conclusions. Since genetic polymorphisms can also modify the extent of genetic damage occurring in subjects exposed to carcinogens, we measured the frequency of micronuclei in peripheral blood lymphocytes of a subgroup of MM cases. The limited number of cases (28) did not allow to observe significant effects. In conclusion, these results strengthen the hypothesis that individual susceptibility to MM can be modulated by the interaction between polymorphic genes involved in the metabolism and the intensity of asbestos exposure.

  5. [Epidemiological surveillance of malignant mesothelioma cases in Italy: incidence and asbestos exposure figures by the Italian mesothelioma registry (ReNaM)].

    PubMed

    Marinaccio, Alessandro; Binazzi, Alessandra; Cauzillo, Gabriella; Chellini, Elisabetta; De Zotti, Renata; Gennaro, Valerio; Menegozzo, Massimo; Mensi, Carolina; Merler, Enzo; Mirabelli, Dario; Musti, Marina; Pannelli, Franco; Romanelli, Antonio; Scarselli, Alberto; Tosi, Sergio; Tumino, Rosario; Nesti, Massimo

    2007-01-01

    The Study describes the epidemiological surveillance of mesothelioma cases carried out by the Italian mesothelioma register (ReNaM). A Regional Operating Centre (COR) is present in nearly all Italian regions (17 out of 20) and it collects malignant mesothelioma cases and investigate the modalities of asbestos exposure by using a structured questionnaire. The register produces malignant mesothelioma incidence measures and analyses of the modalities of the asbestos exposure. The standardized incidence rate of malignant mesothelioma in 2001 was 2.98 (in 100,000 inhabitants) among men and 0.98 among women; a professional (certain, probable, possible) exposure has been detected in 67.4% of defined cases. In addition to the conventional sectors (shipbuilding, railways repair and demolition, asbestos-cement production), also textile, building, transport, chemical and glass industries, petroleum and sugar refineries, electricity production and distribution plants are getting involved. Despite the absence of some regions completing the national coverage and the non homogeneity in collecting and coding data, the epidemiological surveillance of malignant mesothelioma carried out by ReNaM is an important tool for the scientific knowledge and the prevention of asbestos-related diseases.

  6. Survival of pleural malignant mesothelioma in Italy: a population-based study.

    PubMed

    Montanaro, Fabio; Rosato, Rosalba; Gangemi, Manuela; Roberti, Sara; Ricceri, Fulvio; Merler, Enzo; Gennaro, Valerio; Romanelli, Antonio; Chellini, Elisabetta; Pascucci, Cristiana; Musti, Marina; Nicita, Carmela; Barbieri, Pietro Gino; Marinaccio, Alessandro; Magnani, Corrado; Mirabelli, Dario

    2009-01-01

    A median survival time of about 9 months is generally reported among malignant pleural mesothelioma cases. Recently, better results in terms of survival and performance status have been reported in clinical trials that included highly selected patients. We describe the survival of pleural mesothelioma patients and the factors predictive of survival in an unselected, population-based setting. Pleural mesothelioma cases (4,100) registered from 1990 to 2001 by 9 Italian regional mesothelioma registries contributing to the network of the National Mesothelioma Registry were followed until December 31, 2005. Univariate (Kaplan-Meier) and multivariate (Cox proportional hazards regression) analyses of survival were carried out according to selected individual characteristics, including limited information on treatment in a subset of 578 cases. The median survival time was 9.8 months (95% confidence interval: 9.4-10.1). In multivariate analysis, younger age at diagnosis and epithelioid histotype were associated with significantly reduced hazard ratios. Positive effects of gender (women) and being diagnosed in a hospital with a thoracic surgery unit were of border-line statistical significance. No association with calendar period of diagnosis or asbestos exposure was present. Treatment was not associated with a statistically significant improvement in survival. This is the largest population-based study on survival in patients with pleural mesothelioma to date. Age and morphology were the main prognostic factors. Results regarding the effect of treatment were disappointing but may be useful to assess the future impact, at the population level, of recently introduced therapies.

  7. Coalescent pleural malignant mesothelioma and adenocarcinoma of the lung, involving only minor asbestos exposure.

    PubMed

    Tsuzuki, Toyonori; Ninomiya, Hironori; Natori, Yuji; Ishikawa, Yuichi

    2008-07-01

    Coexistence of pulmonary adenocarcinoma and pleural malignant mesothelioma is extremely rare, although both are asbestos-related. Herein is presented a rare case of coalescent lung tumor made up of a malignant mesothelioma and a pulmonary adenocarcinoma in a 62-year-old Japanese man, a high-school teacher with only minor asbestos exposure. Preoperative diagnosis of adenocarcinoma was made on transbronchial biopsy. At surgery, multiple small white nodules were observed on the parietal pleural surface, opposite to the lung tumor. They were confirmed to be malignant mesothelioma on histopathology of paraffin section. The pulmonary tumor mass itself consisted of two distinct portions. The major part contained papillary proliferation of hobnail and columnar cells. Peripherally, neoplastic cells grew in a lepidic fashion and micropapillary growth was also detected. The other component featured tubular structures. The former was positive for adenocarcinoma markers such as CEA, Ber-EP4, PE-10, thyroid transcription factor-1 and Napsin A, and negative for mesothelial markers including calretinin, D2-40, WT-1 and HBME, while the latter was the opposite, resulting in a diagnosis of coalescing malignant mesothelioma and adenocarcinoma. The panel of antibodies used for immunohistochemistry was useful to distinguish the two different components in the one tumor.

  8. Helical tomotherapy for resected malignant pleural mesothelioma: dosimetric evaluation and toxicity.

    PubMed

    Giraud, Philippe; Sylvestre, Alma; Zefkili, Sofia; Lisbona, Albert; Bonnette, Pierre; Le Pimpec Barthes, Françoise; Paris, Edouard; Perigaud, Christian; Savignoni, Alexia; Mahé, Marc-André

    2011-11-01

    This study evaluated adjuvant helical tomotherapy after extrapleural pneumonectomy ± neo-adjuvant chemotherapy in 24 patients with malignant pleural mesothelioma. Toxicity was judged acceptable despite 2 cases (8%) of suspected grade 5 pneumonitis. With a mean follow-up of 7 months, 5 patients had distant and 2 local and distant failure.

  9. The influence of occupational and environmental asbestos exposure on the incidence of malignant mesothelioma in Connecticut.

    PubMed

    Lewinsohn, H C; Meigs, J W; Teta, M J; Flannery, J T

    1980-01-01

    Medical, occupational and demographic data were collected for 229 cases of malignant mesothelioma and 38 other pleural tumours, their spouses, and 605 controls. Methods were developed for classifying subjects into probable asbestos exposure categories. Although disease incidence rates exhibited a rapid increase from 1955 to 1977, there remains a serious question of diagnostic reliability. A case review is being undertaken.

  10. Familial aggregation of malignant mesothelioma in former workers and residents of Wittenoom, Western Australia.

    PubMed

    de Klerk, Nicholas; Alfonso, Helman; Olsen, Nola; Reid, Alison; Sleith, Jan; Palmer, Lyle; Berry, Geoffrey; Musk, Aw Bill

    2013-03-15

    Clustering of cases of malignant mesothelioma within families has often been observed, but disentangling genetic and exposure effects has not been done. Former workers and residents exposed to crocidolite at Wittenoom, Western Australia, where many families shared exposure to asbestos, have had high rates of mesothelioma. Our study aimed to estimate the additional risk of mesothelioma in relatives, after allowance for common exposure to crocidolite. More than 11,000 former asbestos workers and residents from Wittenoom have been followed up in cancer and death registries. Levels of exposure for all members of the Wittenoom cohorts have been estimated previously. Relationships between family members of all mesothelioma cases were established from questionnaires, birth and death certificates. Expected numbers of cases of mesothelioma were estimated by fitting a Weibull survival model to all data, based on time from first asbestos exposure, duration and intensity of exposure and age. For each family group, the earliest case was considered the index case. Predicted risk was estimated for each subject from the time of diagnosis of the index case. Familial risk ratios were estimated by dividing observed cases by the sum of risks of all same degree relatives of index cases. There were 369 family groups with at least one case of mesothelioma and a further 25 cases of mesothelioma among relatives in the same families, with 12.9 expected. The risk ratio for blood relatives was 1.9 (95% confidence interval [CI] = 1.3-2.9, p = 0.002). These findings suggest an important, but not large, genetic component in mesothelioma, similar to many other cancers.

  11. Pharmacological targeting of p53 through RITA is an effective antitumoral strategy for malignant pleural mesothelioma.

    PubMed

    Di Marzo, Domenico; Forte, Iris Maria; Indovina, Paola; Di Gennaro, Elena; Rizzo, Valeria; Giorgi, Francesca; Mattioli, Eliseo; Iannuzzi, Carmelina Antonella; Budillon, Alfredo; Giordano, Antonio; Pentimalli, Francesca

    2014-01-01

    Malignant mesothelioma, a very aggressive tumor associated to asbestos exposure, is expected to increase in incidence, and unfortunately, no curative modality exists. Reactivation of p53 is a new attractive antitumoral strategy. p53 is rarely mutated in mesothelioma, but it is inactivated in most tumors by the lack of p14(ARF). Here, we evaluated the feasibility of this approach in pleural mesothelioma by testing RITA and nutlin-3, two molecules able to restore p53 function through a different mechanism, on a panel of mesothelioma cell lines representing the epithelioid (NCI-H28, NCI-H2452, IST-MES 2), biphasic (MSTO-211H), and sarcomatoid (NCI-H2052) histotypes compared with the normal mesothelial HMC-hTERT. RITA triggered robust caspase-dependent apoptosis specifically in epithelioid and biphasic mesothelioma cell lines, both through wild-type and mutant p53, concomitant to p21 downregulation. Conversely, nutlin-3 induced a p21-dependent growth arrest, rather than apoptosis, and was slightly toxic on HMC-hTERT.   Interestingly, we identified a previously undetected point mutation of p53 (p.Arg249Ser) in IST-MES 2, and showed that RITA is also able to reactivate this p53 mutant protein and its apoptotic function. RITA reduced tumor growth in a MSTO-211H-derived xenograft model of mesothelioma and synergized with cisplatin, which is the mainstay of treatment for this tumor. Our data indicate that reactivation of p53 and concomitant p21 downregulation effectively induce cell death in mesothelioma, a tumor characterized by a high intrinsic resistance to apoptosis. Altogether, our findings provide the preclinical framework supporting the use of p53-reactivating agents alone, or in combination regimens, to improve the outcome of patients with mesothelioma.

  12. Familial aggregation of malignant mesothelioma in former workers and residents of Wittenoom, Western Australia.

    PubMed

    de Klerk, Nicholas; Alfonso, Helman; Olsen, Nola; Reid, Alison; Sleith, Jan; Palmer, Lyle; Berry, Geoffrey; Musk, Aw Bill

    2013-03-15

    Clustering of cases of malignant mesothelioma within families has often been observed, but disentangling genetic and exposure effects has not been done. Former workers and residents exposed to crocidolite at Wittenoom, Western Australia, where many families shared exposure to asbestos, have had high rates of mesothelioma. Our study aimed to estimate the additional risk of mesothelioma in relatives, after allowance for common exposure to crocidolite. More than 11,000 former asbestos workers and residents from Wittenoom have been followed up in cancer and death registries. Levels of exposure for all members of the Wittenoom cohorts have been estimated previously. Relationships between family members of all mesothelioma cases were established from questionnaires, birth and death certificates. Expected numbers of cases of mesothelioma were estimated by fitting a Weibull survival model to all data, based on time from first asbestos exposure, duration and intensity of exposure and age. For each family group, the earliest case was considered the index case. Predicted risk was estimated for each subject from the time of diagnosis of the index case. Familial risk ratios were estimated by dividing observed cases by the sum of risks of all same degree relatives of index cases. There were 369 family groups with at least one case of mesothelioma and a further 25 cases of mesothelioma among relatives in the same families, with 12.9 expected. The risk ratio for blood relatives was 1.9 (95% confidence interval [CI] = 1.3-2.9, p = 0.002). These findings suggest an important, but not large, genetic component in mesothelioma, similar to many other cancers. PMID:22858896

  13. [Risk of developing mesothelioma due to neighborhood exposure to asbestos].

    PubMed

    Kumagai, Shinji; Kurumatani, Norio

    2007-05-01

    Routes of asbestos exposure consist of occupational and non-occupational exposures, and furthermore the latter is classified as para-occupational, neighborhood or true general environmental exposure. Consequently, in order to evaluate health risk caused by neighborhood exposure to asbestos, it is necessary to exclude risk due to the other exposure routes from overall risk. We reviewed epidemiological studies on the relationship between neighborhood asbestos exposure and risk of mesothelioma. In studies on a crocidolite mine in South Africa and a chrysotile mine in Canada, occupational exposure was not excluded. In studies on a crocidolite mine in Australia and an asbestos manufacturing factory in U.S.A., risk caused by non-occupational exposure was evaluated, but the risk was not classified as para-occupational and neighborhood exposures. In a study on an asbestos cement factory in Italy, first, occupational and para-occupational exposures were excluded, and next, the incidence rate of mesothelioma in neighborhood residents was calculated, so that risk caused by neighborhood exposure could be evaluated. In case-control studies in Italy, South Africa, three European countries and the U.K., risks caused by occupational, para-occupational and neighborhood exposures were evaluated separately. As a whole, relative risk (RR) of neighborhood exposure in crocidolite and amosite mines was about 10 to 30 and RR in major asbestos factories was about 5 to 20. On the other hand, statistically significant RR of neighborhood exposure was not observed in chrysotile mines and some asbestos facilities.

  14. Shoulder ring complaints as a rare first symptom of malignant pleural mesothelioma.

    PubMed

    Lorkowski, J; Grzegorowska, O; Kotela, A; Weryński, W; Kotela, I

    2015-01-01

    The prevalence of malignant pleural mesothelioma is often encountered in the areas highly exposed to asbestos. The aim of this paper was a retrospective analysis of shoulder pain as a rare, first symptom of pleural mesothelioma, which constitutes an interdisciplinary diagnostic problem concerning both orthopedics and pulmonology. The research was based on a retrospective review of the patients' medical records. The considered period of time included the years 2006-2012. The study group included a total of 49 patients. Seven patients (14.3%) presented a complain of shoulder pain, as the first symptom of mesothelioma. The remaining 42 mesothelioma patients, without this symptom, constituted a reference group. The intensity of shoulder pain was, on average, 4/10 on an analog scale. A concomitant limitation of mobility was observed in five out of the seven subjects. In one case, limitation of motion and dysfunction of the shoulder joint were at an advanced stage. Neuralgia of upper limbs was found in two cases. We conclude that shoulder pain may be a manifesting symptom of malignant pleural mesothelioma. The neoplasm appears to have a pleiotropic effect on human body, reflected in different ways of its primary manifestation which may also include the motor system.

  15. Second line therapy in malignant pleural mesothelioma: A systematic review.

    PubMed

    Buikhuisen, Wieneke A; Hiddinga, Birgitta I; Baas, Paul; van Meerbeeck, Jan P

    2015-09-01

    After the implementation of standard first line chemotherapy with platinum and antifolates in pleural mesothelioma, patients are confronted with a need for second line treatment at relapse or progression. We conducted a systematic review of the literature for the activity, effectiveness and toxicity of second line treatment. The results are presented according to the class of drugs: chemotherapy and targeted or biological agent.

  16. Analysis of latency time and its determinants in asbestos related malignant mesothelioma cases of the Italian register.

    PubMed

    Marinaccio, Alessandro; Binazzi, Alessandra; Cauzillo, Gabriella; Cavone, Domenica; Zotti, Renata De; Ferrante, Pierpaolo; Gennaro, Valerio; Gorini, Giuseppe; Menegozzo, Massimo; Mensi, Carolina; Merler, Enzo; Mirabelli, Dario; Montanaro, Fabio; Musti, Marina; Pannelli, Franco; Romanelli, Antonio; Scarselli, Alberto; Tumino, Rosario

    2007-12-01

    Italy was an important producer of raw asbestos until 1992 (when it was banned) and it is now experiencing severe public health consequences due to large-scale industrial use of asbestos in shipbuilding and repair, asbestos-cement production, railways, buildings, chemicals and many other industrial sectors. Latency of malignant mesothelioma generally shows a large variability and the relationship with the modality of asbestos exposure is still not fully clarified. We present an analysis of latency period among the case list collected by the Italian mesothelioma register (ReNaM) in the period of diagnosis 1993-2001 (2544 malignant mesothelioma (MM) cases with asbestos exposure history). Exposure is assessed retrospectively by interview. Statistical univariate analyses were performed to estimate median and variability measures of latency time by anatomical site, gender and diagnosis period. The role of diagnostic confidence level, the morphology of the tumour and the modalities of asbestos exposure were verified in a regression multivariate model. We found a median latency period of 44.6 years increasing in recent years with a linear trend. Anatomical site, gender and morphology were not relevant for MM latency time whereas a shorter latency period was documented among occupationally exposed subjects (43 years) with respect to environmentally and household exposed ones (48 years).

  17. A case of diffused malignant pleural mesothelioma forming small multiple disseminations with intraoperatively suspicious carcinoid tumors.

    PubMed

    Suemitsu, Ryuichi; Takeo, Sadanori; Hamatake, Motoharu; Furuya, Kiyomi; Uesugi, Noriko

    2011-01-01

    A 65-year-old male, having symptoms suggestive of pulmonary malignant tumor, underwent video-assisted thoracic surgery (VATS). Surgery revealed a solid tumor originating from the thoracic wall, with many small solid tumors in the thoracic wall and diaphragm near the tumor. The intraoperative observation of a frozen section typed the tumor as carcinoid; however, hematoxylin-eosin staining and immunohistological findings provided the definitive diagnosis of diffused, malignant pleural mesothelioma (MPM).

  18. Asbestosis, laryngeal carcinoma, and malignant peritoneal mesothelioma in an insulation worker.

    PubMed Central

    Fischbein, A; Luo, J C; Pinkston, G R

    1991-01-01

    Asbestos associated diseases consist of both benign and malignant conditions. A rare constellation of asbestosis, laryngeal carcinoma, and malignant peritoneal mesothelioma occurring in a patient with long term occupational exposure to airborne asbestos fibres is presented. The observation illustrates the powerful disease-causing potential of occupational exposure to asbestos. A brief discussion of multiple primary neoplasms associated with exposure to asbestos is also presented. Images PMID:2039746

  19. Scoring system for differential diagnosis of malignant mesothelioma and reactive mesothelial cells on cytology specimens.

    PubMed

    Kimura, Noriko; Dota, Kimiko; Araya, Yoshikazu; Ishidate, Takuzo; Ishizaka, Masanori

    2009-12-01

    Cytology is the only useful tool in the detection of malignant mesothelioma (MM) at an early stage. No other methods, such as immunocytochemistry or electron microscopy, are available to distinguish MM from reactive mesothelial cells (RMC). Some objective analysis of cytology specimens is necessary. On the basis of our case review and cytological features described in previous articles, we developed a scoring system for malignant mesothelioma (SSMM) of effusion cytology to distinguish MM cells from RMC. Mesothelioma cells in effusions from 22 patients (20 pleural and 2 peritoneal mesotheliomas) were compared with RMC from 20 patients without obvious tumor cells and 50 effusions containing metastatic carcinoma cells. The SSMM is based on characteristic features of mesothelial and malignant cells. The total achievable score is 10 points: one point each is given for variety of cell size, cyanophilic cytoplasm with villosity/windows/bleb, sheet-like arrangement, mirror-ball-like cell clusters, nuclear atypia, and cannibalism, respectively. Further two points each are ascribed for acidophilic large nucleoli and multinucleated cells with more than eight nuclei. The total score for each of the 22 mesotheliomas was more than 5 points. On the other hand, all RMC and the 50 metastatic carcinoma cases scored less than 3 points, aside from two cases that were treated with OK432. No single characteristic feature was observed to be consistent within the 22 mesotheliomas analyzed. Ancillary use of immunocytochemistry, such as podoplanin (D2-40) and calretinin, supported the diagnostic accuracy of the SSMM. SSMM is useful for the differential diagnosis of MM. PMID:19572412

  20. Primary diffuse malignant peritoneal mesothelioma in a striped skunk (Mephitis mephitis).

    PubMed

    Kim, Su-Min; Oh, Yeonsu; Oh, Suk-Hun; Han, Jeong-Hee

    2016-03-01

    A 10-year-old female striped skunk (Mephitis mephitis) was admitted with severe abdominal distension and lethargy. Cytological examination of the peritoneal fluid revealed activated mesothelial cells. At necropsy, numerous growing together, projecting, 2 to 20 mm in diameter tawny to white masses were scattered throughout the peritoneum including the mesentery, omentum and intestinal serosa. Microscopically, the tumor was composed of prominent papillo-tubular structures, and immunohistochemically, the spindle to polygonal-shaped tumor cells with nuclear polymorphism were strongly reactive for calretinin. Based on those diagnostic features, the neoplasia was diagnosed as malignant mesothelioma. This is the first case report of mesothelioma in the skunk. PMID:26568187

  1. Primary diffuse malignant peritoneal mesothelioma in a striped skunk (Mephitis mephitis).

    PubMed

    Kim, Su-Min; Oh, Yeonsu; Oh, Suk-Hun; Han, Jeong-Hee

    2016-03-01

    A 10-year-old female striped skunk (Mephitis mephitis) was admitted with severe abdominal distension and lethargy. Cytological examination of the peritoneal fluid revealed activated mesothelial cells. At necropsy, numerous growing together, projecting, 2 to 20 mm in diameter tawny to white masses were scattered throughout the peritoneum including the mesentery, omentum and intestinal serosa. Microscopically, the tumor was composed of prominent papillo-tubular structures, and immunohistochemically, the spindle to polygonal-shaped tumor cells with nuclear polymorphism were strongly reactive for calretinin. Based on those diagnostic features, the neoplasia was diagnosed as malignant mesothelioma. This is the first case report of mesothelioma in the skunk.

  2. Primary diffuse malignant peritoneal mesothelioma in a striped skunk (Mephitis mephitis)

    PubMed Central

    KIM, Su-Min; OH, Yeonsu; OH, Suk-Hun; HAN, Jeong-Hee

    2015-01-01

    A 10-year-old female striped skunk (Mephitis mephitis) was admitted with severe abdominal distension and lethargy. Cytological examination of the peritoneal fluid revealed activated mesothelial cells. At necropsy, numerous growing together, projecting, 2 to 20 mm in diameter tawny to white masses were scattered throughout the peritoneum including the mesentery, omentum and intestinal serosa. Microscopically, the tumor was composed of prominent papillo-tubular structures, and immunohistochemically, the spindle to polygonal-shaped tumor cells with nuclear polymorphism were strongly reactive for calretinin. Based on those diagnostic features, the neoplasia was diagnosed as malignant mesothelioma. This is the first case report of mesothelioma in the skunk. PMID:26568187

  3. Malignant mesothelioma of tunica vaginalis: an extremely rare case presenting without risk factors

    PubMed Central

    Akin, Yigit; Bassorgun, Ibrahim; Basara, Isil; Yucel, Selcuk

    2015-01-01

    Testicular tumours have many different manifestations, including hydrocele formation. Herein, we present an extremely rare case of testicular mesothelioma presenting with left hydrocele, but without risk factors. Left radical inguinal orchidectomy was performed, and pathological examination revealed a malignant mesothelioma of the tunica vaginalis of the testis. No infiltration of the spermatic cord was evident, and upon advanced radiological evaluation, no sign of metastasis was detected. Follow-up was still ongoing in our urology outpatient clinic at the time of this report. Although hydrocele is a simple and common condition that is easy to diagnose, a detailed investigation should be performed. Thus, when encountering a patient with hydrocele, the clinician should evaluate the possibility of the presence of an underlying testicular/paratesticular tumour, including a rare one such as mesothelioma of the tunica vaginalis. PMID:25820862

  4. Survival of peritoneal malignant mesothelioma in Italy: a population-based study.

    PubMed

    Mirabelli, Dario; Roberti, Sara; Gangemi, Manuela; Rosato, Rosalba; Ricceri, Fulvio; Merler, Enzo; Gennaro, Valerio; Mangone, Lucia; Gorini, Giuseppe; Pascucci, Cristiana; Cavone, Domenica; Nicita, Carmela; Barbieri, Pietro Gino; Marinaccio, Alessandro; Magnani, Corrado; Montanaro, Fabio

    2009-01-01

    In some population-based studies, a shorter median survival was observed in peritoneal as compared with pleural, malignant mesothelioma, but in others, longer median survival times or higher proportions of long-term survivors were reported. Statistical instability could have caused these differences. We analyzed survival in peritoneal mesothelioma in a large and unselected population-based case series. Cases (338) registered from 1990 to 2001 by 9 Italian regional mesothelioma registries contributing to the network of the National Mesothelioma Registry were followed until December 31, 2005. Univariate (Kaplan-Meier) and multivariate (Cox proportional hazards regression) analyses of survival were performed according to selected individual characteristics, including limited treatment information in a subset of 194 cases. The results were compared with those obtained in a parallel study on pleural mesothelioma cases. Epithelioid histotype, younger age at diagnosis and, to a lesser degree, gender (women), and being diagnosed in a hospital with a thoracic surgery unit positively and significantly affected survival. The effect of treatment was positive but not statistically significant. No trend in the risk of death according to calendar period of diagnosis was present. Peritoneal mesothelioma cases had shorter median survival time than pleural cases, but a larger proportion of long-term survivors. Survival patterns after peritoneal and pleural mesothelioma differed markedly. Treatment was not associated with a statistically significant improvement in survival, but our study included cases first diagnosed before the introduction of the most recent therapeutic approaches. This provides a large historical comparison for future studies on survival trends at the population level.

  5. [Malignant mesothelioma (MM) in women: findings of the Mesothelioma Register of the Friuli Venezia Giulia Region].

    PubMed

    De Zotti, R; Damian, A; Muran, A

    2007-01-01

    During the period 2000-2003, the Mesothelioma Register of the Friuli Venezia Giulia identified 248 cases of MM, 44 of which (18%) were female. In 36 cases the diagnosis was "certain" and in 8 "probable" or "possible". Mean age at diagnosis was 72.8 years (SD = 12.7), and the site of the disease was the pleura in 93% of cases. Information about previous exposure to asbestos was collected in accordance with the guidelines of the National Mesothelioma Register Occupational exposure to asbestos was documented in only 8 cases and family exposure in 6 others. In the remaining cases the source of exposure was "unknown" because of insufficient data, or there were no data at all. The study highlights the role played by extra-occupational exposure to asbestos among women and the need for careful investigation into previous asbestos exposure in all females with MM. In order to improve our knowledge of the part played by factors other than occupational exposure to asbestos in triggering the disease, it is crucial to reduce he number of cases with no information or "unknown" exposure to this dangerous substance.

  6. Malignant pleural mesothelioma in a 17-year old boy: A case report and literature review

    PubMed Central

    Pérez-Guzmán, C.; Barrera-Rodríguez, R.; Portilla-Segura, J.

    2016-01-01

    Background Malignant pleural mesothelioma is a rare, invasive and often fatal neoplasm that develops in the thin layer of tissue surrounding the lungs known as the pleura. Although rare, mesotheliomas do occur in the young; their characteristics are distinct from those of older patients. Case presentation This is a case report of a 17-year-old boy who had moderate dyspnea, cough, right-sided pleuritic chest pain, fever, headache and no weight loss. Physical examination showed a right pleural effusion and chest roentgenograms revealed a homogenous opacity on lower right hemithorax. Biochemical analysis of pleural fluid showed hemorrhagic/turbid effusion compatible with exudate. It was initially treated as an empyema. The pleural fluid culture was negative. Adenosine deaminase level was 34.3 U/L (admission) and 19.02 U/L (two weeks after). Pleural fluid smear and culture for Mtb were negative. During the open pleural biopsy, thickened pleura and multiple pale yellow nodules in the lung were observed. The histopathological report was compatible with malignant pleural mesothelioma. With this diagnosis, a chemotherapy regimen with cisplatin was initiated. After two cycles, the patient had no clinical and radiological improvement. The patient is currently under regular follow up. Conclusion MPM is rare in young adults and its clinical presentation makes it different from mesothelioma in elderly patients, so it will be necessary to identify the new risk factors that can identify these patients. PMID:27222787

  7. Pleural plaques as risk indicators for malignant pleural mesothelioma: a necropsy-based study.

    PubMed

    Bianchi, C; Brollo, A; Ramani, L; Zuch, C

    1997-11-01

    Pleural plaque is recognized as a reliable marker of previous exposure to asbestos. However, it is controversial whether pleural plaque is a risk indicator for asbestos-related malignancies. In the present study, the thoracic cavities were examined for pleural plaques in 3,005 necropsies performed at the Monfalcone Hospital in people aged 15 years or older. Plaques were classified into three classes: 1, small (plaques measuring 1-4 cm in major diameter); 3, large (plaques involving a major part of a hemithorax); and 2, moderate (intermediate conditions). The prevalences of pleural plaques were 70.9% among men, and 24.0% among women. The prevalences of plaques (total plaques, various classes) among subjects with pleural mesothelioma were compared with those observed in the remaining cases. The series included 92 subjects with malignant pleural mesothelioma (82 men and 10 women). Mesothelioma cases showed higher prevalences of total plaques as well as higher prevalences of classes 1, 2, and 3, when compared with controls. These differences reached the statistical significance for total plaques, and classes 2, 3. The present data are consistent with the idea that pleural plaque is a risk indicator for pleural mesothelioma.

  8. Prognostic significance of p16/cdkn2a loss in pleural malignant mesotheliomas.

    PubMed

    Dacic, Sanja; Kothmaier, Hannelore; Land, Stephanie; Shuai, Yongli; Halbwedl, Iris; Morbini, Patrizia; Murer, Bruno; Comin, Camilla; Galateau-Salle, Françoise; Demirag, Funda; Zeren, Handan; Attanoos, Richard; Gibbs, Alan; Cagle, Philip; Popper, Helmut

    2008-12-01

    Homozygous deletion of p16/CDKN2A is the most common genetic abnormality in malignant mesotheliomas. The aim of this study was to determine prognostic significance of p16/CDKN2A loss in malignant pleural mesotheliomas (MPM) as defined by immunohistochemistry and fluorescence in situ hybridization (FISH). High-density tissue microarrays were constructed from archival formalin-fixed paraffin-embedded samples of 48 MPM. Long survival (LS) was defined as survival greater than 3 years from the time of diagnosis, and short survival was defined as less than 3 years from the time of diagnosis. Both loss of p16 protein expression by immunohistochemistry and homozygous deletion of p16 by FISH were associated with adverse prognosis. Female gender, positive p16 immunoexpression, and lack of p16/CDKN2A deletion significantly predicted the survival for the LS group. Statistical analysis showed a very strong correlation of immunohistochemistry and FISH data. Cases positive for p16 immunoexpression and negative for 9p21 deletion showed the best survival time. Our study is the first to demonstrate decreased frequency of homozygous deletion of 9p21 and loss of p16 immunoreactivity in pleural mesotheliomas from patients with long-term survival of greater than 3 years in contrast to patients with rapidly fatal mesotheliomas. A possible implementation of these tests into preoperative prognostication of MPM and therapeutic decisions should be considered.

  9. Malignant mesothelioma in 2004: How advanced technology and new drugs are changing the perspectives of mesothelioma patients. Highlights from the VIIth Meeting of the International Mesothelioma Interest Group.

    PubMed

    Porta, C; Ardizzoni, A; Gaudino, G; Maio, M; Mutti, L; Pinto, C; Porru, S; Puntoni, R; Tassi, G; Tognon, M

    2005-01-01

    Malignant mesothelioma (MMe) is a seemingly uncommon tumour whose incidence has in fact increased steadily and progressively over the last 30 years. Indeed, an actual "epidemic" is expected in the next 20 years, with over 1300 new cases a year till 2020 at least. Despite unquestionable improvement in the diagnostic methods at our disposal and the availability of new treatment strategies, the prognosis of MMe patients remains dramatically poor. For all the above reasons, translational research is the key to success; indeed, ever increasing knowledge of the molecular mechanisms underlying MMe pathogenesis could lead (and is actually leading) to new, hopefully more active, treatment options. To foster discussion among investigators working in this field, and to exchange different viewpoints concerning the newest advances in MMe pathogenesis and treatment, the VII International Mesothelioma Interest Group (IMIG) meeting was held in Brescia (Italy) between 24 and 26 June 2004 in cooperation with the Italian Group for the Study and Therapy of MMe (GIMe). The aim of this report is to summarize the most significant advances in the different disciplines applied to MMe presented and discussed during the IMIG meeting and how these advances will be changing the perspective of patients with MMe.

  10. Newly synthesized anticancer drug HUHS1015 is effective on malignant pleural mesothelioma.

    PubMed

    Kaku, Yoshiko; Nagaya, Hisao; Tsuchiya, Ayako; Kanno, Takeshi; Gotoh, Akinobu; Tanaka, Akito; Shimizu, Tadashi; Nakao, Syuhei; Tabata, Chiharu; Nakano, Takashi; Nishizaki, Tomoyuki

    2014-07-01

    The newly synthesized naftopidil analogue HUHS1015 reduced cell viability in malignant pleural mesothelioma cell lines MSTO-211H, NCI-H28, NCI-H2052, and NCI-H2452, with the potential greater than that for the anticancer drugs paclitaxel or cisplatin at concentrations higher than 30 μM. HUHS1015 induced both necrosis and apoptosis of MSTO-211H and NCI-H2052 cells. HUHS1015 upregulated expression of mRNAs for Puma, Hrk, and Noxa in MSTO-211H and NCI-H2052 cells, suggesting HUHS1015-induced mitochondrial apoptosis. HUHS1015 clearly suppressed tumor growth in mice inoculated with NCI-H2052 cells. Taken together, the results of the present study indicate that HUHS1015 could be developed as an effective anticancer drug for treatment of malignant pleural mesothelioma.

  11. The Third Italian Consensus Conference for Malignant Pleural Mesothelioma: State of the art and recommendations.

    PubMed

    Novello, S; Pinto, C; Torri, V; Porcu, L; Di Maio, M; Tiseo, M; Ceresoli, G; Magnani, C; Silvestri, S; Veltri, A; Papotti, M; Rossi, G; Ricardi, U; Trodella, L; Rea, F; Facciolo, F; Granieri, A; Zagonel, V; Scagliotti, G

    2016-08-01

    Malignant Pleural Mesothelioma (MPM) remains a relevant public health issue, and asbestos exposure is the most relevant risk factor. The incidence has considerably and constantly increased over the past two decades in the industrialized countries and is expected to peak in 2020-2025. In Italy, a standardized-rate incidence in 2011 among men was 3.5 and 1.25 per 100,000 in men and women, respectively, and wide differences are noted among different geographic areas. The disease remains challenging in terms of diagnosis, staging and treatment and an optimal strategy has not yet been clearly defined. The Third Italian Multidisciplinary Consensus Conference on Malignant Pleural Mesothelioma was held in Bari (Italy) in January 30-31, 2015. This Consensus has provided updated recommendations on the MPM management for health institutions, clinicians and patients. PMID:27286698

  12. Expression profile and function of Wnt signaling mechanisms in malignant mesothelioma cells

    SciTech Connect

    Fox, Simon A.; Richards, Alex K.; Kusumah, Ivonne; Perumal, Vanathi; Bolitho, Erin M.; Mutsaers, Steven E.; Dharmarajan, Arun M.

    2013-10-11

    Highlights: •Expression profile of Wnt pathway related genes in mesothelioma cells. •Differential expression of key Wnt pathway molecules and regulators. •Wnt3a stimulated mesothelioma growth whereas sFRP4 was inhibitory. •Targeting β-Catenin can sensitise mesothelioma cells to cytotoxic drugs. -- Abstract: Malignant mesothelioma (MM) is an uncommon and particularly aggressive cancer associated with asbestos exposure, which currently presents an intractable clinical challenge. Wnt signaling has been reported to play a role in the neoplastic properties of mesothelioma cells but has not been investigated in detail in this cancer. We surveyed expression of Wnts, their receptors, and other key molecules in this pathway in well established in vitro mesothelioma models in comparison with primary mesothelial cultures. We also tested the biological response of MM cell lines to exogenous Wnt and secreted regulators, as well as targeting β-catenin. We detected frequent expression of Wnt3 and Wnt5a, as well as Fzd 2, 4 and 6. The mRNA of Wnt4, Fzd3, sFRP4, APC and axin2 were downregulated in MM relative to mesothelial cells while LEF1 was overexpressed in MM. Functionally, we observed that Wnt3a stimulated MM proliferation while sFRP4 was inhibitory. Furthermore, directly targeting β-catenin expression could sensitise MM cells to cytotoxic drugs. These results provide evidence for altered expression of a number of Wnt/Fzd signaling molecules in MM. Modulation of Wnt signaling in MM may prove a means of targeting proliferation and drug resistance in this cancer.

  13. Extrapleural pneumonectomy in the multimodality therapy of malignant pleural mesothelioma. Results in 120 consecutive patients.

    PubMed Central

    Sugarbaker, D J; Garcia, J P; Richards, W G; Harpole, D H; Healy-Baldini, E; DeCamp, M M; Mentzer, S J; Liptay, M J; Strauss, G M; Swanson, S J

    1996-01-01

    OBJECTIVE: The authors examine the feasibility and efficacy of trimodality therapy in the treatment of malignant pleural mesothelioma and identify prognostic factors. BACKGROUND: Mesothelioma is a rare, uniformly fatal disease that has increased in incidence in recent decades. Single and bimodality therapies do not improve survival. METHODS: From 1980 to 1995, 120 patients underwent treatment for pathologically confirmed malignant mesothelioma at Brigham and Women's Hospital and Dana-Farber Cancer Institute (Boston, MA). Initial patient evaluation was performed by a multimodality team. Patients meeting selection criteria and with resectable disease identified by computed tomography scan or magnetic resonance imaging underwent extrapleural pneumonectomy followed by combination chemotherapy and radiotherapy. RESULTS: The cohort included 27 women and 93 men with a mean age of 56 years. Operative mortality rate was 5.0%, with a major morbidity rate of 22%. Overall survival rates were 45% at 2 years and 22% at 5 years. Two and 5-year survival rates were 65% and 27%, respectively, for patients with epithelial cell type, and 20% and 0%, respectively, for patients with sarcomatous or mixed histology tumors. Nodal involvement was a significant negative prognostic factor. Patients who were node negative with epithelial histology had 2- and 5-year survival rates of 74% and 39%, respectively. Involvement of margins at time of resection did not affect survival, except in the case of full-thickness, transdiaphragmatic invasion. Classification on the basis of a revised staging system stratified median survivals, which were 22, 17, and 11 months for stages I, II, and III, respectively (p = 0.04). CONCLUSIONS: Extrapleural pneumonectomy with adjuvant therapy is appropriate treatment for selected patients with malignant mesothelioma selected using a revised staging system. PMID:8813257

  14. Occupational exposure and regional variation of malignant mesothelioma in Norway, 1970-79.

    PubMed

    Mowé, G; Gylseth, B

    1986-01-01

    This investigation is based on a study of 117 men and 24 women with malignant mesothelioma registered by the Cancer Registry of Norway, 1970-79. The age-adjusted incidence rate in men for each county varied from 1.7 to 13.3 per million per year. Eighty-two percent of the men revealed possible occupational asbestos exposure. They were evenly distributed between counties with high and low mesothelioma incidence. Only 17% of the women had possible occupational asbestos exposure. Total lung fiber concentration was analyzed with scanning electron microscopy in 65 men and 13 women. The median lung fiber concentration in men was 2.4 million per gram of dried tissue (range less than 0.4-490), in women 1.0 million per gram (range less than 0.4-41), and in male controls less than 0.4 million per gram (range less than 0.4-4.8). The median year of first exposure was 1937 (range 1909-60) for men from counties with a high incidence rate and 1945 (range 1938-59) for men from counties with a low incidence rate. The counties with a high compared to a low incidence rate of malignant mesothelioma, 1970-79, showed an apparent difference in the percentage of population employed in industry in 1946. The regional variation in the incidence of malignant mesothelioma in men is mainly attributable to the proportion of population exposed to asbestos in industry per county prior the 1950s and the time since exposure started.(ABSTRACT TRUNCATED AT 250 WORDS)

  15. Advances in the diagnosis, treatment and prognosis of malignant pleural mesothelioma

    PubMed Central

    Zhang, Weiquan; Wu, Xinshu; Wu, Licun; Zhang, Weidong

    2015-01-01

    Malignant pleural mesothelioma (MPM) is a rare cancer originated from pleural mesothelial cells. MPM has been associated with long-term exposure to asbestos. The prognosis of MPM is poor due to the difficulty of making diagnosis in the early stage, the rapid progression, the high invasiveness and the lack of effective treatment. Although the incidence of MPM is low in China to date, it has a tendency to increase in the coming years. The variety of clinical features may cause the delay of diagnosis and high rate of misdiagnosis. The diagnosis of MPM is based on biopsy of the pleura and immunohistochemistry. As China has become the largest country in the consumption of asbestos, it would give rise to a new surge of MPM in the future. The current treatment of MPM is multimodality therapy including surgery, radiotherapy, chemotherapy and immunotherapy. Two surgical procedures are commonly applied: extrapleural pneumonectomy (EPP) and pleurectomy/decortication (P/D). Three dimensional conformal radiotherapy is used to denote a spectrum of radiation planning and delivery techniques that rely on the 3D imaging to define the tumor. Cisplatin combined with pemetrexed (PEM) is the first-line chemotherapy for MPM. The principal targets in immunotherapy include T cells (Treg), CTLA-4 and PD-1. The diagnosis, treatment and prognosis still remain a major challenge for clinical research and will do so for years to come. PMID:26366399

  16. Malignant mesothelioma after environmental exposure to blue asbestos.

    PubMed

    Hansen, J; de Klerk, N H; Eccles, J L; Musk, A W; Hobbs, M S

    1993-06-19

    To determine the magnitude of the population at risk from non-occupational exposure to crocidolite at Wittenoom, Western Australia (WA), a cohort of 4,890 residents who never worked for the mining company Australian Blue Asbestos (ABA) has been assembled from all 18,553 available records: the local school register, hospital attendances, the WA electoral roll, birth certificates, workers who answered a mailed questionnaire in 1979, participants in a cancer-prevention programme using vitamin-A dietary supplements, and other sources. The majority of subjects were relatives and friends of ABA employees, and nearly half the cohort were either born at Wittenoom or first went there as children under 10 years of age. As most residents were at Wittenoom when the mine and mill were in operation during the period 1943 to 1966, 82% were first exposed to crocidolite 20 or more years ago. The proportion of other workers (i.e., not employed by ABA) and their families increased once the mining operations ceased. To date, 24 cases of mesothelioma have been reported in this cohort: 9 males and 15 females. Time from first exposure to diagnosis ranged from 23 to 44 years and residence in Wittenoom ranged from 6 weeks to 11 years.

  17. Clinical features and epidemiology of malignant pleural mesothelioma in west Glasgow 1987-1992.

    PubMed

    McLean, A N; Patel, K R

    1997-04-01

    Malignant pleural mesothelioma is almost exclusively caused by exposure to asbestos dust. Recent epidemiological studies have suggested that the national incidence of disease may continue to rise until 2020 and that asbestos exposure in the building trade may be replacing shipyard related exposure as the main source of disease. The objective of the study was to determine if the incidence of malignant pleural mesothelioma was rising in the west of Glasgow from 1987-1992 and whether there had been a change in clinical features compared to previous studies from the same population. Case notes identified from coded returns and the local cancer registry were retrospectively examined: 144 cases were identified. This is an increase in incidence of over 50% compared to the previous study but the yearly incidence did not rise over the period studied. The clinical features and survival times have not changed since previous studies: median survival remains 30 weeks. Only three patients were given definitive treatment reflecting the lack of effective therapy. We suggest that the incidence of mesothelioma in the population studied may already have peaked resulting from the decline in the local shipyard industry over 20 years ago. Non-shipyard sources of asbestos exposure may be less important in this area.

  18. Expert opinions of the first italian consensus conference on the management of malignant pleural mesothelioma.

    PubMed

    Pinto, Carmine; Ardizzoni, Andrea; Betta, Pier Giacomo; Facciolo, Francesco; Tassi, Gianfranco; Tonoli, Sandro; Zompatori, Maurizio; Alessandrini, Gabriele; Magrini, Stefano Maria; Tiseo, Marcello; Mutri, Vita

    2011-02-01

    Malignant pleural mesothelioma (MPM) is a very important public health issue. A large amount of data indicates a relationship between mesothelioma and asbestos exposure. The incidence has both considerably and constantly increased over the past 2 decades in the industrialized countries and is expected to peak in 2010-2020. In Italy, a standardized-rate incidence in 2002 among men was 2.98 per 100,000 and 0.98 per 100,000 among women, with wide differences from one region to another. Stage diagnosis and definition may be difficult. Management of patients with MPM remains complex, so an optimal treatment strategy has not yet been clearly defined. The First Italian Consensus Conference on Malignant Pleural Mesothelioma was held Bologna (Italy) in May 20, 2008. The Consensus Conference was given the patronage of the Italian scientific societies AIOM, AIRO, AIPO, SIC, SICO, SICT, SIAPEC-IAP, AIOT, GOAM, and GIME. This Consensus did not answer all of the unresolved questions in MPM management, but the Expert Opinions have nonetheless provided recommendations, presented in this report, on MPM management for clinicians and patients. PMID:20414089

  19. Functional Alteration of Natural Killer Cells and Cytotoxic T Lymphocytes upon Asbestos Exposure and in Malignant Mesothelioma Patients

    PubMed Central

    Nishimura, Yasumitsu; Kumagai-Takei, Naoko; Matsuzaki, Hidenori; Lee, Suni; Maeda, Megumi; Kishimoto, Takumi; Fukuoka, Kazuya; Nakano, Takashi; Otsuki, Takemi

    2015-01-01

    Malignant mesothelioma is caused by exposure to asbestos, which is known to have carcinogenic effects. However, the development of mesothelioma takes a long period and results from a low or intermediate dose of exposure. These findings have motivated us to investigate the immunological effects of asbestos exposure and analyze immune functions of patients with mesothelioma and pleural plaque, a sign of exposure to asbestos. Here, we review our knowledge concerning natural killer (NK) cells and cytotoxic T lymphocytes (CTL). NK cells showed impaired cytotoxicity with altered expression of activating receptors upon exposure to asbestos, while induction of granzyme+ cells in CD8+ lymphocytes was suppressed by asbestos exposure. It is interesting that a decrease in NKp46, a representative activating receptor, is common between NK cells in PBMC culture with asbestos and those of mesothelioma patients. Moreover, it was observed that CD8+ lymphocytes may be stimulated by some kind of “nonself” cells in plaque-positive individuals and in mesothelioma patients, whereas CTL in mesothelioma is impaired by poststimulation maintenance of cytotoxicity. These findings suggest that analysis of immunological parameters might contribute to the evaluation of health conditions of asbestos-exposed individuals and to a greater understanding of the pathology of malignant mesothelioma. PMID:26161391

  20. Biomolecular and clinical practice in malignant pleural mesothelioma and lung cancer: what thoracic surgeons should know†

    PubMed Central

    Opitz, Isabelle; Bueno, Raphael; Lim, Eric; Pass, Harvey; Pastorino, Ugo; Boeri, Mattia; Rocco, Gaetano

    2014-01-01

    Today, molecular-profile-directed therapy is a guiding principle of modern thoracic oncology. The knowledge of new biomolecular technology applied to the diagnosis, prognosis, and treatment of lung cancer and mesothelioma should be part of the 21st century thoracic surgeons' professional competence. The European Society of Thoracic Surgeons (ESTS) Biology Club aims at providing a comprehensive insight into the basic biology of the diseases we are treating. During the 2013 ESTS Annual Meeting, different experts of the field presented the current knowledge about diagnostic and prognostic biomarkers in malignant pleural mesothelioma including new perspectives as well as the role and potential application of microRNA and genomic sequencing for lung cancer, which are summarized in the present article. PMID:24623168

  1. Management of malignant pleural mesothelioma-part 2: therapeutic approaches : Consensus of the Austrian Mesothelioma Interest Group (AMIG).

    PubMed

    Hoda, Mir Alireza; Klikovits, Thomas; Arns, Madeleine; Dieckmann, Karin; Zöchbauer-Müller, Sabine; Geltner, Christian; Baumgartner, Bernhard; Errhalt, Peter; Machan, Barbara; Pohl, Wolfgang; Hutter, Jörg; Eckmayr, Josef; Studnicka, Michael; Flicker, Martin; Cerkl, Peter; Klepetko, Walter

    2016-09-01

    Treatment of malignant pleural mesothelioma (MPM) depends on performance status of the patient, tumor stage, and histological differentiation. Chemotherapy (CHT) can be administered as first- and second-line treatment in unresectable MPM or as neoadjuvant or adjuvant treatment before or after surgery. A combination of an antifolate and platinum-based CHT is the only approved standard of care. Several targeted and immunotherapies are in evaluation and further studies are warranted to determine the therapeutic value of these new treatment options. Radiotherapy (RT) can be considered either as adjuvant treatment after surgery or for palliation of pain-related tumor growth. Recent data support the use of RT in a neoadjuvant setting. Macroscopic complete resection by pleurectomy/decortication (P/D) or extrapleural pneumonectomy (EPP) is indicated in selected patients with good performance status. Surgery should only be applied as part of a multimodality treatment (MMT) in combination with chemo- and/or radiotherapy. In a large number of cases, palliative attempts are needed to improve quality of life and to achieve symptom control. PMID:27457872

  2. Management of malignant pleural mesothelioma-part 2: therapeutic approaches : Consensus of the Austrian Mesothelioma Interest Group (AMIG).

    PubMed

    Hoda, Mir Alireza; Klikovits, Thomas; Arns, Madeleine; Dieckmann, Karin; Zöchbauer-Müller, Sabine; Geltner, Christian; Baumgartner, Bernhard; Errhalt, Peter; Machan, Barbara; Pohl, Wolfgang; Hutter, Jörg; Eckmayr, Josef; Studnicka, Michael; Flicker, Martin; Cerkl, Peter; Klepetko, Walter

    2016-09-01

    Treatment of malignant pleural mesothelioma (MPM) depends on performance status of the patient, tumor stage, and histological differentiation. Chemotherapy (CHT) can be administered as first- and second-line treatment in unresectable MPM or as neoadjuvant or adjuvant treatment before or after surgery. A combination of an antifolate and platinum-based CHT is the only approved standard of care. Several targeted and immunotherapies are in evaluation and further studies are warranted to determine the therapeutic value of these new treatment options. Radiotherapy (RT) can be considered either as adjuvant treatment after surgery or for palliation of pain-related tumor growth. Recent data support the use of RT in a neoadjuvant setting. Macroscopic complete resection by pleurectomy/decortication (P/D) or extrapleural pneumonectomy (EPP) is indicated in selected patients with good performance status. Surgery should only be applied as part of a multimodality treatment (MMT) in combination with chemo- and/or radiotherapy. In a large number of cases, palliative attempts are needed to improve quality of life and to achieve symptom control.

  3. A multicentre phase II study of cisplatin and gemcitabine for malignant mesothelioma

    PubMed Central

    Nowak, A K; Byrne, M J; Williamson, R; Ryan, G; Segal, A; Fielding, D; Mitchell, P; Musk, A W; Robinson, B W S

    2002-01-01

    Our previous phase II study of cisplatin and gemcitabine in malignant mesothelioma showed a 47.6% (95% CI 26.2–69.0%) response rate with symptom improvement in responding patients. Here we confirm these findings in a multicentre setting, and assess the effect of this treatment on quality of life and pulmonary function. Fifty-three patients with pleural malignant mesothelioma received cisplatin 100 mg m−2 i.v. day 1 and gemcitabine 1000 mg m−2 i.v. days 1, 8, and 15 of a 28 day cycle for a maximum of six cycles. Quality of life and pulmonary function were assessed at each cycle. The best response achieved in 52 assessable patients was: partial response, 17 (33%, 95% CI 20–46%); stable disease, 31 (60%); and progressive disease, four (8%). The median time to disease progression was 6.4 months, median survival from start of treatment 11.2 months, and median survival from diagnosis 17.3 months. Vital capacity and global quality of life remained stable in all patients and improved significantly in responding patients. Major toxicities were haematological, limiting the mean relative dose intensity of gemcitabine to 75%. This schedule of cisplatin and gemcitabine is active in malignant mesothelioma in a multicentre setting. Investigation of alternative scheduling is needed to decrease haematological toxicity and increase the relative dose intensity of gemcitabine whilst maintaining response rate and quality of life. British Journal of Cancer (2002) 87, 491–496. doi:10.1038/sj.bjc.6600505 www.bjcancer.com © 2002 Cancer Research UK PMID:12189542

  4. A Histomorphologic Grading System That Predicts Overall Survival in Diffuse Malignant Peritoneal Mesothelioma With Epithelioid Subtype

    PubMed Central

    Blackham, Aaron U.; Levine, Edward; Russell, Greg; Votanopoulos, Konstantinos I.; Stewart, John H.; Shen, Perry; Geisinger, Kim R.; Sirintrapun, Sahussapont J.

    2016-01-01

    Diffuse malignant peritoneal mesothelioma (MPeM) is rare and arises from peritoneal serosal surfaces. Although it shares similar histomorphology with its counterpart, malignant pleural mesothelioma, etiologies, clinical courses, and therapies differ. Nuclear grading and level of mitoses have been correlated with prognosis in malignant pleural mesothelioma with epithelioid subtype. Whether nuclear grading and level of mitoses correlate with prognosis in MPeM is still unknown. Our study utilizes a 2 tier system incorporating nuclear features and level of the mitoses to stratify cases of MPeM with epithelioid subtype. Fifty-one cases of MPeM with clinical follow-up underwent retrospective microscopic review. From that subset, 46 cases were of epithelioid subtype, which were then stratified into a low-grade or high-grade tier. Survival times were calculated on the basis of Kaplan-Meier analysis. The low-grade tier had higher overall survival with a median of 11.9 years and 57% at 5 years when compared with the high-grade tier with a median of 3.3 years and 21% at 5 years (P=0.002). Although not statistically significant, the low-grade tier had higher progression-free survival with a median of 4.7 years and 65% at 5 years when compared with the high-grade tier with a median of 1.9 years and 35% at 5 years (P=0.089). Our study is first to specifically evaluate and correlate nuclear features and level of mitoses with overall survival in MPeM with epithelioid subtype. PMID:27438989

  5. Combinatorial anti-angiogenic gene therapy in a human malignant mesothelioma model.

    PubMed

    Kubo, Shuji; Takagi-Kimura, Misato; Kasahara, Noriyuki

    2015-08-01

    Anti-angiogenic gene therapy represents a promising strategy for cancer; however, it has rarely been tested in malignant mesothelioma, a highly aggressive tumor associated with asbestos with poor prognosis. In the present study, we investigated whether anti-angiogenic factors such as angiostatin, endostatin and the soluble form of vascular endothelial growth factor receptor 2 (sFlk1) were able to inhibit endothelial cell proliferation via lentivirus-mediated gene transfer into malignant mesothelioma cells in culture. We also assessed whether a dual-agent strategy had greater therapeutic benefit. Human malignant pleural mesothelioma MSTO-211H cells were transduced using lentiviral vectors that individually expressed angiostatin, endostatin and sFlk1 and linked to enhanced green fluorescent protein (EGFP) marker gene expression via an internal ribosome entry site. The lentivirus expressing EGFP alone was used as a control. The resultant cells designated as MSTO-A, MSTO-E, MSTO-F and MSTO-C were confirmed by western blot analysis and fluorescence microscopy to stably express the corresponding proteins. No differences were observed in the in vitro growth rates between any of these cells. However, co-culture of MSTO-A, MSTO-E and MSTO-F showed significant suppression of human umbilical endothelial cell growth in vitro compared with that of MSTO-C. Furthermore, a combination of any two among MSTO-A, MSTO-E and MSTO-F significantly enhanced efficacy. These results suggest that combinatorial anti-angiogenic gene therapy targeting different pathways of endothelial growth factor signaling has the potential for greater therapeutic efficacy than that of a single-agent regimen.

  6. What is the survival after surgery for localized malignant pleural mesothelioma?†

    PubMed Central

    Gelvez-Zapata, Sandra M.; Gaffney, Daniel; Scarci, Marco; Coonar, Aman S.

    2013-01-01

    A best evidence topic in thoracic surgery was written according to a structured protocol. This was with the purpose of assisting our management of patients with localized malignant mesothelioma of the pleura (LMM). Although the terminology is used inconsistently, this variant has been formally defined by the WHO as a distinct entity defined as localized disease histologically identical to the diffuse form but without any evidence of pleural spread. Treatments for LMM include different combinations of surgery, chemotherapy and radiotherapy. There is an impression that LMM may have a better outcome than the commoner diffuse form of malignant mesothelioma that has been reported to have a survival between 8 and 14 months. In order to advise our patients on prognosis, we studied the duration of survival after surgical resection of LMM. A total of 150 papers were found, of which 16 represented the best evidence to answer the question. The authors, journal, date, country of publication, study type, relevant outcomes and results of these papers are tabulated. It is difficult to combine the results of these 16 papers because both treatments and results are reported differently. Some report median survival (range: 11.6–36 months) and others disease-free survival (range: 0 months to 11 years). Median survival to the longest follow-up was 29 months when calculated by pooling data from informative papers using the Kaplan–Meier method. Our review suggests that survival in LMM is longer than that generally quoted for the more common diffuse form of malignant mesothelioma. Hence, aggressive treatment of LMM may be reasonable in appropriate patients. PMID:23328002

  7. Pleural malignant mesothelioma in Tuscany, Italy (1970-1988): II. Identification of occupational exposure to asbestos.

    PubMed

    Chellini, E; Fornaciai, G; Merler, E; Paci, E; Costantini, A S; Silvestri, S; Zappa, M; Buiatti, E

    1992-01-01

    Following the finding of an unexpected cluster of mesotheliomas in textile workers, a surveillance system of malignant mesotheliomas was implemented in the region of Tuscany, Italy. This article reports on the investigation of 124 cases of mesothelioma diagnosed and reviewed by the Institutes of Morbid Anatomy and Histopathology at the Universities of Florence, Pisa, and Siena between 1970 and 1988. A complete occupational and asbestos exposure history was assessed through a semi-structured questionnaire directly administered to resident cases of Tuscany or, if deceased, to their closest living relatives, for a total of 100 interviews. The hypothesis of past occupational asbestos exposure was verified and documented. Seventy-two cases have been classified as occupationally exposed to asbestos; four were classified in the category of "possible domestic" exposure to asbestos. For two others, the role of other risk factors was stressed, and for 22 cases, either no asbestos exposure was found or the available data were not adequate to define it. The present study allowed identification of some unknown or scarcely known occupational asbestos exposures in the study area.

  8. Indomethacin augments lymphokine-activated killer cell generation by patients with malignant mesothelioma

    SciTech Connect

    Manning, L.S.; Bowman, R.V.; Davis, M.R.; Musk, A.W.; Robinson, B.W. )

    1989-10-01

    Human malignant mesothelioma (MM) cells are resistant to natural killer (NK) cell lysis but susceptible to lysis by lymphokine-activated killer (LAK) cells from control individuals. The present study was performed to determine the capacity of patients with MM (n = 22) and individuals occupationally exposed to asbestos (the major population at risk of developing this disease, n = 52) to generate LAK cells capable of effectively lysing human mesothelioma cells. Compared to controls (n = 20), both patient groups demonstrated significantly depressed LAK cell activity against mesothelioma tumor cell targets (55 +/- 3% lysis by controls vs 34 +/- 3% lysis by patients with MM, P less than 0.005; and 45 +/- 3% lysis by asbestos-exposed individuals, P less than 0.025). Addition of 10 micrograms/ml indomethacin during LAK cell generation restored normal LAK cell activity for patients with MM (52 +/- 6% lysis of cultured human MM cells, P = NS compared to controls), suggesting that the defective cytolytic cell function observed in some patients with MM is a result of prostaglandin-induced immunosuppression. The ability of indomethacin to restore suppressed LAK cell activity in patients with MM suggests that the concomitant use of this agent in ex vivo LAK cell generation and in patients undergoing interleukin/LAK cell therapy may be beneficial.

  9. Malignant mesothelioma and duration of asbestos exposure: correlation with tissue mineral fibre content.

    PubMed

    Roggli, V L

    1995-06-01

    Among 441 cases of malignant mesothelioma in the author's files, there were 324 for whom reliable information was available regarding the duration of exposure to asbestos. Included were 298 pleural and 26 peritoneal mesotheliomas. The mean duration of exposure to asbestos was 23 +/- 14 years for all cases, and was not different for the pleural and peritoneal groups. Lung tissue was available for analysis of mineral fibre content in 94 cases. Linear regression analysis showed a significant correlation between duration of exposure and asbestos bodies per gramme of wet lung as determined by light microscopy, and between duration of exposure and total uncoated fibres (5 microns or greater in length) as well as commercial amphibole fibres per gramme as determined by scanning electron microscopy (P < 0.05). Individuals with direct exposures had on average higher asbestos contents than patients with indirect exposures. Furthermore, for each duration of exposure, shipyard workers had on average higher asbestos contents than non-shipyard workers (P < 0.05). Mesotheliomas are associated with a wide range of durations of exposure to asbestos and pulmonary asbestos burdens, and there is a rough correlation between duration of exposure and pulmonary commercial amphibole content.

  10. Pathogenesis of malignant pleural mesothelioma and the role of environmental and genetic factors

    PubMed Central

    Weiner, Shoshana J; Neragi-Miandoab, Siyamek

    2008-01-01

    Malignant pleural mesothelioma (MPM) is a rare, aggressive tumor for which no effective therapy exists despite the discovery of many possible molecular and genetic targets. Many risk factors for MPM development have been recognized including environmental exposures, genetic susceptibility, viral contamination, and radiation. However, the late stage of MPM diagnosis and the long latency that exists between some exposures and diagnosis have made it difficult to comprehensively evaluate the role of risk factors and their downstream molecular effects. In this review, we discuss the current molecular and genetic contributors in MPM pathogenesis and the risk factors associated with these carcinogenic processes. PMID:18662397

  11. New and emerging therapeutic options for malignant pleural mesothelioma: review of early clinical trials

    PubMed Central

    Kotova, Svetlana; Wong, Raymond M; Cameron, Robert B

    2015-01-01

    Malignant pleural mesothelioma (MPM) is a rare tumor that is challenging to control. Despite some benefit from using the multimodality-approach (surgery, combination chemotherapy and radiation), survival remains poor. However, current research produced a list of potential therapies. Here, we summarize significant new preclinical and early clinical developments in treatment of MPM, which include mesothelin specific antibody and toxin therapies, interleukin-4 (IL-4) receptor toxins, dendritic cell vaccines, immune checkpoint inhibitors, and gene-based therapies. In addition, several local modalities such as photodynamic therapy, postoperative lavage using betadine, and cryotherapy for local recurrence, have also shown to be effective for local control of disease. PMID:25670913

  12. Malignant mesothelioma induced by asbestos and zeolite in the mouse peritonenal cavity

    SciTech Connect

    Suzuki, Y.; Kohyama, N.

    1984-10-01

    The carcinogenicity of asbestos (amosite and chrysotile) and zeolite (fibrous erionite, mordenite, and synthetic zeolite 4A) were studied in the peritoneum of 586 BALB/C male mice after a single intraperitoneal or intraabdominal wall injection. Tumors developed in 93 of 394 animals (23.6%) treated with asbestos or fibrous erionite 7 months or more after administration. All of the induced peritoneal tumors were intimately associated with marked peritoneal fibrosis, in which asbestos or erionite fibers were regularly detected. Histopathologically, 83 of 93 were consistent with malignant mesotheliomas. Other tumors consisted of 6 plasmacytomas, 1 histiocytoma, 1 liposarcoma, 1 osteosarcoma, and 1 adenocarcinoma of the pancreas. Two of the cases of mesotheliomas were associated with plasmacytoma. In many instances, the primary site of the mesotheliomas seemed to be multiple, the favorite sites being the omentum, mesentery, serosae of the gastrointestinal and genital organs, the diaphragm, the capsule of the liver and spleen, and the abdominal wall peritoneum. In addition to the 93 peritoneal tumors, 3 extraperitoneal tumors (1 fibrosarcoma and 2 rhabdomyosarcomas) were induced by amosite which was probably accidentally injected into the extraperitoneal connective tissue and the striated muscle tissue of the abdominal wall, respectively. These three tumors were also intimately associated with focal fibrosis in which amosite fibers were detected. Among the three different types of zeolite, only fibrous erionite showed striking carcinogenicity and marked fibrogenicity. The erionite-induced mesotheliomas were similar to those induced by asbestos in exhibiting long latency, in gross appearance, in histology, and in close association with fibrosis.

  13. Identification of cancer stem cell markers in human malignant mesothelioma cells

    SciTech Connect

    Ghani, Farhana Ishrat; Yamazaki, Hiroto; Iwata, Satoshi; Okamoto, Toshihiro; Aoe, Keisuke; Okabe, Kazunori; Mimura, Yusuke; Fujimoto, Nobukazu; Kishimoto, Takumi; Yamada, Taketo; Xu, C. Wilson; Morimoto, Chikao

    2011-01-14

    Research highlights: {yields} We performed serial transplantation of surgical samples and established new cell lines of malignant mesothelioma. {yields} SP cell and expressions of CD9/CD24/CD26 were often observed in mesothelioma cell lines. {yields} SP and CD24{sup +} cells proliferated by asymmetric cell division-like manner. CD9{sup +} and CD24{sup +} cells have higher potential to generate spheroid colony. {yields} The marker-positive cells have clear tendency to generate larger tumors in mice. -- Abstract: Malignant mesothelioma (MM) is an aggressive and therapy-resistant neoplasm arising from the pleural mesothelial cells and usually associated with long-term asbestos exposure. Recent studies suggest that tumors contain cancer stem cells (CSCs) and their stem cell characteristics are thought to confer therapy-resistance. However, whether MM cell has any stem cell characteristics is not known. To understand the molecular basis of MM, we first performed serial transplantation of surgical samples into NOD/SCID mice and established new cell lines. Next, we performed marker analysis of the MM cell lines and found that many of them contain SP cells and expressed several putative CSC markers such as CD9, CD24, and CD26. Interestingly, expression of CD26 closely correlated with that of CD24 in some cases. Sorting and culture assay revealed that SP and CD24{sup +} cells proliferated by asymmetric cell division-like manner. In addition, CD9{sup +} and CD24{sup +} cells have higher potential to generate spheroid colony than negative cells in the stem cell medium. Moreover, these marker-positive cells have clear tendency to generate larger tumors in mouse transplantation assay. Taken together, our data suggest that SP, CD9, CD24, and CD26 are CSC markers of MM and could be used as novel therapeutic targets.

  14. A one-generation cluster of malignant mesothelioma within a family reveals exposure to asbestos-contaminated jute bags in Naples, Italy.

    PubMed

    Ascoli, V; Carnovale-Scalzo, C; Nardi, F; Efrati, C; Menegozzo, M

    2003-01-01

    Substantial evidence supports the role of asbestos in malignant mesothelioma. Clustering for this malignancy among relatives not only suggests genetic susceptibility as a relevant component but also provides a clue to investigate non-occupational sources of exposure. We identified five cases of malignant mesothelioma within one family with exposure to asbestos experienced during childhood, as 'next door' residents of a workshop recycling asbestos-contaminated jute sacks in Naples, Italy. This cluster discloses the health risk in the reuse of bags that previously had contained asbestos. Furthermore, it emphasizes the role of asbestos in the genetic-environmental interaction issue of malignant mesothelioma.

  15. Multimodality imaging for characterization, classification, and staging of malignant pleural mesothelioma.

    PubMed

    Nickell, Larry T; Lichtenberger, John P; Khorashadi, Leila; Abbott, Gerald F; Carter, Brett W

    2014-10-01

    Malignant pleural mesothelioma (MPM) is the most common primary malignancy of the pleura and is associated with asbestos exposure in approximately 80% of patients. The patient prognosis is poor, with a median survival of 9-17 months after diagnosis. However, improved survival and decreased morbidity and mortality have been demonstrated when the diagnosis is made in the early stages of disease and specific treatment strategies are implemented. A staging system that focuses on the extent of primary tumor (T), lymph node involvement (N), and metastatic disease (M) has been devised by the International Mesothelioma Interest Group and emphasizes factors related to overall survival. Radiologists should recognize the manifestations of MPM across multiple imaging modalities, translate these findings into the updated staging system, and understand the effects of appropriate staging on treatment and survival. Computed tomography (CT) remains the primary imaging modality used to evaluate MPM and efficiently demonstrates the extent of primary tumor, intrathoracic lymphadenopathy, and extrathoracic spread. However, additional imaging modalities, such as magnetic resonance (MR) imaging of the thorax and positron emission tomography (PET)/CT with fluorodeoxyglucose, have emerged in recent years and are complementary to CT for disease staging and evaluation of patients with MPM. Thoracic MR imaging is particularly useful for identifying invasion of the chest wall, mediastinum, and diaphragm, and PET/CT can accurately demonstrate intrathoracic and extrathoracic lymphadenopathy and metastatic disease.

  16. A pilot study of volumetric-modulated arc therapy for malignant pleural mesothelioma.

    PubMed

    Runxiao, Li; Yankun, Cao; Lan, Wang

    2016-01-01

    Malignant pleural mesothelioma (MPM) is an extremely difficult disease to treat. This pilot study investigates the feasibility of using volumetric-modulated arc therapy (VMAT) for malignant pleural mesothelioma (MPM), and compares VMAT to static field intensity-modulated radiotherapy (IMRT) for five patients. To identify the best treatment technique for MPM, in five patients, we made a representative comparative analysis of two kinds of techniques for radiation therapy planning: IMRT and VMAT. The plans were created for an Elekta Synergy linear accelerator with 6 MV photons using Oncentra version 4.3 treatment planning system. Dose prescription was 50 Gy to the average of the planning target volume (PTV). PTV coverage and homogeneity, dose of organs at risk, numbers of segments, MUs, and delivery time were evaluated for all techniques. VMAT allowed better homogeneous and conformity indices compared with IMRT (HI = 0.17 vs. 0.12, CI = 0.64 vs. 0.77, respectively, p < 0.05). VMAT plan had a significantly shorter delivery time (326 s) compared with in IMRT plans (510 s), (p < 0.05). In the dose verification, an average of 93.16% of the detector points passed the 3%/3 mmγ criterion for VMAT plans, while in IMRT plans the dose verification was 95.12%.(p > 0.05). PMID:27074478

  17. Docetaxel for malignant mesothelioma: phase II study of the Eastern Cooperative Oncology Group.

    PubMed

    Belani, Chandra P; Adak, Sudeshna; Aisner, Seena; Stella, Philip J; Levitan, Nathan; Johnson, David H

    2004-07-01

    This Eastern Cooperative Oncology Group phase II trial was conducted to study the effectiveness of docetaxel in patients with malignant mesothelioma. Patients were treated with docetaxel 100 mg/m2 intravenously administered as a 1-hour infusion repeated every 3 weeks. The study accrued a total of 20 patients, 1 of whom was considered ineligible. Of the 19 eligible patients, 1 patient (5%) achieved a partial response, 3 patients (16%) had stable disease, 11 patients (58%) had progressive disease, and 4 patients (21%) were unevaluable. The study was terminated after the first accrual stage because of an insufficient number of complete or partial responses. To date, only 1 patient (with stable disease) has not relapsed. The estimated median survival time is 4 months and the estimated median time to treatment failure is 2.2 months. There were 3 early deaths associated with the treatment regimen: severe gastrointestinal toxicity, hemorrhage, and an acute pulmonary event. Docetaxel as a single agent does not demonstrate evidence of activity in malignant mesothelioma.

  18. Malignant peritoneal mesothelioma in a patient with intestinal fistula, incisional hernia and abdominal infection: A case report

    PubMed Central

    HONG, SEN; BI, MIAO-MIAO; ZHAO, PING-WEI; WANG, XU; KONG, QING-YANG; WANG, YONG-TAO; WANG, LEI

    2016-01-01

    Malignant mesothelioma is a rare type of cancer, most commonly associated with exposure to asbestos. Mesothelioma of the peritoneum, the membrane lining the abdominal cavity, is extremely rare. The current study reports the case of a 60-year-old female who presented with intestinal fistula, recurrent incisional hernia and abdominal infection, with no history of asbestos exposure, and was diagnosed with clear cell MPM. Computed tomography scans of the abdomen revealed extensive small bowel adhesions and massive peritoneal effusion. Histological examination of biopsy specimens indicated a diagnosis of malignant peritoneal mesothelioma with clear cell morphology. A laparotomy was performed, with subsequent resection of the bowel with fistula. Follow-up examination performed at 1-year post-surgery revealed that the patient was alive and in generally good health. PMID:26998119

  19. Inhibition of autophagy potentiates pemetrexed and simvastatin-induced apoptotic cell death in malignant mesothelioma and non-small cell lung cancer cells

    PubMed Central

    Jung, Jae-Wan; Kwon, Su-Jin; Park, Do-Sim; Cha, Byong-Ki; Oh, Seon-Hee; Yoon, Kwon-Ha; Jeong, Eun-Taik; Kim, Hak-Ryul

    2015-01-01

    Pemetrexed, a multitarget antifolate used to treat malignant mesothelioma and non-small cell lung cancer (NSCLC), has been shown to stimulate autophagy. In this study, we determined whether autophagy could be induced by pemetrexed and simvastatin cotreatment in malignant mesothelioma and NSCLC cells. Furthermore, we determined whether inhibition of autophagy drives apoptosis in malignant mesothelioma and NSCLC cells. Malignant mesothelioma MSTO-211H and A549 NSCLC cells were treated with pemetrexed and simvastatin alone and in combination to evaluate their effect on autophagy and apoptosis. Cotreatment with pemetrexed and simvastatin induced greater caspase-dependent apoptosis and autophagy than either drug alone in malignant mesothelioma and NSCLC cells. 3-Methyladenine (3-MA), ATG5 siRNA, bafilomycin A, and E64D/pepstatin A enhanced the apoptotic potential of pemetrexed and simvastatin, whereas rapamycin and LY294002 attenuated their induction of caspase-dependent apoptosis. Our data indicate that pemetrexed and simvastatin cotreatment augmented apoptosis and autophagy in malignant mesothelioma and NSCLC cells. Inhibition of pemetrexed and simvastatin-induced autophagy was shown to enhance apoptosis, suggesting that this could be a novel therapeutic strategy against malignant mesothelioma and NSCLC. PMID:26334320

  20. Inhibition of autophagy potentiates pemetrexed and simvastatin-induced apoptotic cell death in malignant mesothelioma and non-small cell lung cancer cells.

    PubMed

    Hwang, Ki-Eun; Kim, Young-Suk; Jung, Jae-Wan; Kwon, Su-Jin; Park, Do-Sim; Cha, Byong-Ki; Oh, Seon-Hee; Yoon, Kwon-Ha; Jeong, Eun-Taik; Kim, Hak-Ryul

    2015-10-01

    Pemetrexed, a multitarget antifolate used to treat malignant mesothelioma and non-small cell lung cancer (NSCLC), has been shown to stimulate autophagy. In this study, we determined whether autophagy could be induced by pemetrexed and simvastatin cotreatment in malignant mesothelioma and NSCLC cells. Furthermore, we determined whether inhibition of autophagy drives apoptosis in malignant mesothelioma and NSCLC cells. Malignant mesothelioma MSTO-211H and A549 NSCLC cells were treated with pemetrexed and simvastatin alone and in combination to evaluate their effect on autophagy and apoptosis. Cotreatment with pemetrexed and simvastatin induced greater caspase-dependent apoptosis and autophagy than either drug alone in malignant mesothelioma and NSCLC cells. 3-Methyladenine (3-MA), ATG5 siRNA, bafilomycin A, and E64D/pepstatin A enhanced the apoptotic potential of pemetrexed and simvastatin, whereas rapamycin and LY294002 attenuated their induction of caspase-dependent apoptosis. Our data indicate that pemetrexed and simvastatin cotreatment augmented apoptosis and autophagy in malignant mesothelioma and NSCLC cells. Inhibition of pemetrexed and simvastatin-induced autophagy was shown to enhance apoptosis, suggesting that this could be a novel therapeutic strategy against malignant mesothelioma and NSCLC.

  1. Mechanisms of cisplatin-induced cell death in malignant mesothelioma cells: role of inhibitor of apoptosis proteins (IAPs) and caspases.

    PubMed

    Cregan, Inez L; Dharmarajan, Arun M; Fox, Simon A

    2013-02-01

    Malignant mesothelioma (MM) is an aggressive and highly chemoresistant tumour. Although cisplatin is used in frontline therapy of this disease treatment remains palliative at best. The biochemical pathways activated by cisplatin and the mechanisms of resistance in mesothelioma cells are poorly understood. Overexpression of inhibitor of apoptosis proteins (IAPs) has been described in clinical mesothelioma tumours and proposed as therapeutic targets. In this study, we examined cisplatin-induced cell death pathways and IAPs in three mesothelioma-derived cell lines. Cisplatin induced cell death in mesothelioma cell lines was characterised by biochemical mechanisms classically associated with apoptosis including: mitochondrial depolarisation, phosphatidylserine translocation and caspase activation. Surprisingly mRNA expression of IAPs in mesothelioma was not upregulated relative to primary mesothelial cells except for survivin which was higher in the most resistant cell line. In contrast, protein expression of both XIAP and survivin was upregulated in all mesothelioma cells, consistent with post-translational regulation. Knockdown of either XIAP or survivin by RNAi did not affect the sensitivity to cisplatin in any of the cell lines. Survivin RNAi did, however, inhibit proliferation in the highest expressing cell line, ONE58. The pan-caspase inhibitor z-VAD and the more selective caspase 3/7 inhibitor z-DEVD had no effect upon the sensitivity of any of the cell lines to cisplatin indicating that caspase-independent pathways predominate. The findings of the present study provide insights into cisplatin-induced mechanisms in mesothelioma cells and show that alternative pathways are operating which may provide new options for targeting this extremely resistant tumour.

  2. CD26-mediated regulation of periostin expression contributes to migration and invasion of malignant pleural mesothelioma cells

    SciTech Connect

    Komiya, Eriko; Ohnuma, Kei; Yamazaki, Hiroto; Hatano, Ryo; Iwata, Satoshi; Okamoto, Toshihiro; Dang, Nam H.; Morimoto, Chikao

    2014-05-16

    Highlights: • CD26-expressing MPM cells upregulate production of periostin. • The intracytoplasmic region of CD26 mediates the upregulation of periostin. • CD26 expression leads to nuclear translocation of Twist1 via phosphorylation of Src. • Secreted periostin enhances migration and invasion of MPM cells. - Abstract: Malignant pleural mesothelioma (MPM) is an aggressive malignancy arising from mesothelial lining of pleura. It is generally associated with a history of asbestos exposure and has a very poor prognosis, partly due to the lack of a precise understanding of the molecular mechanisms associated with its malignant behavior. In the present study, we expanded on our previous studies on the enhanced motility and increased CD26 expression in MPM cells, with a particular focus on integrin adhesion molecules. We found that expression of CD26 upregulates periostin secretion by MPM cells, leading to enhanced MPM cell migratory and invasive activity. Moreover, we showed that upregulation of periostin expression results from the nuclear translocation of the basic helix-loop-helix transcription factor Twist1, a process that is mediated by CD26-associated activation of Src phosphorylation. While providing new and profound insights into the molecular mechanisms involved in MPM biology, these findings may also lead to the development of novel therapeutic strategies for MPM.

  3. Tsc1-Tp53 loss induces mesothelioma in mice, and evidence for this mechanism in human mesothelioma

    PubMed Central

    Guo, Yanan; Chirieac, Lucian R.; Bueno, Raphael; Pass, Harvey; Wu, Wenhao; Malinowska, Izabela A.; Kwiatkowski, David J.

    2014-01-01

    Mesothelioma is diagnosed in approximately 2,500 patients in the United States every year, most often arising in the pleural space, but also occurring as primary peritoneal mesothelioma. The vast majority of patients with mesothelioma die from their disease within 3 years. We developed a new mouse model of mesothelioma by bladder or intra-peritoneal injection of adenovirus Cre into mice with conditional alleles of each of Tp53 and Tsc1. Such mice began to develop malignant ascites about 6 months after injection, which was due to peritoneal mesothelioma, based on tumor morphology and immunohistochemical staining. Mesothelioma cell lines were established which showed loss of both Tsc1 and Tp53, with mTORC1 activation. Treatment of mice with malignant ascites due to mesothelioma with rapamycin led to a marked reduction in ascites, extended survival, and a 95–99% reduction in mesothelioma tumor volume, in comparison to vehicle-treated mice. To see if TSC1/TSC2 loss was a common genetic event in human mesothelioma, we examined 9 human mesothelioma cell lines, and found that 4 of 9 showed persistent activation of mTORC1 though none had loss of TSC1 or TSC2. A tissue microarray analysis of 198 human mesothelioma specimens showed that 33% of cases had reduced TSC2 expression and 60% showed activation of mTOR, indicating that mTOR activation is common in human mesothelioma and suggesting that it is a potential therapeutic target. PMID:23851502

  4. Anti-Yo antibody-mediated paraneoplastic cerebellar degeneration in a female patient with pleural malignant mesothelioma.

    PubMed

    Tanriverdi, Ozgur; Meydan, Nezih; Barutca, Sabri; Ozsan, Nazan; Gurel, Duygu; Veral, Ali

    2013-05-01

    Paraneoplastic cerebellar degeneration is a rare non-metastatic complication of malignancies. It presents with acute or subacute onset of ataxia, dysarthria and intention tremor. Paraneoplastic cerebellar degeneration is most commonly associated with malignancies of the ovary, breast and lung. The anti-Yo (anti-Purkinje cells) antibodies that specifically damage the Purkinje cells of the cerebellum are found in the serum and cerebrospinal fluid. Anti-Yo-related paraneoplastic cerebellar degeneration is most commonly found in women with gynecological and breast cancers, but it is reported in other malignancies. Patients with paraneoplastic syndromes most often present with neurologic symptoms before an underlying cancer is detected. We report a case of anti-Yo-related paraneoplastic cerebellar degeneration associated with pleural malignant mesothelioma in a 51-year-old female patient. She presented to our department with a 2-week history after the last chemotherapy of progressive dizziness related to head movement, nausea, vomiting, ataxia and unsteady gait. A western blot assay was negative for anti-Hu, anti-Ri, anti-Ma2, anti-CV2 and anti-amphiphysin paraneoplastic antibody markers but positive for anti-Yo. In conclusion, we report a case of paraneoplastic cerebellar degeneration in a patient with pleural malignant mesothelioma because of the rarity of this neurologic presentation after the diagnosis of malignant mesothelioma and of the association with anti-Yo antibodies.

  5. Combination effect of photodynamic therapy using NPe6 with pemetrexed for human malignant pleural mesothelioma cells.

    PubMed

    Maehara, Sachio; Usuda, Jitsuo; Ishizumi, Taichiro; Ichinose, Shuji; Ohtani, Keishi; Inoue, Tatsuya; Imai, Kentaro; Furumoto, Hideyuki; Kudo, Yujin; Kajiwara, Naohiro; Ohira, Tatsuya; Ikeda, Norihiko

    2015-02-01

    To identify a possible new treatment modality for malignant pleural mesothelioma (MPM), we examined whether combination treatment consisting of pemetrexed chemotherapy and photodynamic therapy (PDT) using the photosensitizer NPe6, enhanced the antitumor effect in both in vitro and in vivo models. We also investigated preclinical treatment schedules. Four human malignant mesothelioma cell lines (MSTO‑211H, H2052, H2452 and H28) were assayed using the WST assay after treatment with pemetrexed and NPe6‑PDT. The treatment schedule for the combination treatment was examined using nude mice. Pemetrexed pre‑treatment enhanced the lethal effect of NPe6‑PDT in the four malignant mesothelioma cell lines, but NPe6‑PDT followed by pemetrexed treatment did not enhance cell lethality in the in vitro assay. Pemetrexed pre‑treatment did not enhance the intracellular accumulation of NPe6, which is one of the determinants of the antitumor effect of PDT. In nude mice injected with MSTO‑211H cells and then treated using a combination of pemetrexed and NPe6‑PDT (10 mg/kg NPe6, 10 J/cm(2) laser irradiation), the tumor volume decreased by 50% but subsequently increased, reaching the pre‑treatment value after 14 days. Pemetrexed treatment followed by NPe6‑PDT resulted in an 80% reduction in the tumor size and inhibited re‑growth. NPe6‑PDT followed by pemetrexed treatment resulted in a 60% reduction in tumor size but did not inhibit re‑growth. NPe6‑PDT induced the expression of thymidylate synthase (TS), which confers resistance to pemetrexed, and NPe6‑PDT followed by pemetrexed treatment did not enhance the treatment outcome in vivo. In conclusion, combination treatment, consisting of pemetrexed followed by NPe6‑PDT, should be further investigated as a new treatment modality for MPM. In the future, this combination treatment may contribute to a reduction in local recurrence and a prolonged survival period in patients with MPM.

  6. PI3 Kinase Pathway and MET Inhibition is Efficacious in Malignant Pleural Mesothelioma.

    PubMed

    Kanteti, Rajani; Riehm, Jacob J; Dhanasingh, Immanuel; Lennon, Frances E; Mirzapoiazova, Tamara; Mambetsariev, Bolot; Kindler, Hedy L; Salgia, Ravi

    2016-01-01

    Malignant pleural mesothelioma (MPM) is an aggressive cancer that is commonly associated with prior asbestos exposure. Receptor tyrosine kinases (RTKs) such as MET and its downstream target PI3K are overexpressed and activated in a majority of MPMs. Here, we studied the combinatorial therapeutic efficacy of the MET/ALK inhibitor crizotinib, with either a pan-class I PI3K inhibitor, BKM120, or with a PI3K/mTOR dual inhibitor, GDC-0980, in mesothelioma. Cell viability results showed that MPM cells were highly sensitive to crizotinib, BKM120 and GDC-0980 when used individually and their combination was more effective in suppressing growth. Treatment of MPM cells with these inhibitors also significantly decreased cell migration, and the combination of them was synergistic. Treatment with BKM120 alone or in combination with crizotinib induced G2-M arrest and apoptosis. Both crizotinib and BKM120 strongly inhibited the activity of MET and PI3K as evidenced by the decreased phosphorylation of MET, AKT and ribosomal S6 kinase. Using a PDX mouse model, we showed that a combination of crizotinib with BKM120 was highly synergetic in inhibiting MPM tumor growth. In conclusion our findings suggest that dual inhibition of PI3K and MET pathway is an effective strategy in treating MPM as compared to a single agent. PMID:27623107

  7. PI3 Kinase Pathway and MET Inhibition is Efficacious in Malignant Pleural Mesothelioma

    PubMed Central

    Kanteti, Rajani; Riehm, Jacob J.; Dhanasingh, Immanuel; Lennon, Frances E.; Mirzapoiazova, Tamara; Mambetsariev, Bolot; Kindler, Hedy L.; Salgia, Ravi

    2016-01-01

    Malignant pleural mesothelioma (MPM) is an aggressive cancer that is commonly associated with prior asbestos exposure. Receptor tyrosine kinases (RTKs) such as MET and its downstream target PI3K are overexpressed and activated in a majority of MPMs. Here, we studied the combinatorial therapeutic efficacy of the MET/ALK inhibitor crizotinib, with either a pan-class I PI3K inhibitor, BKM120, or with a PI3K/mTOR dual inhibitor, GDC-0980, in mesothelioma. Cell viability results showed that MPM cells were highly sensitive to crizotinib, BKM120 and GDC-0980 when used individually and their combination was more effective in suppressing growth. Treatment of MPM cells with these inhibitors also significantly decreased cell migration, and the combination of them was synergistic. Treatment with BKM120 alone or in combination with crizotinib induced G2-M arrest and apoptosis. Both crizotinib and BKM120 strongly inhibited the activity of MET and PI3K as evidenced by the decreased phosphorylation of MET, AKT and ribosomal S6 kinase. Using a PDX mouse model, we showed that a combination of crizotinib with BKM120 was highly synergetic in inhibiting MPM tumor growth. In conclusion our findings suggest that dual inhibition of PI3K and MET pathway is an effective strategy in treating MPM as compared to a single agent. PMID:27623107

  8. MicroRNA gene expression signatures in long-surviving malignant pleural mesothelioma patients.

    PubMed

    Lin, Ruby C Y; Kirschner, Michaela B; Cheng, Yuen Yee; van Zandwijk, Nico; Reid, Glen

    2016-09-01

    Malignant pleural mesothelioma (MPM) is a tumor originating in the mesothelium, the membrane lining the thoracic cavities, and is induced by exposure to asbestos. Australia suffers one of the world's highest rates of MPM and the incidence is yet to peak. The prognosis for patients with MPM is poor and median survival following diagnosis is 4-18 months. Currently, no or few effective therapies exist for MPM. Trials of targeted agents such as antiangiogenic agents (VEGF, EGFR) or ribonuclease inhibitors (ranpirnase) largely failed to show efficacy in MPM Tsao et al. (2009) [1]. A recent study, however, showed that cisplatin/pemetrexed + bevacizumab (a recombinant humanized monoclonal antibody that inhibit VEGF) treatment has a survival benefit of 2.7 months Zalcman et al. (2016) [2]. It remains to be seen if this targeted therapy will be accepted as a new standard for MPM. Thus the unmet needs of MPM patients remain very pronounced and almost every patient will be confronted with drug resistance and recurrence of disease. We have identified unique gene signatures associated with prolonged survival in mesothelioma patients undergoing radical surgery (EPP, extrapleural pneumonectomy), as well as patients who underwent palliative surgery (pleurectomy/decortication). In addition to data published in Molecular Oncology, 2015;9:715-26 (GSE59180) Kirschner et al. (2015) , we describe here additional data using a system-based approach that support our previous observations. This data provides a resource to further explore microRNA dynamics in MPM. PMID:27408810

  9. Unique fractal evaluation and therapeutic implications of mitochondrial morphology in malignant mesothelioma

    PubMed Central

    Lennon, Frances E.; Cianci, Gianguido C.; Kanteti, Rajani; Riehm, Jacob J.; Arif, Qudsia; Poroyko, Valeriy A.; Lupovitch, Eitan; Vigneswaran, Wickii; Husain, Aliya; Chen, Phetcharat; Liao, James K.; Sattler, Martin; Kindler, Hedy L.; Salgia, Ravi

    2016-01-01

    Malignant mesothelioma (MM), is an intractable disease with limited therapeutic options and grim survival rates. Altered metabolic and mitochondrial functions are hallmarks of MM and most other cancers. Mitochondria exist as a dynamic network, playing a central role in cellular metabolism. MM cell lines display a spectrum of altered mitochondrial morphologies and function compared to control mesothelial cells. Fractal dimension and lacunarity measurements are a sensitive and objective method to quantify mitochondrial morphology and most importantly are a promising predictor of response to mitochondrial inhibition. Control cells have high fractal dimension and low lacunarity and are relatively insensitive to mitochondrial inhibition. MM cells exhibit a spectrum of sensitivities to mitochondrial inhibitors. Low mitochondrial fractal dimension and high lacunarity correlates with increased sensitivity to the mitochondrial inhibitor metformin. Lacunarity also correlates with sensitivity to Mdivi-1, a mitochondrial fission inhibitor. MM and control cells have similar sensitivities to cisplatin, a chemotherapeutic agent used in the treatment of MM. Neither oxidative phosphorylation nor glycolytic activity, correlated with sensitivity to either metformin or mdivi-1. Our results suggest that mitochondrial inhibition may be an effective and selective therapeutic strategy in mesothelioma, and identifies mitochondrial morphology as a possible predictor of response to targeted mitochondrial inhibition. PMID:27080907

  10. Unique fractal evaluation and therapeutic implications of mitochondrial morphology in malignant mesothelioma.

    PubMed

    Lennon, Frances E; Cianci, Gianguido C; Kanteti, Rajani; Riehm, Jacob J; Arif, Qudsia; Poroyko, Valeriy A; Lupovitch, Eitan; Vigneswaran, Wickii; Husain, Aliya; Chen, Phetcharat; Liao, James K; Sattler, Martin; Kindler, Hedy L; Salgia, Ravi

    2016-01-01

    Malignant mesothelioma (MM), is an intractable disease with limited therapeutic options and grim survival rates. Altered metabolic and mitochondrial functions are hallmarks of MM and most other cancers. Mitochondria exist as a dynamic network, playing a central role in cellular metabolism. MM cell lines display a spectrum of altered mitochondrial morphologies and function compared to control mesothelial cells. Fractal dimension and lacunarity measurements are a sensitive and objective method to quantify mitochondrial morphology and most importantly are a promising predictor of response to mitochondrial inhibition. Control cells have high fractal dimension and low lacunarity and are relatively insensitive to mitochondrial inhibition. MM cells exhibit a spectrum of sensitivities to mitochondrial inhibitors. Low mitochondrial fractal dimension and high lacunarity correlates with increased sensitivity to the mitochondrial inhibitor metformin. Lacunarity also correlates with sensitivity to Mdivi-1, a mitochondrial fission inhibitor. MM and control cells have similar sensitivities to cisplatin, a chemotherapeutic agent used in the treatment of MM. Neither oxidative phosphorylation nor glycolytic activity, correlated with sensitivity to either metformin or mdivi-1. Our results suggest that mitochondrial inhibition may be an effective and selective therapeutic strategy in mesothelioma, and identifies mitochondrial morphology as a possible predictor of response to targeted mitochondrial inhibition. PMID:27080907

  11. Malignant mesothelioma--clinical and epidemiological features. A report of 80 cases.

    PubMed

    Solomons, K

    1984-09-15

    The clinical and epidemiological features of 80 cases of malignant mesothelioma (as proved by examination of biopsy specimens) referred to the clinic at the National Centre for Occupational Health between January 1977 and June 1983 are reviewed. There was a positive history of asbestos exposure in 89% of cases. The mean survival time from diagnosis to death was 8,6 months and from the onset of symptoms to death 13,6 months. Survival time was unaffected by stage of the tumour, treatment, histological features, smoking status, presenting symptoms, presence or absence of effusion and asbestosis, side of the lesion, source of exposure and lag period from first exposure to diagnosis. The duration of survival was significantly affected by age at diagnosis, duration of asbestos exposure and the number, rather than the type, of treatment regimens used. Caution is advocated in interpreting these data since the number of cases was small and the study design was retrospective. A reference group of 546 cases notified over the same period was drawn from the records of the South African Asbestos Tumour Reference Panel. The incompleteness of national mesothelioma incidence data was noted, and an incidence figure of 7,2 per million per year was calculated from the best-available data for South Africa. This figure is an underestimate because not all diagnosed cases are reflected and, more important, significant numbers of cases are never diagnosed. The extent to which the compensation machinery functions is mentioned.

  12. Asbestos exposure in malignant mesothelioma of the pleura: a survey of 557 cases.

    PubMed

    Bianchi, C; Brollo, A; Ramani, L; Bianchi, T; Giarelli, L

    2001-04-01

    A series of 557 malignant mesotheliomas of the pleura diagnosed in the Trieste-Monfalcone area, Italy, in the period 1968-2000 were reviewed. The series included 492 men and 65 women, aged between 32 and 93 years (median age 69 years). Necropsy findings were available in 456 cases (82%). Occupational histories were obtained from the patients themselves or from their relatives by personal or telephone interviews. Routine lung sections were examined for asbestos bodies in 442 cases. In 109 cases isolation and counting of asbestos bodies were performed. A majority of people had histories of working in the shipyards. Asbestos bodies were observed in lung sections in 67% of the cases. Lung asbestos body burdens after isolation ranged between 20 bodies and about 10 millions of bodies/g dried tissue. Latency periods (time intervals between first exposure to asbestos and death) ranged between 14 and 75 years (mean 48.8 years, median 51.0). Latency periods among insulators and dock workers were shorter than among the other categories. High asbestos consumption occurred in many countries in the 1960s and in the 1970s. The data on latency periods obtained in the present study suggest that a world mesothelioma epidemic has to be expected in the coming decades.

  13. Intracellular lactate-mediated induction of estrogen receptor beta (ERβ) in biphasic malignant pleural mesothelioma cells

    PubMed Central

    Zonca, Sara; Cilli, Michele; Rinaldi, Maurizio; Daga, Antonio; Nilsson, Stefan; Moro, Laura

    2015-01-01

    Biphasic malignant pleural mesothelioma (MPM) is the second most common histotype of MPM. It is histologically characterized by the concomitant presence of epithelioid and sarcomatoid features, the latter associated with worse prognosis. In this report we describe that silencing of AKT1 in spindle-shaped biphasic MPM cells promotes the shift toward an epithelioid phenotype. Furthermore, AKT1 silencing resulted in decreased expression of the lactate/H+ symporter MCT4 and its chaperone CD147/Basigin, and in the induction of estrogen receptor β (ERβ) expression. We provide evidence that ERβ expression is induced by increased intracellular lactate concentration. Spheroid culturing and tumor growth of ERβ negative biphasic MPM in nude mice resulted in the induction of ERβ expression and response to the selective agonist KB9520. In both models, the treatment with the ERβ agonist results in reduced cell proliferation, decreased expression of MCT4 and CD147/Basigin and increased acetylation and inactivation of AKT1. Collectively, in response to metabolic changes, ERβ expression is induced and exerts an anti-tumor effect through selective agonist activation. The possibility to reverse the more aggressive biphasic mesothelioma histotype by targeting ERβ with a selective agonist could represent a new effective treatment strategy. PMID:26208479

  14. [Hyperthermic chemoperfusion of the pleural cavity in the combined treatment for malignant pleural mesothelioma].

    PubMed

    Levchenko, E V; Mamontov, O Iu; Senchik, K Iu; Barchuk, A S; Gel'fond, M L

    2014-01-01

    The literature and our own experience were analyzed in multimodal approach to the treatment of patients with malignant pleural mesothelioma (MPM). Survival and quality of life of patients with MPM who underwent multimodal treatment, according to modern standards, are often limited by the occurrence of local recurrences. The value of a number of local therapy methods is still being explored in order to determine the possible side effects as well as the duration of disease-free survival. Photodynamic therapy and intraoperative hyperthermic chemoperfusion of the pleural cavity are the methods of the local treatment of this disease, applied after surgery. These approaches have been investigated separately in several studies, but their efficacy and tolerability is still not clear. The authors wanted to find the best indications for the use of these methods and to assess the immediate and long-term results. PMID:25552068

  15. Dose-Dependent Pulmonary Toxicity After Postoperative Intensity-Modulated Radiotherapy for Malignant Pleural Mesothelioma

    SciTech Connect

    Rice, David C. Smythe, W. Roy; Liao Zhongxing; Guerrero, Thomas; Chang, Joe Y.; McAleer, Mary F.; Jeter, Melenda D.; Correa, Arlene Ph.D.; Vaporciyan, Ara A.; Liu, H. Helen; Komaki, Ritsuko; Forster, Kenneth M.; Stevens, Craig W.

    2007-10-01

    Purpose: To determine the incidence of fatal pulmonary events after extrapleural pneumonectomy and hemithoracic intensity-modulated radiotherapy (IMRT) for malignant pleural mesothelioma. Methods and Materials: We retrospectively reviewed the records of 63 consecutive patients with malignant pleural mesothelioma who underwent extrapleural pneumonectomy and IMRT at University of Texas M. D. Anderson Cancer Center. The endpoints studied were pulmonary-related death (PRD) and non-cancer-related death within 6 months of IMRT. Results: Of the 63 patients, 23 (37%) had died within 6 months of IMRT (10 of recurrent cancer, 6 of pulmonary causes [pneumonia in 4 and pneumonitis in 2], and 7 of other noncancer causes [pulmonary embolus in 2, sepsis after bronchopleural fistula in 1, and cause unknown but without pulmonary symptoms or recurrent disease in 4]). On univariate analysis, the factors that predicted for PRD were a lower preoperative ejection fraction (p = 0.021), absolute volume of lung spared at 10 Gy (p = 0.025), percentage of lung volume receiving {>=}20 Gy (V{sub 20}; p 0.002), and mean lung dose (p = 0.013). On multivariate analysis, only V{sub 20} was predictive of PRD (p = 0.017; odds ratio, 1.50; 95% confidence interval, 1.08-2.08) or non-cancer-related death (p = 0.033; odds ratio, 1.21; 95% confidence interval, 1.02-1.45). Conclusion: The results of our study have shown that fatal pulmonary toxicities were associated with radiation to the contralateral lung. V{sub 20} was the only independent determinant for risk of PRD or non-cancer-related death. The mean V{sub 20} of the non-PRD patients was considerably lower than that accepted during standard thoracic radiotherapy, implying that the V{sub 20} should be kept as low as possible after extrapleural pneumonectomy.

  16. Malignant pleural mesothelioma in US automotive mechanics: reported vs expected number of cases from 1975 to 2007.

    PubMed

    Finley, Brent L; Pierce, Jennifer S; Paustenbach, Dennis J; Scott, Laura L F; Lievense, Laura; Scott, Paul K; Galbraith, David A

    2012-10-01

    Until the 1980s, chrysotile asbestos was a component of automotive brakes manufactured in the US. The current OSHA Bulletin (2006) for brake repair cites a single study (Lemen, 2004) which concluded that the number of mesothelioma cases reported in the literature in "end-product users of friction materials" indicated an asbestos-related risk for auto mechanics. However, Lemen (2004) did not compare the reported number of cases to an "expected" value, even though pleural mesothelioma occurs in the general population in the absence of asbestos exposure. We compare the number of malignant pleural mesothelioma (MPM) cases reported in the US literature among auto mechanics between 1975-2007 to an expected value derived from estimated numbers of current and former auto mechanics. A total of 106 cases categorized as mesothelioma or malignant neoplasm of the pleura were found in the literature. Using background incidence rates for MPM of two and three cases per million individuals per year, we estimated that a range of 278-515 cases of non-asbestos-related MPM, respectively, would have occurred in current or former auto mechanics from 1975-2007. Our findings are consistent with the numerous epidemiology studies that have found no increased risk of MPM in auto mechanics.

  17. Multicentric study on malignant pleural mesothelioma and non-occupational exposure to asbestos

    PubMed Central

    Magnani, C; Agudo, A; González, C A; Andrion, A; Calleja, A; Chellini, E; Dalmasso, P; Escolar, A; Hernandez, S; Ivaldi, C; Mirabelli, D; Ramirez, J; Turuguet, D; Usel, M; Terracini, B

    2000-01-01

    Insufficient evidence exists on the risk of pleural mesothelioma from non-occupational exposure to asbestos. A population-based case–control study was carried out in six areas from Italy, Spain and Switzerland. Information was collected for 215 new histologically confirmed cases and 448 controls. A panel of industrial hygienists assessed asbestos exposure separately for occupational, domestic and environmental sources. Classification of domestic and environmental exposure was based on a complete residential history, presence and use of asbestos at home, asbestos industrial activities in the surrounding area, and their distance from the dwelling. In 53 cases and 232 controls without evidence of occupational exposure to asbestos, moderate or high probability of domestic exposure was associated with an increased risk adjusted by age and sex: odds ratio (OR) 4.81, 95% confidence interval (CI) 1.8–13.1. This corresponds to three situations: cleaning asbestos-contaminated clothes, handling asbestos material and presence of asbestos material susceptible to damage. The estimated OR for high probability of environmental exposure (living within 2000 m of asbestos mines, asbestos cement plants, asbestos textiles, shipyards, or brakes factories) was 11.5 (95% CI 3.5–38.2). Living between 2000 and 5000 m from asbestos industries or within 500 m of industries using asbestos could also be associated with an increased risk. A dose–response pattern appeared with intensity of both sources of exposure. It is suggested that low-dose exposure to asbestos at home or in the general environment carries a measurable risk of malignant pleural mesothelioma. © 2000 Cancer Research Campaign PMID:10883677

  18. Genetic Variants Associated with Increased Risk of Malignant Pleural Mesothelioma: A Genome-Wide Association Study

    PubMed Central

    Matullo, Giuseppe; Guarrera, Simonetta; Betti, Marta; Fiorito, Giovanni; Ferrante, Daniela; Voglino, Floriana; Cadby, Gemma; Di Gaetano, Cornelia; Rosa, Fabio; Russo, Alessia; Hirvonen, Ari; Casalone, Elisabetta; Tunesi, Sara; Padoan, Marina; Giordano, Mara; Aspesi, Anna; Casadio, Caterina; Ardissone, Francesco; Ruffini, Enrico; Betta, Pier Giacomo; Libener, Roberta; Guaschino, Roberto; Piccolini, Ezio; Neri, Monica; Musk, Arthur W. B.; de Klerk, Nicholas H.; Hui, Jennie; Beilby, John; James, Alan L.; Creaney, Jenette; Robinson, Bruce W.; Mukherjee, Sutapa; Palmer, Lyle J.; Mirabelli, Dario; Ugolini, Donatella; Bonassi, Stefano; Magnani, Corrado; Dianzani, Irma

    2013-01-01

    Asbestos exposure is the main risk factor for malignant pleural mesothelioma (MPM), a rare aggressive tumor. Nevertheless, only 5–17% of those exposed to asbestos develop MPM, suggesting the involvement of other environmental and genetic risk factors. To identify the genetic risk factors that may contribute to the development of MPM, we conducted a genome-wide association study (GWAS; 370,000 genotyped SNPs, 5 million imputed SNPs) in Italy, among 407 MPM cases and 389 controls with a complete history of asbestos exposure. A replication study was also undertaken and included 428 MPM cases and 1269 controls from Australia. Although no single marker reached the genome-wide significance threshold, several associations were supported by haplotype-, chromosomal region-, gene- and gene-ontology process-based analyses. Most of these SNPs were located in regions reported to harbor aberrant alterations in mesothelioma (SLC7A14, THRB, CEBP350, ADAMTS2, ETV1, PVT1 and MMP14 genes), causing at most a 2–3-fold increase in MPM risk. The Australian replication study showed significant associations in five of these chromosomal regions (3q26.2, 4q32.1, 7p22.2, 14q11.2, 15q14). Multivariate analysis suggested an independent contribution of 10 genetic variants, with an Area Under the ROC Curve (AUC) of 0.76 when only exposure and covariates were included in the model, and of 0.86 when the genetic component was also included, with a substantial increase of asbestos exposure risk estimation (odds ratio, OR: 45.28, 95% confidence interval, CI: 21.52–95.28). These results showed that genetic risk factors may play an additional role in the development of MPM, and that these should be taken into account to better estimate individual MPM risk in individuals who have been exposed to asbestos. PMID:23626673

  19. [Malignant pleural mesothelioma incidence and mortality in Tuscany in 1988-1999].

    PubMed

    Gorini, Giuseppe; Chellini, Elisabetta; Merler, Enzo; Cacciarini, Valentina; Silvestri, Stefano; Seniori Costantini, Adele

    2003-01-01

    In the period 1988-1999, the Tuscan Mesothelioma Registry (ARTMM) recorded 436 cases of pleural malignant mesothelioma (MMP); 81% were males. The Tuscan MMP incidence rate (age standardized on European population; per 100,000 per year), was 0.97 in 1988-1993, 1.64 in 1994-1999 for males; 0.22 and 0.23 for females, respectively. In the period 1988-1999 the Tuscan Mortality Registry (RMR) recorded 676 pleural cancer (TMP) deaths (ICD IX 163; 464 in males). In the periods 1988-1993 and 1994-1999 Tuscan TMP mortality rate (per 100,000 per year) was 1.54; 1.70 for men; 0.46 and 0.53 for women, respectively. The highest incidence and mortality rates for males were recorded in Massa Carrara (MMP incidence in the period 1994-1999: 5.20) e Livorno (MMP incidence in the period 1994-1999: 4.64) provinces. In order to study differences between incidence and mortality for males, an analysis of distribution of incident MMP cases and TMP deaths by municipality in Tuscany was carried out. It is usually assumed for projections of MMP mortality that the ratio of MMP mortality to TMP mortality is 1:1. However, in order to evaluate more precisely projections of MMP mortality, the exact ratio was calculated for men. In the period 1994-1999, 82% (154/188) of the male MMP deaths were correctly coded as TMP deaths in the RMR; 60% (154/256) of male TMP deaths were definite MMP cases, as they were recorded in ARTMM. The ratio of MMP mortality to TMP mortality is, therefore, 0.73:1 (0.60/0.82) for males in Tuscany.

  20. Multicentric study on malignant pleural mesothelioma and non-occupational exposure to asbestos.

    PubMed

    Magnani, C; Agudo, A; González, C A; Andrion, A; Calleja, A; Chellini, E; Dalmasso, P; Escolar, A; Hernandez, S; Ivaldi, C; Mirabelli, D; Ramirez, J; Turuguet, D; Usel, M; Terracini, B

    2000-07-01

    Insufficient evidence exists on the risk of pleural mesothelioma from non-occupational exposure to asbestos. A population-based case-control study was carried out in six areas from Italy, Spain and Switzerland. Information was collected for 215 new histologically confirmed cases and 448 controls. A panel of industrial hygienists assessed asbestos exposure separately for occupational, domestic and environmental sources. Classification of domestic and environmental exposure was based on a complete residential history, presence and use of asbestos at home, asbestos industrial activities in the surrounding area, and their distance from the dwelling. In 53 cases and 232 controls without evidence of occupational exposure to asbestos, moderate or high probability of domestic exposure was associated with an increased risk adjusted by age and sex: odds ratio (OR) 4.81, 95% confidence interval (CI) 1.8-13.1. This corresponds to three situations: cleaning asbestos-contaminated clothes, handling asbestos material and presence of asbestos material susceptible to damage. The estimated OR for high probability of environmental exposure (living within 2000 m of asbestos mines, asbestos cement plants, asbestos textiles, shipyards, or brakes factories) was 11.5 (95% CI 3.5-38.2). Living between 2000 and 5000 m from asbestos industries or within 500 m of industries using asbestos could also be associated with an increased risk. A dose-response pattern appeared with intensity of both sources of exposure. It is suggested that low-dose exposure to asbestos at home or in the general environment carries a measurable risk of malignant pleural mesothelioma.

  1. Management of malignant pleural mesothelioma - part 1: epidemiology, diagnosis, and staging : Consensus of the Austrian Mesothelioma Interest Group (AMIG).

    PubMed

    Geltner, Christian; Errhalt, Peter; Baumgartner, Bernhard; Ambrosch, Gerhard; Machan, Barbara; Eckmayr, Josef; Klikovits, Thomas; Hoda, Mir Alireza; Popper, Helmut; Klepetko, Walter

    2016-09-01

    Malignant pleural mesothelioma is a rare malignant disease that in the majority of cases is associated with asbestos exposure. The incidence in Europe is about 20 per million inhabitants and it is increasing worldwide. Initial symptoms are shortness of breath, pleural effusion, cough, and chest pain. The typical growth pattern is along the pleural surface; however, infiltration of the lung and/or mediastinal and chest wall structures can occur in a more advanced stage. Ultimately, distant metastases outside the chest can result. Several histological subtypes of pleural mesothelioma exist, which must be differentiated from either benign diseases or metastases in the pleural space by other tumor entities. This differential diagnosis can be very difficult and a large panel of immunohistochemical markers is required to establish the exact diagnosis. The standard procedure for confirming the disease and obtaining sufficient tissue for the diagnosis is videothoracoscopy. Full thickness biopsies are required, while transthoracic needle puncture of pleural fluid or tissue is considered to be insufficient for a cytological diagnosis. Complete and detailed staging is mandatory for categorization of the disease as well as for therapeutic decision making.

  2. Management of malignant pleural mesothelioma - part 1: epidemiology, diagnosis, and staging : Consensus of the Austrian Mesothelioma Interest Group (AMIG).

    PubMed

    Geltner, Christian; Errhalt, Peter; Baumgartner, Bernhard; Ambrosch, Gerhard; Machan, Barbara; Eckmayr, Josef; Klikovits, Thomas; Hoda, Mir Alireza; Popper, Helmut; Klepetko, Walter

    2016-09-01

    Malignant pleural mesothelioma is a rare malignant disease that in the majority of cases is associated with asbestos exposure. The incidence in Europe is about 20 per million inhabitants and it is increasing worldwide. Initial symptoms are shortness of breath, pleural effusion, cough, and chest pain. The typical growth pattern is along the pleural surface; however, infiltration of the lung and/or mediastinal and chest wall structures can occur in a more advanced stage. Ultimately, distant metastases outside the chest can result. Several histological subtypes of pleural mesothelioma exist, which must be differentiated from either benign diseases or metastases in the pleural space by other tumor entities. This differential diagnosis can be very difficult and a large panel of immunohistochemical markers is required to establish the exact diagnosis. The standard procedure for confirming the disease and obtaining sufficient tissue for the diagnosis is videothoracoscopy. Full thickness biopsies are required, while transthoracic needle puncture of pleural fluid or tissue is considered to be insufficient for a cytological diagnosis. Complete and detailed staging is mandatory for categorization of the disease as well as for therapeutic decision making. PMID:27619223

  3. A case of malignant peritoneal mesothelioma revealed with limitation of PET-CT in the diagnosis of thoracic metastasis

    PubMed Central

    Saraya, Takeshi; Yokoyama, Takuma; Ishii, Haruyuki; Tanaka, Yasutaka; Tsujimoto, Naoki; Ogawa, Yukari; Sohara, Erei; Nakajima, Akira; Inui, Toshiya; Sayuki, Hiraoka; Fujiwara, Masachika; Oka, Teruaki; Kawachi, Riken; Goya, Tomoyuki; Takizawa, Hajime

    2013-01-01

    A 47-year-old man was referred to our hospital because of a 2-month history of dry cough, 2-kg weight loss, and a feeling of abdominal fullness. The PET-CT scan depicts the intense standard uptake values (SUVs) of the anterior and subphrenic lymphnodes, and intraperitoneal cavity, especially in the omentum, while, no uptake was found in the pleural cavity. Based on the pathological findings of the open lung biopsy specimens, he was diagnosed with malignant peritoneal mesothelioma of epithelioid type with thoracic metastasis. The present case demonstrated the some of the limitations of PET-CT in the diagnosis of malignant mesothelioma, which failed to detect pleural involvement despite aggressive invasion by this tumor. PMID:23372960

  4. Yes is a central mediator of cell growth in malignant mesothelioma cells.

    PubMed

    Sato, Ayami; Sekine, Miki; Virgona, Nantiga; Ota, Masako; Yano, Tomohiro

    2012-11-01

    The constitutive activation of the Src family kinases (SFKs) has been established as a poor prognostic factor in malignant mesothelioma (MM), however, the family member(s) which contribute to the malignancy have not been defined. This study aimed to identify the SFK member(s) contributing to cell growth using RNA interference in various MM cell lines. Silencing of Yes but not of c-Src or Fyn in MM cells leads to cell growth suppression. This suppressive effect caused by Yes silencing mainly depends on G1 cell cycle arrest and partly the induction of apoptosis. Also, the knockout of Yes induces the inactivation of β-catenin signaling and subsequently decreases the levels of cyclin D necessary for G1-S transition in the cell cycle. In addition, Yes knockout has less effect on cell growth suppression in β-catenin-deficient H28 MM cells compared to other MM cells which express the catenin. Overall, we conclude that Yes is a central mediator for MM cell growth that is not shared with other SFKs such as c-Src.

  5. Calpeptin Prevents Malignant Pleural Mesothelioma Cell Proliferation via the Angiopoietin1/Tie2 System.

    PubMed

    Tabata, Chiharu; Tabata, Rie; Nakano, Takashi

    2016-01-01

    Malignant pleural mesothelioma (MPM), an aggressive malignant tumor of mesothelial origin associated with asbestos exposure, shows a limited response to conventional chemotherapy and radiotherapy. Therefore, the overall survival of MPM patients remains very poor. Progress in the development of therapeutic strategies for MPM has been limited. We recently reported that the calpain inhibitor, calpeptin exerted inhibitory effects on pulmonary fibrosis by inhibiting the proliferation of lung fibroblasts. In the present study, we examined the preventive effects of calpeptin on the cell growth of MPM, the origin of which is mesenchymal cells, similar to lung fibroblasts. Calpeptin inhibited the proliferation of MPM cells, but not mesothelial cells. It also prevented 1) the expression of angiopoietin (Ang)1 and Tie2 mRNA in MPM cells, but not mesothelial cells and 2) the Ang1induced proliferation of MPM cells through an NFkB dependent pathway, which may be the mechanism underlying the preventive effects of calpeptin on the growth of MPM cells. These results suggest potential clinical use of calpeptin for the treatment of MPM. PMID:27509983

  6. Malignant mesotheliomas in former miners and millers of crocidolite at Wittenoom (Western Australia) after more than 50 years follow-up

    PubMed Central

    Berry, G; Reid, A; Aboagye-Sarfo, P; de Klerk, N H; Olsen, N J; Merler, E; Franklin, P; Musk, A W

    2012-01-01

    Background: To report the number of malignant pleural and peritoneal mesotheliomas that have occurred in former Wittenoom crocidolite workers to the end of 2008, to compare this with earlier predictions, and to relate the mesothelioma rate to amount of exposure. Methods: A group of 6489 men and 419 women who had worked for the company operating the former Wittenoom crocidolite mine and mill at some time between 1943 and 1966 have been followed up throughout Australia and Italy to the end of 2008. Results: The cumulative number of mesotheliomas up to 2008 was 316 in men (268 pleural, 48 peritoneal) and 13 (all pleural) in women. There had been 302 deaths with mesothelioma in men and 13 in women, which was almost 10% of all known deaths. Mesothelioma rate, both pleural and peritoneal, increased with time since first exposure and appeared to reach a plateau after about 40 to 50 years. The mesothelioma rate increased with amount of exposure and the peritoneal mesotheliomas occurred preferentially in the highest exposure group, 37% compared with 15% overall. Conclusion: By the end of 2008, the number of mesothelioma deaths had reached 4.7% for all the male workers and 3.1% for the females. Over the past 8 years the numbers were higher than expected. It is predicted that about another 60 to 70 deaths with mesothelioma may occur in men by 2020. PMID:22315054

  7. Multiwalled carbon nanotubes intratracheally instilled into the rat lung induce development of pleural malignant mesothelioma and lung tumors.

    PubMed

    Suzui, Masumi; Futakuchi, Mitsuru; Fukamachi, Katsumi; Numano, Takamasa; Abdelgied, Mohamed; Takahashi, Satoru; Ohnishi, Makoto; Omori, Toyonori; Tsuruoka, Shuji; Hirose, Akihiko; Kanno, Jun; Sakamoto, Yoshimitsu; Alexander, David B; Alexander, William T; Jiegou, Xu; Tsuda, Hiroyuki

    2016-07-01

    Multiwalled carbon nanotubes (MWCNT) have a fibrous structure and physical properties similar to asbestos and have been shown to induce malignant mesothelioma of the peritoneum after injection into the scrotum or peritoneal cavity in rats and mice. For human cancer risk assessment, however, data after administration of MWCNT via the airway, the exposure route that is most relevant to humans, is required. The present study was undertaken to investigate the carcinogenicity of MWCNT-N (NIKKISO) after administration to the rat lung. MWCNT-N was fractionated by passing it through a sieve with a pore size of 25 μm. The average lengths of the MWCNT were 4.2 μm before filtration and 2.6 μm in the flow-through fraction; the length of the retained MWCNT could not be determined. For the present study, 10-week-old F344/Crj male rats were divided into five groups: no treatment, vehicle control, MWCNT-N before filtration, MWCNT-N flow-through and MWCNT-N retained groups. Administration was by the trans-tracheal intrapulmonary spraying (TIPS) method. Rats were administered a total of 1 mg/rat during the initial 2 weeks of the experiment and then observed up to 109 weeks. The incidences of malignant mesothelioma and lung tumors (bronchiolo-alveolar adenomas and carcinomas) were 6/38 and 14/38, respectively, in the three groups administered MWCNT and 0/28 and 0/28, respectively, in the control groups. All malignant mesotheliomas were localized in the pericardial pleural cavity. The sieve fractions did not have a significant effect on tumor incidence. In conclusion, administration of MWCNT to the lung in the rat induces malignant mesothelioma and lung tumors. PMID:27098557

  8. Accumulation of radium in ferruginous protein bodies formed in lung tissue: association of resulting radiation hotspots with malignant mesothelioma and other malignancies

    PubMed Central

    Nakamura, Eizo; Makishima, Akio; Hagino, Kyoko; Okabe, Kazunori

    2009-01-01

    While exposure to fibers and particles has been proposed to be associated with several different lung malignancies including mesothelioma, the mechanism for the carcinogenesis is not fully understood. Along with mineralogical observation, we have analyzed forty-four major and trace elements in extracted asbestos bodies (fibers and proteins attached to them) with coexisting fiber-free ferruginous protein bodies from extirpative lungs of individuals with malignant mesothelioma. These observations together with patients’ characteristics suggest that inhaled iron-rich asbestos fibers and dust particles, and excess iron deposited by continuous cigarette smoking would induce ferruginous protein body formation resulting in ferritin aggregates in lung tissue. Chemical analysis of ferruginous protein bodies extracted from lung tissues reveals anomalously high concentrations of radioactive radium, reaching millions of times higher concentration than that of seawater. Continuous and prolonged internal exposure to hotspot ionizing radiation from radium and its daughter nuclides could cause strong and frequent DNA damage in lung tissue, initiate different types of tumour cells, including malignant mesothelioma cells, and may cause cancers. PMID:19644223

  9. MSLN gene silencing has an anti-malignant effect on cell lines overexpressing mesothelin deriving from malignant pleural mesothelioma.

    PubMed

    Melaiu, Ombretta; Stebbing, Justin; Lombardo, Ylenia; Bracci, Elisa; Uehara, Norihisa; Bonotti, Alessandra; Cristaudo, Alfonso; Foddis, Rudy; Mutti, Luciano; Barale, Roberto; Gemignani, Federica; Giamas, Georgios; Landi, Stefano

    2014-01-01

    Genes involved in the carcinogenetic mechanisms underlying malignant pleural mesothelioma (MPM) are still poorly characterized. So far, mesothelin (MSLN) has aroused the most interest. It encodes for a membrane glycoprotein, frequently over-expressed in various malignancies such as MPM, and ovarian and pancreatic cancers. It has been proposed as a diagnostic and immunotherapeutic target with promising results. However, an alternative therapeutic approach seems to rise, whereby synthetic molecules, such as antisense oligonucleotides, could be used to inhibit MSLN activity. To date, such a gene-level inhibition has been attempted in two studies only, both on pancreatic and ovarian carcinoma cell lines, with the use of silencing RNA approaches. With regard to MPM, only one cell line (H2373) has been employed to study the effects of MSLN depletion. Indeed, the knowledge on the role of MSLN in MPM needs expanding. Accordingly, we investigated the expression of MSLN in a panel of three MPM cell lines, i.e., NCI-H28, Mero-14, and IstMes2; one non-MPM cell line was used as reference (Met5A). MSLN knock-down experiments on MSLN-overexpressing cells were also performed through silencing RNA (siRNA) to verify whether previous findings could be generalized to a different set of cell cultures. In agreement with previous studies, transient MSLN-silencing caused decreased proliferation rate and reduced invasive capacity and sphere formation in MSLN-overexpressing Mero-14 cells. Moreover, MSLN-siRNA combined with cisplatin, triggered a marked increase in apoptosis and a decrease in proliferation as compared to cells treated with each agent alone, thereby suggesting a sensitizing effect of siRNA towards cisplatin. In summary, our findings confirm that MSLN should be considered a key molecular target for novel gene-based targeted therapies of cancer.

  10. Malignant mesothelioma in south east England: clinicopathological experience of 272 cases [published erratum appears in Thorax 1997 Nov;52(11):1018

    PubMed Central

    Yates, D. H.; Corrin, B.; Stidolph, P. N.; Browne, K.

    1997-01-01

    BACKGROUND: Malignant mesothelioma is a rare pleural tumour associated with asbestos exposure. The proportion of malignant mesothelioma unrelated to asbestos exposure, and any differentiating features between exposed and unexposed cases, are not well described. This study describes occupational, clinical, and pathological features in a large cohort of cases of malignant mesothelioma from south east England. METHODS: All 272 cases from this region were studied, either in life or after death when necropsy examination suggested malignant mesothelioma. Detailed information was gathered regarding the occupational history, clinical course, and mode of death. Necropsies were performed in 98% of cases. Lung tissue was examined histologically to confirm the diagnosis, subtype of tumour, presence or absence of asbestosis and asbestos bodies. RESULTS: Exposure to asbestos was documented in 87% of cases, while in the remainder, no asbestos exposure was found nor were asbestos bodies seen; 94.5% were pleural, 5.1% peritoneal, and 0.4% pericardial. Right sided tumours were more common than left sided tumours (ratio 1.6:1). Patients usually presented with breathlessness and chest pain, but 33% presented with pleural effusion in the absence of chest pain. The mean (SD) time from first exposure to asbestos to symptoms was 40 (12) years with a median (interquartile range (IQR) survival of 14 (12.5) months. The median (IQR) survival time in sarcomatous, epithelial, and mixed cell type malignant mesothelioma was 9.4 (10) months, 12.5 (18) months, and 11 (14) months, respectively, and was significantly greater in cases detected by chance. Clinical features were similar in asbestos related and non-asbestos related malignant mesothelioma. CONCLUSIONS: In south east England most cases of malignant mesothelioma are associated with asbestos exposure. Clinical features do not differentiate between asbestos related and non- asbestos related disease. 


 PMID:9227715

  11. Overexpression of activin-A and -B in malignant mesothelioma – Attenuated Smad3 signaling responses and ERK activation promote cell migration and invasive growth

    SciTech Connect

    Tamminen, Jenni A.; Yin, Miao; Rönty, Mikko; Sutinen, Eva; Pasternack, Arja; Ritvos, Olli; Myllärniemi, Marjukka; Koli, Katri

    2015-03-01

    Activin-A and activin-B, members of the TGF-β superfamily, are regulators of reproductive functions, inflammation and wound healing. These dimeric molecules regulate various cellular activities such as proliferation, migration and suvival. Malignant mesothelioma is an asbestos exposure related tumor affecting mainly pleura and it usually has a dismal prognosis. Here, we demonstrate that both activin-A and -B are abundantly expressed in mesothelioma tumor tissue as well as in cultured primary and established mesothelioma cells. Migratory and invasive mesothelioma cells were also found to have attenuated activation of the Smad2/3 pathway in response to activins. Migration and invasive growth of the cells in three-dimentional matrix was prevented by inhibition of activin activity using a soluble activin receptor 2B (sActR2B-Fc). This was associated with decreased ERK activity. Furthermore, migration and invasive growth was significantly inhibited by blocking ERK phosphorylation. Mesothelioma tumors are locally invasive and our results clearly suggest that acivins have a tumor-promoting function in mesothelioma through increasing expression and switching from canonical Smad3 pathway to non-canonical ERK pathway signaling. Blocking activin activity offers a new therapeutic approach for inhibition of mesothelioma invasive growth. - Highlights: • Activin-A and activin-B are highly expressed in mesothelioma. • Mesothelioma cell migration and invasive growth can be blocked with sActR2B. • Activin induced Smad3 activity is attenuated in invasive mesothelioma cells. • Activins induce ERK activity in mesothelioma cells.

  12. Usefulness of Aquaporin 1 as a Prognostic Marker in a Prospective Cohort of Malignant Mesotheliomas

    PubMed Central

    Driml, Jack; Pulford, Emily; Moffat, David; Karapetis, Christos; Kao, Steven; Griggs, Kim; Henderson, Douglas Warrington; Klebe, Sonja

    2016-01-01

    (1) Background: Malignant mesothelioma (MM) is an aggressive tumour of the serosal membranes, associated with exposure to asbestos. Survival is generally poor, but prognostication for individual patients is difficult. We recently described Aquaporin 1 (AQP1) as independent prognostic factor in two separate retrospective cohorts of MM patients. Here we assess the usefulness of AQP1 prospectively, and determine the inter-observer agreement in assessing AQP1 scores; (2) Methods: A total of 104 consecutive cases of MM were included. Sufficient tissue for immunohistochemistry was available for 100 cases, and these cases were labelled for AQP1. Labelling was assessed by two pathologists. Complete clinical information and follow up was available for 91 cases; (3) Results: Labelling of ≥50% of tumour cells for AQP indicated improved prognosis in a univariate model (median survival 13 versus 8 months, p = 0.008), but the significance was decreased in a multivariate analysis. Scoring for AQP1 was robust, with an inter-observer kappa value of 0.722, indicating substantial agreement between observers; (4) Conclusion: AQP1 is a useful prognostic marker that can be easily incorporated in existing diagnostic immunohistochemical panels and which can be reliably interpreted by different pathologists. PMID:27376267

  13. Immunological effects of the TGFβ-blocking antibody GC1008 in malignant pleural mesothelioma patients

    PubMed Central

    Stevenson, James P; Kindler, Hedy L; Papasavvas, Emmanouil; Sun, Jing; Jacobs-Small, Mona; Hull, Jennifer; Schwed, Daniel; Ranganathan, Anjana; Newick, Kheng; Heitjan, Daniel F; Langer, Corey J; McPherson, John M; Montaner, Luis J; Albelda, Steven M

    2013-01-01

    We evaluated a neutralizing anti-TGFβ antibody (GC1008) in cancer patients with malignant pleura mesothelioma (MPM). The goal of this study was to assess immunoregulatory effects in relation to clinical safety and clinical response. Patients with progressive MPM and 1–2 prior systemic therapies received GC1008 at 3mg/kg IV over 90 min every 21 d as part of an open-label, two-center Phase II trial. Following TGFβ blockade therapy, clinical safety and patient survival were monitored along with the effects of anti-TGFβ antibodies on serum biomarkers and peripheral blood mononuclear cells (PBMC). Although designed as a larger trial, only 13 patients were enrolled when the manufacturer discontinued further development of the antibody for oncology indications. All participants tolerated therapy. Although partial or complete radiographic responses were not observed, three patients showed stable disease at 3 mo. GC1008 had no effect in the expression of NK, CD4+, or CD8+ T cell activating and inhibitory markers, other than a decrease in the expression of 2B4 and DNAM-1 on NK cells. However, serum from 5 patients showed new or enhanced levels of antibodies against MPM tumor lysates as measured by immunoblotting. Patients who produced anti-tumor antibodies had increased median overall survival (OS) (15 vs 7.5 mo, p < 0.03) compared with those who did not. To our knowledge, these data represent the first immune analysis of TGFβ- blockade in human cancer patients. PMID:24179709

  14. Pemetrexed Maintenance Therapy Following Bevacizumab-Containing First-Line Chemotherapy in Advanced Malignant Pleural Mesothelioma

    PubMed Central

    Jing, Xu-Quan; Zhou, Lei; Sun, Xin-Dong; Yu, Jin-Ming; Meng, Xue

    2016-01-01

    Abstract Malignant pleural mesothelioma (MPM) is a lethal disease with poor prognosis. The combination of cisplatin and pemetrexed has been confirmed as the standard of care for nonoperable MPM. Data have shown that the adoption of pemetrexed maintenance therapy (PMT) following first-line treatment appears extremely promising. We describe a 57-year-old man diagnosed as advanced MPM. We treated this patient with PMT after first-line cisplatin-based bevacizumab-containing chemotherapy and residual tumor disappeared after 6 course of PMT. A perfect response and a long progression-free survival (PFS) were reached with tumor mass disappearing and 14 months duration of PFS. This case suggests that adding bevacizumab to standard first-line chemotherapy is feasible and that PMT could be promising and useful for treating advanced MPM. We further entail a review of the literature on the first-line treatment, continuation maintenance therapy, switch maintenance therapy, and second-line treatment of patients with advanced MPM. PMID:27057918

  15. Malignant mesotheliomas in a small village in the Anatolian region of Turkey: an epidemiologic study.

    PubMed

    Artvinli, M; Bariş, Y I

    1979-07-01

    An epidemiologic and cause-related study was done in Tuzköy, a small village in the city of Nevşehir, in the Anatolian region of Turkey. The neighboring village of Kizilböy was used as a control. People 25 years of age or older were studied: 312 persons (145 males and 167 females) from Tuzköy and 95 persons (45 males and 50 females) from the control village. The annual incidence of malignant pleural mesothelioma (MPM) was found to be 6.5 cases (22 cases per 10,000 people) in Tuzköy. Several other respiratory disorders were detected as well. Although no type of asbestos could be found in Tuzköy and its vicinity, the asbestiform mineral zeolite was found in soil samples from the roads and fields of Tuzköy, in its building stones, and in lung tissues of the villagers. Chest X-rays revealed no cases of MPM or other respiratory abnormalities in the control group. No zeolite could be found in the control village. Therefore, zeolite was thought to be the cause of MPM and the other respiratory disorders in Tuzköy.

  16. Implementation of a molecular epidemiology approach to human pleural malignant mesothelioma.

    PubMed

    Puntoni, Riccardo; Filiberti, Rosangela; Cerrano, Paolo G; Neri, Monica; Andreatta, Rossana; Bonassi, Stefano

    2003-11-01

    The carcinogenic effect of asbestos has been reported in the literature since 40 years, and early studies describing the epidemic occurrence of malignant mesothelioma (MM) in asbestos workers, have become a paradigm of occupational cancer research. Research on MM was abandoned for many years since MM was considered as an asbestos-related disease, interesting only from a perspective of disease control and preventive policies. The introduction of new biological endpoints in the epidemiological studies has boosted research in the field, providing new tools for the study of emerging priority in cancer research and in public health. This approach, known as molecular epidemiology has a great potential in the study of MM, contributing to the understanding of susceptibility factors, to the evaluation of cancer risk in people occupationally or environmentally exposed to carcinogens, and to the enhancement of diagnosis and therapy. A comprehensive approach based on the use of banks of biological samples is presented and its advantages discussed here. The application of innovative endpoints, such as oncoproteins in biologic fluids, genetic polimorphisms, or gene function is discussed, and relevant literature reviewed.

  17. Diffuse malignant mesothelioma of the pleura in Ontario and Quebec: a retrospective study of 332 patients.

    PubMed

    Ruffie, P; Feld, R; Minkin, S; Cormier, Y; Boutan-Laroze, A; Ginsberg, R; Ayoub, J; Shepherd, F A; Evans, W K; Figueredo, A

    1989-08-01

    Three-hundred thirty-two cases of pleural diffuse malignant mesothelioma (DMM) seen at large centers in Ontario and Quebec from 1965 to 1984 were reviewed retrospectively. Previous asbestos exposure was found in 44% of patients. Diagnosis was most often made by exploratory thoracotomy; pleural biopsy or cytology were rarely contributory. The delay in diagnosis was often long (median time, 3.5 months) and thrombocytosis (platelets greater than or equal to 400,000/microL) was common (41% of cases). The median survival (MS) was only 9 months. Eleven clinical variables were analyzed for prognostic significance. The three most important prognostic factors using a univariate analysis were stage, weight loss, and histologic type. For 118 patients with complete data, multivariate analysis showed that the stage of disease, high platelet count, and asbestos exposure were the most important prognostic factors. There was no cure of DMM, and we did not find any drastic differences in survival among groups of patients subjected to the different therapeutic measures. Radical surgery and radiotherapy were ineffective and we confirmed the low response rate to chemotherapeutic agents. This large retrospective trial can serve as a baseline for future studies in this field. In particular, it provides the basis for appropriate stratification variables to be used in future therapeutic trials.

  18. New Insights into Understanding the Mechanisms, Pathogenesis, and Management of Malignant Mesotheliomas

    PubMed Central

    Mossman, Brooke T.; Shukla, Arti; Heintz, Nicholas H.; Verschraegen, Claire F.; Thomas, Anish; Hassan, Raffit

    2014-01-01

    Malignant mesothelioma (MM) is a relatively rare but devastating tumor that is increasing worldwide. Yet, because of difficulties in early diagnosis and resistance to conventional therapies, MM remains a challenge for pathologists and clinicians to treat. In recent years, much has been revealed regarding the mechanisms of interactions of pathogenic fibers with mesothelial cells, crucial signaling pathways, and genetic and epigenetic events that may occur during the pathogenesis of these unusual, pleiomorphic tumors. These observations support a scenario whereby mesothelial cells undergo a series of chronic injury, inflammation, and proliferation in the long latency period of MM development that may be perpetuated by durable fibers, the tumor microenvironment, and inflammatory stimuli. One culprit in sustained inflammation is the activated inflammasome, a component of macrophages or mesothelial cells that leads to production of chemotactic, growth-promoting, and angiogenic cytokines. This information has been vital to designing novel therapeutic approaches for patients with MM that focus on immunotherapy, targeting growth factor receptors and pathways, overcoming resistance to apoptosis, and modifying epigenetic changes. PMID:23395095

  19. Anticancer property of bromelain with therapeutic potential in malignant peritoneal mesothelioma.

    PubMed

    Pillai, Krishna; Akhter, Javed; Chua, Terence C; Morris, David Lawson

    2013-05-01

    Bromelain is a mixture of proteolytic enzymes that is capable of hydrolyzing glycosidic linkages in glycoprotein. Glycoprotein's are ubiquitously distributed throughout the body and serve a variety of physiologic functions. Faulty glycosylation of proteins may lead to cancer. Antitumor properties of bromelain have been demonstrated in both, in vitro and in vivo studies, along with scanty anecdotal human studies. Various mechanistic pathways have been proposed to explain the anticancer properties of bromelain. However, proteolysis by bromelain has been suggested as a main pathway by some researchers. MUC1 is a glycoprotein that provides tumor cells with invasive, metastatic, and chemo-resistant properties. To date, there is no study that examines the effect of bromelain on MUC1. However, the viability of MUC1 expressing pancreatic and breast cancer cells are adversely affected by bromelain. Further, the efficacy of cisplatin and 5-FU are enhanced by adjuvant treatment with bromelain, indicating that the barrier function of MUC1 may be affected. Other studies have also indicated that there is a greater accumulation of 5-FU in the cell compartment on treatment with 5-FU and bromelain. Malignant peritoneal mesothelioma (MPM) expresses MUC1 and initial studies have shown that the viability of MPM cells is adversely affected by exposure to bromelain. Further, bromelain in combination with either 5-FU or cisplatin, the efficacy of the chemotherapeutic drug is enhanced. Hence, current evidence indicates that bromelain may have the potential of being developed into an effective anticancer agent for MPM.

  20. Anticancer effect of bromelain with and without cisplatin or 5-FU on malignant peritoneal mesothelioma cells.

    PubMed

    Pillai, Krishna; Ehteda, Anahid; Akhter, Javid; Chua, Terence C; Morris, David L

    2014-02-01

    Malignant peritoneal mesothelioma (MPM) is a rare neoplasm of the peritoneum, causally related to asbestos exposure. Nonspecific symptoms with a late diagnosis results in poor survival (<1 year). Treatment with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy has improved survival in some patients (median 3-5 years). Hence, new therapies are urgently needed. MUC1 is a glycosylation-dependent protein that confers tumours with invasiveness, metastasis and chemoresistance. Bromelain (cysteine proteinase) hydrolyses glycosidic bonds. Therefore, we investigated the antitumour effect of bromelain on MUC1-expressing MPM cell lines. MUC1 expressions in cells were assessed using immunofluorescent probes with cells grown on cover slips and western blot analysis on cell lysates. The cell lines were treated with various concentrations of bromelain and after 4 and 72 h, their viability was assessed using standard sulforhodamine assays. The cells were also treated with combinations of bromelain and cytotoxic drugs (cisplatin or 5-FU) and their viability was assessed at 72 h. Finally, with western blotting, the effects of bromelain on cellular survival proteins were investigated. PET cells expressed more MUC1 compared with YOU cells. The cell viability of both PET and YOU cells was adversely affected by bromelain, with PET cells being slightly resistant. The addition of bromelain increased the cytotoxicity of cisplatin significantly in both cell lines. However, 5-FU with bromelain did not show any significant increase in cytotoxicity. Bromelain-induced cell death is by apoptosis and autophagy. Bromelain has the potential of being developed as a therapeutic agent in MPM.

  1. Kinesin family members KIF11 and KIF23 as potential therapeutic targets in malignant pleural mesothelioma.

    PubMed

    Kato, Tatsuya; Lee, Daiyoon; Wu, Licun; Patel, Priya; Young, Ahn Jin; Wada, Hironobu; Hu, Hsin-Pei; Ujiie, Hideki; Kaji, Mitsuhito; Kano, Satoshi; Matsuge, Shinichi; Domen, Hiromitsu; Kaga, Kichizo; Matsui, Yoshiro; Kanno, Hiromi; Hatanaka, Yutaka; Hatanaka, Kanako C; Matsuno, Yoshihiro; de Perrot, Marc; Yasufuku, Kazuhiro

    2016-08-01

    Malignant pleural mesothelioma (MPM) is a rare and aggressive form of cancer commonly associated with asbestos exposure that stems from the thoracic mesothelium with high mortality rate. Currently, treatment options for MPM are limited, and new molecular targets for treatments are urgently needed. Using quantitative reverse transcription-polymerase chain reaction (RT-PCR) and an RNA interference-based screening, we screened two kinesin family members as potential therapeutic targets for MPM. Following in vitro investigation of the target silencing effects on MPM cells, a total of 53 MPMs were analyzed immunohistochemically with tissue microarray. KIF11 and KIF23 transcripts were found to be overexpressed in the majority of clinical MPM samples as well as human MPM cell lines as determined by quantitative RT-PCR. Gene knockdown in MPM cell lines identified growth inhibition following knockdown of KIF11 and KIF23. High expression of KIF11 (KIF11-H) and KIF23 (KIF23-H) were found in 43.4 and 50.9% of all the MPM cases, respectively. Patients who received curative resection with tumors displaying KIF23-H showed shorter overall survival (P=0.0194). These results provide that inhibition of KIF11 and KIF23 may hold promise for treatment of MPMs, raising the possibility that kinesin-based drug targets may be developed in the future. PMID:27279560

  2. Usefulness of Aquaporin 1 as a Prognostic Marker in a Prospective Cohort of Malignant Mesotheliomas.

    PubMed

    Driml, Jack; Pulford, Emily; Moffat, David; Karapetis, Christos; Kao, Steven; Griggs, Kim; Henderson, Douglas Warrington; Klebe, Sonja

    2016-01-01

    (1) BACKGROUND: Malignant mesothelioma (MM) is an aggressive tumour of the serosal membranes, associated with exposure to asbestos. Survival is generally poor, but prognostication for individual patients is difficult. We recently described Aquaporin 1 (AQP1) as independent prognostic factor in two separate retrospective cohorts of MM patients. Here we assess the usefulness of AQP1 prospectively, and determine the inter-observer agreement in assessing AQP1 scores; (2) METHODS: A total of 104 consecutive cases of MM were included. Sufficient tissue for immunohistochemistry was available for 100 cases, and these cases were labelled for AQP1. Labelling was assessed by two pathologists. Complete clinical information and follow up was available for 91 cases; (3) RESULTS: Labelling of ≥50% of tumour cells for AQP indicated improved prognosis in a univariate model (median survival 13 versus 8 months, p = 0.008), but the significance was decreased in a multivariate analysis. Scoring for AQP1 was robust, with an inter-observer kappa value of 0.722, indicating substantial agreement between observers; (4) CONCLUSION: AQP1 is a useful prognostic marker that can be easily incorporated in existing diagnostic immunohistochemical panels and which can be reliably interpreted by different pathologists. PMID:27376267

  3. Preclinical studies identify novel targeted pharmacological strategies for treatment of human malignant pleural mesothelioma

    PubMed Central

    Favoni, Roberto E; Daga, Antonio; Malatesta, Paolo; Florio, Tullio

    2012-01-01

    The incidence of human malignant pleural mesothelioma (hMPM) is still increasing worldwide. hMPM prognosis is poor even if the median survival time has been slightly improved after the introduction of the up-to-date chemotherapy. Nevertheless, large phase II/III trials support the combination of platinum derivatives and pemetrexed or raltitrexed, as preferred first-line schedule. Better understanding of the molecular machinery of hMPM will lead to the design and synthesis of novel compounds targeted against pathways identified as crucial for hMPM cell proliferation and spreading. Among them, several receptors tyrosine kinase show altered activity in subsets of hMPM. This observation suggests that these kinases might represent novel therapeutic targets in this chemotherapy-resistant disease. Over these foundations, several promising studies are ongoing at preclinical level and novel molecules are currently under evaluation as well. Yet, established tumour cell lines, used for decades to investigate the efficacy of anticancer agents, although still the main source of drug efficacy studies, after long-term cultures tend to biologically diverge from the original tumour, limiting the predictive potential of in vivo efficacy. Cancer stem cells (CSCs), a subpopulation of malignant cells capable of self-renewal and multilineage differentiation, are believed to play an essential role in cancer initiation, growth, metastasization and relapse, being responsible of chemo- and radiotherapy refractoriness. According to the current carcinogenesis theory, CSCs represent the tumour-initiating cell (TIC) fraction, the only clonogenic subpopulation able to originate a tumour mass. Consequently, the recently described isolation of TICs from hMPM, the proposed main pharmacological target for novel antitumoural drugs, may contribute to better dissect the biology and multidrug resistance pathways controlling hMPM growth. PMID:22289125

  4. BAP1 facilitates diagnostic objectivity, classification, and prognostication in malignant pleural mesothelioma.

    PubMed

    McGregor, Stephanie M; Dunning, Ryan; Hyjek, Elizabeth; Vigneswaran, Wickii; Husain, Aliya N; Krausz, Thomas

    2015-11-01

    BRCA-associated protein 1 (BAP1) has emerged as a promising biomarker for malignant pleural mesothelioma (MPM). Loss of BAP1 expression can occur by a variety of mechanisms, but reports on incidence are variable and the clinical significance is unclear. In order to investigate the diagnostic and prognostic significance of BAP1, we constructed a tissue microarray consisting of 111 MPM cases and performed BAP1 immunohistochemistry. BAP1 was lost in 77% of epithelioid cases (n=58) but was retained in all sarcomatoid cases (n=10); 49% of biphasic cases showed loss (n=43), and BAP1-negative cases demonstrated loss of staining in both the epithelioid and sarcomatoid components. All non-neoplastic mesothelial tissues (n=20) retained BAP1, resulting in a sensitivity, specificity, positive predictive value, and negative predictive value of 61%, 100%, 100%, and 32%, respectively. Moreover, BAP1 expression in spindled mesothelium enabled discrimination of reactive and malignant cells, thus providing a more objective means of distinguishing epithelioid from biphasic morphology compared to histology alone. Nonetheless, BAP1 staining was patchy in some benign mesothelial neoplasms, which raises concern for using BAP1 in small biopsies. Kaplan-Meier analysis demonstrated a significant improvement in overall survival with BAP1 loss, but this did not reach significance in multivariate analysis accounting for histologic subtype. When only epithelioid cases were analyzed there was a trend toward increased survival, but it did not reach significance. We conclude that BAP1 loss is frequent in epithelioid MPM, which is in turn associated with improved survival, and that it can have additional clinical significance by facilitating histologic classification.

  5. Establishment and molecular characterization of cell lines from Japanese patients with malignant pleural mesothelioma

    PubMed Central

    SUZAWA, KEN; YAMAMOTO, HIROMASA; MURAKAMI, TOMOYUKI; KATAYAMA, HIDEKI; FURUKAWA, MASASHI; SHIEN, KAZUHIKO; HASHIDA, SHINSUKE; OKABE, KAZUNORI; AOE, KEISUKE; SOH, JUNICHI; ASANO, HIROAKI; TSUKUDA, KAZUNORI; MIMURA, YUSUKE; TOYOOKA, SHINICHI; MIYOSHI, SHINICHIRO

    2016-01-01

    Malignant pleural mesothelioma (MPM) is an aggressive disease that is resistant to conventional therapies. Cell lines are useful models for studying the biological characteristics of tumors; therefore, the establishment of MPM cell lines is valuable for exploring novel therapeutic strategies for MPM. In the present study, 4 MPM cell lines (YUMC8, YUMC44, YUMC63, and YUMC64) were established, which consisted of 2 epithelioid and 2 sarcomatoid mesothelioma histological subtypes, from Japanese patients with MPM. The DNA methylation status, mutations, copy number gains, protein expression of representative genes, and the sensitivity to several drugs were examined in these 4 cell lines. Methylation of P16 was demonstrated in 3/4 cell lines, in which the protein expression of p16 was lost. Methylation of RASSF1A was observed in 3/4 cell lines. Copy number gains of EGFR, HER2 or MET were not detected in the 4 cell lines. Mutations in various genes, including EGFR, KRAS, HER2, BRAF, and PIK3CA, which are frequently detected in non-small cell lung cancer, were not detected in the 4 cell lines. microRNA-34b/c is a direct transcriptional target of p53 and is often silenced in MPM by promoter methylation. In the present study, miR-34b/c was heavily methylated in 2/4 established MPM cell lines. For cell adhesion molecules, E-cadherin expression was detected in the 2 epithelioid MPM cell lines, whereas N-cadherin expression was detected in all 4 established cell lines by western blotting. Vimentin was strongly expressed in the 2 sarcomatoid MPM cell lines. None of the established MPM cell lines demonstrated significant responses to the drugs tested, including NVP-AUY922, 17-DMAG, Trichostatin A, and Vorinostat. Although novel molecular findings were not observed in the current characterization of these MPM cell lines, these lines will be useful for future extensive analyses of the biological behavior of MPM and the development of novel therapeutic strategies. PMID:26870271

  6. Lack of apparent excess of malignant mesothelioma but increased overall malignancies of peritoneal cavity in Japanese autopsies with Thorotrast injection into blood vessels.

    PubMed

    Ishikawa, Y; Mori, T; Machinami, R

    1995-01-01

    The carcinogenicity of thorium dioxide sol (Thorotrast), an X-ray contrast medium used in 1930-1955, in the liver and bone marrow has been established and agrees well with the effects of a high dosage of alpha radiation in the organs. Recently, however, German and Danish epidemiologic studies have shown excess mesotheliomas in the pleura and peritoneum that are unlikely to have been heavily irradiated by alpha particles. To confirm these observations, we examined the incidence of the cancer in those who underwent Thorotrast injections into blood vessels (n = 370) by using autopsy files of the Japanese Thorotrast study. Only one malignant mesothelioma of the peritoneum was registered, whereas three peritoneal or retroperitoneal sarcomas were observed. Thus, our study did not find any increment of mesothelioma in Thorotrast patients. However, when we took the pleuroperitoneal and retroperitoneal malignancies altogether, the incidence (4/370 = 1.1%) was five times more frequent than that (344/162,000 = 0.2%) in the controls (P < 0.005). Clinicopathological data of the four cases are also presented.

  7. Metabolic genotypes as modulators of asbestos-related pleural malignant mesothelioma risk: a comparison of Finnish and Italian populations.

    PubMed

    Neri, Monica; Taioli, Emanuela; Filiberti, Rosangela; Paolo Ivaldi, Giovanni; Aldo Canessa, Pier; Verna, Anna; Marroni, Paola; Puntoni, Riccardo; Hirvonen, Ari; Garte, Seymour

    2006-07-01

    The role of CYP1A1, GSTM1, GSTT1, EPHX1, and NAT2 genotypes in susceptibility to malignant mesothelioma (MM) was compared in two case-control studies, previously conducted in two countries where different types of asbestos fibers have been used [Hirvonen et al., 1995. Inherited GSTM1 and NAT2 defects as concurrent risk modifiers in asbestos-related human malignant mesothelioma. Cancer Res. 55, 2981-2983; Hirvonen et al., 1996. Glutathione S-Transferase and N-Acetyltransferase genotypes and asbestos-associated pulmonary disorders. J. Natl. Cancer Inst.88, 1853-1856; Neri et al., 2005. Pleural malignant mesothelioma, genetic susceptibility and asbestos exposure. Mutat. Res. 592, 36-44]. Fifty-seven asbestos-exposed MM patients and 255 controls were recruited in Italy, 48 cases and 121 controls in Finland. In order to make the two studies comparable, they have been updated and new genotyping analyses have been performed. The NAT2 fast acetylator and EPHX1 low-activity genotypes were positively associated with MM in the Italian study, while they were negatively associated with this malignancy in the Finnish one. A combined significant effect was also observed in the Italian study for the NAT2 fast acetylator and EPHX1 low-activity genotypes, while this combination was protective in the Finnish study. Combination of NAT2 fast acetylator and GSTM1 null genotype posed a significantly increased risk of MM in the Italian, but not in the Finnish study. The opposite results obtained in Finland and Italy may be ascribed to random chance, but a role may be hypothesized for the fact that different types of asbestos have been used in the two countries.

  8. Presence of simian virus 40 sequences in malignant mesotheliomas and mesothelial cell proliferations.

    PubMed

    Shivapurkar, N; Wiethege, T; Wistuba, I I; Salomon, E; Milchgrub, S; Muller, K M; Churg, A; Pass, H; Gazdar, A F

    1999-12-01

    Malignant mesotheliomas (MMs) are pleural-, pericardial-, or peritoneal-based neoplasms usually associated with asbestos exposure. Mesothelial cells are biphasic and may give rise to epithelial and sarcomatous MMs. In addition, benign or atypical proliferations of mesothelial cells may occur in response to many stimuli. There have been recent reports of simian virus 40 (SV40) DNA large T antigen (Tag) sequences in pleural MMs. To further understand the relationship between SV40, MMs, and mesothelial proliferations, we studied 118 MMs from multiple sites in Germany and North America, including 93 epithelial pleural, 14 sarcomatous or mixed pleural MMs, and 11 peritoneal MMs. In 12 pleural MMs, adjacent noninvasive tumor foci were identified and studied separately. Information about asbestos exposure (detailed history and/or microscopic examination for asbestos bodies) was available from 43 German patients. In addition, 13 examples of reactive mesothelium and 20 lung cancers from the United States were tested. DNA was extracted from frozen tumor and adjacent nontumorous tissues or after microdissection of archival formalin-fixed, paraffin-embedded microslides. Two rounds of PCR were performed with primers SVFor 3 and SVRev, which amplify a 105 bp region specific for SV40 Tag. The specificity of the PCR product was confirmed in some cases by sequencing. Our major findings were: 1) Specific SV40 viral sequences were present in 57% of epithelial invasive MMs, of both pleural and peritoneal origin. No significant geographic differences were found, and frozen and paraffin-embedded tissues were equally suitable for analysis. 2) There was no apparent relationship between the presence of SV40 sequences and asbestos exposure. 3) SV40 sequences were present in the surface (noninvasive) components of epithelial MMs. 4) SV40 sequences were not detected in MMs of sarcomatous or mixed histologies. 5) Viral sequences were present in two of 13 samples (15%) of reactive mesothelium

  9. Dendritic cell-based immunotherapy in mesothelioma.

    PubMed

    Cornelissen, Robin; Lievense, Lysanne A; Heuvers, Marlies E; Maat, Alexander P; Hendriks, Rudi W; Hoogsteden, Henk C; Hegmans, Joost P; Aerts, Joachim G

    2012-10-01

    Mesothelioma is a rare thoracic malignancy with a dismal prognosis. Current treatment options are scarce and clinical outcomes are rather disappointing. Due to the immunogenic nature of mesothelioma, several studies have investigated immunotherapeutic strategies to improve the prognosis of patients with mesothelioma. In the last decade, progress in knowledge of the modulation of the immune system to attack the tumor has been remarkable, but the optimal strategy for immunotherapy has yet to be unraveled. Because of their potent antigen-presenting capacity, dendritic cells are acknowledged as a promising agent in immunotherapeutic approaches in a number of malignancies. This review gives an update and provides a future perspective in which immunotherapy may improve the outcome of mesothelioma therapy.

  10. Antagonizing the Hedgehog Pathway with Vismodegib Impairs Malignant Pleural Mesothelioma Growth In Vivo by Affecting Stroma.

    PubMed

    Meerang, Mayura; Bérard, Karima; Felley-Bosco, Emanuela; Lauk, Olivia; Vrugt, Bart; Boss, Andreas; Kenkel, David; Broggini-Tenzer, Angela; Stahel, Rolf A; Arni, Stephan; Weder, Walter; Opitz, Isabelle

    2016-05-01

    An autocrine-driven upregulation of the Hedgehog (Hh) signaling pathway has been described in malignant pleural mesothelioma (MPM), in which the ligand, desert Hh (DHH), was produced from tumor cells. However, our investigation revealed that the Hh pathway is activated in both tumor and stroma of MPM tumor specimens and an orthotopic immunocompetent rat MPM model. This was demonstrated by positive immunohistochemical staining of Glioma-associated oncogene 1 (GLI1) and Patched1 (PTCH1) in both tumor and stromal fractions. DHH was predominantly expressed in the tumor fractions. To further investigate the role of the Hh pathway in MPM stroma, we antagonized Hh signaling in the rat model of MPM using a Hh antagonist, vismodegib, (100 mg/kg orally). Daily treatment with vismodegib efficiently downregulated Hh target genes Gli1, Hedgehog Interacting Protein (Hhip), and Ptch1, and caused a significant reduction of tumor volume and tumor growth delay. Immunohistochemical analyses revealed that vismodegib treatment primarily downregulated GLI1 and HHIP in the stromal compartment along with a reduced expression of previously described fibroblast Hh-responsive genes such as Fibronectin (Fn1) and Vegfa Primary cells isolated from the rat model cultured in 3% O2 continued to express Dhh but did not respond to vismodegib in vitro However, culture supernatant from these cells stimulated Gli1, Ptch1, and Fn1 expression in mouse embryonic fibroblasts, which was suppressed by vismodegib. Our study provides new evidence regarding the role of Hh signaling in MPM stroma in the maintenance of tumor growth, emphasizing Hh signaling as a treatment target for MPM. Mol Cancer Ther; 15(5); 1095-105. ©2016 AACR. PMID:26839306

  11. p53 autoantibodies in patients with malignant mesothelioma: stability through disease progression

    PubMed Central

    Creaney, J; McLaren, B M; Stevenson, S; Musk, A W; Klerk, N de; Robinson, B W S; Lake, R A

    2001-01-01

    Malignant mesothelioma (MM) generally occurs as a pleural tumour, related to the inhalation of asbestos fibres. It is highly aggressive and largely unresponsive to treatment. The incidence of MM is particularly high in Western Australia because of the extensive blue asbestos mining operations that occurred in the north of the state until 1966. MM is unusual in that mutations in the tumour suppressor gene p53 are rarely observed, whilst over-expression of p53 protein is common. As the level of antibodies directed against p53 is thought to be of prognostic value in some cancers and as MM is known to be immunogenic, we studied a cohort of Western Australian patients to determine the prevalence of anti-p53 antibodies and their value as diagnostic markers or prognostic indicators. 6/88 (7%) of patients had high titres (>2 SD above the mean of controls) of anti-p53 antibodies. There was no correlation between antibody titre and survival. Although 3/38 (8%) of sera obtained from patients exposed to asbestos but prior to a diagnosis of MM contained antibodies, the same proportion of sera obtained from patients exposed to asbestos but who remained disease free also contained antibodies (2/40; 8%). Sera collected sequentially demonstrated a profound temporal stability in the titre of anti-p53 antibodies in patients with MM throughout the course of their illness. These results show that anti-p53 antibodies are observed only at a low frequency in the sera of MM patients and where they do occur, their elicitation is an early event that may be unrelated to antigen load. The occurrence of anti-p53 antibodies does not serve as either a useful prognostic or diagnostic indicator in MM. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11139313

  12. High Incidence of Somatic BAP1 Alterations in Sporadic Malignant Mesothelioma

    PubMed Central

    Nasu, Masaki; Emi, Mitsuru; Pastorino, Sandra; Tanji, Mika; Powers, Amy; Luk, Hugh; Baumann, Francine; Zhang, Yu-an; Gazdar, Adi; Kanodia, Shreya; Tiirikainen, Maarit; Flores, Erin; Gaudino, Giovanni; Becich, Michael J.; Pass, Harvey I.; Yang, Haining; Carbone, Michele

    2015-01-01

    Background BAP1 is a nuclear deubiquitinase that regulates gene expression, transcription, DNA repair, and more. Several findings underscore the apparent “driver” role of BAP1 in malignant mesothelioma (MM). However the reported frequency of somatic BAP1 mutations in MM varies considerably, a discrepancy that appeared related to either methodological or ethnical differences across various studies. Methods To address this discrepancy, we carried out comprehensive genomic and immunohistochemical (IHC) analyses to detect somatic BAP1 gene alterations in 22 frozen MM biopsies from US MM patients. Results By combining Sanger sequencing, Multiplex Ligation-Dependent Probe Amplification, copy number analysis and cDNA sequencing, we found alteration of BAP1 in 14/22 biopsies (63.6%). No changes in methylation were observed. IHC revealed normal nuclear BAP1 staining in the 8 MM containing wild-type BAP1, while no nuclear staining was detected in the 14 MM biopsies containing tumor cells with mutated BAP1. Thus, IHC results were in agreement with those obtained by genomic analyses. We then extended IHC analysis to an independent cohort of 70 MM biopsies, of which there was insufficient material to perform molecular studies. IHC revealed loss of BAP1 nuclear staining in 47 out of these 70 MM biopsies (67.1%). Conclusions Our findings conclusively establish BAP1 as the most commonly mutated gene in MM, regardless of ethnic background or other clinical characteristics. Our data point to IHC as the most accessible and reliable technique to detect BAP1 status in MM biopsies. PMID:25658628

  13. Genetic susceptibility to malignant pleural mesothelioma and other asbestos-associated diseases.

    PubMed

    Neri, Monica; Ugolini, Donatella; Dianzani, Irma; Gemignani, Federica; Landi, Stefano; Cesario, Alfredo; Magnani, Corrado; Mutti, Luciano; Puntoni, Riccardo; Bonassi, Stefano

    2008-01-01

    Exposure to asbestos fibers is a major risk factor for malignant pleural mesothelioma (MPM), lung cancer, and other non-neoplastic conditions, such as asbestosis and pleural plaques. However, in the last decade many studies have shown that polymorphism in the genes involved in xenobiotic and oxidative metabolism or in DNA repair processes may play an important role in the etiology and pathogenesis of these diseases. To evaluate the association between diseases linked to asbestos and genetic variability we performed a review of studies on this topic included in the PubMed database. One hundred fifty-nine citations were retrieved; 24 of them met the inclusion criteria and were evaluated in the review. The most commonly studied GSTM1 polymorphism showed for all asbestos-linked diseases an increased risk in association with the null genotype, possibly linked to its role in the conjugation of reactive oxygen species. Studies focused on GSTT1 null and SOD2 Ala16Val polymorphisms gave conflicting results, while promising results came from studies on alpha1-antitrypsin in asbestosis and MPO in lung cancer. Among genetic polymorphisms associated to the risk of MPM, the GSTM1 null genotype and two variant alleles of XRCC1 and XRCC3 showed increased risks in a subset of studies. Results for the NAT2 acetylator status, SOD2 polymorphism and EPHX activity were conflicting. Major limitations in the study design, including the small size of study groups, affected the reliability of these studies. Technical improvements such as the use of high-throughput techniques will help to identify molecular pathways regulated by candidate genes.

  14. Orotate phosphoribosyltransferase is overexpressed in malignant pleural mesothelioma: Dramatically responds one case in high OPRT expression

    PubMed Central

    Hamamoto, Yoichiro; Takeoka, Shinjiro; Mouri, Atsuto; Fukusumi, Munehisa; Wakuda, Kazushige; Ibe, Tatsuya; Honma, Chie; Arimoto, Yoshihito; Yamada, Kazuaki; Wagatsuma, Miyuki; Tashiro, Akito; Kamoshida, Shingo; Kamimura, Mitsuhiro

    2016-01-01

    ABSTRACT Objective: Malignant pleural mesothelioma (MPM) is a rare and aggressive, treatment-resistant cancer. Pemetrexed, an inhibitor of thymidylate synthase (TS), is used worldwide for MPM as a first-line chemotherapy regimen. However, there is little consensus for a second-line chemotherapy. S-1, a highly effective dihydropyrimidine dehydrogenase (DPD)-inhibitory fluoropyrimidine, mainly acts via a TS inhibitory mechanism similar to pemetrexed. Orotate phosphoribosyltransferase (OPRT) is a key enzyme related to the first step activation of 5-fluorouracil (5-FU) for inhibiting RNA synthesis. We investigated 5-FU related-metabolism proteins, especially focusing on OPRT expression, in MPM Methods and Patients: Fifteen MPM patients who were diagnosed between July 2004 and December 2013 were enrolled. We examined the protein levels of 5-FU metabolism-related enzymes (TS, DPD, OPRT, and thymidine phosphorylase [TP]) in 14 cases Results: High TS, DPD, OPRT, and TP expressions were seen in 28.6%, 71.4%, 85.7%, and 35.7% of patients, respectively. We found that OPRT expression was extremely high in MPM tissue. We experienced one remarkable case of highly effective S-1 combined therapy for pemetrexed refractory MPM. This case also showed high OPRT protein expression Conclusion: The present study suggests that OPRT expression is high in MPM tumors. Although pemetrexed is mainly used for MPM chemotherapy as a TS inhibitor, S-1 has potential as an anticancer drug not only as a TS inhibitor but also inhibiting RNA synthesis through the OPRT pathway. This is the first report investigating OPRT protein expressions in MPM. PMID:27274438

  15. Simian virus 40 may be associated with developing malignant pleural mesothelioma

    PubMed Central

    THANH, TRAN DINH; THO, NGUYEN VAN; LAM, NGUYEN SON; DUNG, NGUYEN HUY; TABATA, CHIHARU; NAKANO, YASUTAKA

    2016-01-01

    Malignant pleural mesothelioma (MPM) is associated with a history of heavy, long-term exposure to asbestos. However, MPM may also be associated with simian virus 40 (SV40), a polyomavirus. The association between SV40 and MPM remains unclear. The present study was conducted in order to investigate the proportion of SV40 presence in the histological specimens of Vietnamese patients with MPM. Histological specimens were obtained from 45 patients (19 men and 26 women) with MPM at the Pham Ngoc Thach Hospital in Ho Chi Minh City, Vietnam. The specimens were processed and examined in order to detect the presence of the SV40 large T antigen (SV40 Tag) expression using immunohistochemistry. Of the 45 patients, 23 (51%) were epithelioid, 7 (16%) were biphasic, 6 (13%) were sarcomatoid, 4 (9%) were desmoplastic, 4 (9%) were well-differentiated papillary and 1 (2%) was the anaplastic subtype. In total, 9/45 patients (20%) demonstrated SV40 Tag expression. The proportion of patients that demonstrated SV40 Tag expression was not significantly different between the epithelioid subtype and the other subtypes (22 vs. 18%; P=1.000) or between the patients with stage IV disease and other stages (20 vs. 20%; P=1.000). The median survival time was not significantly different between the patients with or without SV40 Tag expression (196 vs. 236 days, P=0.8949). In summary, a 5th of the Vietnamese patients with MPM were associated with infection with SV40. SV40 may be a potential cause of MPM in Vietnam and this potential association requires additional studies. PMID:26998120

  16. The assessment of the malignant mesothelioma cases and environmental asbestos exposure in Sivas province, Turkey.

    PubMed

    Berk, Serdar; Yalcin, Huseyin; Dogan, Omer Tamer; Epozturk, Kursat; Akkurt, Ibrahim; Seyfikli, Zehra

    2014-02-01

    One of the most significant diseases related to environmental asbestos exposure is malignant mesothelioma (MM). Sivas province is located in the Central Anatolia where asbestos exposure is common. We aimed to study clinical, demographical and epidemiologic features of the patients with MM in Sivas, along with the history of asbestos exposure. In total, 219 patients with MM who were diagnosed in our hospital between 1993 and 2010 were retrospectively analyzed in terms of demographical and clinical features. Rock, soil and house plaster samples were taken from the habitats of those patients and were evaluated with optical microscopy and X-ray diffraction methods. The age of the patients ranged between 18 and 85 years. The male-to-female ratio was 1.4:1. Most of the patients confirmed an asbestos exposure history. The most frequent symptoms of the patients were chest pain (60 %) and dyspnea (50 %). The gap between the start of first symptoms and the diagnosis date was approximately 4 months in average. The plaster materials used in most of the houses were made up of mainly carbonate and silicate minerals and some chrysotile. Ophiolitic units contained fibrous minerals such as serpentine (clino + orthochrysotile) chiefly and pectolite, brucite, hydrotalcite and tremolite/actinolite in smaller amounts. MM is not primarily related to occupational asbestos exposure in our region, and hence, environmental asbestos exposure may be indicted. Yet, single or combined roles and/or interactions of other fibrous and non-fibrous minerals in the etiology of MM are not yet fully understood and remain to be investigated.

  17. Malignant pleural mesothelioma from nonoccupational asbestos exposure in Metsovo (north-west Greece): slow end of an epidemic?

    PubMed

    Sakellariou, K; Malamou-Mitsi, V; Haritou, A; Koumpaniou, C; Stachouli, C; Dimoliatis, I D; Constantopoulos, S H

    1996-06-01

    Inhabitants of the Metsovo area, north-west Greece have been exposed since childhood to inhalation of asbestos, from a material containing tremolite, used for whitewashing ("luto soil"). This has resulted in endemic pleural calcifications (47% of adult population) and increased incidence of malignant pleural mesothelioma (MPM). In 1987, we reported that the incidence of MPM between 1981-1985 was around 300 times higher than expected in a nonasbestos exposed population (seven cases in 5 yrs in a population of 4,000-5,000). The present study is an updated report regarding this "mesothelioma epidemic", in conjunction with the diminished use and final abandonment of "luto soil" in the early 1980s. It appears that the incidence of MPM in Metsovo has dropped considerably since our first report. Between 1985-1994, we diagnosed six such cases (incidence rate = 1.4 cases per 10,000 person-years), whilst between 1980-1984 eight cases had been diagnosed (incidence rate = 3.7 cases per 10,000 person-years). Although, because of the small number of cases, this did not reach statistical significance (p = 0.08), we note that the incidence is now considerably lower than before. Had it remained unchanged, we would have expected 17 cases of MPM instead of six. This drop follows the diminished use of "luto" whitewash (by 92% of the population in 1950 and only 18% in 1980). If we take into account a 30-40 year latency period for mesothelioma, we expect that the "Metsovo mesothelioma epidemic" will fade away by the year 2020-2030, since the material has not been used since 1985.

  18. Detection, modeling and matching of pleural thickenings from CT data towards an early diagnosis of malignant pleural mesothelioma

    NASA Astrophysics Data System (ADS)

    Chaisaowong, Kraisorn; Kraus, Thomas

    2014-03-01

    Pleural thickenings can be caused by asbestos exposure and may evolve into malignant pleural mesothelioma. While an early diagnosis plays the key role to an early treatment, and therefore helping to reduce morbidity, the growth rate of a pleural thickening can be in turn essential evidence to an early diagnosis of the pleural mesothelioma. The detection of pleural thickenings is today done by a visual inspection of CT data, which is time-consuming and underlies the physician's subjective judgment. Computer-assisted diagnosis systems to automatically assess pleural mesothelioma have been reported worldwide. But in this paper, an image analysis pipeline to automatically detect pleural thickenings and measure their volume is described. We first delineate automatically the pleural contour in the CT images. An adaptive surface-base smoothing technique is then applied to the pleural contours to identify all potential thickenings. A following tissue-specific topology-oriented detection based on a probabilistic Hounsfield Unit model of pleural plaques specify then the genuine pleural thickenings among them. The assessment of the detected pleural thickenings is based on the volumetry of the 3D model, created by mesh construction algorithm followed by Laplace-Beltrami eigenfunction expansion surface smoothing technique. Finally, the spatiotemporal matching of pleural thickenings from consecutive CT data is carried out based on the semi-automatic lung registration towards the assessment of its growth rate. With these methods, a new computer-assisted diagnosis system is presented in order to assure a precise and reproducible assessment of pleural thickenings towards the diagnosis of the pleural mesothelioma in its early stage.

  19. Multidetector CT Findings and Differential Diagnoses of Malignant Pleural Mesothelioma and Metastatic Pleural Diseases in Korea

    PubMed Central

    Kim, Yoon Kyung; Lee, Kyung Won; Yi, Chin A; Koo, Jin Mo; Jung, Soon-Hee

    2016-01-01

    Objective To compare the multidetector CT (MDCT) features of malignant pleural mesothelioma (MPM) and metastatic pleural disease (MPD). Materials and Methods The authors reviewed the MDCT images of 167 patients, 103 patients with MPM and 64 patients with MPD. All 167 cases were pathologically confirmed by sonography-guided needle biopsy of pleura, thoracoscopic pleural biopsy, or open thoracotomy. CT features were evaluated with respect to pleural effusion, pleural thickening, invasion of other organs, lung abnormality, lymphadenopathy, mediastinal shifting, thoracic volume decrease, asbestosis, and the presence of pleural plaque. Results Pleural thickening was the most common CT finding in MPM (96.1%) and MPD (93.8%). Circumferential pleural thickening (31.1% vs. 10.9%, odds ratio [OR] 3.670), thickening of fissural pleura (83.5% vs. 67.2%, OR 2.471), thickening of diaphragmatic pleura (90.3% vs. 73.4%, OR 3.364), pleural mass (38.8% vs. 23.4%, OR 2.074), pericardial involvement (56.3% vs. 20.3%, OR 5.056), and pleural plaque (66.0% vs. 21.9%, OR 6.939) were more frequently seen in MPM than in MPD. On the other hand, nodular pleural thickening (59.2% vs. 76.6%, OR 0.445), hilar lymph node metastasis (5.8% vs. 20.3%, OR 0.243), mediastinal lymph node metastasis (10.7% vs. 37.5%, OR 0.199), and hematogenous lung metastasis (9.7% vs. 29.2%, OR 0.261) were less frequent in MPM than in MPD. When we analyzed MPD from extrathoracic malignancy (EMPD) separately and compared them to MPM, circumferential pleural thickening, thickening of interlobar fissure, pericardial involvement and presence of pleural plaque were significant findings indicating MPM than EMPD. MPM had significantly lower occurrence of hematogenous lung metastasis, as compared with EMPD. Conclusion Awareness of frequent and infrequent CT findings could aid in distinguishing MPM from MPD. PMID:27390546

  20. Treatment Factors Associated With Long-Term Survival Following Cytoreductive Surgery and Regional Chemotherapy for Patients with Malignant Peritoneal Mesothelioma

    PubMed Central

    Alexander, H. Richard; Bartlett, David L.; Pingpank, James F.; Libutti, Steven K.; Royal, Richard; Hughes, Marybeth S.; Holtzman, Matthew; Hanna, Nader; Turner, Keli; Beresneva, Tatiana; Zhu, Yue

    2013-01-01

    OBJECTIVES Malignant peritoneal mesothelioma (MPM) is a primary cancer that arises diffusely from the serosa of the peritoneum. Morbidity and mortality are almost invariably due to loco-regional progression; cytoreduction with intra-operative or peri-operative high dose regional chemotherapy has been established as the preferred approach in selected patients. This study was performed to identify factors associated with long-term outcome. METHODS Between January, 1992 and 2010, 211 patients with MPM treated at three major referral centers with operative cytoreduction and hyperthermic intra-operative peritoneal chemotherapy (HIPEC) were analyzed. RESULTS The median actuarial overall survival was 38.4 months; the actuarial 5 and 10 year survivals were 41% and 26%, respectively. On multivariate analysis, factors independently associated with favorable outcome were age less than 60 years (p< 0.01), complete or near complete (R0–1) versus incomplete (R2–3) resection (p< 0.02), low versus high histologic grade (P< 0.01), and the use of cisplatin versus mitomycin-C during HIPEC (p< 0.01). There was an insignificant trend towards female gender and improved survival (male Hazard Ratio: 1.46, 95% CI: 0.89–2.41, p=0.13). CONCUSIONS Operative cytoreduction with HIPEC is associated with long term survival in patients with MPM. Factors associated with survival include age, complete or near complete gross tumor resection, histologic tumor grade, and HIPEC with cisplatin. The fact that cisplatin versus mitomycin-c was independently associated with improved survival demonstrates a salutary effect for HIPEC with cisplatin in the management of patients with MPM. PMID:23489943

  1. [Environmental and indoor air exposure to asbestos fiber dust as a risk and causal factor of diffuse malignant pleural mesothelioma].

    PubMed

    Schneider, J; Rödelsperger, K; Pohlabeln, H; Woitowitz, H J

    1996-11-01

    In an interdisciplinary, multicentre case control study of the causal factors of the diffuse malignant mesothelioma (DMM) standardised histories where taken from n = 324 Patients suffering from DMM, n = 315 hospital control patients (KK) and n = 182 population controls (PK). For 66 DMM, 149 KK and 107 PK a risk from asbestos fibre dust at the workplace was not detectable. For latter persons indoor and outdoor asbestos exposure outside of the workplace were investigated. The following factors were examined: neighbourhood exposure from companies using asbestos, living in big cities and nearby main traffic roads, building materials containing asbestos, electric storage heaters and household contacts. For using electric storage heaters a statistically significant increased odds ratio (OR) was observed for DMM as well in comparison with KK (OR = 2.42; 95%-CI: 1.01-5.72) and in comparison for PK (OR = 2.91; 95%-CI: 1.08-7.80). Only outside of Hamburg an increased OR compared to KK was observed for people living in the neighbourhood of asbestos factories (OR = 16.3; 95%-CI: 1.35-196.8) and also, but only in Hamburg, compared to PK living nearby main traffic roads. There is only a trend for a mesothelioma-risk for household-contacts based on a few cases. In one DMM-patient without an occupational asbestos exposure the lung dust fibre analysis yielded 2.912 FB and 1.459 x 10(3) crocydolithe fibres per gram dried lung tissue. As a child he lived in the immediate vicinity of the blue asbestos mine in Wittenoom, Australia. Therefore in special cases a para-occupational asbestos or a neighbourhood asbestos exposure can be demonstrated as a risk factor of diffuse malignant mesothelioma.

  2. Malignant mesothelioma and occupational exposure to asbestos: a clinicopathological correlation of 1445 cases.

    PubMed

    Roggli, Victor L; Sharma, Anupama; Butnor, Kelly J; Sporn, Thomas; Vollmer, Robin T

    2002-01-01

    Asbestos exposure is indisputably associated with development of mesothelioma. However, relatively few studies have evaluated the type of occupational exposure in correlation with asbestos fiber content and type. This study reports findings in 1445 cases of mesothelioma with known exposure history; 268 of these also had fiber burden analysis. The 1445 cases of mesothelioma were subclassified into 23 predominant occupational or exposure categories. Asbestos body counts per gram of wet lung tissue were determined by light microscopy. Asbestos fiber content and type were determined by scanning electron microscopy and energy dispersive x-ray analysis. Results were compared with a control group of 19 lung tissue samples. Ninety-four percent of the cases occurred among 19 exposure categories. Median asbestos body counts and levels of commercial and noncommercial amphibole fibers showed elevated levels for each of these 19 categories. Chrysotile fibers were detectable in 36 of 268 cases. All but 2 of these also had above-background levels of commercial amphiboles. When compared to commercial amphiboles, the median values for noncommercial amphibole fibers were higher in 4 of the 19 exposure groups. Most mesotheliomas in the United States fall into a limited number of exposure categories. Although a predominant occupation was ascertained for each of these cases, there was a substantial overlap in exposure types. All but 1 of the occupational categories analyzed had above-background levels of commercial amphiboles. Commercial amphiboles are responsible for most of the mesothelioma cases observed in the United States.

  3. Diarachidonoylphosphoethanolamine induces apoptosis of malignant pleural mesothelioma cells through a Trx/ASK1/p38 MAPK pathway.

    PubMed

    Tsuchiya, Ayako; Kaku, Yoshiko; Nakano, Takashi; Nishizaki, Tomoyuki

    2015-11-01

    1,2-Diarachidonoyl-sn-glycero-3-phosphoethanolamine (DAPE) induces both necrosis/necroptosis and apoptosis of NCI-H28 malignant pleural mesothelioma (MPM) cells. The present study was conducted to understand the mechanism for DAPE-induced apoptosis of NCI-H28 cells. DAPE induced caspase-independent apoptosis of NCI-H28 malignant pleural mesothelioma (MPM) cells, and the effect of DAPE was prevented by antioxidants or an inhibitor of NADPH oxidase (NOX). DAPE generated reactive oxygen species (ROS) and inhibited activity of thioredoxin (Trx) reductase (TrxR). DAPE decreased an association of apoptosis signal-regulating kinase 1 (ASK1) with thioredoxin (Trx), thereby releasing ASK1. DAPE activated p38 mitogen-activated protein kinase (MAPK), which was inhibited by an antioxidant or knocking-down ASK1. In addition, DAPE-induced NCI-H28 cell death was also prevented by knocking-down ASK1. Taken together, the results of the present study indicate that DAPE stimulates NOX-mediated ROS production and suppresses TrxR activity, resulting in the decrease of reduced Trx and the dissociation of ASK1 from a complex with Trx, allowing sequential activation of ASK1 and p38 MAPK, to induce apoptosis of NCI-H28 MPM cells.

  4. Comparison of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy with mitomycin or carboplatin for diffuse malignant peritoneal mesothelioma.

    PubMed

    Shetty, Shreya J; Bathla, Lokesh; Govindarajan, Venkatesh; Thomas, Peter; Loggie, Brian W

    2014-04-01

    Diffuse malignant peritoneal mesothelioma is a rare, aggressive disease. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have improved outcomes where systemic chemotherapy has not succeeded. In this study, we compare outcomes of patients treated with mitomycin or carboplatin as perfusate. In this retrospective study, 47 procedures (CRS + HIPEC) were conducted on 44 patients between March 2003 and August 2010 with either mitomycin or carboplatin. χ(2) and Student's t test were used for comparison of clinicopathological variables and Kaplan-Meier curves and log rank test were used to compare overall survival. Median survival of the mitomycin group was 18 months with 1- and 5-year survivals of 72.3 and 27.3 per cent, respectively. Median survival of the carboplatin group was not reached and 1- and 5-year survivals were 89.7 and 62.5 per cent, respectively (P = 0.014). Mean hospital and intensive care unit length of stay was 18.9 and 8.7 days in the mitomycin group and 12.5 and 2.3 days in the carboplatin group (P = 0.0069). Mean number of packed red blood cell units transfused was higher in the mitomycin group compared with the carboplatin group (3.54 vs 0.83, P < 0.05). There was no postoperative mortality. HIPEC with carboplatin in diffuse malignant peritoneal mesothelioma is associated with improved overall survival and shorter hospital stay compared with HIPEC with mitomycin.

  5. Auto-Antibodies to β-F1-ATPase and Vimentin in Malignant Mesothelioma

    PubMed Central

    Creaney, Jenette; Dick, Ian M.; Yeoman, Deborah; Wong, Sarah; Robinson, Bruce W. S.

    2011-01-01

    Patients with Malignant Mesothelioma (MM) develop unidentified auto-antibodies to MM tumour antigens. This study was conducted to identify the targets of MM patient auto-antibodies in order to try to understand more of the anti-tumour response and to determine if these antibodies might be helpful for diagnosis or prognostication. Using MM patient sera in a Western immunoblott screening strategy, no common immunoreactive proteins were identified. The sera from one long-term survivor recognised a protein band of 50–60 kDa present in cell lysates from four of five MM cell lines tested. The immunoreactive proteins in this band were identified by 2D electrophoretic separation of a MM cell line protein lysate, followed by analysis of excised immunoreactive proteins on a MALDI TOF mass spectrometer and peptide mass fingerprinting. The immunoreactive proteins identified were vimentin (accession gi55977767) and the ATP synthase (F1-ATPase) beta chain (accession gi114549 and gi47606749). ELISA assays were developed for antibodies to these proteins. Neither vimentin (median and 95% CI 0.346; 0.32–0.468 for MM patients, 0.327; 0.308–0.428 for controls) nor ß-F1-ATPase (0.257; 0.221–0.453 for MM patients, 0.263; 0.22–0.35 for controls) showed significant differences in autoantibody levels between a group of MM patients and controls. Using a dichotomized antibody level (high, low) for these targets we demonstrated that vimentin antibody levels were not associated with survival. In contrast, high ß-F1-ATPase antibody levels were significantly associated with increased median survival (18 months) compared to low ß F1 ATPase antibody levels (9 months; p = 0.049). Immunohistochemical analysis on a MM tissue microarray showed cytoplasmic staining in 28 of 33 samples for vimentin and strong cytoplasmic staining in14 and weak in 16 samples for ß-F1-ATPase. Therefore antibodies to neither vimentin nor ß-F1-ATPase are useful for differential diagnosis of MM, however

  6. Expression of the Stem Cell Factor Nestin in Malignant Pleural Mesothelioma Is Associated with Poor Prognosis

    PubMed Central

    Thies, Svenja; Friess, Martina; Frischknecht, Lukas; Korol, Dimitri; Felley-Bosco, Emanuela; Stahel, Rolf; Vrugt, Bart; Weder, Walter; Opitz, Isabelle; Soltermann, Alex

    2015-01-01

    Background The epithelioid and sarcomatoid histologic variants of malignant pleural mesothelioma (MPM) can be considered as E- and M-parts of the epithelial-mesenchymal transition (EMT) axis; the biphasic being an intermediate. EMT is associated with an increase of stem cell (SC) traits. We correlated the neural crest SC marker nestin and the EMT marker periostin with histology, type of neo-adjuvant chemotherapy (CT) and overall survival (OS) of MPM patients. Patients and Methods Tumor tissues of a historic cohort 1 (320 patients) and an intended induction chemotherapy followed by extrapleural pneumonectomy (EPP) cohort 2 (145 patients) were immunohistochemically H-scored (intensity of immunoreactivity multiplied by frequency of stained cells). Paired chemo-naïve biopsies and -treated surgical specimens were available for 105/145 patients. CT included platinum/gemcitabine (Pla/Gem) or platinum/pemetrexed (Pla/Pem). Results Expression of any cytosolic nestin progressively increased from epithelioid to biphasic to sarcomatoid MPM in cohort 1, whereas the diagnostic markers calretinin and podoplanin decreased. In cohort 2, Pla/Pem CT increased the expression level of nestin in comparison to Pla/Gem, whereas the opposite was found for periostin. In Pla/Pem treated patients, nestin was higher in biphasic MPM compared to epithelioid. In addition to non-epithelioid histology, any expression of nestin in chemo-naïve biopsies (median overall survival: 22 vs. 17 months) and chemo-treated surgical specimens (18 vs. 12 months) as well as high periostin in biopsies (23 vs. 15 months) were associated with poor prognosis. In the multivariate survival analysis, any nestin expression in chemo-naïve biopsies proved to be an independent prognosticator against histology. In both pre- and post-CT situations, the combination of nestin or periostin expression with non-epithelioid histology was particularly/ dismal (all p-values <0.05). Conclusions The SC marker nestin and the EMT

  7. Florid mesothelial hyperplasia of the tunica vaginalis mimicking malignant mesothelioma: a clinicopathologic study of 12 cases.

    PubMed

    Lee, Stephen; Illei, Peter B; Han, Jeong S; Epstein, Jonathan I

    2014-01-01

    The tunica vaginalis is an embryologically derived mesothelium-lined outpouching of the peritoneal cavity, which may develop neoplastic mesothelial proliferations similar to, although much less commonly than, pleural or peritoneal surfaces. We herein report our experience with 12 cases of florid paratesticular mesothelial hyperplasia, highlighting the spectrum of morphologic changes seen and the utility of fluorescence in situ hybridization analysis of homozygous deletion of 9p21 as an adjunct diagnostic tool. All cases were referred because of concern regarding the nature of the mesothelial proliferation. The median age of patients at presentation was 44.5 years (range, 16 to 71 y). Ten of 12 patients clinically presented with hydroceles (2 of which were complicated by infection or hemorrhage), 1 with "paraepididymal cyst" and 1 patient with an epididymal cyst. In contrast to the normal tunica consisting of a thin fibrous wall lined by a monolayer of flattened bland mesothelium and no significant inflammation, all of our cases were characterized by background changes of fibroblastic organization and stromal chronic inflammation. In all cases, the mesothelial proliferation within the fibrous and inflamed stroma was sparse and consisted of linear arrays of widely spaced horizontally orientated simple nonbranching elongated tubules and small solid nests and cords that were well spaced apart. There was an abrupt linear demarcation of tubules at the deep aspect of the fibrous tissue, with no evidence of definite invasion into the submesothelial tissue. Fluorescence in situ hybridization for 9p21 was negative in all 5 cases in which tissue was available for analysis. Nine patients with extended follow-up were alive (median 8 y; range, 1 to 13 y). In summary, the proliferative changes seen in reactive mesothelial hyperplasia associated with hydroceles may be florid and mimic malignant mesothelioma. In particular, the entrapment of isolated mesothelial clusters within

  8. Increased but low incidence and poor survival of malignant mesothelioma in the southeastern part of The Netherlands since 1970: a population-based study.

    PubMed

    Janssen-Heijnen, M L; Damhuis, R A; Klinkhamer, P J; Schipper, R M; Coebergh, J W

    1999-08-01

    Changes in the incidence and survival rates for malignant mesothelioma in the southeastern part of The Netherlands since 1970 were investigated, using data from the Eindhoven Cancer Registry (ECR). The exposure to asbestos in this area is presumed to be limited. Most of the mesotheliomas occurred in the pleura, where there were 119 (88%) against 15 (11%) in the peritoneum and two in the tunica vaginalis testis. Compared to other European countries, the incidence rate for the southeastern part of The Netherlands was fairly low in the second half of the 1980s. Between 1975 and 1994 the age-adjusted incidence rates (ESR) for pleural mesothelioma increased twofold (from 10 to 19 per one million person-years among men and from 2.4 to 3.8 among women). The rate for peritoneal mesothelioma remained constant. The overall relative 0.5-, 1-, and 3-year survival rates remained 68, 42, and 8%, respectively. The fourfold higher incidence rate for men compared with women reflects the fact that mesothelioma is mainly an occupational disease. In view of presumed limited exposure to asbestos and small geographical variation, the incidence of mesothelioma in the southeastern part of The Netherlands will probably remain low, despite an increase in the past decades.

  9. p53, p21 and metallothionein immunoreactivities in patients with malignant pleural mesothelioma: correlations with the epidemiological features and prognosis of mesotheliomas with environmental asbestos exposure.

    PubMed

    Isik, R; Metintas, M; Gibbs, A R; Metintas, S; Jasani, B; Oner, U; Harmanci, E; Demircan, S; Işiksoy, S

    2001-07-01

    The aim of this study is to investigate immunoreactivity for p53, p21 and metallothionein in diffuse malignant pleural mesothelioma (DMPM) and to determine the relationships between the age, sex, asbestos exposure time, survival of DMPM patients with environmental asbestos exposure and immunoreactivity to p53, p21 and metallothionein. Sixty-seven histopathologically-confirmed DMPMs, 38 of whom had environmental and 29 had occupational asbestos exposure, were included. The tumour tissue samples were immunostained with antibodies against p53, p21 and metallothionein. Epidemiological data and the survival times for the DMPM patients with environmental asbestos exposures were obtained from hospital records. Thirty-three per cent of the DMPMs were positive for p53, 35% for p21 and 52% for metallothionein. There was no statistical difference between the histological subtypes of DMPM in terms of immunoreactivity for p53, p21 and metallothionein. For p21 and metallothionein there was a statistically significant difference between the exposure characteristics: patients with environmental asbestos exposure had shown more immunopositivity. There were statistically significant differences between age groups and between asbestos exposure times for metallothionein, and between asbestos exposure times and p21. The patients with positive immunostaining had longer exposure times and were older than those having negative immunostaining. The differences between survival of the patients were not statistically significant in terms of the immunohistochemical results for p53, p21 and metallothionein.

  10. Antigen spreading-induced CD8+T cells confer protection against the lethal challenge of wild-type malignant mesothelioma by eliminating myeloid-derived suppressor cells

    PubMed Central

    Lee, Boon Kiat; Tang, Jiansong; Wu, Xilin; Cheung, Ka-Wai; Lok Lo, Nathan Tin; Man, Kwan; Liu, Li; Chen, Zhiwei

    2015-01-01

    A key focus in cancer immunotherapy is to investigate the mechanism of efficacious vaccine responses. Using HIV-1 GAG-p24 in a model PD1-based DNA vaccine, we recently reported that vaccine-elicited CD8+ T cells conferred complete prevention and therapeutic cure of AB1-GAG malignant mesothelioma in immunocompetent BALB/c mice. Here, we further investigated the efficacy and correlation of protection on the model vaccine-mediated antigen spreading against wild-type AB1 (WT-AB1) mesothelioma. We found that this vaccine was able to protect mice completely from three consecutive lethal challenges of AB1-GAG mesothelioma. Through antigen spreading these animals also developed tumor-specific cytotoxic CD8+ T cells, but neither CD4+ T cells nor antibodies, rejecting WT-AB1 mesothelioma. A majority of these protected mice (90%) were also completely protected against the lethal WT-AB1 challenge. Adoptive cell transfer experiments further demonstrated that antigen spreading-induced CD8+ T cells conferred efficacious therapeutic effects against established WT-AB1 mesothelioma and prevented the increase of exhausted PD-1+ and Tim-3+ CD8+ T cells. A significant inverse correlation was found between the frequency of functional PD1−Tim3− CD8+ T cells and that of MDSCs or tumor mass in vivo. Mechanistically, we found that WT-AB1 mesothelioma induced predominantly polymorphonuclear (PMN) MDSCs in vivo. In co-cultures with efficacious CD8+ T cells, a significant number of PMN-MDSCs underwent apoptosis in a dose-dependent way. Our findings indicate that efficacious CD8+ T cells capable of eliminating both tumor cells and MDSCs are likely necessary for fighting wild-type malignant mesothelioma. PMID:26431275

  11. Signal transducer and activator of transcription 1 (STAT1) acts like an oncogene in malignant pleural mesothelioma.

    PubMed

    Arzt, Lisa; Kothmaier, Hannelore; Halbwedl, Iris; Quehenberger, Franz; Popper, Helmut H

    2014-07-01

    Malignant pleural mesothelioma (MPM) is the most common primary tumor of the pleura. Its incidence is increasing in Europe and the prognosis remains poor. We compared epithelioid MPM in short and long survivors, and identified signal transducer and activator of transcription 1 (STAT1) as probably being responsible for antiapoptotic signaling and chemoresistance. Six mesothelioma cell lines were evaluated by Western Blot. We also analyzed 16 epithelioid MPM tissue samples for the phosphorylation status of STAT1 and the expression of its negative regulator, the suppressor of cytokine signaling 1 (SOCS1). Formalin-fixed and paraffin-embedded tissue specimens were evaluated by protein-lysate microarray and immunohistochemistry. We found STAT1 to be highly expressed and STAT3 downregulated in MPM cell lines. The expression of STAT1 phosphorylated on tyrosine 701 (Y701) was increased by interferon-gamma (IFN-γ) treatment, whereas SOCS1 was not expressed. The expression of STAT1 phosphorylated on serine 727 (S727) was not detected in mesothelioma cell lines and was not stimulated by IFN-γ. STAT1 was phosphorylated on tyrosine 701 and serine 727 in MPM tissue samples. The expression of pSTAT1-Y701 was increased compared to pSTAT1-S727. SOCS1 was again not detectable. STAT1 is upregulated in MPM, and its action may be prolonged by a loss of the negative regulator SOCS1. STAT1 might, therefore, be a target for therapeutic intervention, with the intention to restore apoptotic mechanisms and sensitivity to chemotherapy. However, other regulatory mechanisms need to be investigated to clarify if lack of expression of SOCS1 is the only reason for sustained STAT1 expression in MPM.

  12. Unusually high incidence of malignant pleural mesothelioma in a town of eastern Sicily: an epidemiological and environmental study.

    PubMed

    Paoletti, L; Batisti, D; Bruno, C; Di Paola, M; Gianfagna, A; Mastrantonio, M; Nesti, M; Comba, P

    2000-01-01

    In a recent epidemiological study, researchers investigated mortality from malignant pleural neoplasms in Italy, and they detected some geographic clusters of cases of this disease. We found a town located in a volcanic area of eastern Sicily to be of special interest. The residents, some of whom were diagnosed with pleural mesothelioma, had never had any relevant exposure to asbestos during their professional lives. The results of an environmental survey suggested that a possible cause of asbestos exposure was the stone quarries near the town. The products of the quarries contain fibrous amphiboles, which are used widely in the local building industry. These fibrous amphiboles were identified as intermediate phases between tremolite and actinolite. Samples were collected from buildings in the town, and concentrations of amphibole fibers were evaluated. Fibrous phases were detected in 71% of the samples, and fiber concentrations ranged from a few thousand to more than 4 x 10(4) fibers/mg of material. In addition, we conducted a study on the mineral fiber lung burden in a pleural mesothelioma case. Many mineral fibers that were classified as the same tremolite-actinolite fibrous amphibole found in the quarries and in the building materials were detected in the lung tissue. The results suggest that the inhabitants of the town we studied had been exposed for several decades to asbestos fibers that were present in the material extracted from the local stone quarries. The material was subsequently used in the building industry, and this has caused an increased risk of pleural mesothelioma in the area.

  13. Outcomes of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Mesothelioma: Experience of a Peritoneal Surface Malignancy Center.

    PubMed

    Aydin, Nail; Sardi, Armando; Milovanov, Vladimir; Nieroda, Carol; Sittig, Michelle; Nunez, Maria F; Jimenez, William; Gushchin, Vadim

    2015-12-01

    Diffuse malignant peritoneal mesothelioma (DMPM) is an uncommon malignancy, which can be difficult to treat. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have evolved as the treatment of choice when complete cytoreduction is to be achieved. This study reports the outcomes of CRS/HIPEC for peritoneal mesothelioma performed in a center for peritoneal surface malignancy. A retrospective analysis of a prospective database of 389 CRS/HIPEC procedures identified 23 patients who underwent CRS/HIPEC for DMPM from 1999 to 2014. Gender, age at diagnosis, age at surgery, previous surgeries, follow-up time, peritoneal cancer index (PCI) score, completeness of cytoreduction (CC), pathology, and overall survival (OS) were analyzed. The univariate analysis was used to determine the prognostic value of age, gender, neoadjuvant chemotherapy, histopathology of the tumor, PCI, CC, and lymph node status on survival. Mean follow-up time from surgery was 31 months (range = 0.5-124). The median PCI score was 28, and 77 per cent had PCI ≥20. CC 0-1 was achieved in 65 per cent of cases. One- and 5-year actuarial OS rates from diagnosis were 86 per cent and 60 per cent, respectively. One- and 5-year actuarial OS from HIPEC was 70 per cent and 64 per cent, respectively. The univariate analysis showed that the CC was the only significant prognostic factor. Patients with DMPM may achieve long-term survival when treated with CRS/HIPEC. The CC is the most significant prognostic factor for long-term survival.

  14. [The incidence of malignant mesothelioma (1977-1996) and asbestos exposure in the population of an area neighboring Lake Iseo, northern Italy].

    PubMed

    Barbieri, P G; Migliori, M; Merler, E

    1999-01-01

    The study was stimulated by the occurrence of malignant mesotheliomas among the workers of two adjacent factories located in Sarnico, near Lake Iseo (province of Brescia, northern Italy), one of which manufactured crocidolite and chrysotile ropes and gaskets until 1993. The aim of the study was: identification of malignant mesotheliomas occurring between 1977 and 1996 among the residents of 11 villages, which constituted the recruitment area of the work-force; estimation of the incidence of malignant pleural mesothelioma; collection of working histories of all cases to evaluate previous exposure to asbestos and radiation therapy. 21 cases of mesothelioma were detected (20 pleural, 1 peritoneal; 9 among males), and 20 were supported by histopathologic diagnosis. The incidence (x 100,000 person-years, standard: European population) was 2.5 (0.7-4.2) and 2.8 (1.2-4.3) among males and females, respectively, corresponding to a three-fold increase among males and a more than ten fold increase among women in comparison with the incidence reported by the Lombardy Cancer Registry. No cases had been exposed to radiation therapy, whereas all cases had been occupationally exposed to asbestos. Occupational exposure to asbestos had occurred in work on the production of crocidolite and chrysotile ropes and gaskets (6 males); in work in a textile factory producing cotton garments that was adjacent to and polluted by the former, where, in addition, chrysotile blankets were used for fireproofing in the weaving area and pipes were insulated using amosite-containing materials (10 cases, 6 among females); 5 cases occurred among women working in silk factories, where asbestos exposure was possible because of the presence of pipes insulated with asbestos and because women were handling temperature-controlled trays insulted with asbestos. In conclusion, the study demonstrated that the occurrence of mesothelioma was higher among females than males in the study area and that all cases of

  15. Data-driven information retrieval in heterogeneous collections of transcriptomics data links SIM2s to malignant pleural mesothelioma

    PubMed Central

    Caldas, José; Gehlenborg, Nils; Kettunen, Eeva; Faisal, Ali; Rönty, Mikko; Nicholson, Andrew G.; Knuutila, Sakari; Brazma, Alvis; Kaski, Samuel

    2012-01-01

    Motivation: Genome-wide measurement of transcript levels is an ubiquitous tool in biomedical research. As experimental data continues to be deposited in public databases, it is becoming important to develop search engines that enable the retrieval of relevant studies given a query study. While retrieval systems based on meta-data already exist, data-driven approaches that retrieve studies based on similarities in the expression data itself have a greater potential of uncovering novel biological insights. Results: We propose an information retrieval method based on differential expression. Our method deals with arbitrary experimental designs and performs competitively with alternative approaches, while making the search results interpretable in terms of differential expression patterns. We show that our model yields meaningful connections between biological conditions from different studies. Finally, we validate a previously unknown connection between malignant pleural mesothelioma and SIM2s suggested by our method, via real-time polymerase chain reaction in an independent set of mesothelioma samples. Availability: Supplementary data and source code are available from http://www.ebi.ac.uk/fg/research/rex. Contact: samuel.kaski@aalto.fi Supplementary Information: Supplementary data are available at Bioinformatics online. PMID:22106335

  16. SV40 enhances the risk of malignant mesothelioma among people exposed to asbestos: a molecular epidemiologic case-control study.

    PubMed

    Cristaudo, Alfonso; Foddis, Rudy; Vivaldi, Agnese; Buselli, Rodolfo; Gattini, Vittorio; Guglielmi, Giovanni; Cosentino, Francesca; Ottenga, Franco; Ciancia, Eugenio; Libener, Roberta; Filiberti, Rosangela; Neri, Monica; Betta, Piergiacomo; Tognon, Mauro; Mutti, Luciano; Puntoni, Riccardo

    2005-04-15

    We conducted a case-control study on asbestos exposure and presence of SV40 in tumor samples of malignant mesotheliomas (MMs) and bladder urotheliomas (BUs). PCR analysis revealed the presence of SV40 DNA (SV40+) in eight (42.1%) MMs and 6 (33.3%) BUs. The odds ratio for MM Asb- and SV40+ was 0.4 [95% confidence interval (95% CI), 0.03-4.0], for Asb+ and SV40- was 3.6 (95% CI, 0.6-21.0), and for Asb+ and SV40+ was 12.6 (95% CI, 1.2-133.9). Our results suggest that SV40 increases the risk of MM among individuals exposed to asbestos.

  17. Polymorphisms in DNA repair genes as risk factors for asbestos-related malignant mesothelioma in a general population study.

    PubMed

    Dianzani, I; Gibello, L; Biava, A; Giordano, M; Bertolotti, M; Betti, M; Ferrante, D; Guarrera, S; Betta, G P; Mirabelli, D; Matullo, G; Magnani, C

    2006-07-25

    Differences in response to carcinogenic agents are due to the allelic variants of the genes that control it. Key genes are those involved in the repair of the DNA damage caused by such agents. This paper describes the results of a case-control epidemiological study designed to determine the genotypes of four of these genes in persons exposed to a single genotoxic factor, i.e. asbestos, who had or had not developed malignant mesothelioma (MM). Our working hypothesis was that an imperfect DNA repair, as revealed by subtle polymorphic variants, could reduce protection against the chronic DNA insult provoked by asbestos and eventually result in mutagenesis and cancer. Seven variants (i.e. XRCC1-R399Q-NCBI SNP, XRCC1-R194W, XRCC3-T241M, XRCC3-IVS6-14, XPD-K751Q, XPD-D312N, OGG1-S326C) were investigated in 81 patients and 110 age and sex-matched controls, all residents at Casale Monferrato, a Piedmontese town highly exposed to asbestos pollution. Unconditional multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). When considered as a categorical variable, XRCC1-399Q showed an increased OR both in heterozygotes (OR=2.08; 95% CI=1.00-4.33) and homozygotes (2.38; 95% CI=0.82-6.94), although individual ORs were not significant. When it was considered as a continuous variable OR was significant (OR=1.68; 95% CI: 1.02-2.75). When genotypes were divided into "non-risk" and "risk" genotypes, i.e. those thought to be associated with increased risk in the light of the functional significance of the variants, XRCC1-399Q (Q homozygotes+Q/R heterozygotes versus R homozygotes) had an OR=2.147 (95% CI: 1.08-4.28), whereas that of XRCC3-241T (T homozygotes+M/T heterozygotes versus M homozygotes) was 4.09 (95% CI: 1.26-13.21) and that of OGG1-326C was increased, though not significantly. None of the haplotypes showed a significantly different frequency between patients and controls. This is the first report of an association between

  18. SV40 expression in human neoplastic and non-neoplastic tissues: perspectives on diagnosis, prognosis and therapy of human malignant mesothelioma.

    PubMed

    Procopio, A; Marinacci, R; Marinetti, M R; Strizzi, L; Paludi, D; Iezzi, T; Tassi, G; Casalini, A; Modesti, A

    1998-01-01

    We have recently demonstrated the association of SV40 and human pleural malignant mesothelioma. Here, we have investigated whether SV40 viral sequences may be associated with other human tumours or other non-neoplastic pathology and whether SV40 DNA or protein expression may be of diagnostic, prognostic or therapeutic relevance. DNA was extracted from paraffin embedded tissues. SV40, JC and BK viral sequences were detected by the polymerase chain reaction and molecular hybridization with specific probes. The screening with three different sets of SV40-related primers demonstrated that 7/18 (38.8%) mesothelioma specimens were SV40 positive as well as 5/18 (27.7%) tubercular pleural lesions. None of the 18 lung cancers, nor the 20 pleural non-specific inflammatory specimens tested were positive. Twenty-five blood samples and 18 urinary sediments from MM patients were also negative. We have also found that SV40 Tag proteins are present in mesothelioma cells and tumours. Tag proteins may interfere with tumour suppressor gene products, such as p53. Preliminary results suggest that wild type p53 transgene expression, obtained after infection with recombinant adenovirus (AdCMV.p53), inhibited in vitro and in vivo proliferation, inducing apoptosis of mesothelioma cells. Infections with control viruses were ineffective. Thus, SV40 DNA and Tag expression in mesothelioma tumour cells, though probably not relevant for diagnostic or prognostic purposes, may be crucial for innovative gene therapy strategies.

  19. SV40 expression in human neoplastic and non-neoplastic tissues: perspectives on diagnosis, prognosis and therapy of human malignant mesothelioma.

    PubMed

    Procopio, A; Marinacci, R; Marinetti, M R; Strizzi, L; Paludi, D; Iezzi, T; Tassi, G; Casalini, A; Modesti, A

    1998-01-01

    We have recently demonstrated the association of SV40 and human pleural malignant mesothelioma. Here, we have investigated whether SV40 viral sequences may be associated with other human tumours or other non-neoplastic pathology and whether SV40 DNA or protein expression may be of diagnostic, prognostic or therapeutic relevance. DNA was extracted from paraffin embedded tissues. SV40, JC and BK viral sequences were detected by the polymerase chain reaction and molecular hybridization with specific probes. The screening with three different sets of SV40-related primers demonstrated that 7/18 (38.8%) mesothelioma specimens were SV40 positive as well as 5/18 (27.7%) tubercular pleural lesions. None of the 18 lung cancers, nor the 20 pleural non-specific inflammatory specimens tested were positive. Twenty-five blood samples and 18 urinary sediments from MM patients were also negative. We have also found that SV40 Tag proteins are present in mesothelioma cells and tumours. Tag proteins may interfere with tumour suppressor gene products, such as p53. Preliminary results suggest that wild type p53 transgene expression, obtained after infection with recombinant adenovirus (AdCMV.p53), inhibited in vitro and in vivo proliferation, inducing apoptosis of mesothelioma cells. Infections with control viruses were ineffective. Thus, SV40 DNA and Tag expression in mesothelioma tumour cells, though probably not relevant for diagnostic or prognostic purposes, may be crucial for innovative gene therapy strategies. PMID:9776257

  20. Asbestos content of lung tissue in patients with malignant peritoneal mesothelioma: A study of 42 cases.

    PubMed

    de Ridder, Gustaaf G; Kraynie, Alyssa; Pavlisko, Elizabeth N; Oury, Tim D; Roggli, Victor L

    2016-01-01

    Lung tissue from 42 peritoneal mesothelioma cases was analyzed by light microscopy and scanning electron microscopy/energy dispersive spectrometry. There were 34 men and 8 women with a mean age of 61 ± 10 years. Also, 17% of cases had histologically confirmed asbestosis, and 26% had only parietal pleural plaques. The asbestos body count exceeded our normal range in 22 of 42 cases (52%). Cases with asbestos-related pulmonary disease had higher fiber burdens than those without. The vast majority of fibers were commercial amphiboles (amosite with lesser amounts of crocidolite). These findings concur with previously published epidemiological observations.

  1. Asbestos content of lung tissue in patients with malignant peritoneal mesothelioma: A study of 42 cases.

    PubMed

    de Ridder, Gustaaf G; Kraynie, Alyssa; Pavlisko, Elizabeth N; Oury, Tim D; Roggli, Victor L

    2016-01-01

    Lung tissue from 42 peritoneal mesothelioma cases was analyzed by light microscopy and scanning electron microscopy/energy dispersive spectrometry. There were 34 men and 8 women with a mean age of 61 ± 10 years. Also, 17% of cases had histologically confirmed asbestosis, and 26% had only parietal pleural plaques. The asbestos body count exceeded our normal range in 22 of 42 cases (52%). Cases with asbestos-related pulmonary disease had higher fiber burdens than those without. The vast majority of fibers were commercial amphiboles (amosite with lesser amounts of crocidolite). These findings concur with previously published epidemiological observations. PMID:27281118

  2. Historical cohort study of US man-made vitreous fiber production workers: II. Mortality from mesothelioma.

    PubMed

    Marsh, G M; Gula, M J; Youk, A O; Buchanich, J M; Churg, A; Colby, T V

    2001-09-01

    As part of our ongoing mortality surveillance program for the US man-made vitreous fiber (MMVF) industry, we examined mortality from malignant mesothelioma using data from our 1989 follow-up of 3478 rock/slag wool workers and our 1992 follow-up of 32,110 fiberglass workers. A manual search of death certificates for 1011 rock/slag wool workers and 9060 fiberglass workers revealed only 10 death certificates with any mention of the word "mesothelioma." A subsequent review of medical records and pathology specimens for 3 of the 10 workers deemed two deaths as definitely not due to mesothelioma and one as having a 50% chance of being caused by mesothelioma. Two other deaths, for which only medical records were available, were given less than a 50% chance of being due to mesothelioma. Eight of the 10 decedents had potential occupational asbestos exposure inside or outside the MMVF industry. We also estimated the mortality risk from malignant mesothelioma in the cohort using two cause-of-death categorizations that included both malignant and benign coding rubrics. Using the more comprehensive scheme, we observed overall deficits in deaths among the total cohort and fiberglass workers and an overall excess among rock/slag wool workers. The excess in respiratory system cancer is largely a reflection of elevated lung cancer risks that we attributed mainly to confounding by smoking, to exposures outside the MMVF industry to agents such as asbestos, or to one or more of the several co-exposures present in many of the study plants (including asbestos). The second scheme, which focused on pleural mesothelioma in time periods when specific malignant mesothelioma coding rubrics were available, classified only one cohort death as being caused by malignant mesothelioma, compared with 2.19 expected deaths (local county comparison). We conclude that the overall mortality risk from malignant mesothelioma does not seem to be elevated in the US MMVF cohort.

  3. Mesothelioma after crocidolite exposure during gas mask manufacture.

    PubMed

    McDonald, A D; McDonald, J C

    1978-12-01

    Of 199 persons employed in the manufacture and handling of Canadian military gas mask canisters containing pure crocidolite, 1939 to 1942, by the end of 1975, 56 had died, 120 were still alive, and 23 could not be traced. Nine (16%) of the deaths were probably due to malignant mesothelioma, six involving the peritoneum. The risk of mesothelioma after crocidolite exposure appears to be many times greater than that after chrysotile.

  4. A review of transcriptome studies combined with data mining reveals novel potential markers of malignant pleural mesothelioma.

    PubMed

    Melaiu, Ombretta; Cristaudo, Alfonso; Melissari, Erika; Di Russo, Manuela; Bonotti, Alessandra; Bruno, Rossella; Foddis, Rudy; Gemignani, Federica; Pellegrini, Silvia; Landi, Stefano

    2012-01-01

    Malignant pleural mesothelioma (MPM), a cancer of the serosal pleural cavities, is one of the most aggressive human tumors. In order to identify genes crucial for the onset and progression of MPM, we performed an extensive literature review focused on transcriptome studies (RTS). In this kind of studies a great number of transcripts are analyzed without formulating any a priori hypothesis, thus preventing any bias coming from previously established knowledge that could lead to an over-representation of specific genes. Each study was thoroughly analyzed paying particular attention to: (i) the employed microarray platform, (ii) the number and type of samples, (iii) the fold-change, and (iv) the statistical significance of deregulated genes. We also performed data mining (DM) on MPM using three different tools (Coremine, SNPs3D, and GeneProspector). Results from RTS and DM were compared in order to restrict the number of genes potentially deregulated in MPM. Our main requirement for a gene to be a "mesothelioma gene" (MG) is to be reproducibly deregulated among independent studies and confirmed by DM. A list of MGs was thus produced, including PTGS2, BIRC5, ASS1, JUNB, MCM2, AURKA, FGF2, MKI67, CAV1, SFRP1, CCNB1, CDK4, and MSLN that might represent potential novel biomarkers or therapeutic targets for MPM. Moreover, it was found a sub-group of MGs including ASS1, JUNB, PTGS2, EEF2, SULF1, TOP2A, AURKA, BIRC5, CAV1, IFITM1, PCNA, and PKM2 that could explain, at least in part, the mechanisms of resistance to cisplatin, one first-line chemotherapeutic drug used for the disease. Finally, the pathway analysis showed that co-regulation networks related to the cross-talk between MPM and its micro-environment, in particular involving the adhesion molecules, integrins, and cytokines, might have an important role in MPM. Future studies are warranted to better characterize the role played by these genes in MPM.

  5. Serum anti-p53 autoantibodies in pleural malignant mesothelioma, lung cancer and non-neoplastic lung diseases.

    PubMed

    Neri, Monica; Betta, Piergiacomo; Marroni, Paola; Filiberti, Rosangela; Cafferata, Mara; Mereu, Carlo; Ivaldi, Giampaolo; Montanaro, Fabio; Puntoni, Riccardo; Paganuzzi, Michela

    2003-02-01

    Alterations of the p53 gene may lead to the production of detectable autoantibodies (p53-Abs) in cancer patients. In order to evaluate the association of p53-Abs with pleuropulmonary diseases, four groups of subjects were analyzed by ELISA for serum p53-Abs, in the framework of a molecular epidemiologic study. Two of 30 pleural malignant mesothelioma patients (MM; 6.7%) and 8/48 lung cancer patients (LC; 16.7%) were seropositive, while all 51 healthy controls (HC) were negative. Two of 55 (3.6%) at-risk controls (RC) with non-malignant respiratory diseases were positive and were not subsequently diagnosed any cancer. The difference was statistically significant between LC and RC or HC (P = 0.01), but not between MM and any other group. No correlation was found with age, sex, cancer stage or histology, cigarette smoking or occupational exposure. A longer survival (not significant) was shown in seropositive LC but not in MM. p53 expression in tumor tissue was also evaluated in a subgroup of MM. In conclusion, the presence of detectable p53-Abs in serum was associated in a statistically significant proportion of cases with LC but only occasionally with MM. The longer survival among positive LC patients and the presence of two seropositive among patients with non-neoplastic respiratory diseases should be further investigated.

  6. Generation of reactive oxygen species by human mesothelioma cells

    PubMed Central

    Kahlos, K; Pitkänen, S; Hassinen, I; Linnainmaa, K; Kinnula, V L

    1999-01-01

    Malignant mesothelioma cells contain elevated levels of manganese superoxide dismutase (MnSOD) and are highly resistant to oxidants compared to non-malignant mesothelial cells. Since the level of cellular free radicals may be important for cell survival, we hypothesized that the increase of MnSOD in the mitochondria of mesothelioma cells may alter the free radical levels of these organelles. First, MnSOD activity was compared to the activities of two constitutive mitochondrial enzymes; MnSOD activity was 20 times higher in the mesothelioma cells than in the mesothelial cells, whereas the activities of citrate synthase and cytochrome c oxidase did not differ significantly in the two cell lines. This indicates that the activity of MnSOD per mitochondrion was increased in the mesothelioma cells. Superoxide production was assayed in the isolated mitochondria of these cells using lucigenin chemiluminescence. Mitochondrial superoxide levels were significantly lower (72%) in the mesothelioma cells compared to the mesothelial cells. Oxidant production in intact cells, assayed by fluorimetry using 2′,7′-dichlorodihydrofluorescein as a fluorescent probe, did not differ significantly between these cells. We conclude that mitochondrial superoxide levels are lower in mesothelioma cells compared to nonmalignant mesothelial cells, and that this difference may be explained by higher MnSOD activity in the mitochondria of these cells. Oxidant production was not different in these cells, which may be due to the previously observed increase in H2O2-scavenging mechanisms of mesothelioma cells. © 1999 Cancer Research Campaign PMID:10389973

  7. Germline BAP1 Mutational Landscape of Asbestos-Exposed Malignant Mesothelioma Patients with Family History of Cancer.

    PubMed

    Ohar, Jill A; Cheung, Mitchell; Talarchek, Jacqueline; Howard, Suzanne E; Howard, Timothy D; Hesdorffer, Mary; Peng, Hongzhuang; Rauscher, Frank J; Testa, Joseph R

    2016-01-15

    Heritable mutations in the BAP1 tumor suppressor gene predispose individuals to mesothelioma and other cancers. However, a large-scale assessment of germline BAP1 mutation incidence and associated clinical features in mesothelioma patients with a family history of cancer has not been reported. Therefore, we examined the germline BAP1 mutation status of 150 mesothelioma patients with a family history of cancer, 50 asbestos-exposed control individuals with a family history of cancers other than mesothelioma, and 153 asbestos-exposed individuals without familial cancer. No BAP1 alterations were found in control cohorts, but were identified in nine of 150 mesothelioma cases (6%) with a family history of cancer. Alterations among these cases were characterized by both missense and frameshift mutations, and enzymatic activity of BAP1 missense mutants was decreased compared with wild-type BAP1. Furthermore, BAP1 mutation carriers developed mesothelioma at an earlier age that was more often peritoneal than pleural (five of nine) and exhibited improved long-term survival compared to mesothelioma patients without BAP1 mutations. Moreover, many tumors harboring BAP1 germline mutations were associated with BAP1 syndrome, including mesothelioma and ocular/cutaneous melanomas, as well as renal, breast, lung, gastric, and basal cell carcinomas. Collectively, these findings suggest that mesothelioma patients presenting with a family history of cancer should be considered for BAP1 genetic testing to identify those individuals who might benefit from further screening and routine monitoring for the purpose of early detection and intervention. PMID:26719535

  8. Lethal neuroleptic malignant syndrome due to amisulpride.

    PubMed

    Musshoff, Frank; Doberentz, Elke; Madea, Burkhard

    2013-06-01

    A 42-year old-man was found lying in his bed having seizures. Later he became unconscious and hypotonic developing mydriasis as well as rigidity. The body core temperature (rectal temperature) was above 42 °C. Blood pH was decreased during treatment, and his general condition deteriorated. The patient developed gasping respiration, ventricular fibrillation, and died. During autopsy and histological investigation cerebral and pulmonary edema were noted together with general congestion of the internal organs. Further observations included contraction bands of myocytes, a contracted spleen, fibrosis of the liver, and gall stones. Toxicological analyses of peripheral blood revealed the following results: amisulpride 4.65 mg/l, biperiden 0.12 mg/l, imipramine 0.33 mg/l, and desipramine 0.68 mg/l. An amisulpride-induced neuroleptic malignant syndrome was therefore diagnosed as the patho-physiological mechanism leading to death.

  9. Detection of malignant pleural mesothelioma in exhaled breath by multicapillary column/ion mobility spectrometry (MCC/IMS).

    PubMed

    Lamote, Kevin; Vynck, Matthijs; Van Cleemput, Joris; Thas, Olivier; Nackaerts, Kristiaan; van Meerbeeck, Jan P

    2016-01-01

    Malignant pleural mesothelioma (MPM) is predominantly caused by previous asbestos exposure. Diagnosis often happens in advanced stages restricting any therapeutic perspectives. Early stage detection via breath analysis was explored using multicapillary column/ion mobility spectrometry (MCC/IMS) to detect volatile organic compounds (VOCs) in the exhaled breath of MPM patients in comparison to former occupational asbestos-exposed and non-exposed controls. Breath and background samples of 23 MPM patients, 22 asymptomatic former asbestos (AEx) workers and 21 healthy non-asbestos exposed persons were taken for analysis. After background correction, we performed a logistic least absolute shrinkage and selection operator (lasso) regression to select the most important VOCs, followed by receiver operating characteristic (ROC) analysis. MPM patients were discriminated from both controls with 87% sensitivity, 70% specificity and respective positive and negative predictive values of 61% and 91%. The overall accuracy was 76% and the area under the ROC-curve was 0.81. AEx individuals could be discriminated from MPM patients with 87% sensitivity, 86% specificity and respective positive and negative predictive values of 87% and 86%. The overall accuracy was 87% with an area under the ROC-curve of 0.86. Breath analysis by MCC/IMS allows MPM patients to be discriminated from controls and holds promise for further investigation as a screening tool for former asbestos-exposed persons at risk of developing MPM. PMID:27669062

  10. SOCS-1 gene delivery cooperates with cisplatin plus pemetrexed to exhibit preclinical antitumor activity against malignant pleural mesothelioma.

    PubMed

    Iwahori, Kota; Serada, Satoshi; Fujimoto, Minoru; Ripley, Barry; Nomura, Shintaro; Mizuguchi, Hiroyuki; Shimada, Kazuki; Takahashi, Tsuyoshi; Kawase, Ichiro; Kishimoto, Tadamitsu; Naka, Tetsuji

    2013-01-15

    Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis for which an effective therapy remains to be established. This study investigated the therapeutic potential of gene delivery using suppressor of cytokine signaling 1 (SOCS-1), an endogenous inhibitor of intracellular signaling pathways, for the treatment of MPM. We infected MPM cells (MESO-4, H28 and H226) with adenovirus-expressing SOCS-1 vector to examine the effect of SOCS-1 overexpression on MPM cells. We evaluated the antitumor effect of SOCS-1 gene delivery combined with cisplatin plus pemetrexed by cell proliferation, apoptosis and invasion assay. We also investigated the regulation of NF-κB and STAT3 signaling related to apoptotic pathways. Furthermore, we evaluated the inhibition of tumor growth by SOCS-1 gene delivery combined with cisplatin plus pemetrexed in vivo. SOCS-1 gene delivery cooperated with cisplatin plus pemetrexed to inhibit cell proliferation, invasiveness and induction of apoptosis in MPM cells. SOCS-1 regulated NF-κB and STAT3 signaling to induce apoptosis in MESO-4 and H226 cells. Furthermore, SOCS-1 gene delivery cooperated with cisplatin plus pemetrexed to regulate NF-κB signaling and significantly inhibit tumor growth of MPM in vivo. These results suggest that SOCS-1 gene delivery has a potent antitumor effect against MPM and a potential for clinical use in combination with cisplatin plus pemetrexed.

  11. Are neutrophil/lymphocyte ratio and platelet/lymphocyte ratio reliable parameters as prognostic indicators in malignant mesothelioma?

    PubMed Central

    Tural Onur, Seda; Sokucu, Sinem Nedime; Dalar, Levent; Iliaz, Sinem; Kara, Kaan; Buyukkale, Songül; Altin, Sedat

    2016-01-01

    Background Malignant mesothelioma (MM) is an aggressive asbestos-related pleural tumor. The incidence is increasing with intensive use of asbestos in developing countries. We need an easily accessible, inexpensive, and reliable method for determining the low survival time prognosis of this tumor. The aim of our study was to investigate the viability of neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) as prognostic indicators in MM. Patients and methods Thirty-six patients with MM, whose histopathologic diagnosis and follow-up were performed by our clinic and whose complete archive data were accessible, were included in this retrospective study. The patients’ histopathologic disease types and stages, complete blood count parameters at diagnosis, and survival were recorded. Results Eighteen of the patients with MM were male and the remaining 18 of them were female; the average follow-up period was 24.83±3.61 months. The PLR levels of the patients were statistically significant (P<0.05). The NLR and PLR area under the receiver operating characteristic curve values were 0.559 and 0.749, respectively (P=0.631 and P=0.044, respectively). Conclusion PLR was a significant prognostic indicator of MM at diagnosis on complete blood count parameters; however, NLR was not a significant prognostic indicator. A large number of prospective studies are needed to prove the reliability of the parameters. PMID:27217757

  12. Increased Standardised Incidence Ratio of Malignant Pleural Mesothelioma in Taiwanese Asbestos Workers: A 29-Year Retrospective Cohort Study

    PubMed Central

    Lin, Cheng-Kuan; Chang, Yu-Ying; Wang, Jung-Der; Lee, Lukas Jyuhn-Hsiarn

    2015-01-01

    Objective. This paper aimed to determine the standardised incidence ratio (SIR) of malignant pleural mesothelioma (MPM) in workers exposed to asbestos in Taiwan. Methods. All workers employed in asbestos-related factories and registered by the Bureau of Labour Insurance between 1 March, 1950, and 31 December, 1989, were included in the study and were followed from 1 January, 1980, through 31 December, 2009. Incident cases of all cancers, including MPM (ICD-9 code: 163), were obtained from the Taiwan Cancer Registry. SIRs were calculated based on comparison with the incidence rate of the general population of Taiwan and adjusted for age, calendar period, sex, and duration of employment. Results. The highest SIR of MPM was found for male workers first employed before 1979, with a time since first employment more than 30 years (SIR 4.52, 95% CI: 2.25–8.09). After consideration of duration of employment, the SIR for male MPM was 5.78 (95% CI: 1.19–16.89) for the workers employed for more than 20 years in asbestos-related factories. Conclusions. This study corroborates the association between occupational asbestos exposure and MPM. The highest risk of MPM was found among male asbestos workers employed before 1979 and working for more than 20 years in asbestos-related factories. PMID:26290869

  13. Preclinical Activity of New [1,2]Oxazolo[5,4-e]isoindole Derivatives in Diffuse Malignant Peritoneal Mesothelioma.

    PubMed

    Spanò, Virginia; Pennati, Marzia; Parrino, Barbara; Carbone, Anna; Montalbano, Alessandra; Cilibrasi, Vincenzo; Zuco, Valentina; Lopergolo, Alessia; Cominetti, Denis; Diana, Patrizia; Cirrincione, Girolamo; Barraja, Paola; Zaffaroni, Nadia

    2016-08-11

    A series of 22 derivatives of the [1,2]oxazolo[5,4-e]isoindole system were synthesized through an efficient and versatile procedure that involves the annelation of the [1,2]oxazole moiety to the isoindole ring, producing derivatives with a wide substitution pattern. The structure-activity relationship indicates that the N-4-methoxybenzyl group appears crucial for potent activity. In addition, the presence of a 6-phenyl moiety is important and the best activity is reached with a 3,4,5-trimethoxy substituent. The most active compound, bearing both the structural features, was able to inhibit tumor cell proliferation at nanomolar concentrations when tested against the full NCI human tumor cell line panel. Interestingly, this compound was effective in reducing in vitro and in vivo cell growth, impairing cell cycle progression and inducing apoptosis, as a consequence of the inhibition of tubulin polymerization, in experimental models of diffuse malignant peritoneal mesothelioma (DMPM), a rapidly lethal disease, poorly responsive to conventional therapeutic strategies. PMID:27428868

  14. Frequent co-amplification and co-operation between C-MYC and PVT1 oncogenes promote malignant pleural mesothelioma

    PubMed Central

    Riquelme, Erick; Suraokar, Milind B.; Rodriguez, Jaime; Mino, Barbara; Lin, Heather Y.; Rice, David C.; Tsao, Anne; Wistuba, Ignacio I.

    2014-01-01

    Introduction Malignant pleural mesothelioma (MPM) is a deadly disease with poor prognosis and few treatment options. We characterized and elucidate the roles of C-MYC and PVT1 involved in the pathogenesis of MPM. Methods We used siRNA-mediated knockdown in MPM cell lines to determine the effect of C-MYC and PVT1 abrogation on MPM cells undergoing apoptosis, proliferation, and cisplatin sensitivity. We also characterized the expression of microRNAs (miRNAs) spanning the PVT1 region in MPM cell lines. Copy number analysis was measured by quantitative PCR and fluorescence in situ hybridization. Results Copy number analysis revealed copy number gains (CNGs) in chromosomal region 8q24 in six of twelve MPM cell lines. MicroRNA analysis showed high miR-1204 expression in MSTO-211H cell lines with ≥4 copies of PVT1. Knockdown by siRNA showed increased PARP-C levels in MSTO-211H transfected with siPVT1 but not in cells transfected with siC-MYC. C-MYC and PVT1 knockdown reduced cell proliferation and increased sensitivity to cisplatin. Analysis of the expression of apoptosis-related genes in the MSTO-211H cell line suggested that C-MYC maintains a balance between pro-apoptotic and anti-apoptotic gene expression, whereas PVT1 and to a lesser extent miR-1204, upregulate pro-apoptotic genes and downregulate anti-apoptotic genes. FISH analysis of MPM tumor specimens showed a high frequency of both CNGs (11/75) and trisomy (three copies; 11/75) for the C-MYC locus. Conclusion Our results suggest that C-MYC and PVT1 copy number gain promotes a malignant phenotype of MPM, with C-MYC CNG stimulating cell proliferation and PVT1 both stimulating proliferation and inhibiting apoptosis. PMID:24926545

  15. Up-regulation of DDX39 in human malignant pleural mesothelioma cell lines compared to normal pleural mesothelial cells.

    PubMed

    Kuramitsu, Yasuhiro; Tominaga, Waka; Baron, Byron; Tokuda, Kazuhiro; Wang, Yufeng; Kitagawa, Takao; Nakamura, Kazuyuki

    2013-06-01

    Malignant pleural mesothelioma (MPM) is a malignant tumor originating from mesothelial cells existing in pleura. Since its incidence, it is closely related to the amount and time of exposure to asbestos, and the latency period after exposure to asbestos is very long, the incidence may increase over the next two decades. Since early detection is very difficult and there is no standard curative therapy, it is important to understand the biology of MPM, and to find biomarkers and molecular targets for its therapy. DDX39 is one of the Asp-Glu-Ala-Asp (DEAD)-box RNA helicases, which are required for the export of mRNA out of the nucleus, and transcription, splicing and transport of mRNA. Some reports have shown differential expression of DDX39 in tumor cells or tissues such as lung squamous cell cancer, gastrointestinal stromal tumor and urinary bladder cancer. In the present study, the protein levels of DDX39 in the human MPM cell lines NCI-H28, NCI-H2052 and NCI-H2452, and the human pleural mesothelial cell line MeT-5A were investigated by western blotting. The protein levels of DDX39 were found to be higher in NCI-H28, NCI-H2052 and NCI-H2452 compared to MeT-5A. The intensity of the bands of DDX39 in NCI-H28, NCI-H2052 and NCI-H2452 cells were increased by 1.351-, 1.887- and 2.024-fold, respectively, compared to MPM cells. These results suggest that DDX39 is a possible candidate biomarker for molecular-targeting of MPM.

  16. Characterization of cancer stem cell properties of CD24 and CD26-positive human malignant mesothelioma cells

    SciTech Connect

    Yamazaki, Hiroto; Naito, Motohiko; Ghani, Farhana Ishrat; Dang, Nam H.; Morimoto, Chikao

    2012-03-16

    Highlights: Black-Right-Pointing-Pointer We focused on CD24 and CD26 for further analysis of CSC properties in MM. Black-Right-Pointing-Pointer Their expressions were correlated with chemoresistance, cell growth, and invasion. Black-Right-Pointing-Pointer Their expressions were also correlated with several cancer related genes. Black-Right-Pointing-Pointer The expression of each marker was correlated with different CSC property in Meso1. Black-Right-Pointing-Pointer Phosphorylation of ERK by EGF was regulated by expression of CD26, but not CD24. -- Abstract: Malignant mesothelioma (MM) is an asbestos-related malignancy characterized by rapid growth and poor prognosis. In our previous study, we have demonstrated that several cancer stem cell (CSC) markers correlated with CSC properties in MM cells. Among these markers, we focused on two: CD24, the common CSC marker, and CD26, the additional CSC marker. We further analyzed the CSC properties of CD24 and CD26-positve MM cells. We established RNAi-knockdown cells and found that these markers were significantly correlated with chemoresistance, proliferation, and invasion potentials in vitro. Interestingly, while Meso-1 cells expressed both CD24 and CD26, the presence of each of these two markers was correlated with different CSC property. In addition, downstream signaling of these markers was explored by microarray analysis, which revealed that their expressions were correlated with several cancer-related genes. Furthermore, phosphorylation of ERK by EGF stimulation was significantly affected by the expression of CD26, but not CD24. These results suggest that CD24 and CD26 differentially regulate the CSC potentials of MM and could be promising targets for CSC-oriented therapy.

  17. MicroRNA-126 Suppresses Mesothelioma Malignancy by Targeting IRS1 and Interfering with the Mitochondrial Function

    PubMed Central

    Nocchi, Linda; Staffolani, Sara; Manzella, Nicola; Amati, Monica; Goodwin, Jacob; Kluckova, Katarina; Nguyen, Maria; Strafella, Elisabetta; Bajzikova, Martina; Peterka, Martin; Lettlova, Sandra; Truksa, Jaroslav; Lee, Wan; Dong, Lan-Feng; Santarelli, Lory

    2014-01-01

    Abstract Aims: MiR126 was found to be frequently lost in many types of cancer, including malignant mesothelioma (MM), which represents one of the most challenging neoplastic diseases. In this study, we investigated the potential tumor suppressor function of MiR126 in MM cells. The effect of MiR126 was examined in response to oxidative stress, aberrant mitochondrial function induced by inhibition of complex I, mitochondrial DNA (mtDNA) depletion, and hypoxia. Results: MiR126 was up-regulated by oxidative stress in nonmalignant mesothelial (Met5A) and MM (H28) cell lines. In Met5A cells, rotenone inhibited MiR126 expression, but mtDNA depletion and hypoxia up-regulated MiR126. However, these various stimuli suppressed the levels of MiR126 in H28 cells. MiR126 affected mitochondrial energy metabolism, reduced mitochondrial respiration, and promoted glycolysis in H28 cells. This metabolic shift, associated with insulin receptor substrate-1 (IRS1)-modulated ATP-citrate lyase deregulation, resulted in higher ATP and citrate production. These changes were linked to the down-regulation of IRS1 by ectopic MiR126, reducing Akt signaling and inhibiting cytosolic sequestration of Forkhead box O1 (FoxO1), which promoted the expression of genes involved in gluconeogenesis and oxidative stress defense. These metabolic changes induced hypoxia-inducible factor-1α (HIF1α) stabilization. Consequently, MiR126 suppressed the malignancy of MM cells in vitro, a notion corroborated by the failure of H28MiR126 cells to form tumors in nude mice. Innovation and Conclusion: MiR126 affects mitochondrial energy metabolism, resulting in MM tumor suppression. Since MM is a fatal neoplastic disease with a few therapeutic options, this finding is of potential translational importance. Antioxid. Redox Signal. 21, 2109–2125. PMID:24444362

  18. Volumetric Modulation Arc Radiotherapy Compared With Static Gantry Intensity-Modulated Radiotherapy for Malignant Pleural Mesothelioma Tumor: A Feasibility Study

    SciTech Connect

    Scorsetti, Marta; Bignardi, Mario; Clivio, Alessandro

    2010-07-01

    Purpose: A planning study was performed to evaluate RapidArc (RA), a volumetric modulated arc technique, on malignant pleural mesothelioma. The benchmark was conventional fixed-field intensity-modulated radiotherapy (IMRT). Methods and materials: The computed tomography data sets of 6 patients were included. The plans for IMRT with nine fixed beams were compared against double-modulated arcs with a single isocenter. All plans were optimized for 15-MV photon beams. The dose prescription was 54 Gy to the planning target volume. The planning objectives for the planning target volume were a minimal dose of >95% and maximal dose of <107%. For the organs at risk, the parameters were as follows: contralateral lung, percentage of volume receiving 5 Gy (V{sub 5Gy}) <60%, V{sub 20Gy} < 10%, mean <10.0 Gy; liver, V{sub 30Gy} <33%, mean <31 Gy; heart, V{sub 45Gy} <30%, V{sub 50Gy} <20%, dose received by 1% of the volume (D{sub 1%}) <60 Gy; contralateral kidney, V{sub 15Gy} <20%; spine, D{sub 1%} <45 Gy; esophagus, V{sub 55Gy} <30%; and spleen, V{sub 40Gy} <50%. The monitor units (MUs) and delivery time were scored to measure the treatment efficiency. The pretreatment portal dosimetry scored delivery to the calculation agreement with the Gamma Agreement Index. Results: RA and IMRT provided equivalent coverage and homogeneity. Both techniques fulfilled objectives on organs at risk with a tendency of RA to improve sparing. The conformity index was 1.9 {+-} 0.1 for RA and IMRT. The number of MU/2Gy was 734 {+-} 82 for RA and 2,195 {+-} 317 for IMRT. The planning vs. delivery agreement revealed a Gamma Agreement Index for IMRT of 96.0% {+-} 2.6% and for RA of 95.7% {+-} 1.5%. The treatment time was 3.7 {+-} 0.3min for RA and 13.4 {+-} 0.1min for IMRT. Conclusion: RA demonstrated compared with conventional IMRT, similar target coverage and better dose sparing to the organs at risks. The number of MUs and the time required to deliver a 2-Gy fraction were much lower for RA, allowing

  19. Mesothelioma in Scotland.

    PubMed

    McEwen, J; Finlayson, A; Mair, A; Gibson, A A

    1970-12-01

    In a retrospective study of the incidence of mesothelioma in Scotland for 1950-67 80 cases were traced from pathological reports and biopsy material of malignant tumours invading the pleura and peritoneum. These cases were matched with two sets of controls. Detailed histories of residence, occupation, and degree of exposure to asbestos confirmed that the incidence of mesothelioma in Scotland is similar to that in other parts of Britain.

  20. Methoxyamine, Cisplatin, and Pemetrexed Disodium in Treating Patients With Advanced Solid Tumors or Mesothelioma That Cannot Be Removed by Surgery or Mesothelioma That Is Refractory to Cisplatin and Pemetrexed

    ClinicalTrials.gov

    2016-09-09

    Advanced Peritoneal Malignant Mesothelioma; Advanced Pleural Malignant Mesothelioma; Recurrent Peritoneal Malignant Mesothelioma; Recurrent Pleural Malignant Mesothelioma; Solid Neoplasm; Stage III Pleural Mesothelioma; Stage IIIA Non-Small Cell Lung Cancer; Stage IIIA Ovarian Cancer; Stage IIIB Non-Small Cell Lung Cancer; Stage IIIB Ovarian Cancer; Stage IIIC Ovarian Cancer; Stage IV Non-Small Cell Lung Cancer; Stage IV Ovarian Cancer; Stage IV Pleural Mesothelioma; Thymoma

  1. Guidelines for cytopathologic diagnosis of epithelioid and mixed type malignant mesothelioma. Complementary statement from the International Mesothelioma Interest Group, also endorsed by the International Academy of Cytology and the Papanicolaou Society of Cytopathology

    PubMed Central

    Hjerpe, Anders; Ascoli, Valeria; Bedrossian, Carlos; Boon, Mathilde; Creaney, Jenette; Davidson, Ben; Dejmek, Annika; Dobra, Katalin; Fassina, Ambrogio; Field, Andrew; Firat, Pinar; Kamei, Toshiaki; Kobayashi, Tadao; Michael, Claire W.; Önder, Sevgen; Segal, Amanda; Vielh, Philippe

    2015-01-01

    To provide practical guidelines for the cytopathologic diagnosis of malignant mesothelioma (MM). Cytopathologists involved in the International Mesothelioma Interest Group (IMIG) and the International Academy of Cytology (IAC), who have an interest in the field contributed to this update. Reference material includes peer-reviewed publications and textbooks. This article is the result of discussions during and after the IMIG 2012 conference in Boston, followed by thorough discussions during the 2013 IAC meeting in Paris. Additional contributions have been obtained from cytopathologists and scientists, who could not attend these meetings, with final discussions and input during the IMIG 2014 conference in cape town. During the previous IMIG biennial meetings, thorough discussions have resulted in published guidelines for the pathologic diagnosis of MM. However, previous recommendations have stated that the diagnosis of MM should be based on histological material only.[12] Accumulating evidence now indicates that the cytological diagnosis of MM supported by ancillary techniques is as reliable as that based on histopathology, although the sensitivity with cytology may be somewhat lower.[345] Recognizing that noninvasive diagnostic modalities benefit both the patient and the health system, future recommendations should include cytology as an accepted method for the diagnosis of this malignancy.[67] The article describes the consensus of opinions of the authors on how cytology together with ancillary testing can be used to establish a reliable diagnosis of MM. PMID:26681974

  2. A Tumor-Specific Neo-Antigen Caused by a Frameshift Mutation in BAP1 Is a Potential Personalized Biomarker in Malignant Peritoneal Mesothelioma.

    PubMed

    Lai, Jun; Zhou, Zhan; Tang, Xiao-Jing; Gao, Zhi-Bin; Zhou, Jie; Chen, Shu-Qing

    2016-05-14

    Malignant peritoneal mesothelioma (MPM) is an aggressive rare malignancy associated with asbestos exposure. A better understanding of the molecular pathogenesis of MPM will help develop a targeted therapy strategy. Oncogene targeted depth sequencing was performed on a tumor sample and paired peripheral blood DNA from a patient with malignant mesothelioma of the peritoneum. Four somatic base-substitutions in NOTCH2, NSD1, PDE4DIP, and ATP10B and 1 insert frameshift mutation in BAP1 were validated by the Sanger method at the transcriptional level. A 13-amino acids neo-peptide of the truncated Bap1 protein, which was produced as a result of this novel frameshift mutation, was predicted to be presented by this patient's HLA-B protein. The polyclonal antibody of the synthesized 13-mer neo-peptide was produced in rabbits. Western blotting results showed a good antibody-neoantigen specificity, and Immunohistochemistry (IHC) staining with the antibody of the neo-peptide clearly differentiated neoplastic cells from normal cells. A search of the Catalogue of Somatic Mutations in Cancer (COSMIC) database also revealed that 53.2% of mutations in BAP1 were frameshift indels with neo-peptide formation. An identified tumor-specific neo-antigen could be the potential molecular biomarker for personalized diagnosis to precisely subtype rare malignancies such as MPM.

  3. A Tumor-Specific Neo-Antigen Caused by a Frameshift Mutation in BAP1 Is a Potential Personalized Biomarker in Malignant Peritoneal Mesothelioma

    PubMed Central

    Lai, Jun; Zhou, Zhan; Tang, Xiao-Jing; Gao, Zhi-Bin; Zhou, Jie; Chen, Shu-Qing

    2016-01-01

    Malignant peritoneal mesothelioma (MPM) is an aggressive rare malignancy associated with asbestos exposure. A better understanding of the molecular pathogenesis of MPM will help develop a targeted therapy strategy. Oncogene targeted depth sequencing was performed on a tumor sample and paired peripheral blood DNA from a patient with malignant mesothelioma of the peritoneum. Four somatic base-substitutions in NOTCH2, NSD1, PDE4DIP, and ATP10B and 1 insert frameshift mutation in BAP1 were validated by the Sanger method at the transcriptional level. A 13-amino acids neo-peptide of the truncated Bap1 protein, which was produced as a result of this novel frameshift mutation, was predicted to be presented by this patient’s HLA-B protein. The polyclonal antibody of the synthesized 13-mer neo-peptide was produced in rabbits. Western blotting results showed a good antibody-neoantigen specificity, and Immunohistochemistry (IHC) staining with the antibody of the neo-peptide clearly differentiated neoplastic cells from normal cells. A search of the Catalogue of Somatic Mutations in Cancer (COSMIC) database also revealed that 53.2% of mutations in BAP1 were frameshift indels with neo-peptide formation. An identified tumor-specific neo-antigen could be the potential molecular biomarker for personalized diagnosis to precisely subtype rare malignancies such as MPM. PMID:27187383

  4. Mesothelioma risk associated with asbestos production in Slovenia.

    PubMed

    Vudrag, Marko; Rihtar, Tatja Kostnapfel; Vegnuti, Miljana

    2010-03-01

    The aim of this study was to assess malignant mesothelioma morbidity due to exposure to asbestos in a population living in districts Nova Gorica and Tolmin (49,850 people) near the asbestos manufacturing village Anhovo (Slovenia) and to compare it with the entire Slovene population (1,949,750 people). Crude rates per 100,000 people were calculated from the total number of mesotheliomas, and risk assessment in the studied vs. total population was based on 23 years worth of data. Time series data on mesothelioma cases were also processed as a forecast of new cases by 2010.The crude incidence of mesothelioma per 100,000 individuals for all of Slovenia was 21.4, while for the Nova Gorica district including the village Anhovo it is 170.2 and for the Tolmin district 60.9. The probability of a mesothelioma case in the studied population was 8.5 times the probability of the same diagnosis in the whole of Slovenia. Over 23 years, 28% of all mesothelioma cases in Slovenia were diagnosed in the studied population, which makes only 2.5% of the total Slovene population.The outbreak of asbestosis and mesothelioma epidemics in the studied population is associated with manufacture of asbestos products in the local factory from 1922 to 1996.

  5. [Pericardial mesothelioma. A case report].

    PubMed

    Akoudad, H; Boubel, K; Belmadani, K; Cherti, M; Bouhouche, R; Kettani, F; Benmimoun, E G; Arharbi, M

    1999-06-01

    Primary pericardial mesothelioma is a rare malignancy, with an estimated incidence of 0.0022% in a large autopsy study. We report a case of primary pericardial mesothelioma revealed by a large and recurrent pericardial effusion. Through a literature review, we analyse the clinical findings of this tumor. With or without therapy, prognosis is poor.

  6. Use of immunohistochemical marker calretinin in the diagnosis of a diffuse malignant metastatic mesothelioma in an equine.

    PubMed

    Stoica, G; Cohen, N; Mendes, O; Kim, Hun-Taek

    2004-05-01

    Mesotheliomas are rarely reported in animal species. In this report, the occurrence of a diffuse, metastatic mesothelioma in a 6-year-old gray Arabian mare is described. The mare was presented on clinical examination with ascites, bilateral pleural effusion, and pleural roughening. Necropsy revealed abundant fluid in the abdominal and thoracic cavities. The surface of all organs was thick and fibrosed with multiple raised nodules and hemorrhages. Histology was characteristic of a generalized, biphasic mesothelioma with vascular and lymph nodes metastases. It is believed that the primary tumor developed in the pericardium and spread through lymphatics. In this report, calretinin was used as an immunohistochemical marker in the diagnosis of mesothelioma in an equine species for the first time. PMID:15152842

  7. An exception that proves the rule: recurrence free survival five years after extrapleural pneumonectomy for malignant pleural mesothelioma.

    PubMed

    Treasure, Tom; Macbeth, Fergus

    2014-11-18

    Are case reports at all relevant and useful? A case report of an unusual case of mesothelioma prompts a discussion and concludes that they do have a role but that their observations and conclusions need to be treated with care.

  8. Lapatinib enhances trastuzumab-mediated antibody-dependent cellular cytotoxicity via upregulation of HER2 in malignant mesothelioma cells

    PubMed Central

    OKITA, RIKI; SHIMIZU, KATSUHIKO; NOJIMA, YUJI; YUKAWA, TAKURO; MAEDA, AI; SAISHO, SHINSUKE; NAKATA, MASAO

    2015-01-01

    EGFR/HER2 are frequently expressed in MPM tissues, however, no studies have shown the clinical benefit of using EGFR/HER2-targeting drugs in patients with malignant pleural mesothelioma (MPM). It was reported that the tyrosine kinase inhibitor (TKI) lapatinib enhanced trastuzumab-mediated antibody-dependent cellular cytotoxicity (ADCC) in HER2-positive breast cancer, suggesting that this combination is a promising strategy for MPM treatment. The aim of the present study was to explore the possibility of a TKI combined with trastuzumab to enhance ADCC in MPM cells. Five MPM cell lines were used to test the effects of TKIs targeting EGFR (gefitinib, afatinib and lapatinib) on cell proliferation and the expression of the HER family receptor. The combined effects of TKI with trastuzumab on ADCC were evaluated using the LDH release assay. Additionally, MPM cells were isolated from patients and evaluated for lapatinib-induced upregulation of HER family receptors and trastuzumab- or cetuximab-mediated ADCC. In MPM cell lines, HER2 expression was upregulated by lapatinib, downregulated by afatinib and unaffected by gefitinib. As expected, more trastuzumab bound to MPM cells pretreated with lapatinib than untreated cells, resulting in the enhancement of trastuzumab-mediated ADCC in MPM cells. In patient-derived MPM cells, both HER2 and EGFR were upregulated by lapatinib, resulting in the enhancement of both trastuzumab- and cetuximab-mediated ADCC. Of the three TKIs, only lapatinib enhanced trastuzumab-mediated ADCC via the upregulation of HER2 expression in MPM cells, suggesting that sequential combination of lapatinib and trastuzumab may be a promising strategy for MPM treatment. PMID:26503698

  9. Lapatinib enhances trastuzumab-mediated antibody-dependent cellular cytotoxicity via upregulation of HER2 in malignant mesothelioma cells.

    PubMed

    Okita, Riki; Shimizu, Katsuhiko; Nojima, Yuji; Yukawa, Takuro; Maeda, Ai; Saisho, Shinsuke; Nakata, Masao

    2015-12-01

    EGFR/HER2 are frequently expressed in MPM tissues, however, no studies have shown the clinical benefit of using EGFR/HER2-targeting drugs in patients with malignant pleural mesothelioma (MPM). It was reported that the tyrosine kinase inhibitor (TKI) lapatinib enhanced trastuzumab-mediated antibody-dependent cellular cytotoxicity (ADCC) in HER2-positive breast cancer, suggesting that this combination is a promising strategy for MPM treatment. The aim of the present study was to explore the possibility of a TKI combined with trastuzumab to enhance ADCC in MPM cells. Five MPM cell lines were used to test the effects of TKIs targeting EGFR (gefitinib, afatinib and lapatinib) on cell proliferation and the expression of the HER family receptor. The combined effects of TKI with trastuzumab on ADCC were evaluated using the LDH release assay. Additionally, MPM cells were isolated from patients and evaluated for lapatinib-induced upregulation of HER family receptors and trastuzumab- or cetuximab‑mediated ADCC. In MPM cell lines, HER2 expression was upregulated by lapatinib, downregulated by afatinib and unaffected by gefitinib. As expected, more trastuzumab bound to MPM cells pretreated with lapatinib than untreated cells, resulting in the enhancement of trastuzumab-mediated ADCC in MPM cells. In patient-derived MPM cells, both HER2 and EGFR were upregulated by lapatinib, resulting in the enhancement of both trastuzumab- and cetuximab-mediated ADCC. Of the three TKIs, only lapatinib enhanced trastuzumab-mediated ADCC via the upregulation of HER2 expression in MPM cells, suggesting that sequential combination of lapatinib and trastuzumab may be a promising strategy for MPM treatment. PMID:26503698

  10. Thrombomodulin Is Silenced in Malignant Mesothelioma by a Poly(ADP-ribose) Polymerase-1-mediated Epigenetic Mechanism*

    PubMed Central

    Nocchi, Linda; Tomasetti, Marco; Amati, Monica; Neuzil, Jiri; Santarelli, Lory; Saccucci, Franca

    2011-01-01

    Malignant mesothelioma (MM) is often complicated by thromboembolic episodes, with thrombomodulin (TM) playing a critical role in the anticoagulant process. Heterogeneous expression of TM has been observed in cancer, and low or no TM expression in cancer cells is associated with poor prognosis. In this study, we analyzed TM expression in biopsies of MM patients and compared them with normal mesothelial tissue. The role of DNA methylation-associated gene silencing in TM expression was investigated. To evaluate poly(ADP-ribose) polymerase-1 (PARP1) as responsible for gene promoter epigenetic modifications, nonmalignant mesothelial cells (Met-5A) and MM cells (H28) were silenced for PARP1 and the DNA methylation/acetylation-associated TM expression evaluated. A correlation between low TM expression and high level of TM promoter methylation was found in MM biopsies. Low expression of TM was restored in MM cells by their treatment with 5-aza-2′-deoxycytidine and, to a lesser extent, with trichostatin, whereas the epigenetic agents did not affect TM expression in Met-5A cells. Silencing of PARP1 resulted in a strong down-regulation of TM expression in Met-5A cells, while restoring TM expression in H28 cells. PARP1 silencing induced TM promoter methylation in Met-5A cells and demethylation in MM cells, and this was paralleled by corresponding changes in the DNA methyltransferase activity. We propose that methylation of the TM promoter is responsible for silencing of TM expression in MM tissue, a process that is regulated by PARP1. PMID:21489980

  11. Biphasic effects of l-ascorbate on the tumoricidal activity of non-thermal plasma against malignant mesothelioma cells.

    PubMed

    Shi, Lei; Wang, Yue; Ito, Fumiya; Okazaki, Yasumasa; Tanaka, Hiromasa; Mizuno, Masaaki; Hori, Masaru; Richardson, Des R; Toyokuni, Shinya

    2016-09-01

    Non-thermal plasma (NTP) is a recently developed technology that elicits a variety of biological effects. This includes cancer cell-specific cytotoxicity, which is mainly attributed to the regional generation of reactive oxygen species (ROS). We studied the effects of NTP on malignant mesothelioma (MM) and its modulation by l-ascorbate. l-ascorbate is a major water-soluble anti-oxidant in vivo, but its pro-oxidant activity in vitro has been well recognized. Thus, the effects of ascorbate on the efficacy of NTP is important to examine. NTP exposure dose-dependently killed MM cells, whereas MM cells tolerated 1 mM l-ascorbate. However, brief pre-treatment with a pharmacological dose (250-750 μM) of l-ascorbate immediately prior to NTP exposure significantly increased its cytotoxicity in a dose-dependent manner, which was inhibited by the iron chelator, deferoxamine. However, paradoxically, this potentiating effect of l-ascorbate was completely abolished by a prolonged 4 h pre-incubation with l-ascorbate (500 μM). MM cytotoxicity induced by NTP was associated with immediate oxidative stress evaluated by 2',7'-dichlorodihydrofluorecein diacetate, which was followed by an increase in the expression of the autophagosome marker, LC3B-II. In conclusion, MM can be a target for NTP treatment and l-ascorbate can increase or decrease its efficacy depending on the length of the pre-incubation period.

  12. Determinants of Survival in Malignant Pleural Mesothelioma: A Surveillance, Epidemiology, and End Results (SEER) Study of 14,228 Patients

    PubMed Central

    Taioli, Emanuela; Wolf, Andrea S.; Camacho-Rivera, Marlene; Kaufman, Andrew; Lee, Dong-Seok; Nicastri, Daniel; Rosenzweig, Kenneth; Flores, Raja M.

    2015-01-01

    Introduction Left untreated, malignant pleural mesothelioma (MPM) is associated with uniformly poor prognosis. Better survival has been reported with surgery-based multimodality therapy, but to date, no trial has demonstrated survival benefit of surgery over other therapies. We evaluated whether cancer-directed surgery influenced survival independently from other predictors in a large population-based dataset. Methods The SEER database was explored from 1973 to 2009 to identify all cases of pathologically-proven MPM. Age, sex, race, year of diagnosis, histology stage, cancer-directed surgery, radiation, and vital status were analyzed. The association between prognostic factors and survival was estimated using Cox regression and propensity matched analysis. Results There were 14,228 patients with pathologic diagnosis of MPM. On multivariable analysis, female gender, younger age, early stage, and treatment with surgery were independent predictors of longer survival. In comparison to no treatment, surgery alone was associated with significant improvement in survival [adjusted hazard ratio (adj HR) 0.64 (0.61–0.67)], but not radiation [adj HR 1.15 (1.08–1.23)]. Surgery and radiation combined had similar survival as surgery alone [adj HR 0.69 (0.64–0.76)]. Results were similar when cases diagnosed between 1973 and 1999 were compared to cases diagnosed between 2000 and 2009. Conclusions Despite developments in surgical and radiation techniques, the prognosis for MPM patients has not improved over the past 4 decades. Cancer-directed surgery is independently associated with better survival, suggesting that multimodal surgery-based therapy can benefit these patients. Further research in adjuvant treatment is necessary to improve prognosis in this challenging disease. PMID:26660351

  13. Biallelic germline and somatic mutations in malignant mesothelioma: multiple mutations in transcription regulators including mSWI/SNF genes.

    PubMed

    Yoshikawa, Yoshie; Sato, Ayuko; Tsujimura, Tohru; Otsuki, Taiichiro; Fukuoka, Kazuya; Hasegawa, Seiki; Nakano, Takashi; Hashimoto-Tamaoki, Tomoko

    2015-02-01

    We detected low levels of acetylation for histone H3 tail lysines in malignant mesothelioma (MM) cell lines resistant to histone deacetylase inhibitors. To identify the possible genetic causes related to the low histone acetylation levels, whole-exome sequencing was conducted with MM cell lines established from eight patients. A mono-allelic variant of BRD1 was common to two MM cell lines with very low acetylation levels. We identified 318 homozygous protein-damaging variants/mutations (18-78 variants/mutations per patient); annotation analysis showed enrichment of the molecules associated with mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complexes and co-activators that facilitate initiation of transcription. In seven of the patients, we detected a combination of variants in histone modifiers or transcription factors/co-factors, in addition to variants in mSWI/SNF. Direct sequencing showed that homozygous mutations in SMARCA4, PBRM1 and ARID2 were somatic. In one patient, homozygous germline variants were observed for SMARCC1 and SETD2 in chr3p22.1-3p14.2. These exhibited extended germline homozygosity and were in regions containing somatic mutations, leading to a loss of BAP1 and PBRM1 expression in MM cell line. Most protein-damaging variants were heterozygous in normal tissues. Heterozygous germline variants were often converted into hemizygous variants by mono-allelic deletion, and were rarely homozygous because of acquired uniparental disomy. Our findings imply that MM might develop through the somatic inactivation of mSWI/SNF complex subunits and/or histone modifiers, including BAP1, in subjects that have rare germline variants of these transcription regulators and/or transcription factors/co-factors, and in regions prone to mono-allelic deletion during oncogenesis.

  14. Feasibility of boron neutron capture therapy (BNCT) for malignant pleural mesothelioma from a viewpoint of dose distribution analysis

    SciTech Connect

    Suzuki, Minoru . E-mail: msuzuki@rri.kyoto-u.ac.jp; Sakurai, Yoshinori; Masunaga, Shinichiro; Kinashi, Yuko; Nagata, Kenji; Maruhashi, Akira; Ono, Koji

    2006-12-01

    Purpose: To investigate the feasibility of boron neutron capture therapy (BNCT) for malignant pleural mesothelioma (MPM) from a viewpoint of dose distribution analysis using Simulation Environment for Radiotherapy Applications (SERA), a currently available BNCT treatment planning system. Methods and Materials: The BNCT treatment plans were constructed for 3 patients with MPM using the SERA system, with 2 opposed anterior-posterior beams. The {sup 1}B concentrations in the tumor and normal lung in this study were assumed to be 84 and 24 ppm, respectively, and were derived from data observed in clinical trials. The maximum, mean, and minimum doses to the tumors and the normal lung were assessed for each plan. The doses delivered to 5% and 95% of the tumor volume, D{sub 05} and D{sub 95}, were adopted as the representative dose for the maximum and minimum dose, respectively. Results: When the D{sub 05} to the normal ipsilateral lung was 5 Gy-Eq, the D{sub 95} and mean doses delivered to the normal lung were 2.2-3.6 and 3.5-4.2 Gy-Eq, respectively. The mean doses delivered to the tumors were 22.4-27.2 Gy-Eq. The D{sub 05} and D{sub 95} doses to the tumors were 9.6-15.0 and 31.5-39.5 Gy-Eq, respectively. Conclusions: From a viewpoint of the dose-distribution analysis, BNCT has the possibility to be a promising treatment for MPM patients who are inoperable because of age and other medical illnesses.

  15. Feasibility of large-scale screening using N-ERC/mesothelin levels in the blood for the early diagnosis of malignant mesothelioma

    PubMed Central

    IMASHIMIZU, KOHTA; SHIOMI, KAZU; MAEDA, MASAHIRO; AOKI, NAOKO; IGARASHI, KIYOKO; SUZUKI, FUMIO; KOIZUMI, MITSURU; SUZUKI, KENJI; HINO, OKIO

    2011-01-01

    A large-scale screening involving the measurement of N-ERC/mesothelin levels in blood using an ELISA system for the early diagnosis of malignant mesothelioma (MM) was carried out in individuals with a history of employment at construction sites. Approximately 30,000 subjects were screened. Of the 80 subjects with high-risk values, one male patient was diagnosed as having MM based on a PET study and histopathology. This is the first report of the pre-clinical diagnosis of MM based on blood test screening. In addition, plasma levels of N-ERC/mesothelin may be effectively used for monitoring relapse after surgery. PMID:22977518

  16. Early Detection of Malignant Pleural Mesothelioma in Asbestos-Exposed Individuals with a Noninvasive Proteomics-Based Surveillance Tool

    PubMed Central

    Stewart, Alex; Ayers, Deborah; Brody, Edward N.; Williams, Stephen A.; Levin, Stephen; Black, Brad; Harbut, Michael; Carbone, Michele; Goparaju, Chandra; Pass, Harvey I.

    2012-01-01

    Background Malignant pleural mesothelioma (MM) is an aggressive, asbestos-related pulmonary cancer that is increasing in incidence. Because diagnosis is difficult and the disease is relatively rare, most patients present at a clinically advanced stage where possibility of cure is minimal. To improve surveillance and detection of MM in the high-risk population, we completed a series of clinical studies to develop a noninvasive test for early detection. Methodology/Principal Findings We conducted multi-center case-control studies in serum from 117 MM cases and 142 asbestos-exposed control individuals. Biomarker discovery, verification, and validation were performed using SOMAmer proteomic technology, which simultaneously measures over 1000 proteins in unfractionated biologic samples. Using univariate and multivariate approaches we discovered 64 candidate protein biomarkers and derived a 13-marker random forest classifier with an AUC of 0.99±0.01 in training, 0.98±0.04 in independent blinded verification and 0.95±0.04 in blinded validation studies. Sensitivity and specificity at our pre-specified decision threshold were 97%/92% in training and 90%/95% in blinded verification. This classifier accuracy was maintained in a second blinded validation set with a sensitivity/specificity of 90%/89% and combined accuracy of 92%. Sensitivity correlated with pathologic stage; 77% of Stage I, 93% of Stage II, 96% of Stage III and 96% of Stage IV cases were detected. An alternative decision threshold in the validation study yielding 98% specificity would still detect 60% of MM cases. In a paired sample set the classifier AUC of 0.99 and 91%/94% sensitivity/specificity was superior to that of mesothelin with an AUC of 0.82 and 66%/88% sensitivity/specificity. The candidate biomarker panel consists of both inflammatory and proliferative proteins, processes strongly associated with asbestos-induced malignancy. Significance The SOMAmer biomarker panel discovered and validated in

  17. Malignant transformation in non-recurrent peritoneal cystic mesothelioma Our experience and review of the literature.

    PubMed

    Santangelo, Giuseppe; Accardo, Marina; De Vita, Ferdinando; Del Giudice, Santolo; Gallucci, Federica; Fabozzi, Alessio; De Falco, Massimo

    2016-01-29

    Il mesotelioma peritoneale cistico è un tumore raro. Si tratta di un tumore benigno, che tuttavia va incontro a recidive locali post-chirurgiche in oltre il 50% dei casi. È proprio a seguito di recidive ricorrenti che si possono determinare trasformazioni maligne di questa neoplasia, come descritto in Letteratura. Nel Giugno del 2004 un paziente di 73 anni è giunto presso la nostra struttura con una tumefazione addominale causa di dolore gravativo: si trattava di una massa di 16 cm, la cui struttura, agli esami strumentali (ecografia, TC con m.d.c. e RMN), appariva pluricistica. Attraverso una laparotomia mediana si è provveduto alla sua rimozione e il paziente è stato dimesso in VIII giornata post-operatoria senza complicanze. L’esame istologico, corredato da studio immunoistochimico e di microscopia elettronica, ha consentito di porre diagnosi di mesotelioma peritoneale pluricistico in trasformazione maligna. D’accordo con gli oncologi, in considerazione della scarsa efficacia dei trattamenti adiuvanti e della scarsità dei dati riportati in Letteratura sull’argomento, si è deciso di sottoporre il paziente unicamente ad uno stretto follow-up, con esecuzione di ecografia addominale ogni sei mesi e TC addominale ogni anno. Ad oggi, dieci anni dopo il trattamento, il paziente, di 83 anni, gode di un discreto stato di salute e non si sono verificate riprese o recidive di malattia, né locali, né a distanza. Oltre al fatto di essere risultato maligno alla sua prima manifestazione e non dopo ripetute recidive, il caso presenta altre particolarità: il mesotelioma peritoneale cistico, infatti, solitamente colpisce soggetti di sesso femminile (con un rapporto F:M di 4,5:1) ad un’età media di 60 anni, mentre il caso descritto riguarda un soggetto di sesso maschile di 73 anni. La nostra osservazione dimostra la possibilità che il mesotelioma peritoneale vada incontro a trasformazioni maligne già alla sua prima manifestazione e non esclusivamente dopo

  18. The horses are the first thought but one must not forget the zebras even if they are rare: Stiff person syndrome associated with malignant mesothelioma

    PubMed Central

    Koca, Irfan; Ucar, Mehmet; Kalender, Mehmet Emin; Alkan, Samet

    2014-01-01

    Stiff person syndrome (SPS) is a rare condition that causes rigidity in the muscles of the body and extremities, difficulty in walking, episodic spasms and progressive disability. SPS is generally seen together with autoimmune disorders such as diabetes mellitus, thyroiditis, vitiligo and pernicious anaemia. Rarely, it may develop as a paraneoplastic condition. SPS cases associated with breast cancer, small cell lung carcinoma, thymoma, Hodgkin's lymphoma and colorectal cancer have been reported in the literature. We present a case of a 58-year-old female patient who had malignant mesothelioma-associated SPS. Patients who have muscle spasms and difficulty in movement of joints should be evaluated for SPS before diagnosis of Parkinson's or other neurological disorders, and possible underlying malignancies should be excluded. PMID:24711475

  19. The horses are the first thought but one must not forget the zebras even if they are rare: Stiff person syndrome associated with malignant mesothelioma.

    PubMed

    Koca, Irfan; Ucar, Mehmet; Kalender, Mehmet Emin; Alkan, Samet

    2014-04-07

    Stiff person syndrome (SPS) is a rare condition that causes rigidity in the muscles of the body and extremities, difficulty in walking, episodic spasms and progressive disability. SPS is generally seen together with autoimmune disorders such as diabetes mellitus, thyroiditis, vitiligo and pernicious anaemia. Rarely, it may develop as a paraneoplastic condition. SPS cases associated with breast cancer, small cell lung carcinoma, thymoma, Hodgkin's lymphoma and colorectal cancer have been reported in the literature. We present a case of a 58-year-old female patient who had malignant mesothelioma-associated SPS. Patients who have muscle spasms and difficulty in movement of joints should be evaluated for SPS before diagnosis of Parkinson's or other neurological disorders, and possible underlying malignancies should be excluded.

  20. MicroRNA-302b targets Mcl-1 and inhibits cell proliferation and induces apoptosis in malignant pleural mesothelioma cells

    PubMed Central

    Khodayari, Nazli; Mohammed, Kamal A; Lee, Hungyen; Kaye, Frederick; Nasreen, Najmunnisa

    2016-01-01

    MicroRNAs belonging to the miR-302 family are emerging as key players in the control of cell growth, and maintaining pluripotency during cell fate determination and differentiation in embryonic stem cells. However, the mechanisms whereby ephA2/ephirnA1 signaling regulates miR-302b expression and attenuates malignant pleural mesothelioma (MPM) cell growth are not known. Our study identified a novel mechanism of ephrin-A1 mediated anti-oncogenic signaling in MPM. Ephrin-A1 treatment up regulates miR-302b expression in MPM cells and attenuates cell proliferation and tumorsphere formation via repression of myeloid cell leukemia-1 (Mcl-1). The expression of miR-302b was analyzed by qPCR, the expression of Mcl-1 was analyzed by RT-PCR, immuno-blotting and Immunofluorescence staining. To confirm that ephrin-A1 regulates the expression of Mcl-1 mRNA through miR-302b up regulation, cells were transfected with and without miR-302b and miR-302b inhibitor prior to ephrinA1 treatment. The cell proliferation and tumorsphere formation was measured by WST-1 and matrigel assays respectively. In addition, to confirm the binding of miR-302b to the 3’UTR of Mcl-1 Luciferase assay was performed. Ephrin-A1 treatment induced several fold increases of miR-302b expression in MM cells. In ephrin-A1 treated MM cells, Mcl-1 expression was significantly down regulated when compared to control. Moreover, ephrin-A1 activation significantly inhibited MM cell proliferation and tumorsphere growth. Furthermore, ephrinA1 and miR-302b induced apoptosis in MM cells. The present data suggests that ephrin-A1 induces the expression of miR-302b in MM cells which targets Mcl-1 thereby inhibits MM tumorsphere growth by inducing apoptosis. PMID:27725905

  1. Pleural malignant mesothelioma and environmental asbestos exposure in Casale Monferrato, Piedmont. Preliminary analysis of a case-control study.

    PubMed

    Magnani, C; Ivaldi, C; Botta, M; Terracini, B

    1997-01-01

    A case-control study on pleural malignant mesothelioma (MM) was conducted in Casale Monferrato, where the largest Italian asbestos cement (AC) factory had been operating from 1907 to 1985. In a previous study we observed a five to seven-fold increase in the incidence of MM among people living in that city and never employed in the factory mentioned. The present study includes cases of MM with histological diagnosis over the period 1.1.1987-30.6.1993 among residents in the Local Health Unit (LHU) of Casale Monferrato. Population controls were randomly extracted from the list of the residents in the LHU, matched to cases on sex, date of birth, vital status and date of death. Cases and controls (or their closest relative) were interviewed with a standardised questionnaire focusing on asbestos exposure in the (life-long) residential and occupational histories and in leisure time activities as well as on occupational asbestos exposure of relatives and cohabitants, smoking and chest or occupational diseases. The interview was blind in respect to case or control status. For the analyses the addresses were coded on map grids with a 500 m. mesh size. Statistical analyses were conducted with conditional logistic regression in order to keep the matching between cases and controls. Eighty-eight cases and 244 controls were interviewed (95.6% of cases and 80.1% of controls): 26 and 11 respectively reported an activity in the AC industry. Seven cases and 7 controls were also exposed because of parental occupation. The main analyses are based on the conditional regression model including both occupational and residential exposure. The different modes of exposure are included on an ordinal scale: each subject is classified according to their highest level. Domestic exposure is included as an independent factor. Odds Ratios (OR) are estimated with reference to subjects without either occupational or residential exposure. The OR is 39.3 among subjects reporting occupational exposure

  2. Fibulin-3 as a Blood and Effusion Biomarker for Pleural Mesothelioma

    PubMed Central

    Pass, Harvey I.; Levin, Stephen M.; Harbut, Michael R.; Melamed, Jonathan; Chiriboga, Luis; Donington, Jessica; Huflejt, Margaret; Carbone, Michele; Chia, David; Goodglick, Lee; Goodman, Gary E.; Thornquist, Mark D.; Liu, Geoffrey; de Perrot, Marc; Tsao, Ming-Sound; Goparaju, Chandra

    2012-01-01

    BACKGROUND New biomarkers are needed to detect pleural mesothelioma at an earlier stage and to individualize treatment strategies. We investigated whether fibulin-3 in plasma and pleural effusions could meet sensitivity and specificity criteria for a robust biomarker. METHODS We measured fibulin-3 levels in plasma (from 92 patients with mesothelioma, 136 asbestos-exposed persons without cancer, 93 patients with effusions not due to mesothelioma, and 43 healthy controls), effusions (from 74 patients with mesothelioma, 39 with benign effusions, and 54 with malignant effusions not due to mesothelioma), or both. A blinded validation was subsequently performed. Tumor tissue was examined for fibulin-3 by immunohistochemical analysis, and levels of fibulin-3 in plasma and effusions were measured with an enzyme-linked immunosorbent assay. RESULTS Plasma fibulin-3 levels did not vary according to age, sex, duration of asbestos exposure, or degree of radiographic changes and were significantly higher in patients with pleural mesothelioma (105±7 ng per milliliter in the Detroit cohort and 113±8 ng per milliliter in the New York cohort) than in asbestos-exposed persons without mesothelioma (14±1 ng per milliliter and 24±1 ng per milliliter, respectively; P<0.001). Effusion fibulin-3 levels were significantly higher in patients with pleural mesothelioma (694±37 ng per milliliter in the Detroit cohort and 636±92 ng per milliliter in the New York cohort) than in patients with effusions not due to mesothelioma (212±25 and 151±23 ng per milliliter, respectively; P<0.001). Fibulin-3 preferentially stained tumor cells in 26 of 26 samples. In an overall comparison of patients with and those without mesothelioma, the receiver-operating-characteristic curve for plasma fibulin-3 levels had a sensitivity of 96.7% and a specificity of 95.5% at a cutoff value of 52.8 ng of fibulin-3 per milliliter. In a comparison of patients with early-stage mesothelioma with asbestos

  3. Investigational Approaches for Mesothelioma

    PubMed Central

    Surmont, Veerle F.; van Thiel, Eric R. E.; Vermaelen, Karim; van Meerbeeck, Jan P.

    2011-01-01

    Malignant pleural mesothelioma (MPM) is a rare, aggressive tumor with a poor prognosis. In view of the poor survival benefit from first-line chemotherapy and the lack of subsequent effective treatment options, there is a strong need for the development of more effective treatment approaches for patients with MPM. This review will provide a comprehensive state of the art of new investigational approaches for mesothelioma. In an introductory section, the etiology, epidemiology, natural history, and standard of care treatment for MPM will be discussed. This review provide an update of the major clinical trials that impact mesothelioma treatment, discuss the impact of novel therapeutics, and provide perspective on where the clinical research in mesothelioma is moving. The evidence was collected by a systematic analysis of the literature (2000–2011) using the databases Medline (National Library of Medicine, USA), Embase (Elsevier, Netherlands), Cochrane Library (Great Britain), National Guideline Clearinghouse (USA), HTA Database (International Network of Agencies for Health Technology Assessment – INAHTA), NIH database (USA), International Pleural Mesothelioma Program – WHOLIS (WHO Database), with the following keywords and filters: mesothelioma, guidelines, treatment, surgery, chemotherapy, radiotherapy, review, investigational, drugs. Currently different targeted therapies and biologicals are under investigation for MPM. It is important that the molecular biologic research should first focus on mesothelioma-specific pathways and biomarkers in order to have more effective treatment options for this disease. The use of array technology will be certainly an implicit gain in the identification of new potential prognostic or biomarkers or important pathways in the MPM pathogenesis. Probably a central mesothelioma virtual tissue bank may contribute to the ultimate goal to identify druggable targets and to develop personalized treatment for the MPM patients. PMID

  4. An exception that proves the rule: recurrence free survival five years after extrapleural pneumonectomy for malignant pleural mesothelioma.

    PubMed

    Treasure, Tom; Macbeth, Fergus

    2014-01-01

    Are case reports at all relevant and useful? A case report of an unusual case of mesothelioma prompts a discussion and concludes that they do have a role but that their observations and conclusions need to be treated with care. PMID:25403951

  5. Inverse planned stereotactic intensity modulated radiotherapy (IMRT) in the palliative treatment of malignant mesothelioma of the pleura: the Heidelberg experience.

    PubMed

    Münter, Marc W; Thieke, Christian; Christian, Thieke; Nikoghosyan, Anna; Anna, Nikoghosyan; Nill, Simeon; Simeon, Nill; Debus, Jürgen; Jürgen, Debus

    2005-07-01

    Intensity modulated radiation therapy (IMRT) is a new promising treatment technique, which allows a more conformal application of the dose to the tumor volume, as compared to conventional radio-oncological approaches, while protecting the surrounding normal tissue more accurately. This manuscript presents the final results of IMRT in the treatment of unresectable pleural mesothelioma in Heidelberg.

  6. SV40 replication in human mesothelial cells induces HGF/Met receptor activation: A model for viral-related carcinogenesis of human malignant mesothelioma

    PubMed Central

    Cacciotti, Paola; Libener, Roberta; Betta, Piergiacomo; Martini, Fernanda; Porta, Camillo; Procopio, Antonio; Strizzi, Luigi; Penengo, Lorenza; Tognon, Mauro; Mutti, Luciano; Gaudino, Giovanni

    2001-01-01

    Recent studies suggested that simian virus 40 (SV40) may cause malignant mesothelioma, although the pathogenic mechanism is unclear. We found that in SV40-positive malignant mesothelioma cells, the hepatocyte growth factor (HGF) receptor (Met) was activated. In human mesothelial cells (HMC) transfected with full-length SV40 DNA (SV40-HMC), Met receptor activation was associated with S-phase entry, acquisition of a fibroblastoid morphology, and the assembly of viral particles. Coculture experiments revealed the ability of SV40-HMC to infect permissive monkey cells (CV-1), HMC, and murine BNL CL cells. Cocultured human and murine SV40-positive cells expressed HGF, showed Met tyrosine phosphorylation and S-phase entry, and acquired a spindle-shaped morphology (spBNL), whereas CV-1 cells were lysed. Cocultured HMC inherited from SV40-HMC the infectivity, as they induced lysis in cocultured CV-1 cells. Treatment with suramin or HGF-blocking antibodies inhibited Met tyrosine phosphorylation in all large T antigen (Tag)-positive cells and reverted the spindle-shaped morphology of spBNL. This finding indicated that Met activation and subsequent biological effects were mediated by an autocrine HGF circuit. This, in turn, was causally related to Tag expression, being induced by transfection with the SV40 early region alone. Our findings suggest that when SV40 infects HMC it causes Met activation via an autocrine loop. Furthermore, SV40 replicates in HMC and infects the adjacent HMC, inducing an HGF-dependent Met activation and cell-cycle progression into S phase. This may explain how a limited number of SV40-positive cells may be sufficient to direct noninfected HMC toward malignant transformation. PMID:11572935

  7. Cause-Specific Mortality Due to Malignant and Non-Malignant Disease in Korean Foundry Workers

    PubMed Central

    Yoon, Jin-Ha; Ahn, Yeon-Soon

    2014-01-01

    Background Foundry work is associated with serious occupational hazards. Although several studies have investigated the health risks associated with foundry work, the results of these studies have been inconsistent with the exception of an increased lung cancer risk. The current study evaluated the mortality of Korean foundry workers due to malignant and non-malignant diseases. Methods This study is part of an ongoing investigation of Korean foundry workers. To date, we have observed more than 150,000 person-years in male foundry production workers. In the current study, we stratified mortality ratios by the following job categories: melting-pouring, molding-coremaking, fettling, and uncategorized production work. We calculated standard mortality ratios (SMR) of foundry workers compare to general Korean men and relative risk (RR) of mortality of foundry production workers reference to non-production worker, respectively. Results Korean foundry production workers had a significantly higher risk of mortality due to malignant disease, including stomach (RR: 3.96; 95% CI: 1.41–11.06) and lung cancer (RR: 2.08; 95% CI: 1.01–4.30), compared with non-production workers. High mortality ratios were also observed for non-malignant diseases, including diseases of the circulatory (RR: 1.92; 95% CI: 1.18–3.14), respiratory (RR: 1.71; 95% CI: 1.52–21.42 for uncategorized production worker), and digestive (RR: 2.27; 95% CI: 1.22–4.24) systems, as well as for injuries (RR: 2.36; 95% CI: 1.52–3.66) including suicide (RR: 3.64; 95% CI: 1.32–10.01). Conclusion This study suggests that foundry production work significantly increases the risk of mortality due to some kinds of malignant and non-malignant diseases compared with non-production work. PMID:24505454

  8. An Oncolytic Vaccinia Virus Expressing the Human Sodium Iodine Symporter Prolongs Survival and Facilitates SPECT/CT Imaging in an Orthotopic Model of Malignant Pleural Mesothelioma

    PubMed Central

    Belin, Laurence J.; Ady, Justin W.; Lewis, Christina; Marano, Drew; Gholami, Sepideh; Mojica, Kelly; Eveno, Clarisse; Longo, Valerie; Zanzonico, Pat B.; Chen, Nanhai G.; Szalay, Aladar A.; Fong, Yuman

    2014-01-01

    Background The purpose of this original work is to examine the ability of an oncolytic vaccinia virus expressing the human sodium iodine transporter (hNIS) to provide real time monitoring of viral therapy and effective treatment of malignant pleural mesothelioma (MPM). Methods Infectivity and cytotoxic effect of GLV-1h153 on mesothelioma cell lines of all histologic subtypes was assayed in vitro. Viral replication was examined by standard viral plaque assay. Orthotopic MPM xenografts were generated in athymic nude mice and treated with intrapleural GLV-1h153 and assessed for effect on tumor burden and survival. Orthotopic tumors were also imaged on SPECT/CT after 131I administration. Results GLV-1h153 infected and killed all cell lines in a time and concentration dependent manner. Viral replication demonstrated over a 2.5 log increase in titer over 4 days. Intrapleural treatment of orthotopic MPM xenografts resulted in a significant reduction in tumor burden one week after treatment and an improvement in survival. Infection of orthotopic xenografts was both therapeutic and facilitated monitoring by 131I-SPECT/CT via expression of hNIS in infected tissue. Conclusions Our results suggest GLV-1h153 is a promising therapeutic agent for MPM and warrants further investigation. PMID:23890748

  9. Multicenter randomized controlled trial of the management of unresectable malignant mesothelioma proposed by the British Thoracic Society and the British Medical Research Council.

    PubMed

    Girling, David J; Muers, Martin F; Qian, Wendi; Lobban, Dawn

    2002-02-01

    Malignant mesothelioma is almost invariably fatal. The incidence of the disease is rising rapidly in many countries, and there is no generally accepted standard treatment for patients with unresectable disease. According to current British Thoracic Society (BTS) guidelines, patients should be treated with active symptom control (ASC), involving (1) regular follow-up in a specialist clinic; (2) structured assessments of physical, psychological and social problems with appropriate action; (3) rapid involvement of additional specialists; and (4) parallel nursing support. Although many nonrandomized studies have reported tumor responses to anticancer chemotherapy, few have studied palliation and it is not known whether chemotherapy prolongs survival or provides clinically worthwhile palliation with acceptable toxicity when given in addition to ASC. We therefore plan to conduct a multicenter randomized controlled trial comparing (1) ASC alone, (2) ASC plus mitomycin vinblastine and cisplatin (MVP), and (3) ASC plus vinorelbine (N; Navelbine, Pierre Fabre Oncology, Winchester, UK). We chose these chemotherapy regimens because they have been shown in nonrandomized studies to provide good symptom control as recorded by patients. The outcome measures are overall survival, palliation of symptoms, performance status, analgesic usage, toxicity, quality of life, tumor response, and recurrence/progression-free survival. In a preliminary feasibility study, we are assessing the acceptability of the trial design to patients and the suitability of two standard quality-of-life instruments in mesothelioma. Data will help us to decide the final details of the large multicenter trial. PMID:11836674

  10. Stages of Malignant Mesothelioma

    MedlinePlus

    ... Cancer.gov on the Managing Cancer Care page. Contact Us More information about contacting us or receiving ... Facebook Twitter Instagram YouTube Google+ LinkedIn GovDelivery RSS CONTACT INFORMATION Contact Us LiveHelp Online Chat MORE INFORMATION ...

  11. Pericardial mesothelioma and asbestos exposure.

    PubMed

    Mensi, Carolina; Giacomini, Sara; Sieno, Claudia; Consonni, Dario; Riboldi, Luciano

    2011-06-01

    Pericardial mesothelioma (PM) accounts for 0.7% of all malignant mesotheliomas. Although asbestos exposure is a recognized etiological factor for pleural and peritoneal mesotheliomas, its role in the development of PM is controversial. The aim of this study is to describe the characteristics of PM cases occurred in Lombardy, a highly industrialized Region of Northern Italy. From the Lombardy Mesothelioma Registry we selected the incident cases of PM registered in the Lombardy Region between 2000 and 2009 and we abstracted clinical characteristics and history of asbestos exposure. We identified 8 cases (6 men and 2 women), with a median age at diagnosis of 55.5 years, representing 0.3% of all mesothelioma cases (n = 3059). The age-standardized incidence rate was 0.09 per million/year. Occupational exposure to asbestos was documented in 5 of the 7 cases for which we obtained an interview. Our findings support the role of asbestos in the pathogenesis of PM.

  12. Malignant mesothelioma and radiological chest abnormalities in two villages in Central Turkey. An epidemiological and environmental investigation.

    PubMed

    Baris, Y I; Saracci, R; Simonato, L; Skidmore, J W; Artvinli, M

    1981-05-01

    A comparative epidemiological and environmental study in two neighbouring villages, Karain and Karlin, in Central Turkey showed an excess adult mortality, shortening of life expectancy, and an excess of pleural radiological abnormalities in Karain. This supports an earlier report of an endemic of pleural mesothelioma in the village. Concentrations of airborne respirable fibres were uniformly very low in Karlik and higher in some of the air samples from Karain, the fibres being similar in composition to those of erionite-a mineral of the zeolite family and the major contributor to the Karain clouds. This is compatible with the hypothesis of a causal association between endemic mesothelioma and inhalation of erionite fibres, but the fibre concentrations in all samples are so low as to leave in question the aetiological role of erionite. In addition to their local importance these results may have relevance for the wider scientific and public-health issue of long-term inhalation of mineral fibres at low concentrations.

  13. [Work related mesothelioma: analysis of cases discovered at the Section for Occupational Medicine and Toxicology of Siena University during the years 2000-2007].

    PubMed

    Montomoli, L; Spisso, M; Romeo, R; Spina, D; Ghiribelli, C; Sartorelli, P

    2007-01-01

    This study focuses on the spread of mesothelioma in Siena. The population consisted of 30 patients. The diagnosis was made through histopathological and immunoistochemical or cytological and immunoistochemical analysis. The association between malignant masothelioma and exposure to asbestos was deduced by the occupational history. The mesothelioma was noted both in traditional industries and other jobs such as the chain of manifacture, plumbers, electricians, carpenters, installers of asbestos insulation and construction workers. Thus it is possible to find other malignant and nonmalignant asbestos-related diseases more frequently than mesothelioma. There is an evident risk in rebuilding, so the development of new cases due to these exposures is expected.

  14. Fine needle aspiration biopsy of metastatic malignant mesothelioma with myxoid change and signet ring cells: A case report and review of the literature

    PubMed Central

    Mishra, Manisha M.; Farver, Carol F.; Chute, Deborah J.

    2016-01-01

    Malignant mesothelioma (MM) is a rare neoplasm, which is most commonly encountered in cytology through effusion specimens. Fine needle aspiration biopsy of MM, particularly the epithelioid subtype, can be a source of diagnostic difficulty and may mimic sampling of an adenocarcinoma. This is the first case report to demonstrate abundant extracellular myxoid material and numerous intracellular vacuoles, including signet ring cells, in a fine needle aspirate of metastatic MM. A review of the literature for myxoid change and vacuoles in fine needle aspiration biopsies of MM discloses that vacuoles are found in up to 35% of aspirates of MM, but myxoid change is very rare, reported in <5% of the cases. Cytologists should be aware of this rare morphologic pattern of metastatic epithelioid MM. PMID:27014364

  15. [Cytologic diagnosis of pleural mesothelioma].

    PubMed

    Kirdan, G V; Biriukov, Iu V; Nikolaeva, E P

    1990-08-01

    The efficacy of examination of various cytologic material in patients with mesothelioma was analysed. A total of 48 studies were carried out in 24 patients. Examination of transthoracic aspiration material obtained from the tumor and pleural cavity exudate yielded the best results. When mesothelioma of the pleura is suspected, care should be taken to collect material from different areas of the tumor, bearing in mind the significance of discovering different components of the tumor in it. On grounds of study of various cytologic material, a malignant tumor or adenocarcinoma was diagnosed in 43% and mesothelioma in 48% of patients.

  16. Malignant pleural mesothelioma treated in Clinic for Pulmonary Diseases and Tuberculosis "Podhrastovi" in ten-year period (from 1998 to 2007).

    PubMed

    Cukić, Vesna; Ustamujić, Aida; Lovre, Vladimir; Zutić, Hasan; Genjac, Sadika; Masić-Zecević, Mina

    2008-11-01

    Malignant pleural mesothelioma (MPM) is the most common primary malign tumour of pleura. The aim of this study was to evaluate cases of MPM diagnosed and treated in Clinic for Pulmonary Diseases and Tuberculosis "Podhrastovi" during ten-year period (1998-2007). Study is retrospective. The patients were analysed according to age, sex, histopathologic type of the tumour, cantonal distribution in Federation of Bosnia and Herzegovina and regimen of treatment. MPM presented 0,72% (0-1,56% per year) of all hospitalised malignant patients, and the greatest number of registered cases was in the year of 2007. The series included 16 male (57,14%) and 12 female (42,86%). Cases over 64 years old were the most frequent (14-50%) than 45-54 years (7- not 25%). Histopathology types of hospitalised cases of MPM: epitheloid form (8- 28,57%); sarcomatoid form (2- 7,14 %); other forms (18-64,29%). The most patients came from Canton Sarajevo (12-42,86%); ZE-DO canton (8-28,57%) and the UNA-SANA canton (5-17,86%). The therapy applied: chemotherapy (11-39,29%); radiotherapy (3-10,71%); chemotherapy + radiotherapy (4-14,29%); symptomatic therapy (10-35,71 %).

  17. Differential p16/INK4A cyclin-dependent kinase inhibitor expression correlates with chemotherapy efficacy in a cohort of 88 malignant pleural mesothelioma patients

    PubMed Central

    Jennings, C J; Murer, B; O'Grady, A; Hearn, L M; Harvey, B J; Kay, E W; Thomas, W

    2015-01-01

    Background: Malignant pleural mesothelioma (MPM) is a rare and essentially incurable malignancy most often linked with occupational exposure to asbestos fibres. In common with other malignancies, the development and progression of MPM is associated with extensive dysregulation of cell cycle checkpoint proteins that modulate cell proliferation, apoptosis, DNA repair and senescence. Methods: The expression of cyclin-dependent kinase inhibitor p16/INK4A was evaluated by immunohistochemistry using tumour biopsy specimens from 88 MPM cases and a semi-quantitative score for p16/INK4A expression was obtained. Post-diagnosis survival and the survival benefit of chemotherapeutic intervention was correlated with p16/INK4A expression. Results: A low, intermediate and high score for p16/INK4A expression was observed for 45 (51.1%), 28 (31.8%) and 15 (17.1%) of the MPM cases, respectively. Those cases with intermediate or high p16/INK4A tumour expression had a significantly better post-diagnosis survival than those cases whose tumours lost p16 expression (log-rank P<0.001). Those patients with sustained p16/INK4A expression who received chemotherapy also had a better survival than those treated patients whose tumours had lost p16/INK4A expression (log-rank P<0.001). Conclusions: Sustained p16/INK4A expression predicts better post-diagnosis survival in MPM and also better survival following chemotherapeutic intervention. PMID:26057448

  18. Genetically Modified T Cells in Treating Patients With Stage III-IV Non-small Cell Lung Cancer or Mesothelioma

    ClinicalTrials.gov

    2016-11-01

    Advanced Pleural Malignant Mesothelioma; HLA-A*0201 Positive Cells Present; Recurrent Non-Small Cell Lung Carcinoma; Recurrent Pleural Malignant Mesothelioma; Stage III Pleural Mesothelioma; Stage IIIA Non-Small Cell Lung Cancer; Stage IIIB Non-Small Cell Lung Cancer; Stage IV Non-Small Cell Lung Cancer; Stage IV Pleural Mesothelioma

  19. Distant visceral metastases in pleural mesothelioma.

    PubMed

    Roberts, G H

    1976-10-01

    Distant visceral metastases were found in 15 of 32 cases of pleural mesothelioma (47%). Contrary to earlier reports pleural mesothelioma should be regarded as a tumour in which visceral metastases are not uncommon. No association was found between the histological type of mesothelioma and visceral metastases; the peritoneal involvement found in five cases is probably due to local infiltration and seeding.

  20. Mouse Xenograft Model for Mesothelioma | NCI Technology Transfer Center | TTC

    Cancer.gov

    The National Cancer Institute is seeking parties interested in collaborative research to co-develop, evaluate, or commercialize a new mouse model for monoclonal antibodies and immunoconjugates that target malignant mesotheliomas. Applications of the technology include models for screening compounds as potential therapeutics for mesothelioma and for studying the pathology of mesothelioma.

  1. Pleural mesothelioma in a couple of brothers

    PubMed Central

    Bianchi, Claudio; Bianchi, Tommaso

    2013-01-01

    Malignant mesotheliomas of the pleura, epithelial type, were observed in two brothers. Both the patients had histories of severe exposure to asbestos, having worked as insulators. The latency periods in the two cases were 26 and 38 years, respectively. Available literature data suggest that mesothelioma occurrence among blood-related people is favored by a genetic predisposition. PMID:24872671

  2. Whole exome and targeted deep sequencing identify genome-wide allelic loss and frequent SETDB1 mutations in malignant pleural mesotheliomas

    PubMed Central

    Lee, Sharon; Mendez, Pedro; Kim, James Wansoo; Woodard, Gavitt; Yoon, Jun-Hee; Jen, Kuang-Yu; Fang, Li Tai; Jones, Kirk; Jablons, David M.; Kim, Il-Jin

    2016-01-01

    Malignant pleural mesothelioma (MPM), a rare malignancy with a poor prognosis, is mainly caused by exposure to asbestos or other organic fibers, but the underlying genetic mechanism is not fully understood. Genetic alterations and causes for multiple primary cancer development including MPM are unknown. We used whole exome sequencing to identify somatic mutations in a patient with MPM and two additional primary cancers who had no evidence of venous, arterial, lymphovascular, or perineural invasion indicating dissemination of a primary lung cancer to the pleura. We found that the MPM had R282W, a key TP53 mutation, and genome-wide allelic loss or loss of heterozygosity, a distinct genomic alteration not previously described in MPM. We identified frequent inactivating SETDB1 mutations in this patient and in 68 additional MPM patients (mutation frequency: 10%, 7/69) by targeted deep sequencing. Our observations suggest the possibility of a new genetic mechanism in the development of either MPM or multiple primary cancers. The frequent SETDB1 inactivating mutations suggest there could be new diagnostic or therapeutic options for MPM. PMID:26824986

  3. Asbestos fibres inhibit the in vitro activity of lymphokine-activated killer (LAK) cells from healthy individuals and patients with malignant mesothelioma.

    PubMed Central

    Manning, L S; Davis, M R; Robinson, B W

    1991-01-01

    Asbestos exposure is associated with an increased incidence of several malignancies, including malignant mesothelioma (MM). This study evaluates the relationship between asbestos exposure and the in vitro generation and function of LAK cells, an immune effector cell population with powerful lytic activity against MM cells. Both serpentine (chrysotile) and amphibole (amosite and crocidolite) forms of asbestos fibres suppress LAK cell generation, viability (by 5-11%, P less than 0.02) and cell recovery (by 13-15%, P less than 0.02). However, the LAK cells generated in the presence of the amphiboles were as effective as unexposed cells in lysing both standard tumour cell targets (K562, 56.4% lysis versus 61.5%, respectively, P greater than 0.5; NS; Daudi, 60.5% lysis versus 64.5% P greater than 0.5; NS), and MM tumour cell targets (mean of three MM cell lines 48.3% versus 46.3%, P greater than 0.5; NS), whereas the function of LAK cells generated in the presence of chrysotile was significantly reduced against three out of the five tumour cell targets tested (P less than 0.03). In the presence of asbestos fibres, LAK cell function was reduced against all five tumour cell targets (P less than 0.01), irrespective of whether the cell donors were healthy individuals or patients with MM. NK cell activity was also suppressed (P less than 0.01). The serpentine form of asbestos, chrysotile, was significantly more suppressive of both effector cell functions than either of the amphiboles (P less than 0.01). These findings suggest that asbestos exposure may suppress the function and in some instances the generation of immune effector cell mechanisms, thereby increasing the risk of disease and malignancy. PMID:1846329

  4. Active symptom control with or without chemotherapy in the treatment of patients with malignant pleural mesothelioma (MS01): a multicentre randomised trial

    PubMed Central

    Muers, Martin F; Stephens, Richard J; Fisher, Patricia; Darlison, Liz; Higgs, Christopher MB; Lowry, Erica; Nicholson, Andrew G; O'Brien, Mary; Peake, Michael; Rudd, Robin; Snee, Michael; Steele, Jeremy; Girling, David J; Nankivell, Matthew; Pugh, Cheryl; Parmar, Mahesh KB

    2008-01-01

    Summary Background Malignant pleural mesothelioma is almost always fatal, and few treatment options are available. Although active symptom control (ASC) has been recommended for the management of this disease, no consensus exists for the role of chemotherapy. We investigated whether the addition of chemotherapy to ASC improved survival and quality of life. Methods 409 patients with malignant pleural mesothelioma, from 76 centres in the UK and two in Australia, were randomly assigned to ASC alone (treatment could include steroids, analgesic drugs, bronchodilators, palliative radiotherapy [n=136]); to ASC plus MVP (four cycles of mitomycin 6 mg/m2, vinblastine 6 mg/m2, and cisplatin 50 mg/m2 every 3 weeks [n=137]); or to ASC plus vinorelbine (one injection of vinorelbine 30 mg/m2 every week for 12 weeks [n=136]). Randomisation was done by minimisation, with stratification for WHO performance status, histology, and centre. Follow-up was every 3 weeks to 21 weeks after randomisation, and every 8 weeks thereafter. Because of slow accrual, the two chemotherapy groups were combined and compared with ASC alone for the primary outcome of overall survival. Analysis was by intention to treat. This study is registered, number ISRCTN54469112. Findings At the time of analysis, 393 (96%) patients had died (ASC 132 [97%], ASC plus MVP 132 [96%], ASC plus vinorelbine 129 [95%]). Compared with ASC alone, we noted a small, non-significant survival benefit for ASC plus chemotherapy (hazard ratio [HR] 0·89 [95% CI 0·72–1·10]; p=0·29). Median survival was 7·6 months in the ASC alone group and 8·5 months in the ASC plus chemotherapy group. Exploratory analyses suggested a survival advantage for ASC plus vinorelbine compared with ASC alone (HR 0·80 [0·63–1·02]; p=0·08), with a median survival of 9·5 months. There was no evidence of a survival benefit with ASC plus MVP (HR 0·99 [0·78–1·27]; p=0·95). We observed no between-group differences in four predefined quality

  5. Altered protease-activated receptor-1 expression and signaling in a malignant pleural mesothelioma cell line, NCI-H28, with homozygous deletion of the β-catenin gene.

    PubMed

    Fazzini, Alessandra; D'Antongiovanni, Vanessa; Giusti, Laura; Da Valle, Ylenia; Ciregia, Federica; Piano, Ilaria; Caputo, Antonella; D'Ursi, Anna Maria; Gargini, Claudia; Lucacchini, Antonio; Mazzoni, Maria Rosa

    2014-01-01

    Protease activated receptors (PARs) are G-protein coupled receptors that are activated by an unique proteolytic mechanism. These receptors play crucial roles in hemostasis and thrombosis but also in inflammation and vascular development. PARs have also been implicated in tumor progression, invasion and metastasis. In this study, we investigated expression and signaling of PAR1 in nonmalignant pleural mesothelial (Met-5A) and malignant pleural mesothelioma (NCI-H28) cells. We found that the expression level of PAR1 was markedly higher in NCI-H28 cells compared to Met-5A and human primary mesothelial cells. Other three malignant pleural mesothelioma cell lines, i.e. REN, Ist-Mes2, and Mero-14, did not show any significant PAR1 over-expression compared to Met-5A cell line. Thrombin and PAR1 activating peptides enhanced Met-5A and NCI-H28 cell proliferation but in NCI-H28 cells higher thrombin concentrations were required to obtain the same proliferation increase. Similarly, thrombin caused extracellular signal-regulated kinase 1/2 activation in both cell lines but NCI-H28 cells responded at higher agonist concentrations. We also determined that PAR1 signaling through Gq and G12/13 proteins is severely altered in NCI-H28 cells compared to Met-5A cells. On the contrary, PAR1 signaling through Gi proteins was persistently maintained in NCI-H28 cells. Furthermore, we demonstrated a reduction of cell surface PAR1 expression in NCI-H28 and malignant pleural mesothelioma REN cells. Thus, our results provide evidences for dysfunctional PAR1 signaling in NCI-H28 cells together with reduced plasma membrane localization. The role of PAR1 in mesothelioma progression is just emerging and our observations can promote further investigations focused on this G-protein coupled receptor.

  6. Altered Protease–Activated Receptor-1 Expression and Signaling in a Malignant Pleural Mesothelioma Cell Line, NCI-H28, with Homozygous Deletion of the β-Catenin Gene

    PubMed Central

    Giusti, Laura; Da Valle, Ylenia; Ciregia, Federica; Piano, Ilaria; Caputo, Antonella; D’Ursi, Anna Maria; Gargini, Claudia; Lucacchini, Antonio; Mazzoni, Maria Rosa

    2014-01-01

    Protease activated receptors (PARs) are G-protein coupled receptors that are activated by an unique proteolytic mechanism. These receptors play crucial roles in hemostasis and thrombosis but also in inflammation and vascular development. PARs have also been implicated in tumor progression, invasion and metastasis. In this study, we investigated expression and signaling of PAR1 in nonmalignant pleural mesothelial (Met-5A) and malignant pleural mesothelioma (NCI-H28) cells. We found that the expression level of PAR1 was markedly higher in NCI-H28 cells compared to Met-5A and human primary mesothelial cells. Other three malignant pleural mesothelioma cell lines, i.e. REN, Ist-Mes2, and Mero-14, did not show any significant PAR1 over-expression compared to Met-5A cell line. Thrombin and PAR1 activating peptides enhanced Met-5A and NCI-H28 cell proliferation but in NCI-H28 cells higher thrombin concentrations were required to obtain the same proliferation increase. Similarly, thrombin caused extracellular signal-regulated kinase 1/2 activation in both cell lines but NCI-H28 cells responded at higher agonist concentrations. We also determined that PAR1 signaling through Gq and G12/13 proteins is severely altered in NCI-H28 cells compared to Met-5A cells. On the contrary, PAR1 signaling through Gi proteins was persistently maintained in NCI-H28 cells. Furthermore, we demonstrated a reduction of cell surface PAR1 expression in NCI-H28 and malignant pleural mesothelioma REN cells. Thus, our results provide evidences for dysfunctional PAR1 signaling in NCI-H28 cells together with reduced plasma membrane localization. The role of PAR1 in mesothelioma progression is just emerging and our observations can promote further investigations focused on this G-protein coupled receptor. PMID:25364818

  7. Peritoneal Mesothelioma

    MedlinePlus

    ... Percentage Donations Tribute Wall Other Giving/Fundraising Opportunities Bitcoin Donation Form FAQs The Meso Foundation saves lives ... Percentage Donations Tribute Wall Other Giving/Fundraising Opportunities Bitcoin Donation Form FAQs © 2013 Mesothelioma Applied Research Foundation, ...

  8. Pemetrexed Maintenance Therapy Following Bevacizumab-Containing First-Line Chemotherapy in Advanced Malignant Pleural Mesothelioma: A Case Report and Literatures Review.

    PubMed

    Jing, Xu-Quan; Zhou, Lei; Sun, Xin-Dong; Yu, Jin-Ming; Meng, Xue

    2016-04-01

    Malignant pleural mesothelioma (MPM) is a lethal disease with poor prognosis. The combination of cisplatin and pemetrexed has been confirmed as the standard of care for nonoperable MPM. Data have shown that the adoption of pemetrexed maintenance therapy (PMT) following first-line treatment appears extremely promising.We describe a 57-year-old man diagnosed as advanced MPM. We treated this patient with PMT after first-line cisplatin-based bevacizumab-containing chemotherapy and residual tumor disappeared after 6 course of PMT. A perfect response and a long progression-free survival (PFS) were reached with tumor mass disappearing and 14 months duration of PFS.This case suggests that adding bevacizumab to standard first-line chemotherapy is feasible and that PMT could be promising and useful for treating advanced MPM. We further entail a review of the literature on the first-line treatment, continuation maintenance therapy, switch maintenance therapy, and second-line treatment of patients with advanced MPM.

  9. Licochalcone A induces apoptosis in malignant pleural mesothelioma through downregulation of Sp1 and subsequent activation of mitochondria-related apoptotic pathway.

    PubMed

    Kim, Ka Hwi; Yoon, Goo; Cho, Jung Jae; Cho, Jin Hyoung; Cho, Young Sik; Chae, Jung-Il; Shim, Jung-Hyun

    2015-03-01

    Licochalcone A (LCA) is a natural product derived from the roots of Glycyrrhiza inflata exhibiting a wide range of bioactivities such as antitumor, anti-oxidant and anti-bacterial effects. Malignant pleural mesothelioma (MPM) is an extremely aggressive type of cancer with a poor prognosis because of its rapid progression. However, LCA has not been investigated concerning its effects on MPM. Preliminarily, we observed that LCA negatively modulated not only cell growth, but also specificity protein 1 (Sp1) expression in MSTO-211H and H28 cell lines. It was found that IC50 values of LCA for growth inhibition of MSTO-211H and H28 cells were approximately 26 and 30 µM, respectively. Consistent with downregulation of Sp1, expression of Sp1 regulatory proteins such as Cyclin D1, Mcl-1 and Survivin was substantially diminished. Mechanistically, LCA triggered the mitochondrial apoptotic pathway by affecting the ratio of mitochondrial proapoptotic Bax to anti-apoptotic Bcl-xL. Bid induced loss of mitochondrial membrane potential, eventually leading to multi-caspase activation and increased sub-G1 population. Moreover, nuclear staining with DAPI highlighted nuclear condensation and fragmentation of apoptotic features. Flow cytometry analyses after staining cells with Annexin V and propiodium iodide corroborated LCA-mediated apoptotic cell death of MPM cells. In conclusion, these results present that LCA may be a potential bioactive material to control human MPM cells by apoptosis via the downregulation of Sp1.

  10. Ki67 index is an independent prognostic factor in epithelioid but not in non-epithelioid malignant pleural mesothelioma: a multicenter study

    PubMed Central

    Ghanim, B; Klikovits, T; Hoda, M A; Lang, G; Szirtes, I; Setinek, U; Rozsas, A; Renyi-Vamos, F; Laszlo, V; Grusch, M; Filipits, M; Scheed, A; Jakopovic, M; Samarzija, M; Brcic, L; Stancic–Rokotov, D; Kern, I; Rozman, A; Dekan, G; Klepetko, W; Berger, W; Glasz, T; Dome, B; Hegedus, B

    2015-01-01

    Background: Estimating the prognosis in malignant pleural mesothelioma (MPM) remains challenging. Thus, the prognostic relevance of Ki67 was studied in MPM. Methods: Ki67 index was determined in a test cohort of 187 cases from three centres. The percentage of Ki67-positive tumour cells was correlated with clinical variables and overall survival (OS). The prognostic power of Ki67 index was compared with other prognostic factors and re-evaluated in an independent cohort (n=98). Results: Patients with Ki67 higher than median (>15%) had significantly (P<0.001) shorter median OS (7.5 months) than those with low Ki67 (19.1 months). After multivariate survival analyses, Ki67 proved to be—beside histology and treatment—an independent prognostic marker in MPM (hazard ratio (HR): 2.1, P<0.001). Interestingly, Ki67 was prognostic exclusively in epithelioid (P<0.001) but not in non-epithelioid subtype. Furthermore, Ki67 index was significantly lower in post-chemotherapy samples when compared with chemo-naive cases. The prognostic power was comparable to other recently published prognostic factors (CRP, fibrinogen, neutrophil-to-leukocyte ratio (NLR) and nuclear grading score) and was recapitulated in the validation cohort (P=0.048). Conclusion: This multicentre study demonstrates that Ki67 is an independent and reproducible prognostic factor in epithelioid but not in non-epithelioid MPM and suggests that induction chemotherapy decreases the proliferative capacity of MPM. PMID:25633038

  11. Beta-catenin inhibits cell growth of a malignant mesothelioma cell line, NCI-H28, with a 3p21.3 homozygous deletion.

    PubMed

    Usami, Noriyasu; Sekido, Yoshitaka; Maeda, Osamu; Yamamoto, Kazuhito; Minna, John D; Hasegawa, Yoshinori; Yoshioka, Hiromu; Imaizumi, Munehisa; Ueda, Yuichi; Takahashi, Masahide; Shimokata, Kaoru

    2003-09-11

    We have found that a malignant mesothelioma cell line, NCI-H28, had a chromosome 3p21.3 homozygous deletion containing the beta-catenin gene (CTNNB1), which suggested that the deletion of beta-catenin might have a growth advantage in the development of this tumor. To determine whether beta-catenin has a growth-inhibitory activity, we transfected wild-type beta-catenin, Ser37Cys mutant beta-catenin as an activated type, and C-terminus deletion mutant beta-catenin that lacks the transcription activity, into the NCI-H28 cells. A non-small cell lung cancer cell line, NCI-H1299, which expressed endogenous beta-catenin, was also studied. We tested the localization of exogenous beta-catenin in the NCI-H28 cells with immunofluorescence, and found that the wild-type beta-catenin and the C-terminus deletion mutant were more strongly expressed in the plasma membrane and cytoplasm than in the nucleus, while the Ser37Cys mutant was more in the nucleus than in the cytoplasm. By using luciferase-reporter assay, the beta-catenin/T-cell factor 4-mediated transactivity of the Ser37Cys mutant was shown to be higher than that of the wild-type beta-catenin in both cell lines. However, the transactivity of the C-terminus deletion mutant was strongly reduced in both. Colony formation of the NCI-H28 cells was reduced by 50% after transfection with the wild-type beta-catenin, and 60% with the Ser37Cys mutant, but only 20% with the C-terminus deletion mutant compared to the vector control. Inhibition of colony formation in NCI-H28 cells was because of apoptosis, manifested by positive staining of Annexin V and TUNEL assays in transfected cells. In contrast, when transfected with the wild-type beta-catenin, no significant reduction in colony formation was seen in beta-catenin wild-type NCI-H1299 cells. In conclusion, our data indicate that inactivation of beta-catenin by a 3p21.3 homozygous deletion might be a crucial event in the development of the mesothelioma NCI-H28 cells. Thus, while

  12. Validation of EORTC and CALGB prognostic models in surgical patients submitted to diagnostic, palliative or curative surgery for malignant pleural mesothelioma

    PubMed Central

    Guerrera, Francesco; Roffinella, Matteo; Olivetti, Stefania; Costardi, Lorena; Oliaro, Alberto; Filosso, Pier Luigi; Lausi, Paolo Olivo; Ruffini, Enrico

    2016-01-01

    Background To assess the trend of our surgical patients affected by malignant pleural mesothelioma (MPM) and submitted to diagnostic/palliative or curative surgical procedures and to validate the European Organisation for Research and Treatment of Cancer (EORTC) prognostic score in our patient population. Methods This is a cohort study of patients submitted to surgery for MPM from January 2007 to December 2013. Primary outcome was overall survival (OS). Univariate and multivariate-adjusted comparisons by EORTC prognostic score for OS were accomplished using Cox method. Adjusted models included the following clinical variables: kind of procedure, smoking habit, asbestos exposure, Charlson’s Comorbidity Index (CCI), clinical tumor stage, adjuvant chemotherapy, dyspnoea, chest pain and haematological variables according to the score features. Nomenclature of the surgical procedures matches the International Association for the Study Lung Cancer (IASLC)/International Mesothelioma Interest Group (iMIG). Results One-hundred sixty-six consecutive cases were collected: the median age at surgery was 73 years and 123 patients (75%) had a history of asbestos exposure. Ninty patients (54%) were submitted to a palliative/diagnostic thoracoscopy, 30 to pleurectomy/decortication (P/D), and 6 to extra-pleural pneumonectomy (EPP). Clinical TNM stages were as follows: 99 (60%) stage I–II, 34 (20%) stage III and 33 (20%) stage IV. The median follow-up (FU) was 19 months [interquartile range (IQR), 9–31 months] and the FU-completeness was 98%. By the end of the study 130 patients died (78%). One- and 3-year OS was 60% and 36%, respectively. Patients submitted to EPP and P/D showed a better survival (P=0.013). Multivariable model showed an independent prognostic value of EORTC score (HR =2.86, P<0.001). Conclusions In selected patients, aggressive surgical approaches, although not radical, may still be beneficial. The EORTC prognostic index proved to be an independent prognostic

  13. Validation of EORTC and CALGB prognostic models in surgical patients submitted to diagnostic, palliative or curative surgery for malignant pleural mesothelioma

    PubMed Central

    Guerrera, Francesco; Roffinella, Matteo; Olivetti, Stefania; Costardi, Lorena; Oliaro, Alberto; Filosso, Pier Luigi; Lausi, Paolo Olivo; Ruffini, Enrico

    2016-01-01

    Background To assess the trend of our surgical patients affected by malignant pleural mesothelioma (MPM) and submitted to diagnostic/palliative or curative surgical procedures and to validate the European Organisation for Research and Treatment of Cancer (EORTC) prognostic score in our patient population. Methods This is a cohort study of patients submitted to surgery for MPM from January 2007 to December 2013. Primary outcome was overall survival (OS). Univariate and multivariate-adjusted comparisons by EORTC prognostic score for OS were accomplished using Cox method. Adjusted models included the following clinical variables: kind of procedure, smoking habit, asbestos exposure, Charlson’s Comorbidity Index (CCI), clinical tumor stage, adjuvant chemotherapy, dyspnoea, chest pain and haematological variables according to the score features. Nomenclature of the surgical procedures matches the International Association for the Study Lung Cancer (IASLC)/International Mesothelioma Interest Group (iMIG). Results One-hundred sixty-six consecutive cases were collected: the median age at surgery was 73 years and 123 patients (75%) had a history of asbestos exposure. Ninty patients (54%) were submitted to a palliative/diagnostic thoracoscopy, 30 to pleurectomy/decortication (P/D), and 6 to extra-pleural pneumonectomy (EPP). Clinical TNM stages were as follows: 99 (60%) stage I–II, 34 (20%) stage III and 33 (20%) stage IV. The median follow-up (FU) was 19 months [interquartile range (IQR), 9–31 months] and the FU-completeness was 98%. By the end of the study 130 patients died (78%). One- and 3-year OS was 60% and 36%, respectively. Patients submitted to EPP and P/D showed a better survival (P=0.013). Multivariable model showed an independent prognostic value of EORTC score (HR =2.86, P<0.001). Conclusions In selected patients, aggressive surgical approaches, although not radical, may still be beneficial. The EORTC prognostic index proved to be an independent prognostic

  14. [Epidemiology of malignant pleural mesothelioma in the Nantes-Saint Nazaire region. Course in 1956-1992].

    PubMed

    Chailleux, E; Pioche, D; Chopra, S; Dabouis, G; Germaud, P; De Lajartre, A Y; De Lajartre, M

    1995-01-01

    The aim of this study was to estimate the evolution of the incidence of mesothelioma in the Loire-Atlantique department since 1956 and to register all the cases diagnosed between 1985 and 1992 and to complete the data of earlier studies carried out between 1956 and 1984. The cases were indexed from the files of the pathology department and also from demographic and occupational data concerning the patients which had been gathered retrospectively from an inquiry of patients attached either to private physicians or to a hospital service. From 1956 to 1984 there were 125 cases (119 men, 6 women) who had been diagnosed; 92 cases were registered between 1985 and 1992 (79 men and 13 women). An increase in the annual number of cases was significant. The incidence during the period 1985-1992 was 10.9 per million inhabitants (men 19.4, women 3) against 8.7 (men 17.2, women 0.8) for the period 1975 to 1984 and 2.6 (men 5.2, women 0.2) for the period 1956-1974. The mean age of the subjects at the time of diagnosis rose during the period studied (59.2 +/- 9.4 between 1956-1974 to 63.1 +/- 11.9 between 1975-1984 and 67.0 +/- 9.7 between 1985-1992). Occupational exposure to asbestos was certain or probable in 85 per cent of cases with a median duration of exposure of 25 years (range 2 months to 48 years) with a median interval between the first exposure to diagnosis of 44 years (range 10-70 years). The industrial sector most often implicated was naval construction (127 cases).(ABSTRACT TRUNCATED AT 250 WORDS)

  15. Current evidence base of FDG-PET/CT imaging in the clinical management of malignant pleural mesothelioma: emerging significance of image segmentation and global disease assessment.

    PubMed

    Basu, Sandip; Saboury, Babak; Torigian, Drew A; Alavi, Abass

    2011-10-01

    Increasingly, integrated positron emission tomography-computed tomography (PET/CT) imaging is playing a crucial role in the assessment of patients with known or suspected malignant pleural mesothelioma (MPM). Based on the data reported in the literature, this combined modality is likely to become the instrument of choice for examining patients of MPM. The research on this subject has focused on the following five domains: (1) differentiation of MPM from other benign pleural diseases, (2) preoperative staging for the selection of appropriate candidates for surgery, (3) evaluation for therapy response and post-treatment surveillance for recurrence, (4) prognostication based upon the intensity of 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) uptake, and (5) planning of radiotherapy. These represent the bases for critical decision making in the management of mesothelioma, and FDG-PET/CT offers potential advantages over conventional CT imaging and thus can play a pivotal role in this regard. Optimal characterization of this potentially fatal disease with a high negative predictive value for MPM, superior capability for cancer staging initially and at the later course of disease, and ability for measuring therapeutic response and the precise determination of the target volume for radiotherapy planning represent distinct advantages of this promising molecular imaging tool. In this communication, we have explored the promising role of integrated FDG-PET/CT in the overall management of this serious malignancy. From the available data, the major role of PET-CT at present appears to be in the preoperative disease staging, response to treatment assessment, and post-treatment disease surveillance of MPM. In all these three areas, PET-CT convincingly shows better results than conventional anatomical imaging alone and thereby can aid in exploring novel therapeutic approaches. Disease prognosis and radiotherapy planning are evolving areas where this modality has demonstrated significant

  16. Epidemic of mesothelioma in Egypt.

    PubMed

    Gaafar, R M; Eldin, N H Aly

    2005-07-01

    Asbestos has been recognized in Egypt since a long time as ancient Egyptians were using it in mummification. Mesothelioma in Egypt is mainly attributed to environmental origin with a high incidence of women and young adults affected. The incidence of mesothelioma is rising in Egypt. Epidemiological data for 635 malignant mesothelioma (MM) patients over 4 years in the third Millennium were collected from the National Cancer Institute (NCI), Cairo University and Abbassia Chest hospital. This number is more than four times the number diagnosed in the previous 11 years at NCI. A clinicopathological study was done for 100 malignant pleural mesothelioma (MPM) patients and showed that asbestos exposure and SV40 positivity were evident in 67% and 60% of cases, respectively. The median survival was 14.3 months and the 1 and 2 year survival rates were 60% and 27%, respectively. Evaluation of p53 and pRb immunohistochemically showed that pRb alteration was related to poor survival. Other biological prognostic factors such as EGFR, HER-2, glutathione S transferase (GST) and MDR were evaluated in 50 cases. Overexpression of EGFR was correlated with lack of clinical benefit and poor survival. GST potentiated the effect of EGFR on survival. The use of EGFR inhibitors may have a role in the treatment of MM. Asbestos in Cairo is a silent killer and measures toward eliminating it entirely or at least strictly controlling human contact with this dangerous carcinogen have to be taken in order to combat the coming epidemic of mesothelioma in Egypt.

  17. Survival of asbestos insulation workers with mesothelioma.

    PubMed Central

    Ribak, J; Selikoff, I J

    1992-01-01

    Malignant mesothelioma is a lethal disease. It is rare in the general population; however, workers exposed to asbestos suffer significant burdens of the neoplasm. The survival time of 457 consecutive fatal cases of pleural and peritoneal mesothelioma that occurred among 17,800 asbestos insulation workers observed prospectively from 1 January 1967 to 1 January 1987 was studied. Mean survival time from initial presentation of the disease to death was 11.4 months for the pleural mesothelioma patients compared with 7.4 months for the peritoneal group. This difference was statistically significant. Mean survival time from diagnosis to death was shorter for both groups of patients: 8.4 months for pleural mesothelioma v 5.8 months for the peritoneal cases. In conclusion, survival time in mesothelioma patients is short; most die within a year from the onset of the initial symptoms. No effective therapy is yet available. PMID:1419863

  18. An Integrated Analysis of the Genome-Wide Profiles of DNA Methylation and mRNA Expression Defining the Side Population of a Human Malignant Mesothelioma Cell Line

    PubMed Central

    Kim, Myung-Chul; Kim, Na-Yon; Seo, Yu-Ri; Kim, Yongbaek

    2016-01-01

    Intratumoral heterogeneity is a hallmark of all cancers and functions as the major barrier against effective cancer therapy. In contrast to genetic mutations, the role of epigenetic modifications in the generation and maintenance of heterogeneous cancer cells remains largely undetermined. This study was performed to evaluate the epigenetic mechanisms involved in the tumor cell heterogeneity using side population (SP) and non-SP cells isolated from a human malignant mesothelioma (HMM) cell line. The subpopulations of cancer cells were analyzed by methylated DNA immunoprecipitation combined with high-throughput sequencing (MeDIP-seq) and RNA-seq methodology. The RNA-seq data were analyzed with the MeDIP-seq data in an integrated way to identify the epigenetically modified genes that defined the SP. Concomitant changes in mRNA expression and DNA methylation were found in 122 genes, including 118 down-regulated genes with hypermethylation and 4 up-regulated genes with hypomethylation. Gene ontology revealed that a large portion of the genes belonged to the groups of biological processes such as stem cell maintenance, stem cell development, stem cell differentiation, and the negative regulation of the developmental process. Among these genes, BNC1, RPS6KA3, TWSG1 and DUSP15 contained aberrant methylation in the CpG islands of the promoter region, indicating that the genes regulated by DNA methylation characterized a distinct subpopulation of HMM cells. The present study provided valuable information to shed light on the epigenetic contributions to the generation and maintenance of tumor cell heterogeneity. PMID:27698904

  19. Increased risk of malignant mesothelioma of the pleura after residential or domestic exposure to asbestos: a case-control study in Casale Monferrato, Italy.

    PubMed Central

    Magnani, C; Dalmasso, P; Biggeri, A; Ivaldi, C; Mirabelli, D; Terracini, B

    2001-01-01

    The association of malignant mesothelioma (MM) and nonoccupational asbestos exposure is currently debated. Our study investigates environmental and domestic asbestos exposure in the city where the largest Italian asbestos cement (AC) factory was located. This population-based case-control study included pleural MM (histologically diagnosed) incidents in the area in 1987-1993, matched by age and sex to two controls (four if younger than 60). Diagnoses were confirmed by a panel of five pathologists. We interviewed 102 cases and 273 controls in 1993-1995, out of 116 and 330 eligible subjects. Information was checked and completed on the basis of factory and Town Office files. We adjusted analyses for occupational exposure in the AC industry. In the town there were no other relevant industrial sources of asbestos exposure. Twenty-three cases and 20 controls lived with an AC worker [odds ratio (OR) = 4.5; 95% confidence interval (CI), 1.8-11.1)]. The risk was higher for the offspring of AC workers (OR = 7.4; 95% CI, 1.9-28.1). Subjects attending grammar school in Casale also showed an increased risk (OR = 3.3; 95% CI, 1.4-7.7). Living in Casale was associated with a very high risk (after selecting out AC workers: OR = 20.6; 95% CI, 6.2-68.6), with spatial trend with increasing distance from the AC factory. The present work confirms the association of environmental asbestos exposure and pleural MM, controlling for other sources of asbestos exposure, and suggests that environmental exposure caused a greater risk than domestic exposure. PMID:11673120

  20. Manumycin A induces apoptosis in malignant pleural mesothelioma through regulation of Sp1 and activation of the mitochondria-related apoptotic pathway.

    PubMed

    Kim, Ka Hwi; Chae, Jung-Il; Oh, Hana; Cho, Jin Hyoung; Lee, Ra-Ham; Yoon, Goo; Cho, Seung-Sik; Cho, Young-Sik; Lee, Mee-Hyun; Liu, Kangdong; Lee, Hyun-Jeong; Shim, Jung-Hyun

    2016-07-01

    Manumycin A (Manu A) is a natural product isolated from Streptomyces parvulus and has been reported to have anti-carcinogenic and anti-biotic properties. However, neither its molecular mechanism nor its molecular targets are well understood. Thus, the aim of the present study was to explore the possibility that Manu A has cancer preventive and chemotherapeutic effects on malignant pleural mesothelioma (MPM) through regulation of Sp1 and induction of mitochondrial cell death pathway. Manu A inhibited the cell viability of MSTO-211H and H28 cells in a concentration‑dependent manner as determined by MTS assay. IC50 values were calculated as 8.3 and 4.3 µM in the MSTO-311H and H28 cells following 48 h incubation, respectively. Manu A induced a significant increase in apoptotic indices as shown by DAPI staining, Annexin V assay, multi-caspase activity and mitochondrial membrane potential assay. The downregulation of Sp1 mRNA and protein expression by Manu A led to apoptosis by suppressing Sp1-regulated proteins (cyclin D1, Mcl-1 and survivin). Manu A decreased the protein levels of BID, Bcl-xL and PARP while it increased Bax levels. Manu A caused depolarization of the mitochondrial membrane with induction of CHOP, DR4 and DR5. Our results demonstrated that Manu A exerted anticancer effects by inducing apoptosis via inhibition of the Sp1-related signaling pathway in human MPM.

  1. Increased risk of malignant mesothelioma of the pleura after residential or domestic exposure to asbestos: a case-control study in Casale Monferrato, Italy.

    PubMed

    Magnani, C; Dalmasso, P; Biggeri, A; Ivaldi, C; Mirabelli, D; Terracini, B

    2001-09-01

    The association of malignant mesothelioma (MM) and nonoccupational asbestos exposure is currently debated. Our study investigates environmental and domestic asbestos exposure in the city where the largest Italian asbestos cement (AC) factory was located. This population-based case-control study included pleural MM (histologically diagnosed) incidents in the area in 1987-1993, matched by age and sex to two controls (four if younger than 60). Diagnoses were confirmed by a panel of five pathologists. We interviewed 102 cases and 273 controls in 1993-1995, out of 116 and 330 eligible subjects. Information was checked and completed on the basis of factory and Town Office files. We adjusted analyses for occupational exposure in the AC industry. In the town there were no other relevant industrial sources of asbestos exposure. Twenty-three cases and 20 controls lived with an AC worker [odds ratio (OR) = 4.5; 95% confidence interval (CI), 1.8-11.1)]. The risk was higher for the offspring of AC workers (OR = 7.4; 95% CI, 1.9-28.1). Subjects attending grammar school in Casale also showed an increased risk (OR = 3.3; 95% CI, 1.4-7.7). Living in Casale was associated with a very high risk (after selecting out AC workers: OR = 20.6; 95% CI, 6.2-68.6), with spatial trend with increasing distance from the AC factory. The present work confirms the association of environmental asbestos exposure and pleural MM, controlling for other sources of asbestos exposure, and suggests that environmental exposure caused a greater risk than domestic exposure.

  2. An Integrated Analysis of the Genome-Wide Profiles of DNA Methylation and mRNA Expression Defining the Side Population of a Human Malignant Mesothelioma Cell Line

    PubMed Central

    Kim, Myung-Chul; Kim, Na-Yon; Seo, Yu-Ri; Kim, Yongbaek

    2016-01-01

    Intratumoral heterogeneity is a hallmark of all cancers and functions as the major barrier against effective cancer therapy. In contrast to genetic mutations, the role of epigenetic modifications in the generation and maintenance of heterogeneous cancer cells remains largely undetermined. This study was performed to evaluate the epigenetic mechanisms involved in the tumor cell heterogeneity using side population (SP) and non-SP cells isolated from a human malignant mesothelioma (HMM) cell line. The subpopulations of cancer cells were analyzed by methylated DNA immunoprecipitation combined with high-throughput sequencing (MeDIP-seq) and RNA-seq methodology. The RNA-seq data were analyzed with the MeDIP-seq data in an integrated way to identify the epigenetically modified genes that defined the SP. Concomitant changes in mRNA expression and DNA methylation were found in 122 genes, including 118 down-regulated genes with hypermethylation and 4 up-regulated genes with hypomethylation. Gene ontology revealed that a large portion of the genes belonged to the groups of biological processes such as stem cell maintenance, stem cell development, stem cell differentiation, and the negative regulation of the developmental process. Among these genes, BNC1, RPS6KA3, TWSG1 and DUSP15 contained aberrant methylation in the CpG islands of the promoter region, indicating that the genes regulated by DNA methylation characterized a distinct subpopulation of HMM cells. The present study provided valuable information to shed light on the epigenetic contributions to the generation and maintenance of tumor cell heterogeneity.

  3. Utilisation of a thoracic oncology database to capture radiological and pathological images for evaluation of response to chemotherapy in patients with malignant pleural mesothelioma

    PubMed Central

    Carey, George B; Kazantsev, Stephanie; Surati, Mosmi; Rolle, Cleo E; Kanteti, Archana; Sadiq, Ahad; Bahroos, Neil; Raumann, Brigitte; Madduri, Ravi; Dave, Paul; Starkey, Adam; Hensing, Thomas; Husain, Aliya N; Vokes, Everett E; Vigneswaran, Wickii; Armato, Samuel G; Kindler, Hedy L; Salgia, Ravi

    2012-01-01

    Objective An area of need in cancer informatics is the ability to store images in a comprehensive database as part of translational cancer research. To meet this need, we have implemented a novel tandem database infrastructure that facilitates image storage and utilisation. Background We had previously implemented the Thoracic Oncology Program Database Project (TOPDP) database for our translational cancer research needs. While useful for many research endeavours, it is unable to store images, hence our need to implement an imaging database which could communicate easily with the TOPDP database. Methods The Thoracic Oncology Research Program (TORP) imaging database was designed using the Research Electronic Data Capture (REDCap) platform, which was developed by Vanderbilt University. To demonstrate proof of principle and evaluate utility, we performed a retrospective investigation into tumour response for malignant pleural mesothelioma (MPM) patients treated at the University of Chicago Medical Center with either of two analogous chemotherapy regimens and consented to at least one of two UCMC IRB protocols, 9571 and 13473A. Results A cohort of 22 MPM patients was identified using clinical data in the TOPDP database. After measurements were acquired, two representative CT images and 0–35 histological images per patient were successfully stored in the TORP database, along with clinical and demographic data. Discussion We implemented the TORP imaging database to be used in conjunction with our comprehensive TOPDP database. While it requires an additional effort to use two databases, our database infrastructure facilitates more comprehensive translational research. Conclusions The investigation described herein demonstrates the successful implementation of this novel tandem imaging database infrastructure, as well as the potential utility of investigations enabled by it. The data model presented here can be utilised as the basis for further development of other larger

  4. Protocol for PIT: a phase III trial of prophylactic irradiation of tracts in patients with malignant pleural mesothelioma following invasive chest wall intervention

    PubMed Central

    Bayman, N; Ardron, D; Ashcroft, L; Baldwin, D R; Booton, R; Darlison, L; Edwards, J G; Lang-Lazdunski, L; Lester, J F; Peake, M; Rintoul, R C; Snee, M; Taylor, P; Lunt, C

    2016-01-01

    Introduction Histological diagnosis of malignant mesothelioma requires an invasive procedure such as CT-guided needle biopsy, thoracoscopy, video-assisted thorascopic surgery (VATs) or thoracotomy. These invasive procedures encourage tumour cell seeding at the intervention site and patients can develop tumour nodules within the chest wall. In an effort to prevent nodules developing, it has been widespread practice across Europe to irradiate intervention sites postprocedure—a practice known as prophylactic irradiation of tracts (PIT). To date there has not been a suitably powered randomised trial to determine whether PIT is effective at reducing the risk of chest wall nodule development. Methods and analysis In this multicentre phase III randomised controlled superiority trial, 374 patients who can receive radiotherapy within 42 days of a chest wall intervention will be randomised to receive PIT or no PIT. Patients will be randomised on a 1:1 basis. Radiotherapy in the PIT arm will be 21 Gy in three fractions. Subsequent chemotherapy is given at the clinicians’ discretion. A reduction in the incidence of chest wall nodules from 15% to 5% in favour of radiotherapy 6 months after randomisation would be clinically significant. All patients will be followed up for up to 2 years with monthly telephone contact and at least four outpatient visits in the first year. Ethics and dissemination PIT was approved by NRES Committee North West—Greater Manchester West (REC reference 12/NW/0249) and recruitment is currently on-going, the last patient is expected to be randomised by the end of 2015. The analysis of the primary end point, incidence of chest wall nodules 6 months after randomisation, is expected to be published in 2016 in a peer reviewed journal and results will also be presented at scientific meetings and summary results published online. A follow-up analysis is expected to be published in 2018. Trial registration number ISRCTN04240319; NCT01604005; Pre

  5. [Incidence of pleural mesotheliomas in Poland (preliminary report)].

    PubMed

    Szturmowicz, M; Vertun-Baranowska, B; Rowińska-Zakrzewska, E; Szymańska, D

    1991-01-01

    Mesothelioma is a rare malignancy, difficult to diagnose and rarely found in a population not exposed to asbestos. In the immediate past incidence rates of this disease have increased due to extensive use of this mineral in the industry of the 1950's. The aim of this study was to assess the incidence of mesotheliomas basing on results of a questionnaire posted in 1987 to all pneumonology clinics, oncological departments in Poland, and data from the Central Oncological Register from the years 1970-1985. Incidence of this malignant disease was 1-2 cases per 1,000,000 of general population during the years 1970-1985 and did not rise in 1986. Regional differences were observed, in some areas the incidence rate was 5-6 per 1,000,000. Data from the Occupational Medicine Institute disclosed in these regions more extensive industrial use of this mineral. The authors have also concluded that "at-life" diagnosis of mesothelioma rises, mainly due to the use of open pleural biopsy.

  6. Pelvic limb lameness due to malignant melanoma in a horse.

    PubMed

    Kirker-Head, C A; Loeffler, D; Held, J P

    1985-06-01

    Malignant melanoma in a 21-year-old, gray, Arabian gelding was manifested by rapidly deteriorating lameness of the right pelvic limb. A melanotic, cutaneous mass of small dimensions was identified in the left jugular furrow. Exploratory laparoscopy revealed widespread infiltration of melanotic masses into the structures of the abdominal cavity. Necropsy indicated the lameness to have resulted from infiltration of neoplastic cells into the sacral nerves, dorsal root ganglia, proximal ischiatic nerve, and gluteal muscle fibers. The primary tumor could not be identified.

  7. [Deciduoid Mesothelioma].

    PubMed

    Nishikawa, Toshio; Takahashi, Masahiko; Mori, Masanobu; Kamikawa, Yasuaki; Fujii, Chitose; Inoue, Fumiyuki

    2016-03-01

    A 64-year-old man consulted for an abnormal shadow in November 2012. Chest computed tomography showed a thicking and small nodules of the left pleura and pleural effusion with mediastinal and supracravicular lymphnodes swelling. The cytological study of the pleural effusion showed individual atypical cells surrounded by many lymphocyte. The atypical cells are large, round or ovoid and had welldefined borders, abundant eosinophilic, glassy cytoplasm, and round or elliptic nuclei with clear eosinophilic nucleoli resembling decidua cells. According to immunohistochemistry study, cells were positive for calretinin, EMA, cytokeratinAE1/AE3, WT-1, D2-40 and negative for CEA, desmin, TTF-1, Ber-EP4, synaptophysin, S-100 compatible with deciduoid mesothelioma. The cytological features are important and useful for diagnosis of deciduoid mesothelioma. PMID:27075289

  8. Xanthomatous pleuritis mimicking mesothelioma.

    PubMed

    McGuire, Franklin R; Gourdin, Todd; Finley, James L; Downie, Gordon

    2009-01-01

    Recurrent non-malignant exudative effusions remain a diagnostic and potentially management dilemma. Fluid characteristics frequently narrow the differential but fail to offer a definitive diagnosis. Medical thoracoscopy is well tolerated and allows direct visualization and biopsy of pleural processes under conscious sedation. Rarely, macroscopic appearance and even histology may be misleading. We present a case of xanthomatous pleuritis that mimicked early mesothelioma. Our patient was a 69-year-old female with a large left pleural effusion. Her medical history was significant for a recent small pericardial effusion without cardiac dysfunction. Thoracentesis revealed a non-malignant exudative effusion. Thoracoscopy demonstrated two foci of raised soft plaques with petechial hemorrhage and adhesions. Preliminary evaluation suggested chronic inflammation admixed with proliferating spindle cells and necrosis. The immunohistochemical phenotype of the spindle cells favored a spindle and epithelioid cell neoplasm, mesothelioma. Because of discord between pathologists, we repeated the thoracoscopy through the existing chest tube/thoracoscopy site. We acquired more tissue for special stains and outside review. Following extensive immunohistochemistry, the diagnosis of xanthomatous pleuritis was made. Our patient quickly recovered with steroid therapy and is without recurrence 18 months later. This case demonstrates the utility and nuances of medical thoracoscopy in a perplexing case of xanthomatous pleuritis. PMID:18223309

  9. Targeting glucosylceramide synthase induction of cell surface globotriaosylceramide (Gb3) in acquired cisplatin-resistance of lung cancer and malignant pleural mesothelioma cells

    SciTech Connect

    Tyler, Andreas; Johansson, Anders; Karlsson, Terese; Gudey, Shyam Kumar; Brännström, Thomas; Grankvist, Kjell; Behnam-Motlagh, Parviz

    2015-08-01

    Background: Acquired resistance to cisplatin treatment is a caveat when treating patients with non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM). Ceramide increases in response to chemotherapy, leading to proliferation arrest and apoptosis. However, a tumour stress activation of glucosylceramide synthase (GCS) follows to eliminate ceramide by formation of glycosphingolipids (GSLs) such as globotriaosylceramide (Gb3), the functional receptor of verotoxin-1. Ceramide elimination enhances cell proliferation and apoptosis blockade, thus stimulating tumor progression. GSLs transactivate multidrug resistance 1/P-glycoprotein (MDR1) and multidrug resistance-associated protein 1 (MRP1) expression which further prevents ceramide accumulation and stimulates drug efflux. We investigated the expression of Gb3, MDR1 and MRP1 in NSCLC and MPM cells with acquired cisplatin resistance, and if GCS activity or MDR1 pump inhibitors would reduce their expression and reverse cisplatin-resistance. Methods: Cell surface expression of Gb3, MDR1 and MRP1 and intracellular expression of MDR1 and MRP1 was analyzed by flow cytometry and confocal microscopy on P31 MPM and H1299 NSCLC cells and subline cells with acquired cisplatin resistance. The effect of GCS inhibitor PPMP and MDR1 pump inhibitor cyclosporin A for 72 h on expression and cisplatin cytotoxicity was tested. Results: The cisplatin-resistant cells expressed increased cell surface Gb3. Cell surface Gb3 expression of resistant cells was annihilated by PPMP whereas cyclosporin A decreased Gb3 and MDR1 expression in H1299 cells. No decrease of MDR1 by PPMP was noted in using flow cytometry, whereas a decrease of MDR1 in H1299 and H1299res was indicated with confocal microscopy. No certain co-localization of Gb3 and MDR1 was noted. PPMP, but not cyclosporin A, potentiated cisplatin cytotoxicity in all cells. Conclusions: Cell surface Gb3 expression is a likely tumour biomarker for acquired cisplatin

  10. In arrayed ranks: array technology in the study of mesothelioma.

    PubMed

    Gray, Steven G; Fennell, Dean A; Mutti, Luciano; O'Byrne, Kenneth J

    2009-03-01

    Mesothelioma is a rare malignancy arising from mesothelial cells lining the pleura and peritoneum. Advances in modern technology have allowed the development of array based approaches to the study of disease allowing researchers the opportunity to study many genes or proteins in a high-throughput fashion. This review describes the current knowledge surrounding array based approaches with respect to mesothelioma research.

  11. General Information about Malignant Mesothelioma

    MedlinePlus

    ... Cancer.gov on the Managing Cancer Care page. Contact Us More information about contacting us or receiving ... Facebook Twitter Instagram YouTube Google+ LinkedIn GovDelivery RSS CONTACT INFORMATION Contact Us LiveHelp Online Chat MORE INFORMATION ...

  12. Treatment Option Overview (Malignant Mesothelioma)

    MedlinePlus

    ... Cancer.gov on the Managing Cancer Care page. Contact Us More information about contacting us or receiving ... Facebook Twitter Instagram YouTube Google+ LinkedIn GovDelivery RSS CONTACT INFORMATION Contact Us LiveHelp Online Chat MORE INFORMATION ...

  13. Treatment Options for Malignant Mesothelioma

    MedlinePlus

    ... Cancer.gov on the Managing Cancer Care page. Contact Us More information about contacting us or receiving ... Facebook Twitter Instagram YouTube Google+ LinkedIn GovDelivery RSS CONTACT INFORMATION Contact Us LiveHelp Online Chat MORE INFORMATION ...

  14. How Is Malignant Mesothelioma Diagnosed?

    MedlinePlus

    ... offices because of their limited value. Tests of fluid and tissue samples Symptoms and test results may ... in different ways, depending on the situation. Removing fluid for testing If there is a buildup of ...

  15. Neuroleptic malignant syndrome due to risperidone treatment in a child with Joubert syndrome.

    PubMed

    Vurucu, Sebahattin; Congologlu, Ayhan; Altun, Demet; Unay, Bulent; Akin, Ridvan

    2009-03-01

    Joubert syndrome is a rare autosomal recessive disease characterized by hypotonia, ataxia, episodic hyperpnea, psychomotor retardation, abnormal ocular movements, cerebellar vermian hypoplasia, and molar tooth sign on magnetic resonance imaging. Neuroleptic malignant syndrome is an uncommon and potentially fatal idiosynchratic reaction of antipsychotic drugs, in which the clinical scenario encompass muscular rigidity, hyperthermia, autonomic dysfunction, altered consciousness, high creatinine phosphokinase levels, and leukocytosis. This report describes a case of neuroleptic malignant syndrome due to risperidone in a child with Joubert syndrome.

  16. Respiratory tract cancers: lung and mesothelioma.

    PubMed

    Crosignani, Paolo; Piffer, Silvano

    2004-01-01

    The trend analysis of lung cancer in the database of the Italian Network of Cancer Registries (pool AIRT), showed, among males (52,267 incident cases and 46, 726 deaths included in the study) a statistically significant decrease of incidence and mortality in the period 1986-1997; incidence rates decreased by about 1.4%/year and mortality rates by about 1.6%/year. Among females, lung cancer trends are rather different from that of males, according to diverging trends in tobacco smoking exposures; in fact, both incidence (+1.2%/year) and mortality (+0.9%/year) are increasing. Incidence of mesothelioma (1594 cases), showed for the period 1986-1997, a statistically significant increase among both males and females; standardised rates increased, more than 4% every year. As regards to deaths due to pleural malignant cancers (1393 among males and 664 among females) their trend was stable in the analysed period.

  17. Methodology for lognormal modelling of malignant pleural mesothelioma survival time distributions: a study of 5580 case histories from Europe and USA.

    PubMed

    Mould, Richard F; Lahanas, Michael; Asselain, Bernard; Brewster, David; Burgers, Sjaak A; Damhuis, Ronald A M; De Rycke, Yann; Gennaro, Valerio; Szeszenia-Dabrowska, Neonila

    2004-09-01

    A truncated left-censored and right-censored lognormal model has been validated for representing pleural mesothelioma survival times in the range 5-200 weeks for data subsets grouped by age for males, 40-49, 50-59, 60-69, 70-79 and 80+ years and for all ages combined for females. The cases available for study were from Europe and USA and totalled 5580. This is larger than any other pleural mesothelioma cohort accrued for study. The methodology describes the computation of reference baseline probabilities, 5-200 weeks, which can be used in clinical trials to assess results of future promising treatment methods. This study is an extension of previous lognormal modelling by Mould et al (2002 Phys. Med. Biol. 47 3893-924) to predict long-term cancer survival from short-term data where the proportion cured is denoted by C and the uncured proportion, which can be represented by a lognormal, by (1 - C). Pleural mesothelioma is a special case when C = 0.

  18. Protocol for the surgical and large bore procedures in malignant pleural mesothelioma and radiotherapy trial (SMART Trial): an RCT evaluating whether prophylactic radiotherapy reduces the incidence of procedure tract metastases

    PubMed Central

    Clive, Amelia O; Wilson, Paula; Taylor, Hazel; Morley, Anna J; de Winton, Emma; Panakis, Niki; Rahman, Najib; Pepperell, Justin; Howell, Timothy; Batchelor, Timothy J P; Jordan, Nikki; Lee, Y C Gary; Dobson, Lee; Maskell, Nick A

    2015-01-01

    Introduction Patients with malignant pleural mesothelioma (MPM) may develop painful ‘procedure tract metastasis’ (PTM) at the site of previous pleural interventions. Prophylactic radiotherapy has been used to minimise this complication; however, three small randomised trials have shown conflicting results regarding its effectiveness. The surgical and large bore procedures in malignant pleural mesothelioma and radiotherapy trial (SMART Trial) is a suitably powered, multicentre, randomised controlled trial, designed to evaluate the efficacy of prophylactic radiotherapy within 42 days of pleural instrumentation in preventing the development of PTM in MPM. Methods and analysis 203 patients with a histocytologically proven diagnosis of MPM, who have undergone a large bore pleural intervention (thoracic surgery, large bore chest drain, indwelling pleural catheter or local anaesthetic thoracoscopy) in the previous 35 days, will be recruited from UK hospitals. Patients will be randomised (1:1) to receive immediate radiotherapy (21 Gy in 3 fractions over 3 working days within 42 days of the pleural intervention) or deferred radiotherapy (21 Gy in 3 fractions over 3 working days given if a PTM develops). Patients will be followed up for 12 months. The primary outcome measure is the rate of PTM until death or 12 months (whichever is sooner), as defined by the presence of a clinically palpable nodule of at least 1 cm diameter felt within 7 cm of the margins of the procedure site as confirmed by two assessors. Secondary outcome measures include chest pain, quality of life, analgaesic requirements, healthcare utilisation and safety (including radiotherapy toxicity). Ethics and dissemination The trial has received ethical approval from the Southampton B Research Ethics Committee (11/SC/0408). There is a Trial Steering Committee, including independent members and a patient and public representative. The trial results will be published in a peer

  19. Targeting immune checkpoints: New opportunity for mesothelioma treatment?

    PubMed

    Marcq, Elly; Pauwels, Patrick; van Meerbeeck, Jan P; Smits, Evelien L J

    2015-12-01

    Malignant pleural mesothelioma is an aggressive cancer linked to asbestos exposure in most patients. Due to the long latency between exposure and presentation, incidence is expected to further increase in the next decade, despite the ban on asbestos import which occurred at the end of last century in industrialized countries. Platinum-based palliative chemotherapy is the only treatment with proven benefit on outcome, resulting in selected patients in a median overall survival of about 1 year. Therefore, there is room for therapeutic improvement using a new strategy to prolong survival. Dealing with cancer cell induced immunosuppression is a promising approach. Reactivating immune responses that are silenced by immune checkpoints recently gained a lot of interest. Checkpoint blockade has already shown promising preclinical and clinical results in several cancer types and is currently also being investigated in mesothelioma. Here, we discuss the expression patterns and mechanisms of action of CTLA-4 and PD-1 as the two most studied and of TIM-3 and LAG-3 as two interesting upcoming immune checkpoints. Furthermore, we review the clinical results of molecules blocking these immune checkpoints and point out their future opportunities with a special focus on mesothelioma. PMID:26433514

  20. A mesothelioma presenting with multicentric reticulohistiocytosis.

    PubMed Central

    Honeybourne, D.; Kellett, J. K.

    1985-01-01

    Multicentric reticulohistiocytosis is a rare disorder of the skin and joints, with characteristic histological features. An increasing number of reported cases have been associated with internal malignancy. We report a case of multicentric reticulohistiocytosis in an elderly man with mesothelioma. Images Figure 1 Figure 2 PMID:3991408

  1. Years of life lost due to malignant neoplasms characterized by the highest mortality rate

    PubMed Central

    Pikala, Malgorzata

    2014-01-01

    Introduction The analysis of premature deaths measured with years of life lost between the studied and referential populations helps to emphasize the social and economic aspect of a loss caused by deaths due to malignant neoplasms. The aim of the study was to analyze years of life lost by inhabitants of the Lodz province due to malignant neoplasms. Material and methods The study material included a database which contained information gathered from 313,144 death certificates (including 66,899 people who died of malignant neoplasms) of inhabitants of the Lodz province who died between 1999 and 2008. The SEYLLp (Standard Expected Years of Life Lost per living person) method was used to determine years of life lost. Jointpoint models were used to analyze time trends. Results In males the diseases which mostly contributed to death were tracheal, bronchial and lung malignant neoplasms (SEYLLp = 170.7) and cancer of the large intestine, rectum and anus (SEYLLp = 47.5). In females the principal diseases were tracheal, bronchial and lung malignant neoplasms (SEYLLp = 61.6), breast cancer (SEYLLp = 60.4) and cancer of the large intestine, rectum and anus (SEYLLp = 42.3). The years of life lost were growing in the period under study. Conclusions The number of years lost due to malignant neoplasms in the Lodz province between 1999 and 2008 was growing. The main reasons for deaths in females were tracheal, bronchial and lung malignant neoplasms as well as breast cancer and in males – cancer of the large intestine, rectum and anus as well as prostate cancer. PMID:25395953

  2. Invasive infection due to Saprochaete capitata in a young patient with hematological malignancies.

    PubMed

    Parahym, Ana Maria Rabelo de Carvalho; Rolim Neto, Pedro José; da Silva, Carolina Maria; Domingos, Igor de Farias; Gonçalves, Sarah Santos; Leite, Edinalva Pereira; de Morais, Vera Lúcia Lins; Macêdo, Danielle Patrícia Cerqueira; de Lima Neto, Reginaldo Gonçalves; Neves, Rejane Pereira

    2015-06-01

    We report a case of invasive infection due to Saprochaete capitata in a patient with hematological malignancies after chemotherapy treatment and empiric antifungal therapy with caspofungin. Although severely immunocompromised the patient survived been treated with amphotericin B lipid complex associated with voriconazole. PMID:26273269

  3. Invasive infection due to Saprochaete capitata in a young patient with hematological malignancies

    PubMed Central

    Parahym, Ana Maria Rabelo de Carvalho; Rolim, Pedro José; da Silva, Carolina Maria; Domingos, Igor de Farias; Gonçalves, Sarah Santos; Leite, Edinalva Pereira; de Morais, Vera Lúcia Lins; Macêdo, Danielle Patrícia Cerqueira; de Lima, Reginaldo Gonçalves; Neves, Rejane Pereira

    2015-01-01

    We report a case of invasive infection due to Saprochaete capitata in a patient with hematological malignancies after chemotherapy treatment and empiric antifungal therapy with caspofungin. Although severely immunocompromised the patient survived been treated with amphotericin B lipid complex associated with voriconazole. PMID:26273269

  4. Different types of malignancies due to occupational exposure to benzene: a review of recent observations in Turkey

    SciTech Connect

    Aksoy, M.

    1980-10-01

    Since the first description of a case of leukemia due to occupational exposure to benzene, several types of malignancies following the use of this chemical agent have been reported: leukemia, malignant lymphoma, lung cancer, myeloid metaplasia, paroxysmal noctural hemoglobinuria, and multiple myeloma. The evidence suggesting a causal relationship between occupational exposure to benzene and development of the various types of malignancies is discussed.

  5. Malignant priapism due to penile metastases: Case series and literature review.

    PubMed

    De Luca, Francesco; Zacharakis, Evangelos; Shabbir, Majed; Maurizi, Angela; Manzi, Emy; Zanghì, Antonio; De Dominicis, Carlo; Ralph, David

    2016-01-01

    Malignant priapism secondary to penile metastases is a rare condition. This term was originally used by Peacock in 1938 to describe a condition of painful induration and erection of the penis due to metastatic infiltration by a neoplasm. In the current literature there are 512 case reports. The primary tumor sites are bladder, prostate and rectum. The treatment has only palliative intent and consists of local tumor excision, penectomy, radiotherapy and chemotherapy. We present one case of malignant priapism originated from prostate cancer, and two from urothelial carcinoma of the bladder. Different approaches in diagnosis and therapy were performed. The entire three patient reported a relief of the pain following the treatment, with an improvement of their quality of life, even though it was only temporary as a palliative. Malignant priapism is a rare medical emergency. Penile/pelvis magnetic resonance imaging (MRI) scan and corporal biopsies are considered an effective method of diagnosis of the primary organ site. PMID:27377094

  6. Mesothelioma pathogenesis, facts and expectations.

    PubMed

    Jaurand, Marie-Claude

    2005-02-01

    It is the merit of Dr J.C. Wagner and his co-workers to have triggered the research on mesothelioma, going back to 1960 when they published data demonstrating a relationship between mesothelioma occurrence and exposure to asbestos fibres in the Cape Province, in South Africa. From that time, epidemiological and toxicological investigations were performed in order to better define the occupational and environmental background of this pathology, to identify the fibre parameters accounting for the toxic effects, and to understand their mechanisms of action. Improvements in our knowledge in these areas benefited to health issues, by preventing risks associated with exposure to mineral fibres and by recognising the disease. Due to the actual progresses in the fields of biology and biotechnologies, the research on mesothelioma presently focuses on study of the mechanisms of mesothelial cell transformation, and on development of strategies to kill tumour cells. While mesothelioma benefited to fibre toxicology and allowed to improve the management health related issue, it would be a just return if the present advances in different scientific areas will permit a rapid eradication of the disease.

  7. Incidence trends of mesothelioma in Norway, 1965-1999.

    PubMed

    Ulvestad, Bente; Kjaerheim, Kristina; Møller, Bjørn; Andersen, Aage

    2003-10-20

    Asbestos exposure is considered to be the only important risk factor for malignant mesothelioma. The importation of asbestos to Norway increased after World War II and peaked in 1970. Stringent regulations took effect in 1977, and importation and use of asbestos practically ended in Norway in the late 1970s, until importation was prohibited in 1982. Our study aimed to analyze the incidence of mesothelioma in Norway according to temporal variation, to study the consequences of the use of asbestos and the asbestos ban effectiveness. An age-period-cohort model was used to analyze time trends for pleural mesotheliomas. From 1965-1999, the annual number of pleural mesotheliomas rose gradually both in males and females, and the highest annual number of pleural mesotheliomas was recorded in 1999 with 73 new cases diagnosed. The age-adjusted log linear drift of malignant mesothelioma of the pleura during the observation period rose 31.1% per 5 years among men and 15.9% among women. In 1995-1999, the age-adjusted incidence rate for men was 16.6 per million person-years for men and 2.3 for women. Cohort-specific risks increased for men born up to around 1935. After this the risks seem to stabilize. The rates were determined by age and by birth cohort. The delayed period effect of the asbestos regulation by the late 1970s will probably have its greatest effects on the mesothelioma rates around 2010.

  8. MesobanK UK: an international mesothelioma bioresource.

    PubMed

    Rintoul, Robert C; Rassl, Doris M; Gittins, Jacki; Marciniak, Stefan J

    2016-04-01

    Malignant pleural mesothelioma causes the greatest societal burden of all the asbestos-related diseases. Progress in better understanding tumour biology will be facilitated by the availability of quality-assured annotated tissue. MesobanK has been created to establish a bioresource of pleural mesothelioma tissue linked to detailed anonymised clinical data. When complete, the bioresource will comprise a 750-patient tissue microarray and prospectively collected tissue, blood and pleural fluid from 300 patients with mesothelioma. Twenty-six new cell lines have also been developed. MesobanK meets all appropriate ethical and regulatory procedures and has recently opened to requests for tissue and data.

  9. Accuracy of death certification of pleural mesothelioma in Italy.

    PubMed

    Bruno, C; Comba, P; Maiozzi, P; Vetrugno, T

    1996-08-01

    In order to provide estimates of the accuracy of death certification of malignant pleural mesothelioma in Italy, the causes of death of a series of ascertained cases were investigated. The study included 523 cases of pleural mesothelioma diagnosed in 1984-1988 by 88 hospital departments and clinics. Vital status at 7 May 1990 was ascertained for 92.7% of subjects. The overall concordance between pathological diagnosis and death certification was about 75%.

  10. [Scientific evidence and legal liability in occupational health: indemnity claim based on lack of safety and hygiene controls after a worker's death due to mesothelioma].

    PubMed

    G Benavides, Fernando; Menéndez-Navarro, Alfredo; Delclòs, Jordi; Luque, Manuel

    2012-01-01

    The aim of this paper is to reflect, under the precautionary principle, on the relationship between scientific causation and legal liability in connection with a lawsuit regarding compensation for lack of occupational safety and hygiene controls following the death of a worker with mesothelioma that had been previously accepted as an occupational disease. The worker had spent 28 years as a shipyard welder, with a diagnosis of occupationally-related mesothelioma in 2007, and who died in 2009. After reviewing the advances in a) scientific knowledge on the health effects of asbestos exposure, which were consolidated between 1955 and 1976, and b) the development of a regulatory framework for the protection of workers in Spain that began generically in 1940 and became more specific in 1982, we conclude that our case probably would have benefited from application of the precautionary principle, which is now widely accepted.

  11. Mesothelioma in Great Britain in 1968-1983.

    PubMed

    Jones, R D; Smith, D M; Thomas, P G

    1988-06-01

    The British mesothelioma register records deaths in Great Britain when the word "mesothelioma" is on the death certificate. In 1968-1983 the mesothelioma deaths among men increased from 114 to 467, while those among women increased from 38 to 90. In 1983 the crude mesothelioma death rates were 17.5 per million and 3.2 per million for the men and women, respectively. The Northern region had the highest crude rates. At the county level, the highest crude deaths rates in 1976-1983 were recorded for the men in Devon and for the women in Lancashire. Marked differences occurred in the ratio of deaths among men to deaths among women for mesothelioma of the pleura (4.6:1) and for mesothelioma of the peritoneum (2:1). The age-specific death rates for men and women diverged markedly for pleural mesothelioma but not for peritoneal mesothelioma. Trends in the use of asbestos and in age- and sex-specific death rates suggest that the annual number of mesothelioma deaths will continue to increase, possibly until the turn of the century. This increase will be concentrated among the men as the main asbestos exposure of women occurred during the war and the annual deaths due to this exposure may have already peaked.

  12. French National Registry of Rare Peritoneal Surface Malignancies

    ClinicalTrials.gov

    2016-07-12

    Rare Peritoneal Surface Malignancies; Pseudomyxoma Peritonei; Peritoneal Mesothelioma; Desmoplastic Small Round Cell Tumor; Psammocarcinoma; Primary Peritoneal Serous Carcinoma; Diffuse Peritoneal Leiomyomatosis; Appendiceal Mucinous Neoplasms

  13. The French National Mesothelioma Surveillance Program

    PubMed Central

    Goldberg, M; Imbernon, E; Rolland, P; Ilg, A Gilg Soit; Savès, M; de Quillacq, A; Frenay, C; Chamming's, S; Arveux, P; Boutin, C; Launoy, G; Pairon, J C; Astoul, P; Galateau‐Sallé, F; Brochard, P

    2006-01-01

    Objectives The French National Mesothelioma Surveillance Program (NMSP) was established in 1998 by the National Institute for Health Surveillance (InVS). Its objectives are to estimate the trends in mesothelioma incidence and the proportion attributable to occupational asbestos exposure, to help improve its pathology diagnosis, to assess its compensation as an occupational disease, and to contribute to research. Methods The NMSP records incident pleural tumours in 21 French districts that cover a population of approximately 16 million people (a quarter of the French population). A standardised procedure of pathological and clinical diagnosis ascertainment is used. Lifetime exposure to asbestos and to other factors (man made mineral fibres, ionising radiation, SV40 virus) is reconstructed, and a case‐control study was also conducted. The proportion of mesothelioma compensated as an occupational disease was assessed. Results Depending on the hypothesis, the estimated number of incident cases in 1998 ranged from 660 to 761 (women: 127 to 146; men: 533 to 615). Among men, the industries with the highest risks of mesothelioma are construction and ship repair, asbestos industry, and manufacture of metal construction materials; the occupations at highest risk are plumbers, pipe‐fitters, and sheet‐metal workers. The attributable risk fraction for occupational asbestos exposure in men was 83.2% (95% CI 76.8 to 89.6). The initial pathologist's diagnosis was confirmed in 67% of cases, ruled out in 13%, and left uncertain in the others; for half of the latter, the clinical findings supported a mesothelioma diagnosis. In all, 62% applied for designation of an occupational disease, and 91% of these were receiving workers' compensation. Conclusions The NMSP is a large scale epidemiological surveillance system with several original aspects, providing important information to improve the knowledge of malignant pleural mesothelioma, such as monitoring the evolution of its

  14. Sarcomatoid mesothelioma: a clinical-pathologic correlation of 326 cases.

    PubMed

    Klebe, Sonja; Brownlee, Noel A; Mahar, Annabelle; Burchette, James L; Sporn, Thomas A; Vollmer, Robin T; Roggli, Victor L

    2010-03-01

    Sarcomatoid mesothelioma is the least common, but most aggressive of the three major histological types of mesotheliomas. This study comprises 326 cases of sarcomatoid mesotheliomas among 2000 consecutive malignant mesothelioma cases received in consultation (16%). Patients included 312 men (96%) and 14 women (4%), with a median age of 70 years (range 41-94 years). Most tumors were pleural (319; 98%), and 7 were peritoneal (2%). Some desmoplastic features were identified in 110 cases (34%), and 70 (21%) were classified as desmoplastic. Rare subtypes included two cases with a lymphohistiocytoid pattern (<1%) and eight heterologous mesotheliomas (2%). Labeling for cytokeratins (CKs) was observed in 261/280 cases (93%), and for calretinin and vimentin in 31 and 91%, respectively. Pleural plaques were present in 79% of cases for which information was available, and asbestosis was diagnosed in 34/127 cases (27%). Median survival was 3.5 months. Fiber analysis was performed in 61 cases. The median asbestos body count was 1640/g wet lung tissue (by light microscopy). Amosite fibers were the most commonly identified fibers using energy-dispersive X-ray analysis and were significantly higher in the sarcomatoid cases, as were uncoated fibers using scanning electron microscopy. This study represents the largest series of sarcomatoid and desmoplastic malignant mesotheliomas to date and confirms the diagnostic usefulness of CK immunohistochemistry. The relationship with asbestos exposure--particularly amosite--and an association with pleural plaques and less often asbestosis is confirmed.

  15. Percutaneous Treatment of Malignant Jaundice Due to Extrahepatic Cholangiocarcinoma: Covered Viabil Stent Versus Uncovered Wallstents

    SciTech Connect

    Krokidis, Miltiadis; Fanelli, Fabrizio; Orgera, Gianluigi; Bezzi, Mario; Passariello, Roberto; Hatzidakis, Adam

    2010-02-15

    To compare clinical effectiveness of Viabil-covered stents versus uncovered metallic Wallstents, for palliation of malignant jaundice due to extrahepatic cholangiocarcinoma, 60 patients were enrolled in a prospective and randomized study. In half of the patients a bare Wallstent was used, and in the other half a Viabil biliary stent. Patients were followed up until death. Primary patency, survival, complication rates, and mean cost were calculated in both groups. Stent dysfunction occurred in 9 (30%) patients in the bare stent group after a mean period of 133.1 days and in 4 (13.3%) patients in the covered stent group after a mean of 179.5 days. The incidence of stent dysfunction was significantly lower in the covered stent group (P = 0.046). Tumor ingrowth occurred exclusively in the bare stent group (P = 0.007). Median survival was 180.5 days for the Wallstent and 243.5 days for the Viabil group (P = 0.039). Complications and mean cost were similar in the two groups. Viabil stent-grafts proved to be significantly superior to Wallstents for the palliation of malignant jaundice due to extrahepatic cholangiocarcinoma, with comparable cost and complication rates. Appropriate patient selection should be performed prior to stent placement.

  16. Hemithoracic Intensity Modulated Radiation Therapy After Pleurectomy/Decortication for Malignant Pleural Mesothelioma: Toxicity, Patterns of Failure, and a Matched Survival Analysis

    SciTech Connect

    Chance, William W.; Rice, David C.; Allen, Pamela K.; Tsao, Anne S.; Liao, Zhongxing; Chang, Joe Y.; Tang, Chad; Pan, Hubert Y.; Welsh, James W.; Mehran, Reza J.; Gomez, Daniel R.

    2015-01-01

    Purpose: To investigate safety, efficacy, and recurrence after hemithoracic intensity modulated radiation therapy after pleurectomy/decortication (PD-IMRT) and after extrapleural pneumonectomy (EPP-IMRT). Methods and Materials: In 2009-2013, 24 patients with mesothelioma underwent PD-IMRT to the involved hemithorax to a dose of 45 Gy, with an optional integrated boost; 22 also received chemotherapy. Toxicity was scored with the Common Terminology Criteria for Adverse Events v4.0. Pulmonary function was compared at baseline, after surgery, and after IMRT. Kaplan-Meier analysis was used to calculate overall survival (OS), progression-free survival (PFS), time to locoregional failure, and time to distant metastasis. Failures were in-field, marginal, or out of field. Outcomes were compared with those of 24 patients, matched for age, nodal status, performance status, and chemotherapy, who had received EPP-IMRT. Results: Median follow-up time was 12.2 months. Grade 3 toxicity rates were 8% skin and 8% pulmonary. Pulmonary function declined from baseline to after surgery (by 21% for forced vital capacity, 16% for forced expiratory volume in 1 second, and 19% for lung diffusion of carbon monoxide [P for all = .01]) and declined still further after IMRT (by 31% for forced vital capacity [P=.02], 25% for forced expiratory volume in 1 second [P=.01], and 30% for lung diffusion of carbon monoxide [P=.01]). The OS and PFS rates were 76% and 67%, respectively, at 1 year and 56% and 34% at 2 years. Median OS (28.4 vs 14.2 months, P=.04) and median PFS (16.4 vs 8.2 months, P=.01) favored PD-IMRT versus EPP-IMRT. No differences were found in grade 4-5 toxicity (0 of 24 vs 3 of 24, P=.23), median time to locoregional failure (18.7 months vs not reached, P not calculable), or median time to distant metastasis (18.8 vs 11.8 months, P=.12). Conclusions: Hemithoracic intensity modulated radiation therapy after pleurectomy/decortication produced little high-grade toxicity but

  17. Pleural mesothelioma: a descriptive analysis based on a case-control study and mortality data in Ile de France, 1987-1990.

    PubMed

    Iwatsubo, Y; Pairon, J C; Archambault de Beaune, C; Chamming's, S; Bignon, J; Brochard, P

    1994-07-01

    Incidence rates of pleural mesothelioma in Ile de France were examined for the period 1987-1990, on the basis of information collected in a case-control study. This study was designed to include all new cases of pleural mesothelioma occurring in the region. On the other hand, mortality rates from pleural malignancies in the same region were examined on the basis of death certificates recorded by INSERM for the same period. A large difference was found between the two types of data. Average annual incidence rates were 7.5 per million among men and 1.6 per million among women. Average annual mortality rates due to primary pleural malignancies were 25.2 per million in males and 8.9 per million in females. This study confirms discordances between incidence and mortality data for pleural malignancies already reported in several countries. However, contrasting with some previous reports, the annual mortality rate from pleural malignancies was higher than the incidence rate of mesothelioma in this study. This emphasizes the usefulness of a specific investigation to explain such discordances, prior to comparison of data from one country to another.

  18. Accuracy of pathological diagnosis of mesothelioma cases in Japan: clinicopathological analysis of 382 cases.

    PubMed

    Takeshima, Yukio; Inai, Kouki; Amatya, Vishwa Jeet; Gemba, Kenichi; Aoe, Keisuke; Fujimoto, Nobukazu; Kato, Katsuya; Kishimoto, Takumi

    2009-11-01

    Incidences of mesothelioma are on the rise in Japan. However, the accurate frequency of mesothelioma occurrence is still unknown. The aim of this study is to clarify the accuracy of pathological diagnosis of mesothelioma. Among the 2742 mesothelioma death cases extracted from the document "Vital Statistics of Japan" for 2003-2005, pathological materials were obtained for 382 cases. After these materials were reviewed and immunohistochemical analyses were conducted, mesothelioma was diagnosed by discussions based on clinical and radiological information. Sixty-five cases (17.0%) were categorized as "definitely not/unlikely" mesotheliomas, and 273 cases (71.5%) were categorized as "probable/definite" mesotheliomas. The percentage of "probable/definite" pleural and peritoneal mesothelioma cases in males was 74.3% and 87.5%, respectively, and that of pleural cases in females was 59.2%; however, the percentage of "probable/definite" peritoneal cases in females was only 22.2%. These results suggest that the diagnostic accuracy of mesothelioma is relatively low in females and in cases of peritoneal and sarcomatoid subtype mesotheliomas; furthermore, approximately 15% of cases of deaths due to mesothelioma in Japan are diagnostically suspicious.

  19. Markers for the non-invasive diagnosis of mesothelioma: a systematic review

    PubMed Central

    van der Bij, S; Schaake, E; Koffijberg, H; Burgers, J A; de Mol, B A J M; Moons, K G M

    2011-01-01

    Background: Numerous markers have been evaluated to facilitate the non-invasive diagnostic work-up of mesothelioma. The purpose of this study was to conduct a structured review of the diagnostic performance of non-invasive marker tests for the detection of mesothelioma in patients with suspected mesothelioma. Methods: Studies on the diagnostic accuracy of serum and cytological markers published till 31 December 2009, available in either PUBMED or Embase, to detect or exclude the presence of mesothelioma were extracted. Study quality was assessed with use of the Quadas criteria. Results: In total, 82 articles were included in this systemic review. Overall, quality of the incorporated studies to address our objective was poor. The most frequently studied immunohistochemical markers for cytological analysis were EMA, Ber-Ep4, CEA, and calretinin. The most frequently investigated serum marker was soluble mesothelin-related protein (SMRP). The markers CEA, Ber-EP4, and calretinin were most valuable in discriminating mesothelioma from other malignant diseases. Markers EMA and SMRP were most valuable in discriminating mesothelioma from non-malignant diseases. No marker performed well in discriminating between mesothelioma and all other diseases. Conclusion: Currently, there is only limited evidence to properly assess the value of non-invasive marker tests in the diagnosis of mesothelioma. Studies were of limited value to address our objective and results showed considerable unexplained study heterogeneity. PMID:21448170

  20. Physiologic Effect of Stent Therapy for Inferior Vena Cava Obstruction Due to Malignant Liver Tumor

    SciTech Connect

    Kishi, Kazushi Sonomura, Tetsuo; Fujimoto, Hisashi; Kimura, Masashi; Yamada, Katsuya; Sato, Morio; Juri, Masanobu

    2006-02-15

    after stent treatment. Conclusion. The stent therapy for IVC obstruction due to malignant liver tumors was followed by a series of physiologic and hematobiochemical consequences, most of them favorable but some possibly unfavorable. Rational interpretations and predictions of sequelae based on physiologic science including cardiology, hepatology, and nephrology would facilitate the best management of stent therapy for malignant IVC obstruction.

  1. Indications of an increase of occupational pleural mesothelioma in Japan.

    PubMed

    Baba, K

    1983-03-01

    In order to obtain an epidemiological picture of occupational pleural malignant mesotheliomas in Japan, the author surveyed the Annual of Pathological Autopsy Cases (published by the Japanese Pathological Society) from 1974 through 1980. Two hundred and twenty-two malignant mesotheliomas (0.114% of all autopsy cases) were found in that period. One hundred and forty-five cases (0.074%) of them were of pleural origin. Until 1977, there were no pleural malignant mesotheliomas associated with asbestosis, but there were one in 1978, three in 1979 and two in 1980. Two of them were housewives and the others were a ship builder, a welder, a ceramist and a steel factory worker. Two lived in Sakae City, and the others in Kure City, Kaizuka City, Nagasaki City and Kanagawa Prefecture, where large shipyards are located. Compared to the Western countries, there is a time lag of 10 to 20 years in the increase of consumption of asbestos in Japan, where the increase has occurred rapidly after World War II. The epidemiological picture obtained by this study clearly states that the number of occupational pleural malignant mesotheliomas began to increase in the past few years in Japan.

  2. Pleural mesotheliomas are underreported as occupational cancer in Sweden.

    PubMed

    Andersson, E; Torén, K

    1995-04-01

    The aim of this study was to estimate to what degree malignant pleural mesotheliomas were reported as occupational cancers. The study included all malignant pleural mesotheliomas (n = 210) found in the Cancer Registry 1980-1989 from four Swedish counties. Whether or not a case was reported as occupational cancer was found in the Swedish Register of Reported Occupational Diseases. To evaluate the presence of exposure histories, the chest department files for 58 mesotheliomas from one county were reviewed. The reporting was low, with only 75 mesotheliomas (36%) reported. All the cases were men, and for the men, the reporting frequency was 42%. The reporting was significantly lower for the last part of the decade than for the first part. The reporting frequency decreased with age. In the review of the chest department files, an exposure history was found in 93% of the reported cases and in 47% of the unreported cases. It is concluded that physicians must give more priority to exposure histories in patients with pleural mesotheliomas.

  3. Mesothelioma: current perspectives.

    PubMed

    Taylor, R A; Johnson, L P

    1981-05-01

    Thirty patients with the diagnosis of mesothelioma were admitted to the Swedish Hospital Medical Center, Seattle, from 1975 to 1979. Of these, 26 had pleural and 4 had peritoneal mesothelioma. In 20 of the patients with pleural mesothelioma, the diagnosis had been made by open thoractomy and in only one by needle biopsy of the pleura. The average survival of the patients with pleural tumors from time of diagnosis was 15 months, and two are alive at three and eight months, respectively, one of whom had an apparent solitary benign mesothelioma. The average survival of those with peritoneal mesothelioma was ten months, although one has survived six years. There were 17 patients with a known history of exposure to asbestos, 14 while working in shipyards. Because of the relatively high incidence of this previously rare tumor in the Puget Sound, Washington, area, and the generally dismal results of therapy, better methods of diagnosis including thoracoscopy and a more systematic approach to treatment are recommended.

  4. Tumors that mimic asbestos-related mesothelioma: time to consider a genetics-based tumor registry?

    PubMed Central

    Kerger, Brent D.; James, Robert C.; Galbraith, David A.

    2014-01-01

    The diagnosis of mesothelioma is not always straightforward, despite known immunohistochemical markers and other diagnostic techniques. One reason for the difficulty is that extrapleural tumors resembling mesothelioma may have several possible etiologies, especially in cases with no meaningful history of amphibole asbestos exposure. When the diagnosis of mesothelioma is based on histologic features alone, primary mesotheliomas may resemble various primary or metastatic cancers that have directly invaded the serosal membranes. Some of these metastatic malignancies, particularly carcinomas and sarcomas of the pleura, pericardium and peritoneum, may undergo desmoplastic reaction in the pleura, thereby mimicking mesothelioma, rather than the primary tumor. Encasement of the lung by direct spread or metastasis, termed pseudomesotheliomatous spread, occurs with several other primary cancer types, including certain late-stage tumors from genetic cancer syndromes exhibiting chromosomal instability. Although immunohistochemical staining patterns differentiate most carcinomas, lymphomas, and mestastatic sarcomas from mesotheliomas, specific genetic markers in tumor or somatic tissues have been recently identified that may also distinguish these tumor types from asbestos-related mesothelioma. A registry for genetic screening of mesothelioma cases would help lead to improvements in diagnostic criteria, prognostic accuracy and treatment efficacy, as well as improved estimates of primary mesothelioma incidence and of background rates of cancers unrelated to asbestos that might be otherwise mistaken for mesothelioma. This information would also help better define the dose-response relationships for mesothelioma and asbestos exposure, as well as other risk factors for mesothelioma and other mesenchymal or advanced metastatic tumors that may be indistinguishable by histology and staining characteristics. PMID:24910640

  5. [Diagnostic difficulties in primary mesothelioma].

    PubMed

    Khalil, Leila Youssef; Szturmowicz, Monika; Wawrzyńska, Liliana; Fijałkowska, Anna; Kupis, Włodzimierz; Maszkowska-Kopij, Krystyna; Szczepulska, Ewa; Burakowska, Barbara; Tomkowski, Witold; Torbicki, Adam

    2004-01-01

    A 54-year-old woman with a history of fatigue and shortness of breath was found to have a pericardial effusion and mild mediastinal lymphadenopathy. Video-assisted pericardioscopy revealed thickened pericardium studded with multiple nodules. Histologically the tumor was diagnosed as papillary adenocarcinoma. The site of the primary tumor could not be identified. As lung cancer is one of the most frequent causes of pericardial metastases the patient was treated with cisplatin and vinblastin. Following 5 courses of chemotherapy--given over a 4 month period--the amount of pericardial effusion and pericardial thickness did not change. The material from pericardial biopsy was reexamined and positive immunostaining for calretinine was found. The final diagnosis was primary pericardial mesothelioma of epithelioid type. Palliative radiotherapy of mediastinum was planned but the patient deteriorated and died due to disease progression with venous thrombosis and superior vena cava syndrome. The case illustrates the difficulties in establishing diagnosis of primary pericardial mesothelioma which is a rare tumor with poor prognosis. PMID:15757264

  6. Exemestane blocks mesothelioma growth through downregulation of cAMP, pCREB and CD44 implicating new treatment option in patients affected by this disease

    PubMed Central

    2014-01-01

    Background Recent evidence suggests that aromatase may be involved in the pathogenesis of malignant mesothelioma. Here, we evaluated the effect of exemestane, an inhibitor of aromatase, in the treatment of mesothelioma using in vitro and in vivo preclinical models. Results We show a significant reduction of cell proliferation, survival, migration and block of cells in S phase of cell cycle in mesothelioma cells upon exemestane treatment. Moreover, we find that CD44, which is involved in mesothelioma cells migration, was modulated by exemestane via cAMP and pCREB. Most importantly, in mice mesothelioma xenograft exemestane causes a significant decrease in tumor size and the association pemetrexed/exemestane is more effective than pemetrexed/cisplatin. Conclusion The preclinical mesothelioma model suggests that exemestane might be beneficial in mesothelioma treatment. PMID:24655565

  7. Peritoneal mesotheliomas in Danish women: review of histopathologic slides and history of abdominal surgery.

    PubMed

    Nielsen, A M; Olsen, J H; Madsen, P M; Francis, D; Almind, M

    1994-08-01

    An unexpectedly large number of peritoneal mesotheliomas among women was reported to the Danish Cancer Registry during the years 1960 through 1985. In a case-control study, we tested whether this was due to diagnostic misclassification or to direct exposure of the peritoneal membranes to talc during abdominal surgery. Tissue specimens were available from 96 reported peritoneal mesotheliomas; 35 cases (37%) were regarded as verified mesotheliomas, and 33 (34%) as possible mesotheliomas. Information on any intraabdominal surgery was obtained from the hospital records of these 68 cases and for 206 controls with a cancer of the uterine corpus or pancreas. No association was seen between peritoneal mesotheliomas and abdominal surgery performed more than 25 years prior to cancer diagnosis (odds ratio, 0.83; 95% confidence interval, 0.35-1.94). CONCLUSION. Misclassification of other cancers was the reason for the observed excess of peritoneal mesotheliomas.

  8. Mesotheliomas with small cell features: report of eight cases.

    PubMed

    Ordóñez, Nelson G

    2012-05-01

    Mesotheliomas with small cell morphology are rare and only one study of such cases has been published. As a result of their rare occurrence, some investigators have cast doubt on the existence of such a histologic variant of mesothelioma. This investigator reports a series of eight cases of epithelioid mesothelioma with small cell features, all of which originated in the pleura. Seven of the patients were men and one was a woman. Four patients had a history of asbestos exposure. Histologically, four of the mesotheliomas were epithelioid and four biphasic. The proportion of small cells seen in these cases constituted 80 to 100% of the tumor included in the biopsy material and 15 to 20% of the tumor present in the pneumonectomy specimens. Immunoreactivity for calretinin, keratin 5/6, keratin 7, pan-keratin, WT1, podoplanin, and mesothelin was seen in all cases tested for these markers. All of the cases were negative for MOC-31, Ber-EP4, CEA, CD15, TAG-72, TTF-1, chromogranin A, synaptophysin, CD99, and desmin. The mean survival of the six patients for whom this information was available was 8.2 months. It is important for pathologists to be aware that mesotheliomas can present small cell features and, because of this, they can be confused with other malignancies that can exhibit similar morphology. The value of immunohistochemistry in the differential diagnosis of these tumors is discussed.

  9. Epidemiology of malignant mesothelioma in Australia.

    PubMed

    Musk, A William; de Klerk, Nicholas H

    2004-08-01

    In Australia, consumption of asbestos peaked in about 1975 at around 70,000t per year--the majority being used for asbestos cement manufacture. Chrysotile, amphibole and crocidolite have all been mined in Australia and employment records from the single company which mined most of the crocidolite deposits at Wittenoom have formed the basis of an ongoing cohort mortality study of the workforce.

  10. Can Malignant Mesothelioma Be Found Early?

    MedlinePlus

    ... any symptoms.) For people with known exposure to asbestos, some doctors recommend imaging tests such as chest ... of symptoms. People who have been exposed to asbestos should know the possible signs and symptoms of ...

  11. Synergistic anti-tumor efficacy of immunogenic adenovirus ONCOS-102 (Ad5/3-D24-GM-CSF) and standard of care chemotherapy in preclinical mesothelioma model.

    PubMed

    Kuryk, Lukasz; Haavisto, Elina; Garofalo, Mariangela; Capasso, Cristian; Hirvinen, Mari; Pesonen, Sari; Ranki, Tuuli; Vassilev, Lotta; Cerullo, Vincenzo

    2016-10-15

    Malignant mesothelioma (MM) is a rare cancer type caused mainly by asbestos exposure. The median overall survival time of a mesothelioma cancer patient is less than 1-year from diagnosis. Currently there are no curative treatment modalities for malignant mesothelioma, however treatments such as surgery, chemotherapy and radiotherapy can help to improve patient prognosis and increase life expectancy. Pemetrexed-Cisplatin is the only standard of care (SoC) chemotherapy for malignant mesothelioma, but the median PFS/OS (progression-free survival/overall survival) from the initiation of treatment is only up to 12 months. Therefore, new treatment strategies against malignant mesothelioma are in high demand. ONCOS-102 is a dual targeting, chimeric oncolytic adenovirus, coding for human GM-CSF. The safety and immune activating properties of ONCOS-102 have already been assessed in phase 1 study (NCT01598129). In this preclinical study, we evaluated the antineoplastic activity of combination treatment with SoC chemotherapy (Pemetrexed, Cisplatin, Carboplatin) and ONCOS-102 in xenograft BALB/c model of human malignant mesothelioma. We demonstrated that ONCOS-102 is able to induce immunogenic cell death of human mesothelioma cell lines in vitro and showed anti-tumor activity in the treatment of refractory H226 malignant pleural mesothelioma (MPM) xenograft model. While chemotherapy alone showed no anti-tumor activity in the mesothelioma mouse model, ONCOS-102 was able to slow down tumor growth. Interestingly, a synergistic anti-tumor effect was seen when ONCOS-102 was combined with chemotherapy regimens. These findings give a rationale for the clinical testing of ONCOS-102 in combination with first-line chemotherapy in patients suffering from malignant mesothelioma. PMID:27287512

  12. Mesothelioma in Cyprus.

    PubMed

    McConnochie, K; Simonato, L; Mavrides, P; Christofides, P; Mitha, R; Griffiths, D M; Wagner, J C

    1989-01-01

    For many years, the main source of asbestos in Cyprus was thought to be the chrysotile mine in the central mountains. When a woman, who had no connection with the mine, developed mesothelioma, it was surprising to discover tremolite asbestos bodies within her lung. However, further studies have shown that tremolite occurs as a contaminant within the chrysotile ore body. In this study we have shown that both chrysotile and tremolite can be found in domestic and environmental samples throughout the mountain region; in particular, numerous fine fibres of both materials are present in stucco. Preliminary radiological studies have shown pleural disease in the village population and 5 out of 13 known cases of mesothelioma have arisen in persons unconnected with the mine. This suggests an environmental contribution to asbestos-related disease on the island.

  13. Software for Apportionment of Asbestos-Related Mesotheliomas.

    PubMed

    Ross, Robert M

    2016-01-01

    Patients with an asbestos-related mesothelioma may be legally entitled to financial compensation. In this context, a physician may be called upon to apportion the contribution of an asbestos containing product or facility where there was asbestos exposure in the development of that individual's mesothelioma. This task is mathematically not simple. It is a complex function of each and the entire individual's above-background asbestos exposures. Factors to be considered for each of these exposures are the amount of exposure to mesotheliogenic fibers, each of the asbestos containing products' potency to cause mesothelioma, and the time period when the exposures occurred relative to when the mesothelioma was diagnosed. In this paper, the known factors related to asbestos-related mesothelioma risk are briefly reviewed and the software that is downloadable and fully functional in a Windows® environment is also provided. This software allows for rapid assessment of relative contributions and deals with the somewhat tedious mathematical calculations. With this software and a reasonable occupational history, if it is decided that the mesothelioma was due to above-background asbestos exposure, the contribution of an asbestos containing product or a time period of asbestos exposure can be apportioned.

  14. Software for Apportionment of Asbestos-Related Mesotheliomas

    PubMed Central

    Ross, Robert M.

    2016-01-01

    Patients with an asbestos-related mesothelioma may be legally entitled to financial compensation. In this context, a physician may be called upon to apportion the contribution of an asbestos containing product or facility where there was asbestos exposure in the development of that individual's mesothelioma. This task is mathematically not simple. It is a complex function of each and the entire individual's above-background asbestos exposures. Factors to be considered for each of these exposures are the amount of exposure to mesotheliogenic fibers, each of the asbestos containing products' potency to cause mesothelioma, and the time period when the exposures occurred relative to when the mesothelioma was diagnosed. In this paper, the known factors related to asbestos-related mesothelioma risk are briefly reviewed and the software that is downloadable and fully functional in a Windows® environment is also provided. This software allows for rapid assessment of relative contributions and deals with the somewhat tedious mathematical calculations. With this software and a reasonable occupational history, if it is decided that the mesothelioma was due to above-background asbestos exposure, the contribution of an asbestos containing product or a time period of asbestos exposure can be apportioned. PMID:27445546

  15. Software for Apportionment of Asbestos-Related Mesotheliomas.

    PubMed

    Ross, Robert M

    2016-01-01

    Patients with an asbestos-related mesothelioma may be legally entitled to financial compensation. In this context, a physician may be called upon to apportion the contribution of an asbestos containing product or facility where there was asbestos exposure in the development of that individual's mesothelioma. This task is mathematically not simple. It is a complex function of each and the entire individual's above-background asbestos exposures. Factors to be considered for each of these exposures are the amount of exposure to mesotheliogenic fibers, each of the asbestos containing products' potency to cause mesothelioma, and the time period when the exposures occurred relative to when the mesothelioma was diagnosed. In this paper, the known factors related to asbestos-related mesothelioma risk are briefly reviewed and the software that is downloadable and fully functional in a Windows® environment is also provided. This software allows for rapid assessment of relative contributions and deals with the somewhat tedious mathematical calculations. With this software and a reasonable occupational history, if it is decided that the mesothelioma was due to above-background asbestos exposure, the contribution of an asbestos containing product or a time period of asbestos exposure can be apportioned. PMID:27445546

  16. Epidemiologic aspects of childhood mesothelioma.

    PubMed

    Cooper, S P; Fraire, A E; Buffler, P A; Greenberg, S D; Langston, C

    1989-01-01

    Our calculation provides the first population-based incidence rate of childhood mesothelioma in the United States. Based on these data and on our pathology review, we conclude that mesothelioma occurs rarely in children and that this diagnosis is difficult to establish. A more systematic approach to identifying mesothelioma cases in children, as well as adults, will be facilitated by increasing state surveillance of cancer incidence and by the proposed addition of a unique code for mesothelioma in the Tenth Revision of the ICD. There is a critical need for histopathological verification of mesothelioma cases. The increased use of a uniform, reproducible histopathologic classification and mesothelioma panels should address this problem. A thorough microscopic study of individual cases needs to be supplemented by a careful assessment of the clinical findings and environmental factors. The available data thus far do not support an association between childhood mesothelioma and asbestos exposure. However, the ubiquitous nature of asbestos exposures, the known association of asbestos with adult mesothelioma, the unreliability of the diagnosis, and the lack of adequate data regarding asbestos exposures, all indicate that asbestos involvement cannot be categorically ruled out, especially in older children with the potential for a longer duration of exposure and a plausible induction period. Mesothelioma in children, as well as in adults, is likely to have a multifactorial etiology. Radiation, prenatal medications, and genetic factors are all possible etiologic agents in childhood mesothelioma. In addition, other, as of yet unspecified environmental factors may play a role in this disease. When cases are diagnosed, the physician should inquire about the history of exposure to asbestos or other hazardous materials in the patient's environment, prior radiation exposure, medication exposure pre- and postnatally, prior cancer diagnoses, and a family history of cancer. An

  17. Lung and skeleton malignant tumor induction due to high let emitters

    SciTech Connect

    Buldakov, L.A.; Lyubchansky, E.R.; Kalmikova, Z.I.; Buhtoyarova, Z.M.

    1992-06-01

    Experimental studies show that malignant tumor induction is of primary importance in regard to the biological action of transuranium elements on the animal body. Clarification of quantitative relationship between these parameters for low-level radiation is aproblem to be solved by health physics. This report aims at analysis of the dose-response relationship following rat exposure to PU-239, Am-241, and NP-237 over a wide range of doses, and also at comparison between risk fact obtained experimentally and tose recommended by the ICRP. The biological effect of transuranium elements was investigated regarding malignant tumor incidence in rat bone for all the pathways of intake covered and in the lung for intakes of radionuclides into the respiratory system.

  18. Death due to fulminant neuroleptic malignant syndrome induced by low doses of haloperidol: a rare case.

    PubMed

    Zou, Donghua; Shao, Yu; Qin, Zhiqiang; Zhang, Jianhua; Liu, Ningguo; Li, Zhengdong; Huang, Ping; Chen, Yijiu

    2014-05-01

    The paper reports on a rare case of fulminant neuroleptic malignant syndrome (NMS) with several risk factors, typical manifestation and rapid death induced by low doses of haloperidol. The pathological findings, pathogenesis, clinical manifestations, diagnostic criteria, risk factors and other features of NMS are discussed. The importance of forensic pathologists being aware of the possibility of NMS as the cause of death in people taking antipsychotic drugs is stressed. PMID:24794843

  19. [Progress due to networking structures. Challenges for the Competence Network Malignant Lymphomas in the Era of Precision Medicine].

    PubMed

    Hellmich, Silke; Schreiber, Natalie; Fath, Birgit; Hallek, Michael

    2016-04-01

    The Competence Network Malignant Lymphomas (KML), founded in 1999 at the initiative of the Federal Ministry of Education and Research (BMBF), brings together interdisciplinary medical and scientific expertise in research on malignant lymphomas. The network helps to release synergies in evidence-based clinical research and contributes to the accelerated transfer of advances in knowledge gained from therapeutic studies for the health care of lymphoma patients. During the regular BMBF funding period (1999-2009) individual sub-projects were hived off, such as the Cochrane Haematological Malignancies Group (CHMG) or the Scientific Institute of Haematologists and Oncologists in Private Practice (WINHO GmbH). At the end of BMBF funding, pivotal KML projects such as the reference diagnostic panel for KML lymphoma study groups, site management support, health care management and the information and communication section could be continued in the scientific association "Kompetenznetz Maligne Lymphome e. V." which was founded in 2005. Due to the recent in-depth understanding of the molecular and genetic mechanisms of lymphomagenesis and the consequent transformation to precision medicine targeting specialised groups of patients, the KML is currently facing the challenge of developing modern study, health-care and information concepts in ever shorter periods of time.

  20. Fully Covered Self-Expandable Metal Stents for Treatment of Malignant Biliary Strictures due to Pancreatic Carcinoma

    PubMed Central

    Samie, Ahmed Abdel; Stumpf, Michael; Theilmann, Lorenz

    2012-01-01

    Background Transpapillary stents are used to treat malignant biliary strictures. However, there are different stent types and data are controversial in respect to success and complications. Recently, completely covered self-expandable metal stents (CSEMS) have become available. The aim of this study is to present a consecutive series of CSEMS placed to decompress the bile duct in malignant stenosis due to pancreatic carcinoma and to evaluate the effectiveness, complication rate and extractability of these devices. Methods We retrospectively reviewed the courses of 27 consecutive patients who received CSEMS due to malignant biliary strictures because of pancreatic carcinoma regardless of presumed resectability between January 2010 and May 2012 in our endoscopic unit. Results A total of 27 patients (12 male and 15 female) were included in the study. The mean age of the patients was 75 years. Endoscopic retrograde cholangiopancreatography (ERCP), endoscopic sphincterotomy (ES) and stent placement were successful at first attempt in all cases. The mean length of the stenosis was 20 mm. In 24 patients (89%) a stent length of 4 cm was sufficient to bridge the stenosis. In three cases a stent length of 6 cm was necessary. Drainage was achieved as monitored by a significant decrease or normalization of bilirubin in all cases (mean bilirubin 8.5 mg/dL and 1.5 mg/dL before and after stent placement respectively), 15 patients underwent surgery with pylorus preserving duodenopancreatectomy. In all patients who underwent surgery stents could be removed during the operation without difficulties. Leakage of the biliodigestive anastomosis occurred in one patient (6.6%). Four (15%) of the 27 patients developed complications related to the endoscopic procedure and/or stent placement respectively (cholecystitis in two patients, stent occlusion in one patient, and post-sphincterotomy bleeding in one patient). Conclusion The prolonged patency, extractability, and low complication rate

  1. BAP1 Immunohistochemistry and p16 FISH in the Diagnosis of Sarcomatous and Desmoplastic Mesotheliomas.

    PubMed

    Hwang, Harry C; Pyott, Shawna; Rodriguez, Stephanie; Cindric, Ashlie; Carr, April; Michelsen, Carmen; Thompson, Kim; Tse, Christopher H; Gown, Allen M; Churg, Andrew

    2016-05-01

    The separation of sarcomatous and desmoplastic mesotheliomas from benign organizing pleuritis can be morphologically very difficult. Deletion of p16 (CDKN2A) by fluorescence in situ hybridization (FISH) testing appears to be a reliable marker of malignancy in mesothelial proliferations, and more recently it has been reported that, in this setting, loss of BAP1 by immunohistochemistry is only seen in malignant mesotheliomas. To determine how useful these tests are with sarcomatous and desmoplastic mesotheliomas, we examined 20 such tumors. Loss of BAP1 was seen in 3/20 (15%) and deletion of p16 by FISH was seen in 16/20 (80%) cases. Loss of one or the other marker was observed in 17/20 (85%). We also examined 13 sarcomatoid carcinomas, an important differential diagnosis of sarcomatoid mesotheliomas, and found that BAP1 was never lost, but p16 was deleted in 3/11 (27%). We conclude that: (1) BAP1 immunohistochemistry is relatively insensitive in the context of sarcomatous and desmoplastic mesotheliomas, but as a matter of time and cost efficiency may nonetheless be a useful first approach to the problem; (2) deletion of p16 by FISH is considerably more sensitive, but there remain a proportion of cases in which p16 is not deleted; (3) a small improvement in sensitivity can be achieved by using both markers; (4) in the context of a spindle cell malignant tumor in the pleura or peritoneum, which morphologically might be a metastatic sarcomatoid carcinoma or a mesothelioma, the finding of BAP1 loss favors mesothelioma, but p16 FISH cannot be used to separate sarcomatous mesotheliomas from sarcomatoid carcinomas.

  2. Wide complex ventricular tachycardia presenting sign of metastatic pleural mesothelioma

    PubMed Central

    Bhatia, Ashmeet; Ajayi, Tokunbo

    2014-01-01

    Malignant mesothelioma is an uncommon neoplasm of serosal surfaces, such as the pleura, the peritoneum, less frequently pericardium and tunica vaginalis. It usually spreads locally to the lungs and mediastinum. We describe a case of malignant mesothelioma with metastasis to the heart. The patient presented with syncope, chest pain and light-headedness. He was found to have wide complex ventricular tachycardia (Vtach). He was cardioverted and then noted to have multiple (more than 20) similar episodes during the hospital course. He was treated with multiple antiarrhythmic medications. A CT scan of the chest revealed a circumferential rind of soft tissue in the right hemithorax and invasion of the pericardium. The repeated Vtach episodes were secondary to the metastasis of the pericardium. Oncology was involved and as there were no further treatment options available, the patient was discharged home with hospice care. The disease is a huge economic burden and early recognition can lead to better outcomes. PMID:24769661

  3. Wide complex ventricular tachycardia presenting sign of metastatic pleural mesothelioma.

    PubMed

    Bhatia, Ashmeet; Ajayi, Tokunbo

    2014-04-25

    Malignant mesothelioma is an uncommon neoplasm of serosal surfaces, such as the pleura, the peritoneum, less frequently pericardium and tunica vaginalis. It usually spreads locally to the lungs and mediastinum. We describe a case of malignant mesothelioma with metastasis to the heart. The patient presented with syncope, chest pain and light-headedness. He was found to have wide complex ventricular tachycardia (Vtach). He was cardioverted and then noted to have multiple (more than 20) similar episodes during the hospital course. He was treated with multiple antiarrhythmic medications. A CT scan of the chest revealed a circumferential rind of soft tissue in the right hemithorax and invasion of the pericardium. The repeated Vtach episodes were secondary to the metastasis of the pericardium. Oncology was involved and as there were no further treatment options available, the patient was discharged home with hospice care. The disease is a huge economic burden and early recognition can lead to better outcomes.

  4. Role of MIF/CD74 signaling pathway in the development of pleural mesothelioma

    PubMed Central

    D'Amato-Brito, Cintia; Cipriano, Davide; Colin, Didier J.; Germain, Stéphane; Seimbille, Yann; Robert, John H.; Triponez, Frédéric; Serre-Beinier, Véronique

    2016-01-01

    Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine implicated in acute and chronic inflammatory diseases. MIF is overexpressed in various tumors. It displays a number of functions that provide a direct link between the process of inflammation and tumor growth. Our group recently identified the MIF-receptor CD74 as an independent prognostic factor for overall survival in patients with malignant pleural mesothelioma. In the present study, we compared the levels of expression of MIF and CD74 in different human mesothelioma cell lines and investigated their physiopathological functions in vitro and in vivo. Human mesothelioma cells expressed more CD74 and secreted less MIF than non tumoral MeT5A cells, suggesting a higher sensitivity to MIF. In mesothelioma cells, high MIF levels were associated with a high multiplication rate of cells. In vitro, reduction of MIF or CD74 levels in both mesothelioma cell lines showed that the MIF/CD74 signaling pathway promoted tumor cell proliferation and protected MPM cells from apoptosis. Finally, mesothelioma cell lines expressing high CD74 levels had a low tumorigenic potential after xenogeneic implantation in athymic nude mice. All these data highlight the complexity of the MIF/CD74 signaling pathway in the development of mesothelioma. PMID:26883190

  5. Environmental exposure to asbestos and the exposure-response relationship with mesothelioma.

    PubMed

    Madkour, M T; El Bokhary, M S; Awad Allah, H I; Awad, A A; Mahmoud, H F

    2009-01-01

    An epidemiological and environmental study was carried out in Shubra El-Kheima city, greater Cairo, of the exposure-response relationship between asbestos and malignant pleural mesothelioma. Radiological screening was done for 487 people occupationally exposed to asbestos, 2913 environmentally exposed to asbestos and a control group of 979 with no history of exposure. Pleural biopsy was done for suspicious cases. The airborne asbestos fibre concentrations were determined in all areas. There were 88 cases of mesothelioma diagnosed, 87 in the exposed group. The risk of mesothelioma was higher in the environmentally exposed group than other groups, and higher in females than males. The prevalence of mesothelioma increased with increased cumulative exposure to asbestos.

  6. [Clinicopathological study on 100 Japanese patients with peritoneal mesothelioma in Japan].

    PubMed

    Naka, H; Naka, A

    1984-01-01

    We report a clinicopathological study on 100 japanese patients with peritoneal mesothelioma encountered between 1911 and 1982. Fifty-six were males and 44 were females, they ranged in age from 10 months to 83 years. As the inducement materials, asbestos was reported in 5 and thorium in 2 patients. Clinical symptoms were abdominal distension in 56 and abdominal pain in 50 patients. Thrombocytosis and hypoglycemia were observed in 7 and 3 patients, respectively. Macroscopically, the peritoneal mesothelioma was localized in 7, diffuse in 86 and not described in 7 patients. The pathological classification was benign in 5 and malignant in 77 cases. According to Stout's classification, the peritoneal mesothelioma was tubular in 43 mixed in 25 and fibrous type in 11 cases. Based on our findings we suggest that peritoneal mesotheliomas are on the increase in Japan.

  7. Unique uptake of acid-prepared mesoporous spheres by lung epithelial and mesothelioma cells.

    PubMed

    Blumen, Steven R; Cheng, Kai; Ramos-Nino, Maria E; Taatjes, Douglas J; Weiss, Daniel J; Landry, Christopher C; Mossman, Brooke T

    2007-03-01

    Lung cancers, malignant mesotheliomas (MM), and fibrosis are devastating diseases with limited treatment strategies, in part due to poorly-effective drug delivery to affected areas of lung. We hypothesized that acid-prepared mesoporous spheres (APMS) (1-2 microm diameter, 40 A pore size) might be effective vehicles for pulmonary chemotherapeutic drug delivery. To assess this, APMS, chemically modified with different surface molecules (lipid, a linker having a terminal amine group, a thiol group, or tetraethylene glycol [TEG]), were evaluated for uptake and possible cytotoxic effects after in vitro administration to murine alveolar epithelial Type II (C10) and human mesothelioma (MM) cells and after intrapleural or intranasal administration to C57Bl/6 mice. APMS coated with TEG (APMS-TEG) were most efficiently taken up by C10 and MM cells. The mechanism of cell uptake was rapid, actin-dependent, and did not involve clathrin- or caveolae-mediated mechanisms nor fusion of membrane-bound APMS with lysosomes. When injected intrapleurally in mice, APMS-TEG were taken up by both CD45-positive and -negative cells of the diaphragm, lung, and spleen, whereas APMS administered by the intranasal route were predominantly in lung epithelial cells and alveolar macrophages. After intrapleural or intranasal administration, APMS were nonimmunogenic and nontoxic as evaluated by differential cell counts and lactate dehydrogenase levels in bronchoalveolar and pleural lavage fluids. In the treatment of lung and pleural diseases, APMS-TEG may be useful tools to deliver chemotherapeutic drugs or molecular constructs.

  8. Gremlin-1 associates with fibrillin microfibrils in vivo and regulates mesothelioma cell survival through transcription factor slug

    PubMed Central

    Tamminen, J A; Parviainen, V; Rönty, M; Wohl, A P; Murray, L; Joenväärä, S; Varjosalo, M; Leppäranta, O; Ritvos, O; Sengle, G; Renkonen, R; Myllärniemi, M; Koli, K

    2013-01-01

    Malignant mesothelioma is a form of cancer that is highly resistant to conventional cancer therapy for which no major therapeutic advances have been introduced. Here, we identify gremlin-1, a known bone morphogenetic protein inhibitor crucial for embryonic development, as a potential therapeutic target for mesothelioma. We found high expression levels of gremlin-1 in the mesothelioma tumor tissue, as well as in primary mesothelioma cells cultured from pleural effusion samples. Downregulation of gremlin-1 expression by siRNA-mediated silencing in a mesothelioma cell line inhibited cell proliferation. This was associated with downregulation of the transcription factor slug as well as mesenchymal proteins linked to cancer epithelial-to-mesenchymal transition. Further, resistance to paclitaxel-induced cell death was associated with high gremlin-1 and slug expression. Treatment of gremlin-1-silenced mesothelioma cells with paclitaxel or pemetrexed resulted in efficient loss of cell survival. Finally, our data suggest that concomitant upregulation of fibrillin-2 in mesothelioma provides a mechanism for extracellular localization of gremlin-1 to the tumor microenvironment. This was supported by the demonstration of interactions between gremlin-1, and fibrillin-1 and -2 peptides as well as by colocalization of gremlin-1 to fibrillin microfibrils in cells and tumor tissue samples. Our data suggest that gremlin-1 is also a potential target for overcoming drug resistance in mesothelioma. PMID:23978876

  9. Radiological study of pleural changes in relation to mesothelioma in Turkey.

    PubMed

    Hillerdal, G; Baris, Y I

    1983-06-01

    In some villages in central Turkey pleural changes occur as a result of environmental exposure to mineral fibres. In most cases the fibre is asbestos but in some cases the non-asbestos fibre erionite, a zeolite, is responsible. The incidence of malignant mesothelioma is much higher in "erionite villages" than in "asbestos villages" despite similar frequencies of pleural changes. In this study chest radiographs from 466 people from asbestos villages, 549 from erionite villages, and 382 controls were compared. The frequency of pleural calcification was about the same in the two groups of villages studied, but the minor fissures were visible to a greater degree in erionite cases. In people from erionite villages "atypical" pleural calcification, due to calcification of the visceral rather than the parietal pleura, was more common. These differences may indicate that the fibres have different lengths and diameters.

  10. Asbestos-related malignancy

    SciTech Connect

    Talcott, J.A.; Antman, K.H.

    1988-05-01

    Asbestos-associated malignancies have received significant attention in the lay and medical literature because of the increasing frequency of two asbestos-associated tumors, lung carcinoma and mesothelioma; the wide distribution of asbestos; its status as a prototype environmental carcinogen; and the many recent legal compensation proceedings, for which medical testimony has been required. The understanding of asbestos-associated carcinogenesis has increased through study of animal models, human epidemiology, and, recently, the application of modern molecular biological techniques. However, the detailed mechanisms of carcinogenesis remain unknown. A wide variety of malignancies have been associated with asbestos, although the strongest evidence for a causal association is confined to lung cancer and mesothelioma. Epidemiological studies have provided evidence that both the type of asbestos fiber and the industry in which the exposure occurs may affect the rates of asbestos-associated cancers. It has been shown that asbestos exerts a carcinogenic effect independent of exposure to cigarette smoking that, for lung cancers, is synergistically enhanced by smoking. Other questions remain controversial, such as whether pulmonary fibrosis necessarily precedes asbestos-associated lung cancer and whether some threshold level of exposure to asbestos (including low-dose exposures that may occur in asbestos-associated public buildings) may be safe. Mesothelioma, the most closely asbestos-associated malignancy, has a dismal natural history and has been highly resistant to therapy. However, investigational multi-modality therapy may offer benefit to some patients. 179 references.

  11. Case-control study of diet and mesothelioma in Louisiana.

    PubMed

    Schiffman, M H; Pickle, L W; Fontham, E; Zahm, S H; Falk, R; Mele, J; Correa, P; Fraumeni, J F

    1988-05-15

    Data were analyzed from a case-control interview study of malignant mesothelioma in Louisiana, which gathered information on usual diet and on lifetime occupational exposure to asbestos. Thirty-seven patients with malignant mesothelioma of the pleura (n = 32) or peritoneum (n = 5) were matched to controls according to age, sex, race, and factors related to case ascertainment (hospital and date of diagnosis, or parish and date of death). Twenty-one of the 37 cases were judged by masked occupational review to have been exposed to asbestos (57%), compared to seven of 37 controls (19%). Seven additional cases and 10 additional controls had occupational histories suggestive of asbestos exposure. With regard to usual diet before illness, cases reported less frequent consumption of homegrown produce (p = 0.005), cruciferous vegetables (p = 0.005), and all vegetables combined (p = 0.09) than did the controls. An estimate of usual carotene intake was also significantly lower in cases (p = 0.03). Dose-dependent reductions in risk were seen with increasing consumption of vegetables, especially cruciferous vegetables (p for trend = 0.013). These associations were not explained by differences in asbestos exposure as measured by the occupational review. The results indicate that consumption of vegetables or some vegetable-related constituent may have a protective effect on developing mesothelioma.

  12. Asymptomatic peritoneal carcinomatosis originating from benign cystic peritoneal mesothelioma

    PubMed Central

    Iacoponi, S; Calleja, J; Hernandez, G; de la Cuesta, R Sainz

    2015-01-01

    Benign multicystic mesothelioma is a rare tumour that originates from the abdominal peritoneum with a predisposition to the pelvic peritoneum. It typically affects women of reproductive age. There have been less than 200 cases of this rare neoplasia reported to date. We present the case of a 35-year-old woman who was referred to our centre because of the detection of a peritoneal carcinomatosis during a gynaecological exam. A diagnostic laparoscopy was performed. The findings included multiple cysts appearing as ‘a bunch of grapes’ occupying the omentum. Biopsies were taken during the surgery and the results showed benign multicystic peritoneal mesothelioma. Benign multicystic mesothelioma can simulate other conditions, such as malignant ovarian tumours or cystic lymphangioma. It is often diagnosed accidentally during surgery performed for another reason. The diagnosis is interoperative, observing multicystic structures grouped as a ‘bunch of grapes’ containing clear fluid with thin walls made of connective tissue. Immunohistochemistry confirmed mesothelial origin. Surgery is considered the treatment of choice and is based on the removal of the cysts from the abdominal cavity. Hyperthermic intraperitoneal chemotherapy can be considered as a primary treatment in patients with recurrences or even as a part of primary treatment associated with surgery. Survival at 5 years is 100% and invasive or malignant progression is extraordinary. The treatment approach should be multidisciplinary, and the patient should be referred to a referral centre. PMID:26715942

  13. False aneurysm of ascending aorta due to pericardial mesothelioma†

    PubMed Central

    Uspenskiy, Vladimir; Lavreshin, Alexei; Osadchii, Alexei; Gordeev, Michael

    2012-01-01

    Ascending aortic false aneurysm is a rare but serious complication of pericardial mesothelioma. We report a case of ascending aortic pseudoaneurysm due to spindle cell pericardial mesothelioma. In this case, the first symptoms of the disease appeared 18 months before surgery. The final diagnosis was determined only when severe late complications occurred. Palliative tumour excision, aortoplasty and aortic valve prosthesis were performed with subsequent adjuvant chemotherapy. Over 10 months after surgery, the patient is alive and a significant reduction of the tumour mass has been achieved. This case demonstrates that timely lifetime diagnosis of malignant pericardial tumour remains very difficult and effective adjuvant chemotherapy is needed to improve the results of surgery. PMID:22593561

  14. Increased mortality in amateur radio operators due to lymphatic and hematopoietic malignancies

    SciTech Connect

    Milham, S. Jr.

    1988-01-01

    To search for potentially carcinogenic effects of electromagnetic field exposures, the author conducted a population-based study of mortality in US amateur radio operators. Ascertainment of Washington State and California amateur radio operators (67,829 persons) was done through the 1984 US Federal Communications Commission Amateur Radio Station and/or Operator License file. A total of 2485 deaths were located for the period from January 1, 1979 through December 31, 1984, in a population of amateur radio operators which accumulated 232,499 person-years at risk. The all-cause standardized mortality ratio (SMR) was 71, but a statistically significant increased mortality was seen for cancers of the other lymphatic tissues (SMR = 162), a rubric which includes multiple myeloma and non-Hodgkin's lymphomas. The all-leukemia standardized mortality ratio was slightly, but nonsignificantly, elevated (SMR = 124). However, mortality due to acute myeloid leukemia was significantly elevated (SMR = 176).

  15. CDKN2A and BAP1 germline mutations predispose to melanoma and mesothelioma.

    PubMed

    Betti, M; Aspesi, A; Biasi, A; Casalone, E; Ferrante, D; Ogliara, P; Gironi, L C; Giorgione, R; Farinelli, P; Grosso, F; Libener, R; Rosato, S; Turchetti, D; Maffè, A; Casadio, C; Ascoli, V; Dianzani, C; Colombo, E; Piccolini, E; Pavesi, M; Miccoli, S; Mirabelli, D; Bracco, C; Righi, L; Boldorini, R; Papotti, M; Matullo, G; Magnani, C; Pasini, B; Dianzani, I

    2016-08-10

    BAP1 germline mutations predispose to a cancer predisposition syndrome that includes mesothelioma, cutaneous melanoma, uveal melanoma and other cancers. This co-occurrence suggests that these tumors share a common carcinogenic pathway. To evaluate this hypothesis, we studied 40 Italian families with mesothelioma and/or melanoma. The probands were sequenced for BAP1 and for the most common melanoma predisposition genes (i.e. CDKN2A, CDK4, TERT, MITF and POT1) to investigate if these genes may also confer susceptibility to mesothelioma. In two out of six families with both mesothelioma and melanoma we identified either a germline nonsense mutation (c.1153C > T, p.Arg385*) in BAP1 or a recurrent pathogenic germline mutation (c.301G > T, p.Gly101Trp) in CDKN2A. Our study suggests that CDKN2A, in addition to BAP1, could be involved in the melanoma and mesothelioma susceptibility, leading to the rare familial cancer syndromes. It also suggests that these tumors share key steps that drive carcinogenesis and that other genes may be involved in inherited predisposition to malignant mesothelioma and melanoma.

  16. Peritoneal mesothelioma metastasis to the tongue – Comparison with 8 pleural mesothelioma reports with tongue metastases

    PubMed Central

    Vazquez, Melisa V.; Selvendran, Selwyn; Cheluvappa, Rajkumar; McKay, Michael J.

    2015-01-01

    Purpose Malignant mesothelioma (MM) rarely arises from the peritoneum. We describe the 1st such case which metastasised to the head and neck region (tongue). Methods We briefly surveyed the American Surveillance Epidemiology and End Results (SEER) database, and the British Cancer Research UK database for the latest trends in MM incidence. We did a systematic Pubmed search for other MM reports with tongue metastases. Results and presentation of case American and British data show that MM incidence in men has stabilised in the last 10 years, earlier than previously predicted. The tongue is an unusual site for MM spread, with ours being only the 9th such case described. Our summary of published cases of MM metastasising to the tongue brings out our patient to be the least in age(35 years), and the only one to have peritoneal MM as the primary. Seven of the 9 cases were male. Only 2 had a recorded history of exposure to asbestos. All 9 patients had the epithelioid subtype of MM. Surgery was done as the exclusive reported intervention in 4 out of the 9 patients. Only 2 cases received radiotherapy, amongst whom, only our patient responded. Conclusions Metastasis of MM to the tongue is rare and usually in the uncommon context of MM with multiple sites of extra-thoracic or extra-abdominal spread. We have described a unique clinical manifestation of a rare subtype of mesothelioma. Moreover, we have tabulated and summarised details (including responses to surgery or/and radiotherapy) regarding all reported cases of mesotheliomas with tongue metastasis. PMID:26900461

  17. Explaining Alberta's rising mesothelioma rates.

    PubMed

    Cree, M; Lalji, M; Jiang, B; Carriere, K C; Beach, J; Kamruzzaman, A

    2009-01-01

    Although mesothelioma rates have been rising worldwide, little is known about mesothelioma trends in Alberta. This population-based descriptive study used Alberta Cancer Board Registry data from 1980 to 2004 to develop an age-period-cohort model of male pleural mesothelioma incidence rates over time. Both age and cohort effects are associated with incidence rates. The highest-risk cohort comprised men born between 1930 and 1939, reflecting widespread asbestos use and exposure beginning in the 1940s in Canada. We predict that 1393 Albertan men 40 years and older will die of pleural mesothelioma between 1980 and 2024; 783 (56.2%) of these deaths will occur between 2010 and 2024. The total number of mesothelioma deaths in Alberta will be higher when all age groups, both sexes, and all disease sites are included, with numbers likely peaking sometime between 2015 and 2019. In addition to the ongoing efforts that focus on eliminating asbestos-related disease in Alberta, the challenge is to implement surveillance systems to prevent future epidemics of preventable occupational cancers in Alberta.

  18. Evolution of management in peritoneal surface malignancies

    PubMed Central

    Canbay, Emel; Torun, Bahar Canbay; Torun, Ege Sinan; Yonemura, Yutaka

    2016-01-01

    Management of peritoneal surface malignancies has gradually evolved by the introduction of cytoreductive surgery in combination with intraperitoneal chemotherapy applications. Recently, peritoneal metastases of intraabdominal solid organ tumors and primary peritoneal malignancies such as peritoneal mesothelioma are being treated with this new approach. Selection criteria are important to reduce morbidity and mortality rates of patients who will experience minimal or no benefit from these combined treatment modalities. Management of peritoneal surface malignancies with this current trend is presented in this review. PMID:27528813

  19. Evolution of management in peritoneal surface malignancies.

    PubMed

    Canbay, Emel; Torun, Bahar Canbay; Torun, Ege Sinan; Yonemura, Yutaka

    2016-01-01

    Management of peritoneal surface malignancies has gradually evolved by the introduction of cytoreductive surgery in combination with intraperitoneal chemotherapy applications. Recently, peritoneal metastases of intraabdominal solid organ tumors and primary peritoneal malignancies such as peritoneal mesothelioma are being treated with this new approach. Selection criteria are important to reduce morbidity and mortality rates of patients who will experience minimal or no benefit from these combined treatment modalities. Management of peritoneal surface malignancies with this current trend is presented in this review. PMID:27528813

  20. [Primary malignant solitary fibrous tumor/hemangiopericytoma of the parotid gland].

    PubMed

    Messa-Botero, Oscar Alberto; Romero-Rojas, Alfredo Ernesto; Chinchilla Olaya, Sandra Isabel; Díaz-Pérez, Julio Alexander; Tapias-Vargas, Luis Felipe

    2011-01-01

    Solitary fibrous tumor (SFT) was first described in the pleura by Lietaud in 1767; later in 1870, Wagner described the localized nature of this type of tumor and Klemperer and Rabin classified pleural tumors into two types: diffuse mesotheliomas and localized mesotheliomas. Recent years have seen the redefinition of this neoplasm, due to better technology; it is now proven that this neoplasm may have multiple different extrapleural origins including the head and neck regions. This diversity of locations is related to the particular mesenchymal histogenesis of SFT which allows its development from very unusual sites such as the salivary glands (SGs). In this particular site, this neoplasm is very infrequent and most of reported cases refer to benign disease, with just one case informed so far of primary malignant SFT.

  1. Approach to offering remote support to mesothelioma patients: the mesothelioma survivor project

    PubMed Central

    Hashmi, Anisah K.; Bressler, Toby; Zajac, Jill; Hesdorffer, Mary; Taub, Robert N.

    2016-01-01

    Background From the moment of diagnosis, malignant mesothelioma (MM) decreases health-related quality of life (QOL) in patients and their caregivers. In addition to symptoms of disease, aggressive treatments such as surgery, radiation, and chemotherapy can cause extreme side effects—chemotherapy specifically is associated with chronic fatigue, unremitting nausea, vomiting, and systemic pain. These side effects of treatments can be burdensome enough to lead to noncompliance or outright refusal of continuation of care. Methods The platform for the support group was remote, consisting of online and telephone domains. Participants would utilize both online and phone systems during sessions held once a week for a total of six weeks. Sessions were guided and kept closed, available only to those affected by mesothelioma. Follow-up information and session summaries were provided online after support meetings. Results Using a 0–5 Likert Scale, consistent attendees reported support groups as very helpful. Irregular attendees had mixed feelings ranging from extremely helpful to neutral. Eighty per cent of attendees participated in support groups prior to this project. Conclusions Active participation in a guided and closed support group allowed participants to share their experiences and concerns about their diagnoses comfortably, supporting transition beyond active-treatment. Online space gave participants a place to provide more reflective responses outside the main dialogue of support sessions. PMID:27413697

  2. [A case of mesothelioma of perinephric space origin].

    PubMed

    Furuta, N; Machida, T; Ohishi, Y; Akasaka, Y; Ikemoto, I; Nakauchi, K

    1991-12-01

    Cystic mesothelioma of perinephric retroperitoneum origin are very uncommon tumors and considered potentially malignant. We report one such case and discuss the clinical and pathological findings. A 70-year-old man was seen with complaint of discomfort in the right flank and hospitalized in May 1989. Computerized tomography revealed multiple cystic masses in the right retroperitoneal space which appeared to be infiltrating the kidney and the iliopsoas muscles. Magnetic resonance imaging showed deformation of the right kidney with many impressions in the parenchyma. The cystic lesions and the right kidney were extirpated on June 2, 1989. Grossly the specimen was 16 x 10 x 8 cm in size and 630 g in weight. The multiple cysts surrounding the kidney were each approximately 10 mm in diameter and had thin outer walls. The cyst fluid was clear and serous. The kidney had not been infiltrated but had only external impressions caused by the cystic lesions. Microscopically, the cysts were lined by a single layer of cuboidal cells accompanied by some hobnail-shaped cells, and no evidence of malignancy was found. The epithelium was focally positive for periodate acid Schiff and slightly positive for Alcian blue. It was strongly positive for cytokeratin and vimentin, and slightly positive for EMA but negative for lectins. The diagnosis was diffused benign multicystic mesothelioma. However, CT taken four months after the operation revealed local recurrence and radiotherapy (40 Gy) was instituted. Since the cystic mass tended to grow in size thereafter, the lesion appeared to be malignant clinically. We consider this is the first case of cystic mesothelioma of perinephric retroperitoneum origin reported in Japan.

  3. Asbestos-related malignancy.

    PubMed

    Talcott, J A; Antman, K H

    1988-01-01

    Asbestos-associated malignancies have received significant attention in the lay and medical literature because of the increasing frequency of two asbestos-associated tumors, lung carcinoma and mesothelioma; the wide distribution of asbestos; its status as a prototype environmental carcinogen; and the many recent legal compensation proceedings, for which medical testimony has been required. The understanding of asbestos-associated carcinogenesis has increased through study of animal models, human epidemiology, and, recently, the application of modern molecular biological techniques. However, the detailed mechanisms of carcinogenesis remain unknown. A wide variety of malignancies have been associated with asbestos, although the strongest evidence for a causal association is confined to lung cancer and mesothelioma. Epidemiological studies have provided evidence that both the type of asbestos fiber and the industry in which the exposure occurs may affect the rates of asbestos-associated cancers. It has been shown that asbestos exerts a carcinogenic effect independent of exposure to cigarette smoking that, for lung cancers, is synergistically enhanced by smoking. Other questions remain controversial, such as whether pulmonary fibrosis necessarily precedes asbestos-associated lung cancer and whether some threshold level of exposure to asbestos (including low-dose exposures that may occur in asbestos-associated public buildings) may be safe. Mesothelioma, the most closely asbestos-associated malignancy, has a dismal natural history and has been highly resistant to therapy. However, investigational multi-modality therapy may offer benefit to some patients. A description of the processes through which compensation claims for asbestos-associated malignancies are evaluated illustrates for physicians the legal system's approach to possible injury from toxic substances. The differences between scientific and legal reasoning about the causes of diseases with long latency

  4. Mesothelioma among machinists in railroad and other industries.

    PubMed

    Mancuso, T F

    1983-01-01

    The first phase of the exploration of occupation-related cancer among machinists was a retrospective review of deaths among members of the International Association of Machinists and Aerospace Workers in 1973, in which mesotheliomas were identified in workers in railroad and other industries. The second phase of the study initiated in 1982 was the establishment of a cohort study of machinists, employed for railroad company A, who were alive in January 1954. The cohort consisted of 197 machinists who had been employed by the same railroad prior to 1935 and observed to 1982. Causes of death were identified for 132 of the cohort. There were 18 alive and 47 not traced. Among the 29 cancer deaths, there were nine mesotheliomas and one endothelioma of the pleura. Additional retrospective surveys of deaths among members of the railroad lodges of the international union, together with the cohort study, identified a total of 42 mesotheliomas, two endotheliomas of the pleura, and two cancers of the pleura among former railroad machinists. Among the machinists employed in other industries, 16 mesotheliomas and six cancers of the pleura were identified. For decades, machinists, by the nature of their craft, have had a high risk of occupation-related cancer due to asbestos exposure.

  5. Current Treatment of Mesothelioma: Extrapleural Pneumonectomy Versus Pleurectomy/Decortication.

    PubMed

    Wolf, Andrea S; Flores, Raja M

    2016-08-01

    The role of surgical resection in malignant pleural mesothelioma (MPM) is based on the principle of macroscopic resection of a solid tumor with adjuvant therapy to treat micrometastatic disease. Extrapleural pneumonectomy (EPP) and pleurectomy decortication (P/D) have been developed in this context. Cancer-directed surgery for MPM is associated with a 5-year survival rate of 15%. Evidence indicates that P/D is better tolerated by patients and suggests survival is no worse when compared with EPP. Although EPP is still performed in highly selected cases, the authors advocate radical P/D whenever possible for patients with MPM.

  6. Molecular profiling reveals primary mesothelioma cell lines recapitulate human disease.

    PubMed

    Chernova, T; Sun, X M; Powley, I R; Galavotti, S; Grosso, S; Murphy, F A; Miles, G J; Cresswell, L; Antonov, A V; Bennett, J; Nakas, A; Dinsdale, D; Cain, K; Bushell, M; Willis, A E; MacFarlane, M

    2016-07-01

    Malignant mesothelioma (MM) is an aggressive, fatal tumor strongly associated with asbestos exposure. There is an urgent need to improve MM patient outcomes and this requires functionally validated pre-clinical models. Mesothelioma-derived cell lines provide an essential and relatively robust tool and remain among the most widely used systems for candidate drug evaluation. Although a number of cell lines are commercially available, a detailed comparison of these commercial lines with freshly derived primary tumor cells to validate their suitability as pre-clinical models is lacking. To address this, patient-derived primary mesothelioma cell lines were established and characterized using complementary multidisciplinary approaches and bioinformatic analysis. Clinical markers of mesothelioma, transcriptional and metabolic profiles, as well as the status of p53 and the tumor suppressor genes CDKN2A and NF2, were examined in primary cell lines and in two widely used commercial lines. Expression of MM-associated markers, as well as the status of CDKN2A, NF2, the 'gatekeeper' in MM development, and their products demonstrated that primary cell lines are more representative of the tumor close to its native state and show a degree of molecular diversity, thus capturing the disease heterogeneity in a patient cohort. Molecular profiling revealed a significantly different transcriptome and marked metabolic shift towards a greater glycolytic phenotype in commercial compared with primary cell lines. Our results highlight that multiple, appropriately characterised, patient-derived tumor cell lines are required to enable concurrent evaluation of molecular profiles versus drug response. Furthermore, application of this approach to other difficult-to-treat tumors would generate improved cellular models for pre-clinical evaluation of novel targeted therapies.

  7. Molecular profiling reveals primary mesothelioma cell lines recapitulate human disease

    PubMed Central

    Chernova, T; Sun, X M; Powley, I R; Galavotti, S; Grosso, S; Murphy, F A; Miles, G J; Cresswell, L; Antonov, A V; Bennett, J; Nakas, A; Dinsdale, D; Cain, K; Bushell, M; Willis, A E; MacFarlane, M

    2016-01-01

    Malignant mesothelioma (MM) is an aggressive, fatal tumor strongly associated with asbestos exposure. There is an urgent need to improve MM patient outcomes and this requires functionally validated pre-clinical models. Mesothelioma-derived cell lines provide an essential and relatively robust tool and remain among the most widely used systems for candidate drug evaluation. Although a number of cell lines are commercially available, a detailed comparison of these commercial lines with freshly derived primary tumor cells to validate their suitability as pre-clinical models is lacking. To address this, patient-derived primary mesothelioma cell lines were established and characterized using complementary multidisciplinary approaches and bioinformatic analysis. Clinical markers of mesothelioma, transcriptional and metabolic profiles, as well as the status of p53 and the tumor suppressor genes CDKN2A and NF2, were examined in primary cell lines and in two widely used commercial lines. Expression of MM-associated markers, as well as the status of CDKN2A, NF2, the ‘gatekeeper' in MM development, and their products demonstrated that primary cell lines are more representative of the tumor close to its native state and show a degree of molecular diversity, thus capturing the disease heterogeneity in a patient cohort. Molecular profiling revealed a significantly different transcriptome and marked metabolic shift towards a greater glycolytic phenotype in commercial compared with primary cell lines. Our results highlight that multiple, appropriately characterised, patient-derived tumor cell lines are required to enable concurrent evaluation of molecular profiles versus drug response. Furthermore, application of this approach to other difficult-to-treat tumors would generate improved cellular models for pre-clinical evaluation of novel targeted therapies. PMID:26891694

  8. A Case of Unsuspected Peritoneal Mesothelioma Occurring with Colonic Adenocarcinoma Masquerading as Peritoneal Metastases

    PubMed Central

    Green, Linda K.; Patel, Rishi A.; Lai, Syeling

    2014-01-01

    We report a case of synchronous primary colonic adenocarcinoma and malignant mesothelioma. A 61-year-old male presented with a six-month history of fatigue and weight loss. An abdominal computed tomography (CT) scan showed a 5.8 cm partially obstructing mass in the cecum with ascites and peritoneal thickening. A biopsy of the large mass showed an adenocarcinoma. Because the patient was clinically thought to be a T4 colon carcinoma with peritoneal metastatic lesions (M1), prior to initiating chemotherapy, a debulking right hemicolectomy was performed. Resection of the colon and ileum revealed a T3N0 colonic mucinous adenocarcinoma and concurrent diffuse malignant peritoneal mesothelioma. Presenting synchronous colonic and peritoneal mesothelial primary malignancies are exceedingly rare but must be considered to prevent incorrect clinical staging. PMID:24963429

  9. Tumor type influences the effectiveness of pleurodesis in malignant effusions.

    PubMed

    Bielsa, Silvia; Hernández, Paula; Rodriguez-Panadero, Francisco; Taberner, Teresa; Salud, Antonieta; Porcel, José M

    2011-04-01

    Pleurodesis is commonly indicated for symptom relief in patients with malignant pleural effusions. A number of factors may influence pleurodesis outcome, but whether tumor type is one of them is a matter of debate. This study investigates the impact of tumor type on the efficacy of bedside doxycycline and thoracoscopic talc poudrage pleurodesis in order to determine which patients may benefit most from these procedures. A retrospective study of 138 and 450 doxycycline and talc poudrage pleurodesis procedures, respectively, evaluated their overall successes and failures, according to primary tumor types. In addition, a logistic regression model addressed whether the pleurodesis outcome in different tumor types was influenced by or attributable to pleural tumor burden. In the talc group, patients with lung cancer and mesothelioma had significantly lower complete response rates (63 and 61%, respectively) as compared with breast (77%) and other metastatic effusions (74%, p = 0.012). In the doxycycline group, the data followed the same trend in that complete response rates were lower in patients with lung carcinomas (31%) than in those with breast cancer (54%) or metastases from other primary sites (74%, p = 0.001). The regression analysis showed pleural burden and tumor type as independent predictors of pleurodesis failure in the talc group. The tumor type involving the pleural surfaces influences the success of a pleurodesis, regardless of the sclerosing agent used. Malignant effusions due to mesothelioma and lung cancer are particularly prone to a failed procedure.

  10. Tumor type influences the effectiveness of pleurodesis in malignant effusions.

    PubMed

    Bielsa, Silvia; Hernández, Paula; Rodriguez-Panadero, Francisco; Taberner, Teresa; Salud, Antonieta; Porcel, José M

    2011-04-01

    Pleurodesis is commonly indicated for symptom relief in patients with malignant pleural effusions. A number of factors may influence pleurodesis outcome, but whether tumor type is one of them is a matter of debate. This study investigates the impact of tumor type on the efficacy of bedside doxycycline and thoracoscopic talc poudrage pleurodesis in order to determine which patients may benefit most from these procedures. A retrospective study of 138 and 450 doxycycline and talc poudrage pleurodesis procedures, respectively, evaluated their overall successes and failures, according to primary tumor types. In addition, a logistic regression model addressed whether the pleurodesis outcome in different tumor types was influenced by or attributable to pleural tumor burden. In the talc group, patients with lung cancer and mesothelioma had significantly lower complete response rates (63 and 61%, respectively) as compared with breast (77%) and other metastatic effusions (74%, p = 0.012). In the doxycycline group, the data followed the same trend in that complete response rates were lower in patients with lung carcinomas (31%) than in those with breast cancer (54%) or metastases from other primary sites (74%, p = 0.001). The regression analysis showed pleural burden and tumor type as independent predictors of pleurodesis failure in the talc group. The tumor type involving the pleural surfaces influences the success of a pleurodesis, regardless of the sclerosing agent used. Malignant effusions due to mesothelioma and lung cancer are particularly prone to a failed procedure. PMID:21331598

  11. Gene Expression of Mesothelioma in Vinylidene Chloride-Exposed F344/N Rats Reveals Immune Dysfunction, Tissue Damage, and Inflammation Pathways

    PubMed Central

    Blackshear, Pamela E.; Pandiri, Arun R.; Nagai, Hiroaki; Bhusari, Sachin; Hong, Lily; Ton, Thai-Vu T.; Clayton, Natasha P.; Wyde, Michael; Shockley, Keith R.; Peddada, Shyamal D.; Gerrish, Kevin E.; Sills, Robert C.; Hoenerhoff, Mark J.

    2014-01-01

    A majority (~80%) of human malignant mesotheliomas are asbestos-related. However, non-asbestos risk factors (radiation, chemicals, genetic factors) account for up to 30% of cases. A recent two-year National Toxicology Program carcinogenicity bioassay showed that male F344/N rats exposed to the industrial toxicant vinylidene chloride (VDC) resulted in a marked increase in malignant mesothelioma. Global gene expression profiles of these tumors were compared to spontaneous mesotheliomas and the F344/N rat mesothelial cell line (Fred-PE) in order to characterize the molecular features and chemical-specific profiles of mesothelioma in VDC-exposed rats. As expected, mesotheliomas from control and vinylidene chloride-exposed rats shared pathways associated with tumorigenesis, including cellular and tissue development, organismal injury, embryonic development, inflammatory response, cell cycle regulation, and cellular growth and proliferation, while mesotheliomas from vinylidene chloride-exposed rats alone showed overrepresentation of pathways associated with pro-inflammatory pathways and immune dysfunction such as the NF-kB signaling pathway, IL-8 and IL-12 signaling, interleukin responses, Fc receptor signaling, and NK and DC signaling, as well as overrepresentation of DNA damage and repair. These data suggest that a chronic, proinflammatory environment associated with VDC exposure may exacerbate disturbances in oncogene, growth factor and cell cycle regulation, resulting in an increased incidence of mesothelioma. PMID:24958746

  12. Future trends of mesothelioma mortality in Japan based on a risk function.

    PubMed

    Myojin, Tomoya; Azuma, Kenichi; Okumura, Jiro; Uchiyama, Iwao

    2012-01-01

    Mesothelioma is a malignancy with poor prognosis. It is chiefly caused by asbestos exposure and its symptoms can occur about 30-50 yr after the initial exposure. This study aims to predict the future trends in mesothelioma mortality in Japan using a method that is an alternative to the age-cohort model. Our approach is based on a risk function that links mesothelioma mortality combined with data pertaining to the population, size of the labor force, and quantity of asbestos imports. We projected the number of deaths occurring in individuals aged 50-89 for yr 2003-2050 using risk functions. Our results have indicated that mesothelioma mortality among Japanese people aged 50-89 yr will continue to increase until 2027 and reach a maximum of 66,327 deaths in the years 2003-2050. Our estimate has also suggested that the number of mesothelioma deaths could be significantly reduced if there were adequate compliance with the administrative level guidelines for occupational asbestos exposure.

  13. Industrial-grade talc exposure and the risk of mesothelioma.

    PubMed

    Price, Bertram

    2010-07-01

    Industrial-grade talc deposits are complex mixtures of mineral particles and may vary substantially in composition across small geographical areas. Typical industrial-grade talc includes amphibole cleavage fragments, platy talc, serpentine minerals, talc in fibrous form, and a minor presence of transitional fibers. Industrial-grade talc was erroneously determined to be an asbestos-containing material due to an unintended consequence of Occupational Health and Safety Administration's (OSHA's) method for measuring airborne asbestos mandated in 1972. This error was repeated, most notably, by the National Institute for Occupational Safety and Health (NIOSH) in, 1980 for talc mined in northern New York State (NYS) by RT Vanderbilt Company (RTV). Subsequent exposure studies of northern NYS talc conducted through the, 1980s and one study published after, 2000 relied on the conclusion that talc was an asbestos-containing material to infer a causal relationship between talc and mesothelioma. The present review included (1) publications concerning talc's cancer-causing potential issued by organizations concerned with occupational and public health; (2) talc exposure studies and animal and cellular studies of RTV talc; (3) mesothelioma rates in northern NYS; and (4) mesothelioma mortality among RTV mining employees. The review indicated that failure to correctly identify the mineral characteristics of talc resulted in misleading reports concerning the carcinogenic potential of talc. However, the collective data from animal and cellular studies, mesothelioma rates in northern NYS, exposure studies, and a mortality analysis of RTV mining employees do not support a causal relationship between RTV talc and mesothelioma. This conclusion is applicable to all mineral components in RTV talc and to other industrial-grade talcs and mineral aggregates with the same components.

  14. Analysis of Gene Expression in 3D Spheroids Highlights a Survival Role for ASS1 in Mesothelioma

    PubMed Central

    Barbone, Dario; Van Dam, Loes; Follo, Carlo; Jithesh, Puthen V.; Zhang, Shu-Dong; Richards, William G.; Bueno, Raphael; Fennell, Dean A.; Broaddus, V. Courtney

    2016-01-01

    To investigate the underlying causes of chemoresistance in malignant pleural mesothelioma, we have studied mesothelioma cell lines as 3D spheroids, which acquire increased chemoresistance compared to 2D monolayers. We asked whether the gene expression of 3D spheroids would reveal mechanisms of resistance. To address this, we measured gene expression of three mesothelioma cell lines, M28, REN and VAMT, grown as 2D monolayers and 3D spheroids. A total of 209 genes were differentially expressed in common by the three cell lines in 3D (138 upregulated and 71 downregulated), although a clear resistance pathway was not apparent. We then compared the list of 3D genes with two publicly available datasets of gene expression of 56 pleural mesotheliomas compared to normal tissues. Interestingly, only three genes were increased in both 3D spheroids and human tumors: argininosuccinate synthase 1 (ASS1), annexin A4 (ANXA4) and major vault protein (MVP); of these, ASS1 was the only consistently upregulated of the three genes by qRT-PCR. To measure ASS1 protein expression, we stained 2 sets of tissue microarrays (TMA): one with 88 pleural mesothelioma samples and the other with additional 88 pleural mesotheliomas paired with matched normal tissues. Of the 176 tumors represented on the two TMAs, ASS1 was expressed in 87 (50%; staining greater than 1 up to 3+). For the paired samples, ASS1 expression in mesothelioma was significantly greater than in the normal tissues. Reduction of ASS1 expression by siRNA significantly sensitized mesothelioma spheroids to the pro-apoptotic effects of bortezomib and of cisplatin plus pemetrexed. Although mesothelioma is considered by many to be an ASS1-deficient tumor, our results show that ASS1 is elevated at the mRNA and protein levels in mesothelioma 3D spheroids and in human pleural mesotheliomas. We also have uncovered a survival role for ASS1, which may be amenable to targeting to undermine mesothelioma multicellular resistance. PMID:26982031

  15. Asbestos-induced peritoneal mesothelioma in a construction worker.

    PubMed Central

    Fonte, Rodolfo; Gambettino, Salvatore; Melazzini, Mario; Scelsi, Mario; Zanon, Claudio; Candura, Stefano M

    2004-01-01

    Occupational and environmental asbestos exposure continues to represent a public health problem, despite increasingly restrictive laws adopted by most industrialized countries. Peritoneal mesothelioma is a rare and aggressive asbestos-related malignancy. We present the case of a 65-year-old man who developed recurrent ascites after having been exposed to asbestos in the building industry for > 40 years. Liver function and histology were normal. Abdominal computed tomography initially excluded the presence of expansive processes, and no abnormal cells were found in the ascitic fluid. Laparoscopy showed diffuse neoplastic infiltration of the peritoneum. Histopathology of bioptic samples revealed epithelioid neoplastic proliferation with a tubulopapillary pattern, falsely suggesting metastatic adenocarcinomatosis. In consideration of the occupational history, and after further diagnostic procedures had failed to identify the hypothetical primitive tumor, immunostaining of the neoplastic tissue was performed. Results were negative for carcinoembrionary antigen and the epithelial glycoprotein Ber-EP4, whereas results were positive for the mesothelial markers cytokeratins, calretinin, epithelial membrane antigen, and HBME-1, thus leading to the correct diagnosis of peritoneal epithelial mesothelioma. The Italian Workers' Compensation Authority recognized the occupational origin of the disease. Cytoreductive surgery associated with continuous hyperthermic peritoneal perfusion (cisplatin at 42 degrees C, for 1 hr) was performed. The disease relapsed after 4 months and was later complicated by a bowel obstruction requiring palliative ileostomy. The patient died 23 months after diagnosis. This case illustrates the insidious diagnostic problems posed by peritoneal mesothelioma, a tumor which often simulates other malignancies (e.g., metastatic carcinomas) at routine histopathological examination. Occupational history and immunohistochemistry are helpful for the correct

  16. Asbestos-induced peritoneal mesothelioma in a construction worker.

    PubMed

    Fonte, Rodolfo; Gambettino, Salvatore; Melazzini, Mario; Scelsi, Mario; Zanon, Claudio; Candura, Stefano M

    2004-04-01

    Occupational and environmental asbestos exposure continues to represent a public health problem, despite increasingly restrictive laws adopted by most industrialized countries. Peritoneal mesothelioma is a rare and aggressive asbestos-related malignancy. We present the case of a 65-year-old man who developed recurrent ascites after having been exposed to asbestos in the building industry for > 40 years. Liver function and histology were normal. Abdominal computed tomography initially excluded the presence of expansive processes, and no abnormal cells were found in the ascitic fluid. Laparoscopy showed diffuse neoplastic infiltration of the peritoneum. Histopathology of bioptic samples revealed epithelioid neoplastic proliferation with a tubulopapillary pattern, falsely suggesting metastatic adenocarcinomatosis. In consideration of the occupational history, and after further diagnostic procedures had failed to identify the hypothetical primitive tumor, immunostaining of the neoplastic tissue was performed. Results were negative for carcinoembrionary antigen and the epithelial glycoprotein Ber-EP4, whereas results were positive for the mesothelial markers cytokeratins, calretinin, epithelial membrane antigen, and HBME-1, thus leading to the correct diagnosis of peritoneal epithelial mesothelioma. The Italian Workers' Compensation Authority recognized the occupational origin of the disease. Cytoreductive surgery associated with continuous hyperthermic peritoneal perfusion (cisplatin at 42 degrees C, for 1 hr) was performed. The disease relapsed after 4 months and was later complicated by a bowel obstruction requiring palliative ileostomy. The patient died 23 months after diagnosis. This case illustrates the insidious diagnostic problems posed by peritoneal mesothelioma, a tumor which often simulates other malignancies (e.g., metastatic carcinomas) at routine histopathological examination. Occupational history and immunohistochemistry are helpful for the correct

  17. Insulation workers in Belfast. A further study of mortality due to asbestos exposure (1940-75).

    PubMed Central

    Elmes, P C; Simpson, M J

    1977-01-01

    A follow-up study of 162 men already working as insulators (laggers) in 1940 has been extended from 1965 to 1975. By the end of 1975 there were 40 survivors when 108 had been expected. Until 1965 there had been an overall excess of deaths; these were due to asbestosis with or without tuberculosis and to alimentary cancer, as well as to bronchial carcinoma and mesothelioma. From 1965 onwards the overall death rate among survivors is not so excessive but there is still a marked excess of deaths from bronchial cancer and mesothelioma. The continued risk of death attributable to malignancy after asbestosis had ceased to contribute directly, does not appear to be caused by any changes which occurred before 1940 in the conditions at work. PMID:911687

  18. [Retroperitoneal cystic mesothelioma and lymphangioma].

    PubMed

    Segura Martín, M; Lorenzo Romero, J G; Hernández Millán, I; Pastor Guzmán, J M; Salinas Sánchez, A S; Ruiz Mondéjar, R; Virseda Rodríguez, J A

    1998-03-01

    Retroperitoneal cysts are uncommon entities of difficult diagnosis because of their insidious symptomatology. Urinary apparatus involvement is quite often the mode of presentation and the reason for calling on the urologist. The origin of many of these retroperitoneal cysts remains practically unknown. Surgery with exeresis is the choice management method. Follow-up is necessary for cystic mesothelioma because of the highly frequent relapses. The outlook of hormonal conservative therapy for relapses appears as a future alternative to treatment.

  19. Cellular and Molecular Parameters of Mesothelioma

    PubMed Central

    Ramos-Nino, Maria E.; Testa, Joseph R.; Altomare, Deborah A.; Pass, Harvey I.; Carbone, Michele; Bocchetta, Maurizio; Mossman, Brooke T.

    2009-01-01

    Malignant mesotheliomas (MM) are neoplasms arising from mesothelial cells that line the body cavities, most commonly the pleural and peritoneal cavities. Although traditionally recognized as associated with occupational asbestos exposures, MMs can appear in individuals with no documented exposures to asbestos fibers, and emerging data suggest that genetic susceptibility and simian virus 40 (SV40) infections also facilitate the development of MMs. Both asbestos exposure and transfection of human mesothelial cells with SV40 large and small antigens (Tag, tag) cause genetic modifications and cell signaling events, most notably the induction of cell survival pathways and activation of receptors, and other proteins that favor the growth and establishment of MMs as well as their resistance to chemotherapy. Recent advances in high-throughput technologies documenting gene and protein expression in patients and animal models of MMs can now be validated in human MM tissue arrays. These have revealed expression profiles that allow more accurate diagnosis and prognosis of MMs. More importantly, serum proteomics has revealed two new candidates (osteopontin and serum mesothelin-related protein or SMRP) potentially useful in screening individuals for MMs. These mechanistic approaches offer new hope for early detection and treatment of these devastating tumors. PMID:16795078

  20. Serum PDGF-AB in pleural mesothelioma.

    PubMed

    Filiberti, Rosa; Marroni, Paola; Neri, Monica; Ardizzoni, Andrea; Betta, Pier Giacomo; Cafferata, Mara A; Canessa, Pier Aldo; Puntoni, Riccardo; Ivaldi, Giovanni Paolo; Paganuzzi, Michela

    2005-01-01

    Overexpression of platelet-derived growth factor (PDGF) has been observed in lung and pleural tumors. The aim of this study was to evaluate the diagnostic and prognostic role of serum PDGF in pleural mesothelioma (PM). Four groups of subjects were studied: 93 malignant PM patients, 33 primary non small cell lung cancer patients, 51 subjects exposed to asbestos, defined as high-risk controls, and 24 healthy controls. PDGF-AB mean concentration was higher in PM patients (45.8 ng/ml) than in high-risk controls (33.1 ng/ml) and healthy controls (26.8 ng/ml). Using the cut-off level of 49.8 ng/ml, corresponding to the mean+2SD of PDGF-AB in healthy controls, 43% of PM patients showed positive PDGF-AB levels. Survival was evaluated in 82 PM patients. At the end of the follow-up (median 9.8 months) 80.5% of patients had died. Median survival was 13.1 and 7.9 months for patients with PDGF-AB lower and higher than the cut-off, respectively. Adjusting for age, sex, histology and platelet count, positive PDGF-AB levels were associated with lower survival (OR=1.2, 95%CI: 0.9-1.6), even if not significantly so. In conclusion, serum PDGF may represent a useful additional parameter to prognostic factors already available for PM.

  1. Medico-legal aspects of mesothelioma.

    PubMed

    Partemi, Sara; De Giorgio, Fabio

    2007-01-01

    The Authors, reviewing the Literature on asbestos-related Malignant Mesothelioma (MM), found that because of its very peculiar characteristics, the causal link between professional asbestos exposure and the development of this tumour is very difficult to define in respect to: diagnosis, causal link and individuation of possible culpable conducts. The evaluation of causal link in different medico-legal areas is studied by different criteria. In civil law the criterion of weak causality is followed to allow compensation for damages. For institutional purposes in INAIL, the definition of causal link is particularly facilitated by the legal presumption of origin. In fact it is sufficient, that asbestos-related lesions are ascertained in individuals who are or were exposed at any time of their professional life to the risk of inhaling asbestos fibres. In criminal law, the current approach of the Supreme Court is to demand evidence of strong causality, with a high logical probability and rational credibility, and beyond reasonable doubt, because criminal liability is personal as established in article 27 of the Italian Constitution. It is worth pointing out that all the levels of evidence indicated above must pass the test of scientific suitability or possibility.

  2. Endoscopic fistulotomy and biliary drainage as the ultimate palliative treatment for obstruction due to malignant tumors of the papilla of Vater.

    PubMed

    Feretis, C; Tabakopoulos, D; Benakis, P; Xenofontos, M; Golematis, B

    1990-01-01

    This report describes the technique and results of endoscopic fistulotomy as a drainage procedure in cases of malignant obstruction of the biliary system from bulky and friable growths in the papilla of Vater. Fistulotomy, coupled with insertion of stents, was successful in seven of eight patients and was associated with relief of jaundice. It is suggested that the method be applied when conventional transpapillary insertion of stents is impossible either due to distortion of the papilla or bleeding of the growth on touch.

  3. The significance of asbestos exposure in the diagnosis of mesothelioma: a 28-year experience from a major urban hospital.

    PubMed

    Hasan, F M; Nash, G; Kazemi, H

    1977-05-01

    A continued increase in the incidence of diffuse mesothelioma has been attributed to greater industrial use of asbestos but is also due in part to wider acceptance of this tumor by pathologists. In this retrospective study, the epidemiology, clinical presentation, and pathology of asbestos and non-asbestos-related mesothelioma from a major urban hospital were reviewed. Of the 36 cases of mesothelioma on file, 19 were not associated with exposure to asbestos. Although a retrospective study raises the possibility of inadequate occupational histories, the lack of history of asbestos exposure correlated with postmortem histology by light microscopy. When postmortem material was reviewed, evidence of asbestos exposure was present in all cases of mesothelioma with history of exposure to asbestos, and in no cases in which the patient denied history of asbestos exposure. Using strict histologic and histochemical criteria, the diagnosis of mesothelioma was confirmed in 8 of 9 patients with asbestos-related mesothelioma but in only 4 of 13 cases of non-asbestos-related mesothelioma. The diagnosis of diffuse methelioma is often difficult to make even wtih complete autopsy examinations. It should be entertained only with adherence to strict clinical and pathologic criteria, especially in women with no history to exposure to asbestos dust.

  4. Diffuse Pleural Mesothelioma and Asbestos Exposure in the North Western Cape Province

    PubMed Central

    Wagner, J. C.; Sleggs, C. A.; Marchand, Paul

    1960-01-01

    Primary malignant tumours of the pleura are uncommon. Thirty-three cases (22 males, 11 females, ages 31 to 68) of diffuse pleural mesothelioma are described; all but one have a probable exposure to crocidolite asbestos (Cape blue). In a majority this exposure was in the Asbestos Hills which lie to the west of Kimberley in the north west of Cape Province. The tumour is rarely seen elsewhere in South Africa. Images PMID:13782506

  5. Prostaglandin E receptor EP4 antagonist suppresses osteolysis due to bone metastasis of mouse malignant melanoma cells.

    PubMed

    Takita, Morichika; Inada, Masaki; Maruyama, Takayuki; Miyaura, Chisato

    2007-02-01

    We examined the effects of prostaglandin E (PGE) receptor subtype EP4 antagonist on bone metastasis of cancer to clarify PGE's role in bone metastasis. Metastatic regions were detected in femurs accompanying severe bone loss in mice injected with B16 malignant melanoma cells. Administration of EP4 antagonist restored the bone loss induced by B16 melanoma. Adding B16 cells induced osteoclast formation in the coculture of bone marrow cells and osteoblasts without any exogenous bone-resorbing factor, and EP4 antagonist completely suppressed the osteoclast formation induced by B16 cells. Therefore, EP4 antagonist is a possible candidate for the therapy of bone metastasis of cancer.

  6. Targeting Mesothelioma Using an Infectivity Enhanced Survivin-Conditionally Replicative Adenoviruses

    PubMed Central

    Zhu, Zeng B.; Makhija, Sharmila K.; Lu, Baogen; Wang, Minghui; Wang, Shuyi; Takayama, Koichi; Siegal, Gene P.; Reynolds, Paul N.; Curiel, David T.

    2007-01-01

    Mesothelioma is a highly malignant neoplasm with no effective treatment. Conditionally replicative adenoviruses (CRAds) represent a promising new modality for the treatment of cancer in general. A key contribution in this regard is the introduction of tumor-selective viral replication for amplification of the initial inoculum in the neoplastic cell population. Under ideal conditions following cellular infection, the viruses replicate selectively in the infected tumor cells and kill the cells by cytolysis, leaving normal cells unaffected. However, to date there have been two limitations to clinical application of these CRAd agents; viral infectivity and tumor specificity have been poor. Herein we report on two CRAd agents, CRAd-S.RGD and CRAd-S.F5/3, in which the tumor specificity is regulated by a tumor-specific promoter, the survivin promoter, and the viral infectivity is enhanced by incorporating a capsid modification (RGD or F5/3) in the adenovirus fiber region. These CRAd agents effectively target human mesothelioma cell lines, induce strong cytoxicity in these cells in vitro, and viral replication in a H226 murine xenograft model in vivo. In addition, the survivin promoter has extremely low activity both in the non-transformed cell line, HMEC, and in human liver tissue. Our results suggest that the survivin-based CRAds are promising agents for targeting mesothelioma with low host toxicity. These agents should provide important insights into the identification of novel therapeutic strategies for mesothelioma. PMID:17409940

  7. Radiation therapy in the management of patients with mesothelioma

    SciTech Connect

    Gordon, W. Jr.; Antman, K.H.; Greenberger, J.S.; Weichselbaum, R.R.; Chaffey, J.T.

    1982-01-01

    The results of radiation therapy in the management of 27 patients with malignant mesothelioma were reviewed. Eight patients were treated with a curative intent combining attempted surgical excision of tumor (thoracic in 6 and peritoneal in 2), aggressive radiation therapy, and combination chemotherapy using an adriamycin-containing regimen. One patient achieved a 2-year disease-free inteval followed by recurrence of tumor above the thoracic irradiation field. This patient was retreated with localized irradiation and is disease-free after 5 years of initial diagnosis. One patient has persistent abdominal disease at 18 months; the other 6 patients suffered local recurrence within 8-13 months of initiation of treatment. Radiation therapy was used in 19 other patients who received 29 courses for palliation of dyspnea, superior vena cava syndrome, dysphagia, or neurological symptoms of brain metastasis. A palliation index was used to determine the effectiveness of irradiation and revealed that relief of symptoms was complete or substantial in 5 treatment courses, moderately effective in 6 courses and inadequate in 18 treatment courses. Adequate palliation strongly correlated with a dose at or above 4,000 rad in 4 weeks. The management of patients with mesothelioma requires new and innovative approaches to increase the effectiveness of radiation therapy and minimize the significant potential combined toxicity of pulmonary irradiation and adriamycin.

  8. Asbestos and peritoneal mesothelioma among college-educated men.

    PubMed

    Welch, Laura S; Acherman, Yair I Z; Haile, Elizabeth; Sokas, Rosemary K; Sugarbaker, Paul H

    2005-01-01

    The proportion of peritoneal mesotheliomas among all mesotheliomas has been decreasing, leading some to suggest that peritoneal mesothelioma occurs only after high levels of exposure to asbestos. To investigate the relationship between asbestos exposure and the development of peritoneal mesothelioma, a case-control study examined 40 cases of primary peritoneal mesothelioma from a single institution. This series differed from previous reports in that 75% of the cases and controls had attended college. Results show an odds ratio of 6.6 for asbestos exposure among this group of primary peritoneal mesothelioma cases with relatively slight asbestos exposures.

  9. Global mesothelioma epidemic: Trend and features

    PubMed Central

    Bianchi, Claudio; Bianchi, Tommaso

    2014-01-01

    Background: Mesothelioma incidence has taken epidemic proportions in various countries. The trend of the epidemic remains undefined. Objective: To collect the most recent available data on mesothelioma incidence in order to determine the present trend of the epidemic. Materials and Methods: Data of the Cancer and Mesothelioma Registries have been reviewed. In addition, numerous researchers were contacted to obtain supplementary information. Results: The highest incidence rates are reported from some countries in Europe (United Kingdom, The Netherlands, Malta, Belgium), and in Oceania (Australia, New Zealand). Relatively low incidence/mortality rates are reported from Japan and from Central Europe. In many countries a trend to increase continues to be observed. Data are not available for the mostly populous countries. Conclusion: Mesothelioma epidemic does not show signs of attenuation. The lack of data for a large majority of the world does not allow that the consciousness of the risks related to asbestos exposure is reached. PMID:25568603

  10. Intra-abdominal benign multicystic peritoneal mesothelioma.

    PubMed

    Jouvin, I; Dohan, A; Gergi, P; Pocard, M

    2014-04-01

    Benign multicystic peritoneal mesotheliomas are rare: pre-operative diagnosis relies on proper imaging. The differential diagnosis includes pseudomyxoma peritonei and other peritoneal cysts. Absence of previous surgical resection offers the best chance of success when complete resection is performed in a specialized center. We report the case of a 43 year-old man with benign multicystic peritoneal mesothelioma treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. PMID:24433857

  11. SV40 induces mesotheliomas in hamsters.

    PubMed Central

    Cicala, C.; Pompetti, F.; Carbone, M.

    1993-01-01

    In the course of studies to elucidate the relative contribution of simian virus 40 (SV40) large T and small t proteins during oncogenesis, we observed the appearance of pericardial and pleural tumors in 100% of Syrian hamsters injected in the pleural space with wild type SV40. When SV40 was injected via the intracardiac or intraperitoneal routes, more than 50% of hamsters developed mesothelial tumors. Macroscopic, microscopic, ultramicroscopic, and histochemical characteristics identify these neoplasms and derived cell lines as mesotheliomas and mesothelioma-derived cell lines. The SV40 genome was integrated and expressed in the mesotheliomas and derived cell lines. The absence of mesotheliomas in hamsters injected with SV40 small t deletion mutants indicates that the small t protein plays an important role in the development of SV40-induced mesotheliomas. To the best of our knowledge, this is the first definitive report of virus-induced mesotheliomas in mammals. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:8388174

  12. [Pleural mesothelioma: impact of the staging for the therapeutic strategy].

    PubMed

    Greillier, L; Scherpereel, A; Astoul, P

    2007-10-01

    Realistic improvement has been recently done for the treatment of malignant pleural mesothelioma. Besides new findings for the epidemiology of the disease, medico-social impact for patients, the knowledge of biological parameters for diagnosis, prognosis and future therapeutic targets as well, the early diagnosis of the disease mainly based on more extended practice of thoracoscopy allows in association with new imaging techniques a careful staging of the disease and consequently new therapeutic implications. Indeed if new balistic assessment of the disease improves the efficacy of radiotherapy and new combined chemotherapy have shown antitumoral responses, surgical strategy takes part in the armamenterium for this disease and combined with others therapeutic modalities seems to be a raisonnable approach despite the lack of prospective, comparative, randomized study and the drawback of current staging. However, the most important point is the multidisciplinary concertation induced by the management of this disease which represents a "model" in thoracic oncology.

  13. Tumorigenic properties of alternative osteopontin isoforms in mesothelioma

    SciTech Connect

    Ivanov, Sergey V.; Ivanova, Alla V.; Goparaju, Chandra M.V.; Chen, Yuanbin; Beck, Amanda; Pass, Harvey I.

    2009-05-08

    Osteopontin (SPP1) is an inflammatory cytokine that we previously characterized as a diagnostic marker in patients with asbestos-induced malignant mesothelioma (MM). While SPP1 shows both pro- and anti-tumorigenic biological effects, little is known about the molecular basis of these activities. In this study, we demonstrate that while healthy pleura possesses all three differentially spliced SPP1 isoforms (A-C), in clinical MM specimens isoform A is markedly up-regulated and predominant. To provide a clue to possible functions of the SPP1 isoforms we next performed their functional evaluation via transient expression in MM cell lines. As a result, we report that isoforms A-C demonstrate different activities in cell proliferation, wound closure, and invasion assays. These findings suggest different functions for SPP1 isoforms and underline pro-tumorigenic properties of isoforms A and B.

  14. CD-34 and keratin expression distinguishes solitary fibrous tumor (fibrous mesothelioma) of pleura from desmoplastic mesothelioma.

    PubMed

    Flint, A; Weiss, S W

    1995-04-01

    Solitary fibrous tumors (SFTs) often involve the pleura and also may encompass the peritoneum and nonserosal sites. On occasion SFTs mimics other neoplasms, including desmoplastic mesothelioma. CD-34, initially characterized as a hematopoietic progenitor cell antigen, recently has been identified in a small number of SFTs. Based on this observation, we compared the keratin, vimentin, and CD-34 expression of 19 SFTs and eight desmoplastic mesotheliomas. Fifteen of 19 SFTs (78.9%) expressed CD-34, whereas keratin expression was absent in all SFTs. In contrast, none of the desmoplastic mesotheliomas expressed CD-34 and keratin expression was found in seven of eight (87.5%). Vimentin expression was noted in 18 of 19 SFTs and in seven of eight desmoplastic mesotheliomas. We conclude that CD-34 expression distinguishes SFT from desmoplastic mesothelioma. Additionally, the results of our study support the idea that SFT is not derived from or related to conventional mesothelium.

  15. Localised fibrous mesothelioma arising in an intralobar pulmonary sequestration.

    PubMed Central

    Paksoy, N; Demircan, A; Altiner, M; Artvinli, M

    1992-01-01

    A localised fibrous mesothelioma arising from an intralobar lung sequestration occurred in a 64 year old Turkish woman. This appears to be the first report of a mesothelioma occurring within a pulmonary sequestration. Images PMID:1481189

  16. Adenomatoid mesothelioma with intranuclear inclusion bodies: a case report with cytological and histological findings.

    PubMed

    Kawai, Toshiaki; Kawashima, Katsuhiko; Serizawa, Hiromi; Miura, Hiroyuki; Kyeongil, Kim

    2014-05-01

    We report a very unusual cytologic feature, intranuclear inclusion bodies, in mesothelioma of a predominantly adenomatoid type. The patient, a 57-year-old woman, was presented with dyspnea and right pleural effusion. Pleural aspiration cytology revealed many cohesive ball-like clusters, with a tubular pattern, composed of small atypical cells displaying a high-nuclear-cytoplasmic ratio. They had a nuclear groove and irregular intranuclear inclusion bodies. Right lung partial resection with thoracoscopy revealed that a white tumor had proliferated along the pleural surface at S(8) . Histology revealed nodular tumor cells forming dilated structures mixed with small tubular or glandular structures similar to those seen in benign adenomatoid tumors. These tumor cells had invaded peripheral lung tissues. Such inclusion bodies have not been reported earlier in mesothelioma. On the basis of this observation, we propose that the adenomatoid type of malignant mesothelioma be added to the differential diagnosis of malignant effusions when tumor cells with nuclear grooves and intranuclear inclusions are found in pleural aspiration cytology.

  17. [Occupational exposure to asbestos and recognition of pleural mesothelioma as occupational disease in the province of Genoa].

    PubMed

    Montanaro, F; Vitto, V; Lagattolla, N; Lazzarotto, A; Bianchelli, M; Puntoni, R; Gennaro, V

    2001-01-01

    The present study compares the data of pleural mesothelioma (PM) patients resident in the province of Genoa (Italy) who, in the period 1994-1996, applied to the Italian National Insurance Institute for Work Accident (INAIL), for workers' compensation for asbestos-related diseases due to occupational exposure, with the dataset of PM patients collected by the Mesothelioma Registry of Liguria (REM) in the same period and in the same area. As PM is a malignant tumor of a prevalently occupational origin, it is recognized and acknowledged as such by INAIL when clinical and etiological characteristics are matched. Objectives of this study were to describe observed PM cases, to evaluate completeness of collected data and differences between those who requested compensation and those who did not. The REM describes the incidence of PM among Ligurian residents, proposing patients with a specific questionnaire to assess occupational, environmental and indoor asbestos exposures. The REM collected 199 new cases of PM among the residents of both the city of Genoa (1994-96) and the province of Genoa (1995-96). In the same period, INAIL received 48 (24%) applications for compensation. Among these, 43 subjects were included in a subgroup of 98 patients registered in the REM as cases with definite diagnosis and ascertained asbestos exposure; 32 were awarded compensation, while 11 are under evaluation. The data collected by REM do not show proven asbestos exposure and/or PM diagnosis for five other subjects (two compensated and three under judgment). This study reveals that: a) only a 24% of the patients with a diagnosis of PM and asbestos exposure apply for compensation; b) an exchange of information among institutions involved in primary prevention, in the evaluation of occupational exposures to carcinogens and in insurance compensation is useful.

  18. Diffuse malignant biphasic peritoneal mesothelioma with cystic areas.

    PubMed

    Cabibi, Daniela; Tutino, Roberta; Salamone, Giuseppe; Cocorullo, Gianfranco; Agrusa, Antonino; Gulotta, Gaspare

    2016-06-20

    Il mesotelioma peritoneale maligno è una patologia rara la cui diagnosi è resa particolarmente difficile dalla molteplicità delle possibili presentazioni cliniche e morfologiche. A differenza della patologia pleurica, questa sembra avere una minore correlazione con l’esposizione all’asbesto. La prognosi è sfavorevole con una sopravvivenza media di 5.4 mesi. Riportiamo un caso di mesotelioma peritoneale in un paziente di 73 anni con esposizione professionale all’asbesto. La diagnosi è verosimilmente avvenuta dopo diversi inquadramenti clinici, che hanno compreso addominalgie attribuite ad IBD, poi non accertate istologicamente, e ad un’appendicite acuta. Per ultimo il paziente è giunto alla nostra osservazione con un quadro subocclusivo che l’indagine TC attribuiva ad una verosimile carcinosi peritoneale a primitivo sconosciuto. La laparoscopia esplorativa, poi convertita in approccio laparotomico, ha mostrato un quadro di peritonite incapsulante che coinvolgeva estesamente l’intestino tenue. È stata eseguita una resezione intestinale del tenue coinvolto ed una asportazione di un’area nodulare peri-splenica. L’esame istologico con l’integrazione di indagini immunoistochimiche ha permesso la diagnosi di mesotelioma peritoneale cistico maligno con istotipo bifasico che risulta essere il primo descritto in letteratura. Le aree cistiche avevano inizialmente fatto propendere per una diagnosi di mesotelioma multicistico benigno o di mesotelioma cistico con secondaria proliferazione miofibroblastica pseudosarcomatosa. Negli ultimi anni la prognosi di questa patologia ha trovato nell’utilizzo della chirurgia citoriduttiva e della chemioterapia intraperitoneale un miglioramento prognostico, queste nuove tecniche sono disponibili in centri di riferimento e trovano ad oggi indicazione solo in casi selezionati e in istotipi poco aggressivi. Il nostro paziente a causa dell’estensione della malattia, dell’istotipo non favorevole e dell’età avanzata è stato riferito al servizio di oncologia per il prosieguo delle cure. E’ stato sottoposto a chemioterapia con Pemetrexed e Cisplatino e dopo sei mesi presenta soddisfacenti condizioni cliniche generali e la TC di controllo non ha mostrato progressione di malattia.

  19. Three decades of pleural cancer and mesothelioma registration in Austria where asbestos cement was invented.

    PubMed

    Neuberger, Manfred; Vutuc, Christian

    2003-03-01

    Recently, a new mesothelioma epidemic was predicted from observations made in Western Europe. From early observations in Austria the lower increase in cases of mesothelioma compared with neighbor countries had been related to different uses of asbestos. In order to test this hypothesis, incidence and mortality of pleural cancer [International Classification of Diseases (ICD)-8/9 163] were analyzed for three decades and supplemented by data from a cohort study in the factory that had been the largest consumer of asbestos imported to Austria and from all Austrian occupational diseases registered between 1990 and 2001. In men, mortality rates (based on 15 to 45 deaths/year) were lowest in 1980-1989, but similar in 1970-1979 and 1990-2001. No increase in younger-birth cohorts was detected. Incidence rates (based on 13 to 44 cases/year) increased (36%) non-significantly ( P=0.14). In women, a significant decrease in mortality and incidence rates ( P<0.01) was observed from 1970. Rates from work-related mesothelioma (based on only 0-7 men and 0-4 women/year) must be interpreted with caution. In the cohort of 2,816 asbestos cement workers 26 pleural mesotheliomas were registered from 1990 through mid-1999. Six of these cases (three male and three female) had not been registered as an occupational disease, but all of these cases had been encoded under ICD 163 in mortality statistics. One female cohort member registered as having asbestosis according to the death certificate had died from mesothelioma according to the statistics of occupational diseases. We conclude that no epidemic of mesothelioma due to past asbestos exposure is to be expected in Austria.

  20. Mesothelioma mortality in Brazil, 1980-2003.

    PubMed

    Pedra, Francisco; Tambellini, Anamaria Testa; Pereira, Basílio de Bragança; da Costa, Ana Carolina Carioca; de Castro, Hermano Albuquerque

    2008-01-01

    Although asbestos causes asbestosis, lung cancer, and mesothelioma, it remains widely used in Brazil, mostly in cement-fiber products. We report the Brazilian mesothelioma mortality trend 1980-2003, using records of the national System of Mortality Information of DATASUS, including all deaths with IX International Disease Classification (ICD9) codes 163.n--pleura cancer during the period 1980-1995; and ICD10 codes c45.n--mesotheliomas and c38.4--pleura cancer for the years 1996-2003. Mesothelioma mortality rates increased over the period studied, from 0.56 to 1.01 deaths per 1,000,000 [corrected] habitants. The total number of mesothelioma deaths nationwide in the period studied was 2,414; the majority (1,415) were in the Southeast region. Mortality was highest among males and people over age 65. Given the history of asbestos exposure in Brazil, our findings support the need for policies that limit or ban the use of this product.

  1. Targeting Eukaryotic Translation in Mesothelioma Cells with an eIF4E-Specific Antisense Oligonucleotide

    PubMed Central

    Jacobson, Blake A.; Thumma, Saritha C.; Jay-Dixon, Joseph; Patel, Manish R.; Dubear Kroening, K.; Kratzke, Marian G.; Etchison, Ryan G.; Konicek, Bruce W.; Graff, Jeremy R.; Kratzke, Robert A.

    2013-01-01

    Background Aberrant cap-dependent translation is implicated in tumorigenesis in multiple tumor types including mesothelioma. In this study, disabling the eIF4F complex by targeting eIF4E with eIF4E-specific antisense oligonucleotide (4EASO) is assessed as a therapy for mesothelioma. Methods Mesothelioma cells were transfected with 4EASO, designed to target eIF4E mRNA, or mismatch-ASO control. Cell survival was measured in mesothelioma treated with 4EASO alone or combined with either gemcitabine or pemetrexed. Levels of eIF4E, ODC, Bcl-2 and β-actin were assessed following treatment. Binding to a synthetic cap-analogue was used to study the strength of eIF4F complex activation following treatment. Results eIF4E level and the formation of eIF4F cap-complex decreased in response to 4EASO, but not mismatch control ASO, resulting in cleavage of PARP indicating apoptosis. 4EASO treatment resulted in dose dependent decrease in eIF4E levels, which corresponded to cytotoxicity of mesothelioma cells. 4EASO resulted in decreased levels of eIF4E in non-malignant LP9 cells, but this did not correspond to increased cytotoxicity. Proteins thought to be regulated by cap-dependent translation, Bcl-2 and ODC, were decreased upon treatment with 4EASO. Combination therapy of 4EASO with pemetrexed or gemcitabine further reduced cell number. Conclusion 4EASO is a novel drug that causes apoptosis and selectively reduces eIF4E levels, eIF4F complex formation, and proliferation of mesothelioma cells. eIF4E knockdown results in decreased expression of anti-apoptotic and pro-growth proteins and enhances chemosensitivity. PMID:24260583

  2. Cystic mesothelioma of the peritoneum.

    PubMed

    O'Neil, J D; Ros, P R; Storm, B L; Buck, J L; Wilkinson, E J

    1989-02-01

    Cystic mesothelioma (CM) of the peritoneum is a rare, benign neoplasm that occurs predominantly in women and tends to recur locally. It has received little attention (to our knowledge, a single case report) in the radiology literature. Five cases of CM are presented. Computed tomography (CT) was performed in three cases, ultrasound (US) in four cases, and magnetic resonance (MR) imaging in one case. Twenty-eight cases reported in the literature are reviewed for comparison. CM shows a clear predilection for the surfaces of the pelvic viscera but is seen in other areas of the peritoneum and retroperitoneum. The neoplasm was intraperitoneal in three cases and primarily retroperitoneal in the other two cases. In all CT and US studies performed, a single large, multilocular cystic mass was demonstrated. MR imaging, performed in one case, showed that the lesion had signal characteristics typical of a watery collection low in solute concentration. It is concluded that CM of the peritoneum has a nonspecific multilocular cystic appearance on images, which does not permit it to be differentiated from other cystic lesions.

  3. Mesothelioma incidence and community asbestos exposure.

    PubMed

    Berry, M

    1997-10-01

    This study evaluates the environmental, nonoccupational component of mesothelioma incidence among persons living in Manville, Somerset County, New Jersey, the location of the largest asbestos manufacturing plant in North America. Prior to removal of occupational cases, residents of Manville had an average annual (1979-1990) mesothelioma rate of 636 male cases and 96 female cases per million population, about 25 times higher than average state rates. Somerset County had 143 diagnosed mesothelioma cases reported to the population-based. New Jersey State Cancer Registry from 1979 through 1990. Cases were removed from the analysis when their "usual employment" was reported as being at the asbestos plant, as evidenced through union lists or occupational information from either the Cancer Registry or mortality records. Standardized incidence ratios (SIRs) were computed for residents of Manville and Somerset County (less the Manville population) by sex. New Jersey mesothelioma rates less the Somerset County contribution, 1979-1990, were used to generate the expected number of cases. The SIRs for Manville males and females were respectively 10.1 [95% confidence interval (CI): 5.8-16.4] and 22.4 (95% CI: 9.7-44.2). Male and female Somerset County mesothelioma incidence rates were 1.9 (95% CI: 1.4-2.5) and 2.0 (95% CI: 1.0-3.6). This record-based approach demonstrates a strong relationship between past asbestos exposure from living in Manville and eventual development of mesothelioma. The use of methods in this study may be helpful in evaluating hazards of other known occupational carcinogens found in community settings.

  4. Rare thoracic cancers, including peritoneum mesothelioma.

    PubMed

    Siesling, Sabine; van der Zwan, Jan Maarten; Izarzugaza, Isabel; Jaal, Jana; Treasure, Tom; Foschi, Roberto; Ricardi, Umberto; Groen, Harry; Tavilla, Andrea; Ardanaz, Eva

    2012-05-01

    Rare thoracic cancers include those of the trachea, thymus and mesothelioma (including peritoneum mesothelioma). The aim of this study was to describe the incidence, prevalence and survival of rare thoracic tumours using a large database, which includes cancer patients diagnosed from 1978 to 2002, registered in 89 population-based cancer registries (CRs) and followed-up to 31st December 2003. Over 17,688 cases of rare thoracic cancers were selected based on the list of the RACECARE project. Mesothelioma was the most common tumour (19 per million per year) followed by epithelial tumours of the trachea and thymus (1.3 and 1.7, respectively). The age standardised incidence rates of epithelial tumours of the trachea was double in Eastern and Southern Europe versus the other European regions: 2 per million per year. Epithelial tumours of the thymus had the lowest incidence in Northern and Eastern Europe and UK and Ireland(1) and somewhat higher incidence in Central and Southern Europe.(2) Highest incidence in mesothelioma was seen in UK and Ireland(23) and lowest in Eastern Europe.(4) Patients with tumours of the thymus had the best prognosis (1-year survival 85%, 66% at 5 years). Five year survival was lowest for the mesothelioma 5% compared to 14% of patients with tumours of the trachea. Mesothelioma was the most prevalent rare cancer (12,000 cases), followed by thymus (7000) and trachea (1400). Cancer Registry (CR) data play an important role in revealing the burden of rare thoracic cancers and monitoring the effect of regulations on asbestos use and smoking related policies.

  5. Peritoneal mesothelioma in a jaguar (Panthera onca).

    PubMed

    Souza, Francisco de Assis Leite; de Carvalho, Ciro José Sousa; de Almeida, Hatawa M; Pires, Lidiany Viana; Silva, Lucilene dos Santos; Costa, Francisco Assis Lima; Silva, Silvana M Medeiros de Sousa

    2013-09-01

    A 21-yr-old female jaguar (Panthera onca) died in a zoo in Teresina, Piaui, Brazil, following a history of abdominal distension, ascites, anorexia, and dyspnea. At necropsy, a dark red, watery, blood-tinged serous fluid was present in the abdominal cavity. The peritoneum was thick with firm, yellow, villous projections. Histologically, the tumors were composed of a biphasic population of cells, which reacted to anti-cytokeratin and anti-vimentin antibodies, consistent with a biphasic benign mesothelioma of peritoneal origin. This is the first reported case of mesothelioma in a captive jaguar.

  6. Peritoneal mesothelioma in a jaguar (Panthera onca).

    PubMed

    Souza, Francisco de Assis Leite; de Carvalho, Ciro José Sousa; de Almeida, Hatawa M; Pires, Lidiany Viana; Silva, Lucilene dos Santos; Costa, Francisco Assis Lima; Silva, Silvana M Medeiros de Sousa

    2013-09-01

    A 21-yr-old female jaguar (Panthera onca) died in a zoo in Teresina, Piaui, Brazil, following a history of abdominal distension, ascites, anorexia, and dyspnea. At necropsy, a dark red, watery, blood-tinged serous fluid was present in the abdominal cavity. The peritoneum was thick with firm, yellow, villous projections. Histologically, the tumors were composed of a biphasic population of cells, which reacted to anti-cytokeratin and anti-vimentin antibodies, consistent with a biphasic benign mesothelioma of peritoneal origin. This is the first reported case of mesothelioma in a captive jaguar. PMID:24063103

  7. Identifying Thoracic Malignancies Through Pleural Fluid Biomarkers

    PubMed Central

    Porcel, José M.; Esquerda, Aureli; Martínez-Alonso, Montserrat; Bielsa, Silvia; Salud, Antonieta

    2016-01-01

    Abstract The diagnosis of malignant pleural effusions may be challenging when cytological examination of aspirated pleural fluid is equivocal or noncontributory. The purpose of this study was to identify protein candidate biomarkers differentially expressed in the pleural fluid of patients with mesothelioma, lung adenocarcinoma, lymphoma, and tuberculosis (TB). A multiplex protein biochip comprising 120 biomarkers was used to determine the pleural fluid protein profile of 29 mesotheliomas, 29 lung adenocarcinomas, 12 lymphomas, and 35 tuberculosis. The relative abundance of these predetermined biomarkers among groups served to establish the differential diagnosis of: malignant versus benign (TB) effusions, lung adenocarcinoma versus mesothelioma, and lymphoma versus TB. The selected putative markers were validated using widely available commercial techniques in an independent sample of 102 patients. Significant differences were found in the protein expressions of metalloproteinase-9 (MMP-9), cathepsin-B, C-reactive protein, and chondroitin sulfate between malignant and TB effusions. When integrated into a scoring model, these proteins yielded 85% sensitivity, 100% specificity, and an area under the curve (AUC) of 0.98 for labeling malignancy in the verification sample. For lung adenocarcinoma–mesothelioma discrimination, combining CA19-9, CA15-3, and kallikrein-12 had maximal discriminatory capacity (65% sensitivity, 100% specificity, AUC 0.94); figures which also refer to the validation set. Last, cathepsin-B in isolation was only moderately useful (sensitivity 89%, specificity 62%, AUC 0.75) in separating lymphomatous and TB effusions. However, this last differentiation improved significantly when cathepsin-B was used with respect to the patient's age (sensitivity 72%, specificity 100%, AUC 0.94). In conclusion, panels of 4 (i.e., MMP-9, cathepsin-B, C-reactive protein, chondroitin sulfate), or 3 (i.e., CA19-9, CA15-3, kallikrein-12) different protein

  8. NF2 blocks Snail-mediated p53 suppression in mesothelioma

    PubMed Central

    Cho, Jung-Hyun; Lee, Su-Jin; Oh, Ah-Young; Yoon, Min-Ho; Woo, Tae-Geun; Park, Bum-Joon

    2015-01-01

    Although asbestos causes malignant pleural mesothelioma (MPM), rising from lung mesothelium, the molecular mechanism has not been suggested until now. Extremely low mutation rate in classical tumor suppressor genes (such as p53 and pRb) and oncogenes (including Ras or myc) indicates that there would be MPM-specific carcinogenesis pathway. To address this, we treated silica to mimic mesothelioma carcinogenesis in mesothelioma and non-small cell lung cancer cell lines (NSCLC). Treatment of silica induced p-Erk and Snail through RKIP reduction. In addition, p53 and E-cadherin were decreased by silica-treatment. Elimination of Snail restored p53 expression. We found that NF2 (frequently deleted in MPM) inhibited Snail-mediated p53 suppression and was stabilized by RKIP. Importantly, GN25, an inhibitor of p53-Snail interaction, induced p53 and apoptosis. These results indicate that MPM can be induced by reduction of RKIP/NF2, which suppresses p53 through Snail. Thus, the p53-Snail binding inhibitor such as GN25 is a drug candidate for MPM. PMID:25823924

  9. Trends and geographical patterns of pleural mesotheliomas in the Netherlands 1970-87.

    PubMed Central

    Meijers, J M; Planteydt, H T; Slangen, J J; Swaen, G M; van Vliet, C; Sturmans, F

    1990-01-01

    The sex and age related trends and geographical distribution of asbestos related mortality from pleural mesothelioma in the Netherlands between 1970 and 1987 were investigated. Deaths from pleural malignancies recorded by the Dutch Central Bureau of Statistics (CBS) were used and death rates were age adjusted per year by the indirect method. Standardised mortality ratios (SMRs) were computed for 43 regions over the period 1979-86. For men, total mortality increased from 10.8 per million in the period 1970-8 to 20.9 per million during 1979-87. The highest mortality occurred in the group aged between 65 and 74 with 147.7 per million in 1987. The death rate for the group aged between 55 and 64 was 96.5 per million in 1987. For women, total death rates for pleural mesothelioma showed a moderate increase from 2.5 per million in the period 1970-8 to 3.6 per million during 1979-87. The highest mortality occurred in the group aged over 65, fluctuating around 10-15 per million. For men and women under 45 mortality was very low and presented no upward trend. The geographical distribution over the country for the period 1979-86 showed a pattern with a clear concentration of deaths from mesothelioma in men, in conurbations with many harbours, shipyards, and heavy industry near the river mouths and along the North Sea Coast. PMID:2245188

  10. Researchers discover genetic link to mesothelioma

    Cancer.gov

    Scientists have found that individuals who carry a mutation in a gene called BAP1 are susceptible to developing two forms of cancer – mesothelioma, and melanoma of the eye. Additionally, when these individuals are exposed to asbestos or similar mineral f

  11. Retinol supplementation and mesothelioma incidence in workers earlier exposed to blue asbestos (Crocidolite) at Wittenoom, Western Australia.

    PubMed

    Alfonso, Helman S; Reid, Alison; de Klerk, Nicholas H; Olsen, Nola; Mina, Robin; Ambrosini, Gina L; Beilby, John; Berry, Geoffrey; Musk, Bill A W

    2010-09-01

    Owing to the high rates of malignant mesothelioma in workers exposed to crocidolite earlier at Wittenoom and evidence of protection against cancer by vitamin A, a population-based cancer prevention programme providing retinol supplements (25 000 IU/day) was commenced in 1990. The former workers at Wittenoom known to be alive and living in Western Australia in June 1990 constitute the study population. The participants were classified into two groups: those who received supplemental retinol (intervention group) and those who received none (comparison group). The relative rate of mesothelioma for those receiving retinol was estimated using Cox regression, adjusting for cumulative asbestos exposure and age at first exposure to asbestos. Nine hundred and twenty-eight former Wittenoom workers received retinol at some stage of the programme, whereas 1471 workers never received retinol (comparison group). Those who received retinol were younger, had a greater exposure to asbestos and smoked less than the comparison group. There were 65 cases of mesothelioma in the retinol group and 88 in the comparison group. After adjustment, the hazard ratio was 0.99 (95% confidence interval=0.70-1.41). This result did not alter when the participants who received only retinol once or those who received beta-carotene earlier were excluded from the analysis. In conclusion, this study provides little support for possible preventive effects of retinol against mesothelioma in workers exposed to blue asbestos.

  12. Mesothelioma incidence surveillance systems and claims for workers’ compensation. Epidemiological evidence and prospects for an integrated framework

    PubMed Central

    2012-01-01

    Background Malignant mesothelioma is an aggressive and lethal tumour strongly associated with exposure to asbestos (mainly occupational). In Italy a large proportion of workers are protected from occupational diseases by public insurance and an epidemiological surveillance system for incident mesothelioma cases. Methods We set up an individual linkage between the Italian national mesothelioma register (ReNaM) and the Italian workers’ compensation authority (INAIL) archives. Logistic regression models were used to identify and test explanatory variables. Results We extracted 3270 mesothelioma cases with occupational origins from the ReNaM, matching them with 1625 subjects in INAIL (49.7%); 91.2% (1,482) of the claims received compensation. The risk of not seeking compensation is significantly higher for women and the elderly. Claims have increased significantly in recent years and there is a clear geographical gradient (northern and more developed regions having higher claims rates). The highest rates of compensation claims were after work known to involve asbestos. Conclusions Our data illustrate the importance of documentation and dissemination of all asbestos exposure modalities. Strategies focused on structural and systematic interaction between epidemiological surveillance and insurance systems are needed. PMID:22545679

  13. Work-related mesothelioma in Québec, 1967-1990.

    PubMed

    Bégin, R; Gauthier, J J; Desmeules, M; Ostiguy, G

    1992-01-01

    Prior surveys of malignant mesothelioma in Québec have noted that almost all the excess in occupational exposure related mesothelioma was in the manufacture and industrial application of asbestos rather than in the mining and milling operations. To evaluate the current status of malignant pleural mesothelioma in the Québec workforce, we reviewed all cases of pleural mesothelioma seen and accepted by the Québec Workman's Compensation Board (CSST) for work related compensation of industrial disease. We identified 120 cases, 7 of whom were females. They were of an average age of 59 +/- 8.5 yrs (sd) (range 42-84); they were exposed to asbestos dust in the workplace for an average of 26 +/- 14.3 yrs (range 0.5-50). The cases were subdivided into 3 groups according to workplace asbestos exposures. There were 49 cases originating in the mines and mills of the Québec Eastern Township region (primary industry, group 1), 50 cases from the manufacture and industrial application sector (secondary industry, group 2), and 21 cases from industries where asbestos was not a major work material, often an "incidental" material (tertiary industry, group 3). Group 1 was of an average age of 62 +/- 8 years, exposed to asbestos dust 31 +/- 14 years and the distribution of exposure time was as follows: 15% cases with < or = 10 year-exposure and 77% > or = 25 year-exposure. In group 2, the age was significantly lower at 57 +/- 9 years; the exposure time was also significantly lower at 22 +/- 14 years, and the distribution of exposure time differed from the above (29% cases with < or = 10 year-exposure and 48% > or = 25 year-exposure). In group 3, the average age was 58 +/- 7 years, the exposure time was also significantly lower at 28 +/- 12 years and the distribution of exposure time differed from the above (33% cases with < or = 10 year-exposure and 62% > or = 25 year-exposure). Analyses of the yearly incidence of new cases in each group documented the general incremental trend in all

  14. Tumor exosomes induce tunneling nanotubes in lipid raft-enriched regions of human mesothelioma cells

    SciTech Connect

    Thayanithy, Venugopal; Babatunde, Victor; Dickson, Elizabeth L.; Wong, Phillip; Oh, Sanghoon; Ke, Xu; Barlas, Afsar; Fujisawa, Sho; Romin, Yevgeniy; Moreira, André L.; Downey, Robert J.; Steer, Clifford J.; Subramanian, Subbaya; Manova-Todorova, Katia; Moore, Malcolm A.S.; Lou, Emil

    2014-04-15

    Tunneling nanotubes (TnTs) are long, non-adherent, actin-based cellular extensions that act as conduits for transport of cellular cargo between connected cells. The mechanisms of nanotube formation and the effects of the tumor microenvironment and cellular signals on TnT formation are unknown. In the present study, we explored exosomes as potential mediators of TnT formation in mesothelioma and the potential relationship of lipid rafts to TnT formation. Mesothelioma cells co-cultured with exogenous mesothelioma-derived exosomes formed more TnTs than cells cultured without exosomes within 24–48 h; and this effect was most prominent in media conditions (low-serum, hyperglycemic medium) that support TnT formation (1.3–1.9-fold difference). Fluorescence and electron microscopy confirmed the purity of isolated exosomes and revealed that they localized predominantly at the base of and within TnTs, in addition to the extracellular environment. Time-lapse microscopic imaging demonstrated uptake of tumor exosomes by TnTs, which facilitated intercellular transfer of these exosomes between connected cells. Mesothelioma cells connected via TnTs were also significantly enriched for lipid rafts at nearly a 2-fold higher number compared with cells not connected by TnTs. Our findings provide supportive evidence of exosomes as potential chemotactic stimuli for TnT formation, and also lipid raft formation as a potential biomarker for TnT-forming cells. - Highlights: • Exosomes derived from malignant cells can stimulate an increased rate in the formation of tunneling nanotubes. • Tunneling nanotubes can serve as conduits for intercellular transfer of these exosomes. • Most notably, exosomes derived from benign mesothelial cells had no effect on nanotube formation. • Cells forming nanotubes were enriched in lipid rafts at a greater number compared with cells not forming nanotubes. • Our findings suggest causal and potentially synergistic association of exosomes and

  15. Background incidence of mesothelioma: animal and human evidence.

    PubMed

    Ilgren, E B; Wagner, J C

    1991-04-01

    Evidence is presented showing that mesotheliomas can have causes other than exposure to asbestos dust, in both experimental animals and humans. In experimental animals, for example, results from two major experimental laboratories suggest that at least 10% may be taken for background incidence, whereas a third laboratory suggests that the experimental group must have a rate exceeding 30% "Background" also includes mesotheliomas found in association with nonfibrous and fibrous nonasbestiform agents. Mesotheliomas in humans can be broadly classified in a manner similar to those of experimental animals: (1) spontaneously occurring, (2) those with a latent period less than 10 years, (3) childhood mesotheliomas, (4) familial cases, (5) cases before the 20th century, (6) mineralogically negative mesotheliomas, and (7) mesotheliomas caused by nonasbestiform agents. The importance of the acceptance of these "background" cases lies in the fact that a basis is provided for the study of the incidence of disease associated with various types of asbestos.

  16. Predicted risks of second malignant neoplasm incidence and mortality due to secondary neutrons in a girl and boy receiving proton craniospinal irradiation.

    PubMed

    Taddei, Phillip J; Mahajan, Anita; Mirkovic, Dragan; Zhang, Rui; Giebeler, Annelise; Kornguth, David; Harvey, Mark; Woo, Shiao; Newhauser, Wayne D

    2010-12-01

    The purpose of this study was to compare the predicted risks of second malignant neoplasm (SMN) incidence and mortality from secondary neutrons for a 9-year-old girl and a 10-year-old boy who received proton craniospinal irradiation (CSI). SMN incidence and mortality from neutrons were predicted from equivalent doses to radiosensitive organs for cranial, spinal and intracranial boost fields. Therapeutic proton absorbed dose and equivalent dose from neutrons were calculated using Monte Carlo simulations. Risks of SMN incidence and mortality in most organs and tissues were predicted by applying risks models from the National Research Council of the National Academies to the equivalent dose from neutrons; for non-melanoma skin cancer, risk models from the International Commission on Radiological Protection were applied. The lifetime absolute risks of SMN incidence due to neutrons were 14.8% and 8.5%, for the girl and boy, respectively. The risks of a fatal SMN were 5.3% and 3.4% for the girl and boy, respectively. The girl had a greater risk for any SMN except colon and liver cancers, indicating that the girl's higher risks were not attributable solely to greater susceptibility to breast cancer. Lung cancer predominated the risk of SMN mortality for both patients. This study suggests that the risks of SMN incidence and mortality from neutrons may be greater for girls than for boys treated with proton CSI.

  17. [Thoracoscopy in malignant pleural effusions].

    PubMed

    Zhang, D; Chen, Y; Tu, C

    1996-03-01

    To assess the value of thoracoscopy in malignant pleural effusions, the procedure and results of thoracoscopy by using a fiberoptic bronchoscope and a rigid cold-light thoracoscope in 130 cases with malignant pleural effusion are reported. The overall diagnostic rate was 91.5% (119/130). The malignant pleural mesothelioma in 24 cases and metastatic cancers in 95 cases were histopathologically confirmed. Talcum powder, tetracycline and Corynebacterium parvum were separately sprayed through thoracoscope into pleural cavity in 69, 10 and 10 patients, and the success rates of complete and lasting pleurodesis were 87.0%, 5/10 and 8/10 respectively. Postoperative complications included transient fever and chest pain, local subcutaneous emphysema in 6 cases and tumor seeding at thoracoscopy site in 4 cases. It is concluded that thoracoscopy is simple, safe, reliable and of high practical value in the diagnosis of malignant pleural effusions and in assessment before exploratory thoracotomy, and that transendoscopical administration of drugs for pleurodesis is a very effective method for controlling malignant pleural effusions. The efficacy of the talc poudrage is better than tetracycline and Corynebacterium parvum. PMID:9206045

  18. Erionite exposure and mesotheliomas in rats.

    PubMed

    Wagner, J C; Skidmore, J W; Hill, R J; Griffiths, D M

    1985-05-01

    Epidemiological and environmental surveys in the Cappadocian region of Turkey have linked the high incidence of pleural and peritoneal mesothelioma in the occupants of some villages with the zeolite fibres released from the locally occurring volcanic tuff. In view of the low ambient fibre concentrations and the extraordinary incidence of mesothelioma a study to test the hypothesis of high biological activity for the zeolite fibres was required. Experimental studies using both intrapleural inoculation and inhalation techniques have been undertaken with the erionite from this region and from Oregon in the United States. Additionally a non-fibrous zeolite from Japan and a synthetic non-fibrous zeolite of similar chemical composition to erionite have been included in the experiments. In these studies the samples from Oregon and Turkey produced a very high incidence of tumours. All the rats inoculated intrapleurally with Oregon erionite and almost all those inoculated with the Turkish fibre died with a mesothelioma. Inhalation of the Oregon erionite induced a similar effect. No other dusts we have investigated have produced this high incidence of tumours particularly following inhalation. These studies demonstrate that we now have a valuable new fibre for experimental study and a possible hazard to man in regions other then Turkey.

  19. [Ordinary epidemiology: pleural mesothelioma and asbestos].

    PubMed

    Bonazzina, R; Azara, M; Gianera, A; Cannatelli, P; Zocchetti, C

    1997-01-01

    This paper describes a practical experience which took place in a Health District of the Lombardy Region (Northern Italy). This experience was motivated by the publication, on a newspaper, of the results of an epidemiological study which reported the nationwide geographical distribution of the mortality data for pleural mesothelioma during the period 1980-1987. The presence of excesses of pleural mesothelioma cases in two municipalities of Health District captured the attention of some field operators which decided to start working on the topic. Using all information available in the District all cases of pleural mesothelioma occurring during the period 1978-1993 in the two municipalities were identified; possible sources of both occupational and environmental asbestos exposure in the area were identified; and the next-of-kin of the cases was interviewed so as to gain information on the history of possible exposure to asbestos of the cases. For thirteen (out of seventeen) deaths the next-of-kin accepted to be interviewed and for them results are reported: the information presented describes gender, smoking habits, and an evaluation of the potential for exposure to asbestos both of occupational and environmental origin. We discuss the value importance of the experience, with particular emphasis on: a) the routine activities of the Services participating in the study; b) the resources employed; c) the use of epidemiological methods and tools; d) the primary prevention activities originated in the area; e) the personal motivations hat such experiences are capable to convey.

  20. A Case Report of IgG4-Related Disease Clinically Mimicking Pleural Mesothelioma

    PubMed Central

    Choi, In Ho; Jang, Si-Hyong; Lee, Seungeun; Kim, Tae-Sung; Chung, Man-Pyo

    2014-01-01

    An immunoglobulin G4 (IgG4)-related disease is a recently emerging entity, and a few cases of IgG4-related disease in lung and pleura have been reported. Herein, we report the case of a 74-year-old man with IgG4-related disease of lung and pleura, clinically suspicious of malignant mesothelioma. Chest computed tomography showed diffuse nodular pleural thickening, and microscopic finding disclosed diffuse thickening of visceral pleura with infiltrations of many lymphoplasma cells with increased number of IgG4-positive plasma cells and a few multinucleated giant cells. It is important for pathologists and clinicians to recognize this rare entity and its histologic finding, because it can be confused with malignant tumors on the radiologic examination although it can be treated with steroid therapy. PMID:24523818

  1. Surgery in mesothelioma--where do we go after MARS?

    PubMed

    Hiddinga, Birgitta I; van Meerbeeck, Jan P

    2013-05-01

    The role of surgery in the management of malignant pleural mesothelioma remains controversial. Surgical resection consists of different procedures for diagnostic or therapeutic reasons. The latter includes either an extrapleural pleuropneumonectomy (EPP) or lung-sparing operations like debulking of the parietal and visceral pleura by pleurectomy/decortication (P/D) or extended pleurectomy/decortication, in which further debulking of the diaphragm or pericardium is included. Because of the modest outcome of surgery as single-modality therapy, combinations of chemotherapy, surgery, and radiation therapy were initiated as a new treatment strategy to improve prognosis. The observations that patients treated with P/D had an equal to better outcome than those treated with EPP, and that EPP with perioperative chemotherapy was better than EPP alone, raises the issue whether performing a P/D with perioperative chemotherapy would result in a further improvement of outcome with a lower operative mortality than with EPP and perioperative chemotherapy. This is the rationale for the next European Organisation for Research and Treatment of Cancer trial exploring the feasibility of P/D with perioperative chemotherapy.

  2. Multicellular contractility contributes to the emergence of mesothelioma nodules

    NASA Astrophysics Data System (ADS)

    Czirok, Andras

    Malignant pleural mesothelioma (MPM) nodules arise from the mesothelial lining of the pleural cavity by a poorly understood mechanism. We demonstrate that macroscopic multicellular aggregates, reminiscent of the MPM nodules found in patients, develop when MPM cell lines are cultured at high cell densities for several weeks. Surprisingly, the nodule-like aggregates do not arise by excessive local cell proliferation, but by myosin II-driven cell contractility. Contractile nodules contain prominent actin cables that can span several cells. Several features of the in vitro MPM nodule development can be explained by a computational model that assumes uniform and steady intercellular contractile forces within a monolayer of cells, and a mechanical load-dependent lifetime of cell-cell contacts. The model behaves as a self-tensioned Maxwell fluid and exhibits an instability that leads to pattern formation. Altogether, our findings suggest that inhibition of the actomyosin system may provide a hitherto not utilized therapeutic approach to affect MPM growth. NIH R01-GM102801.

  3. Downregulation of thymidylate synthase and E2F1 by arsenic trioxide in mesothelioma.

    PubMed

    Lam, Sze-Kwan; Li, Yuan-Yuan; Zheng, Chun-Yan; Ho, James Chung-Man

    2015-01-01

    Malignant pleural mesothelioma is a global health issue. Arsenic trioxide (ATO) has been shown to suppress thymidylate synthase (TYMS) in lung adenocarcinoma and colorectal cancer, and induce apoptosis in acute promyelocytic leukemia. With TYMS as a putative therapeutic target, the effect of ATO in mesothelioma was therefore studied. A panel of 5 mesothelioma cell lines was used to study the effect of ATO on cell viability, protein expression, mRNA expression and TYMS activity by MTT assay, western blot, qPCR and tritium-release assay, respectively. The knockdown of TYMS and E2F1 was performed with a specific siRNA. Phosphatidylserine externalization and mitochondrial membrane depolarization were measured by Annexin V and JC-1 staining respectively. The in vivo effect of ATO was studied using a nude mouse xenograft model. Application of ATO demonstrated anticancer effects in the cell line model with clinically achievable concentrations. Downregulation of TYMS protein (except H226 cells and 1.25 µM ATO in H2052 cells) and mRNA expression (H28 cells), pRB1 (H28 cells) and E2F1 and TYMS activity (except H226 cells) were also evident. E2F1 knockdown decreased cell viability more significantly than TYMS knockdown. In general, thymidine kinase 1, ribonucleotide reductase M1, c-myc and skp2 were downregulated by ATO. p-c-Jun was downregulated in H28 cells while upregulated in 211H cells. Phosphatidylserine externalization, mitochondrial membrane depolarization, downregulation of Bcl-2 and Bcl-xL, and upregulation of Bak and cleaved caspase-3 were observed. In the H226 xenograft model, the relative tumor growth was aborted, and E2F1 was downregulated while cleaved caspase-3 was elevated and localized to the nucleus in the ATO treatment group. ATO has potent antiproliferative and cytotoxic effects in mesothelioma in vitro and in vivo, partially mediated through E2F1 targeting (less effect through TYMS targeting). There is sound scientific evidence to support the

  4. Mesothelioma in South Africa, 1976-84: incidence and case characteristics.

    PubMed

    Zwi, A B; Reid, G; Landau, S P; Kielkowski, D; Sitas, P; Becklake, M R

    1989-06-01

    Malignant mesothelioma is a rare tumour known to be associated with prior exposure to asbestos. Previous studies have described the occupational and clinical features of cases of mesothelioma in the Republic of South Africa (RSA) but none has set out to determine incidence of this disease. To estimate incidence, a case register was compiled for 1976-84 by contacting all medical practitioners and institutions likely to have seen cases of mesothelioma in this period; demographic, diagnostic and exposure details were sought. Cases were accepted if they provided evidence of histological diagnosis of mesothelioma. Fifty-two per cent of 1347 cases identified were in whites, 31% in blacks, 16% in coloureds and 1% in Asians. Seventy-three per cent of cases occurred in males. The majority of whites were aged 51-70 years, while the majority in other race groups were aged 41-60 years. The ratio of only pleural to only peritoneal mesothelioma was 11:1, although there were marked differences by race. Eighty-five per cent of males with exposure information available had prior exposure to asbestos, mostly occupational. A similar proportion of women had contact with asbestos but mostly through other types of exposure. Standardized incidence rates per million population aged 15 years and over were calculated for sex-race subgroups and were highest in white males (32.9 per million per year, 95% Cl 22.7-46.4), coloured males (24.8 per million per year, 95% Cl 16.2-36.9) and coloured females (13.9 per million per year, 95% Cl 7.7-23.5). These incidence rates are amongst the highest ever reported for a national population. Age-specific standardized incidence rates were highest in white males (over 100 per million per year in men over 55 years). Reasons for the differing rates b