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  1. Malignant mesothelioma

    PubMed Central

    Moore, Alastair J; Parker, Robert J; Wiggins, John

    2008-01-01

    Malignant mesothelioma is a fatal asbestos-associated malignancy originating from the lining cells (mesothelium) of the pleural and peritoneal cavities, as well as the pericardium and the tunica vaginalis. The exact prevalence is unknown but it is estimated that mesotheliomas represent less than 1% of all cancers. Its incidence is increasing, with an expected peak in the next 10–20 years. Pleural malignant mesothelioma is the most common form of mesothelioma. Typical presenting features are those of chest pain and dyspnoea. Breathlessness due to a pleural effusion without chest pain is reported in about 30% of patients. A chest wall mass, weight loss, sweating, abdominal pain and ascites (due to peritoneal involvement) are less common presentations. Mesothelioma is directly attributable to occupational asbestos exposure with a history of exposure in over 90% of cases. There is also evidence that mesothelioma may result from both para-occupational exposure and non-occupational "environmental" exposure. Idiopathic or spontaneous mesothelioma can also occur in the absence of any exposure to asbestos, with a spontaneous rate in humans of around one per million. A combination of accurate exposure history, along with examination radiology and pathology are essential to make the diagnosis. Distinguishing malignant from benign pleural disease can be challenging. The most helpful CT findings suggesting malignant pleural disease are 1) a circumferential pleural rind, 2) nodular pleural thickening, 3) pleural thickening of > 1 cm and 4) mediastinal pleural involvement. Involvement of a multidisciplinary team is recommended to ensure prompt and appropriate management, using a framework of radiotherapy, chemotherapy, surgery and symptom palliation with end of life care. Compensation issues must also be considered. Life expectancy in malignant mesothelioma is poor, with a median survival of about one year following diagnosis. PMID:19099560

  2. Pembrolizumab in Treating Patients With Malignant Mesothelioma

    ClinicalTrials.gov

    2016-05-10

    Biphasic Mesothelioma; Epithelioid Mesothelioma; Peritoneal Malignant Mesothelioma; Pleural Biphasic Mesothelioma; Pleural Epithelioid Mesothelioma; Pleural Malignant Mesothelioma; Pleural Sarcomatoid Mesothelioma; Recurrent Peritoneal Malignant Mesothelioma; Recurrent Pleural Malignant Mesothelioma; Sarcomatoid Mesothelioma

  3. Sorafenib Tosylate in Treating Patients With Malignant Mesothelioma.

    ClinicalTrials.gov

    2013-06-04

    Epithelial Mesothelioma; Recurrent Malignant Mesothelioma; Sarcomatous Mesothelioma; Stage IA Malignant Mesothelioma; Stage IB Malignant Mesothelioma; Stage II Malignant Mesothelioma; Stage III Malignant Mesothelioma; Stage IV Malignant Mesothelioma

  4. Mesothelioma - malignant

    MedlinePlus

    ... the lining of the lung and chest cavity (pleura) or lining of the abdomen (peritoneum). It is ... include: Chest x-ray Chest CT Cytology of pleural fluid Open lung biopsy Pleural biopsy Mesothelioma is ...

  5. 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 ...

  6. 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, ...

  7. [Malignant peritoneal mesothelioma].

    PubMed

    Scripcariu, V; Dajbog, Elena; Lefter, L; Ferariu, D; Pricop, Adriana; Grigoraş, M; Dragomir, Cr

    2006-01-01

    Mesothelioma is a neoplasm originating from the mesothelial surface lining cells of the serous human cavities. It may involve the pleura, less frequently the peritoneum rarely, the pericardium, the tunica vaginalis testis and ovarian epithelium. Asbestos has been widely used in industry. A causal relationship between asbestos exposure and pleural, peritoneal and pericardial malign mesothelioma was suggested, the risk of cancer being correlated to cumulate exposure. Studies from National Cancer Institute, USA, show that the malignant mesothelioma is a rare and aggressive asbestos related malignancy. The symptomatology is insidious and poses difficult problems in diagnosis and treatment. This paper presents the case of a 59 year old patient with malignant peritoneal mesothelioma who worked almost 40 years as an electrician, exposed to asbestos fibers. He was hospitalized for important weight loss, abdominal pain and tiredness being diagnosed after imaging tests with a giant tumor, localized at the abdominal upper level, which seems to originate from the spleen's superior pole. During surgery we discovered a tumor with cystic parts, intense vascularized, which turn to be adherent in the upper side to the lower face of the left midriff cupola, to the spleen superior pole and 1/3 middle level of the great gastric curve. It was performed surgical ablation of the tumor, splenectomy with favorable postoperative evolution, the patient being now under chemotherapy treatment. PMID:17283842

  8. Malignant Pleural Mesothelioma

    PubMed Central

    Tsao, Anne S.; Wistuba, Ignacio; Roth, Jack A.; Kindler, Hedy Lee

    2009-01-01

    Malignant pleural mesothelioma (MPM) is a deadly disease that occurs in 2,000 to 3,000 people each year in the United States. Although MPM is an extremely difficult disease to treat, with the median overall survival ranging between 9 and 17 months regardless of stage, there has been significant progress over the last few years that has reshaped the clinical landscape. This article will provide a comprehensive discussion of the latest developments in the treatment of MPM. We will provide an update of the major clinical trials that impact mesothelioma treatment in the resectable and unresectable settings, discuss the impact of novel therapeutics, and provide perspective on where the clinical research in mesothelioma is moving. In addition, there are controversial issues, such as the role of extrapleural pneumonectomy, adjuvant radiotherapy, and use of intensity-modulated radiotherapy versus hemithoracic therapy that will also be addressed in this manuscript. PMID:19255316

  9. Malignant peritoneal mesothelioma following asbestos exposure.

    PubMed

    Manavoğlu, O; Orhan, B; Evrensel, T; Ozçelik, T; Yolcu, I; Kunt, E

    1996-01-01

    Clinical, epidemiological, and pathological studies have demonstrated that asbestosis plays a major role in the etiology of mesothelioma. The direct exposure of workers in industrialized countries to asbestos fibers and nonoccupational household contact elevate the risk of malignant mesothelioma. An increased risk has been found in certain geographic areas of Turkey due to the presence of asbestos deposits and the use of the material known as "white soil" as an insulation. We present a malignant mesothelioma case from rural eastern Turkey with a history of asbestos exposure from using "white soil". We review the epidemiological aspects of asbestos as they relate to mesothelioma. PMID:9216805

  10. 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

  11. Primary intrahepatic malignant epithelioid mesothelioma

    PubMed Central

    Perysinakis, Iraklis; Nixon, Alexander M.; Spyridakis, Ioannis; Kakiopoulos, George; Zorzos, Charalampos; Margaris, Ilias

    2014-01-01

    INTRODUCTION Primary malignant hepatic mesotheliomas are extremely rare. We report the case of a patient with primary intrahepatic malignant mesothelioma who was treated in our department. PRESENTATION OF CASE A 66-year old male patient was admitted to our department for the evaluation of anemia. An abdominal computed tomography scan revealed a large space occupying lesion in the right liver lobe. DISCUSSION The tumor was subsequently resected and a diagnosis of primary intrahepatic malignant mesothelioma was made after pathologic examination. The patient did not receive adjuvant therapy and is currently alive and free of disease, 36 months after the resection. CONCLUSION To our knowledge this is the eighth adult case of primary intrahepatic malignant mesothelioma reported in the literature. These tumors are rarely diagnosed preoperatively. Absence of previous asbestos exposure does not exclude malignant mesothelioma from the differential diagnosis. Proper surgical treatment may offer prolonged survival to the patient, without adjuvant therapy. PMID:25460485

  12. 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.

  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. Do We Know What Causes Malignant Mesothelioma?

    MedlinePlus

    ... Next Topic Can malignant mesothelioma be prevented? Do we know what causes malignant mesothelioma? Researchers have found ... genes – the instructions for how our cells function. We usually look like our parents because they are ...

  15. What Is Malignant Mesothelioma?

    MedlinePlus

    ... up the remaining 30% to 40% of mesotheliomas. Benign tumors of the mesothelium Benign (non-cancerous) tumors can ... fibrous tumor of the pleura This type of benign tumor can form in the pleura surrounding the lungs. ...

  16. Malignant Mesothelioma: Development to Therapy

    PubMed Central

    Thompson, Joyce; Westbom, Catherine; Shukla, Arti

    2013-01-01

    Malignant mesothelioma (MM) is an aggressive cancer of the mesothelium caused by asbestos. Asbestos use has been reduced but not completely stopped. In addition, natural or man-made disasters will continue to dislodge asbestos from old buildings into the atmosphere and as long as respirable asbestos is available, MM will continue to be a threat. Due to the long latency period of MM development, it would still take decades to eradicate this disease if asbestos was completely removed from our lives today. Therefore, there is a need for researchers and clinicians to work together to understand this deadly disease and find a solution for early diagnosis and treatment. This article focuses on developmental mechanisms as well as current therapies available for MM. PMID:23959774

  17. Malignant mesothelioma: development to therapy.

    PubMed

    Thompson, Joyce K; Westbom, Catherine M; Shukla, Arti

    2014-01-01

    Malignant mesothelioma (MM) is an aggressive cancer of the mesothelium caused by asbestos. Asbestos use has been reduced but not completely stopped. In addition, natural or man-made disasters will continue to dislodge asbestos from old buildings into the atmosphere and as long as respirable asbestos is available, MM will continue to be a threat. Due to the long latency period of MM development, it would still take decades to eradicate this disease if asbestos was completely removed from our lives today. Therefore, there is a need for researchers and clinicians to work together to understand this deadly disease and find a solution for early diagnosis and treatment. This article focuses on developmental mechanisms as well as current therapies available for MM. PMID:23959774

  18. What Are the Key Statistics about Malignant Mesothelioma?

    MedlinePlus

    ... factors for malignant mesothelioma? What are the key statistics about malignant mesothelioma? Mesothelioma is fairly rare in ... rates can be found in the section “ Survival statistics for mesothelioma .” Visit the American Cancer Society’s Cancer ...

  19. Cerebral metastasis from malignant pleural mesothelioma

    PubMed Central

    El Molla, Mohamed; Gragnaniello, Cristian; Al-Khawaja, Darweesh; Chiribao-Negri, Concepcion; Eftekhar, Behzad

    2013-01-01

    Malignant mesothelioma is an uncommon, highly invasive tumor derived from the mesothelial cells of pleura or peritoneum characterized by poor outcome. Mesothelioma was thought to metastasize locally only via direct invasion and not have distant spread. Distant metastases were discovered mostly on post-mortem examination. The authors present a case of 62-year-old man with pleural mesothelioma and brain metastasis. PMID:24963909

  20. Mesothelioma

    MedlinePlus

    ... stomach, heart, and other organs is called mesothelium. Mesothelioma is a tumor of that tissue. It usually ... be benign (not cancer) or malignant (cancer.) Malignant mesothelioma is a rare but serious type of cancer. ...

  1. 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 ...

  2. [Drug carrier nanosystems in malignant pleural mesothelioma].

    PubMed

    Turgut Coşan, Didem; Ak, Güntülü; Dağ, İlknur; Soyocak, Ahu; Dikmen, Gökhan; Dal, Aylin; Güneş, Hasan V; Metintaş, Muzaffer

    2016-03-01

    Malignant pleural mesothelioma (MPM), the incidence increased with each passing day, is an important lethal disease due to the limited survive with available treatment methods and with the lack of a standard treatment. Response and survive rates of cytotoxic agents which is used in MPM treatment are not good enough. Therefore, treatment studies of MPM seem to quite important and urgent. In cancer therapy, convensional chemotherapeutic agent applications, due to the lack of selectivity, lead to systemic toxicity. Besides the limited solubility of the agent used, the distribution between the cells is weak. It is very difficult to the pass through cellular barriers, particularly, drug resistance may develop to the treatment. All of these reasons lead to failure in the treatment process. Because of the fact that cytotoxic drugs either kill the rapidly growing and dividing cells or make them disfunctional by showing toxic effect on them, to avoid the side effects and to make an inherent effect for cytotoxic drug of active ingredient given for treatment on tumor, different studies have been under investigation. At the present time, nanocarriers as one of these solutions seem to have an important place. Nanocarriers are promising for the development of therapeutic effectiveness and safety. It seems that use of the nanocarrier in the treatment of mesothelioma has a potential, as effective alternative a method, with improve of the drug efficacy and reduce of toxicity in normal tissues. PMID:27266287

  3. [Malignant peritoneal mesothelioma: its relation to asbestos].

    PubMed

    Pentimone, F; Moruzzo, D; Siuti, E; del Corso, L

    1995-10-01

    Chronic exposure to asbestos can induce malignant peritoneal mesothelioma (PMM) without pulmonary or pleural involvement (PIMM). The localization to the peritoneum depends on the different susceptibility of the two mesotheliums and, perhaps, on the length of asbestos fibers which can facilitate their direct translocation. PMID:8622811

  4. 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

  5. Diagnosis and treatment of malignant pleural mesothelioma.

    PubMed

    Rodríguez Panadero, Francisco

    2015-04-01

    There are three major challenges in the diagnosis of malignant pleural mesothelioma: mesothelioma must be distinguished from benign mesothelial hyperplasia; malignant mesothelioma (and its subtypes) must be distinguished from metastatic carcinoma; and invasion of structures adjacent to the pleura must be demonstrated. The basis for clarifying the first two aspects is determination of a panel of monoclonal antibodies with appropriate immunohistochemical evaluation performed by highly qualified experts. Clarification of the third aspect requires sufficiently abundant, deep biopsy material, for which thoracoscopy is the technique of choice. Video-assisted needle biopsy with real-time imaging can be of great assistance when there is diffuse nodal thickening and scant or absent effusion. Given the difficulties of reaching an early diagnosis, cure is not generally achieved with radical surgery (pleuropneumonectomy), so liberation of the tumor mass with pleurectomy/decortication combined with chemo- or radiation therapy (multimodal treatment) has been gaining followers in recent years. In cases in which surgery is not feasible, chemotherapy (a combination of pemetrexed and platinum-derived compounds, in most cases) with pleurodesis or a tunneled pleural drainage catheter, if control of pleural effusion is required, can be considered. Radiation therapy is reserved for treatment of pain associated with infiltration of the chest wall or any other neighboring structure. In any case, comprehensive support treatment for pain control in specialist units is essential: this acquires particular significance in this type of malignancy. PMID:25059587

  6. Unusual appearance of malignant peritoneal mesothelioma.

    PubMed

    Haberman, Amy

    2015-01-01

    Malignant peritoneal mesothelioma (MPM) is a rare and fatal cancer arising from the mesothelial cells lining the peritoneum. This typically occurs in men in their fifth and sixth decades, but can be seen in women and any age group. Pleural and extrapleural mesothelioma can arise in the setting of asbestos exposure, but other reported causes of MPM include exposure to silicate fibers and radiation therapy. Because it presents with vague symptoms such as abdominal pain, anorexia, and weight loss, it is generally advanced at diagnosis. This is a case of MPM that presented initially at contrast-enhanced computed tomography as a small focal lesion in the lesser sac, ultimately resulting in death from complications of the disease. PMID:25793652

  7. Positive TTF-1 Expression in Malignant Mesothelioma: A Case Report

    PubMed Central

    Richter, Georg; Heidersdorf, Holger; Hirschfeld, Dieter; Krebbel, Friedhelm

    2016-01-01

    Patient: Female, 70 Final Diagnosis: Malignant mesothelioma Symptoms: — Medication: — Clinical Procedure: Radiation/Chemotherapy Specialty: Oncology Objective: Rare co-existance of disease or pathology Background: The histopathological diagnosis of malignant mesothelioma is based mainly on the immunohistological profile of the neoplasia, using different immunohistochemical markers to distinguish between a malignant mesothelioma and a carcinoma. Case Report: A female patient presented with a right paravertebral rapidly growing tumor and severe pain. Based on the immunohistochemical findings, we present the first case of a malignant mesothelioma with immunohistochemical expression of thyroid transcription factor-1. Conclusions: The detection of a positive reaction for thyroid transcription factor-1 in the tumor cells may not exclude a malignant mesothelioma. PMID:26939861

  8. Disseminated Pleural Siliconoma Mimicking Malignant Pleural Mesothelioma.

    PubMed

    Tanaka, Toshiki; Tao, Hiroyuki; Hayashi, Tatsuro; Yoshiyama, Koichi; Furukawa, Masashi; Yoshida, Kumiko; Okabe, Kazunori

    2015-12-01

    A 48-year-old woman with a 3-month history of back pain was admitted for further examination of multiple left pleural nodules. She had undergone bilateral breast augmentation with silicone implants 10 years previously. Nine years after the operation, both ruptured implants were removed, and autologous fat was injected. Computed tomography revealed multiple pleural nodules suggestive of malignant pleural mesothelioma. Thoracoscopic exploration revealed multiple pleural nodules with massive pleural adhesions. The nodules were filled with viscous liquid and were histologically determined to be siliconomas. Disseminated pleural siliconoma should be recognized as a late adverse event of silicone breast implantation. PMID:26652527

  9. [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

  10. Extrapleural pneumonectomy for malignant pleural mesothelioma.

    PubMed

    Argote-Greene, Luis M; Chang, Michael Y; Sugarbaker, David J

    2005-01-01

    Extrapleural pneumonectomy was introduced in the 1940s for the treatment of extensive infections of the lung and pleural space. Over the past 20 years, the extrapleural pneumonectomy technique has been modified and applied to the treatment of locally advanced malignant pleural mesothelioma, achieving substantial reductions in mortality. The current mortality rate of 3.4% at the Brigham and Women's Hospital has permitted us to expand our use of this operation to treat locally advanced lung cancer and thymoma. The extrapleural pneumonectomy technique consists of five basic steps: (1) Incision and exposure of the parietal pleura: (2) Dissection of the tumor and parietal pleura from the chest wall, diaphragm, and mediastinum: (3) Division and control of the pulmonary vessels and bronchus followed by lymph node dissection: (4) En bloc resection of the lung, pleura, pericardium, and diaphragm; (5) Reconstruction of the diaphragm and pericardium. Extrapleural pneumonectomy is a complex and challenging operation. Accompanied by a 60% minor and major complication rate, it requires a unique management approach to achieve 3.4% mortality. Primary contributing factors to the reduction in mortality include a reduced operative time of 3 h, refinements in operative technique, and improved selection of patients. The technique discussed below is the culmination of 20 years' experience with malignant pleural mesothelioma at the Brigham and Women's Hospital/Dana Farber Cancer Institute, Boston, MA USA. PMID:24414726

  11. Malignant Peritoneum Mesothelioma with Hepatic Involvement: A Single Institution Experience in 5 Patients and Review of the Literature

    PubMed Central

    Su, Shan-shan; Zheng, Guo-qi; Liu, Ya-gang; Chen, Yue-feng; Song, Zhao-wei; Yu, Shu-jing; Sun, Ning-ning; Yang, Yu-xin

    2016-01-01

    Malignant peritoneal mesothelioma with invasion of the liver is an invariably fatal disease. We aimed to clarify the characteristics of malignant peritoneal mesothelioma cases with liver involvement. The clinical presentation, computed tomography images, and immunohistochemical and histopathological features of 5 patients with malignant peritoneal mesothelioma and liver involvement were evaluated. The diagnosis was established by imaging and immune profiles of the tumours. A review of 8 cases with primary or invading malignant mesothelioma in liver is presented. All 5 mesothelioma cases were asbestos-related. CT images of malignant peritoneal mesothelioma with the liver involvement typically showed that the lesion grew inside the liver along the capsule and was possibly accompanied by capsule breakthrough and extrahepatic infiltration. The tumours exhibited a common epithelioid appearance in all 5 patients and most cases revealed positive Cal, CK, and MC with negative CEA and HeP. Different from our findings, the review of literature revealed that most malignant mesothelioma of liver was due to primary intrahepatic malignant mesothelioma. Finally, we concluded that the diagnosis of malignant peritoneal mesothelioma cases with liver invasion is reliably achieved by the history of asbestos exposure, the characteristic CT imaging, and immune profiles of the tumours. PMID:27069474

  12. A catalogue of treatment and technologies for malignant pleural mesothelioma.

    PubMed

    Schunselaar, Laurel M; Quispel-Janssen, Josine M M F; Neefjes, Jacques J C; Baas, Paul

    2016-04-01

    Malignant pleural mesothelioma is an aggressive fatal malignancy with a prognosis that has not significantly improved in the last decades. This review summarizes the current state of treatment and the various attempts that are made to improve overall survival for patients with malignant pleural mesothelioma. It also discusses technologies and protocols to test new and hopefully more effective compounds in a more individualized manner. These developments are expected to improve the prognosis for this group of patients. PMID:26943000

  13. 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. PMID:21059834

  14. Current surgical strategies for malignant pleural mesothelioma.

    PubMed

    Takuwa, Teruhisa; Hasegawa, Seiki

    2016-08-01

    Malignant pleural mesothelioma (MPM) is associated with a poor prognosis. The main components of multimodality treatment include surgery, chemotherapy, and radiation therapy. Surgery remains controversial. Two procedures are currently offered: extrapleural pneumonectomy (EPP) and pleurectomy/decortication (P/D). The recent scientific literature suggests that P/D is a well-tolerated procedure, with the potential of becoming a default procedure in multimodality regimens. However, the precise treatment schemes and surgical procedures are yet to be established. In our study, we review the advantages and disadvantages of EPP and P/D, summarize the post-EPP and post-P/D observations (including mortality, morbidity, and median survival time), and discuss the choice of surgical technique (EPP vs. P/D). Moreover, we highlight the aspects of the multimodality treatments that are offered to MPM patients, including chemotherapy, radiotherapy, intensity-modulated radiation therapy, and other types of therapy. PMID:26590581

  15. Malignant pleural mesothelioma: an epidemiological perspective

    PubMed Central

    2012-01-01

    This paper reviews the aetiology, distribution and projected future incidence of malignant mesothelioma. Asbestos exposure is the most thoroughly established risk factor. Debate continues regarding the relative importance of the different asbestos fibre types and the contribution of Simian virus 40 (SV40). Disease incidence varies markedly within and between countries. The highest annual rates of disease, approximately 30 case per million, are reported in Australia and Great Britain. The risk of disease increases with age and is higher in men. Time from asbestos exposure to disease diagnosis is on average greater than 40 years. Non-occupational asbestos exposures contribute an increasing proportion of disease. With the exception of the United States, incidence continues to increase. In developed countries peak incidence is expected to occur before 2030. PMID:23977542

  16. Malignant mesotheliomas in Kure City, Japan: The relationship of asbestos exposure

    SciTech Connect

    Kishimoto, T.; Sato, T.; Ono, T.; Okada, K.; Masuda, Y.; Ito, H. )

    1989-01-01

    Eighteen patients with malignant mesothelioma were seen at Kure Mutual Aid Hospital over a 10-year period. According to occupational history, chest x-ray manifestations, and evidence of asbestos bodies in the tissue, 13 of these cases were definitely thought to be due to exposure to asbestos as a result of two or three of these items testing positive. Kure City is one of the major ship-building cities in Japan since the 1920s. Most of the 18 patients worked in ship building before and during World War II. Malignant mesothelioma appeared about 40 years after their first exposure to asbestos. In western countries, most malignant mesotheliomas are thought to be induced by exposure to asbestos fibers. Consequently, there has been a serious effort to deal with this problem recently, including lowering rate of exposure. In Japan, however, there have been few reports that asbestos fibers caused malignant mesothelioma. This report suggests that an increased incidence of malignant mesotheliomas in a specific area of Japan may also be due to exposure to asbestos fibers.

  17. 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

  18. Photodynamic therapy of malignant mesothelioma of pleura

    NASA Astrophysics Data System (ADS)

    Warloe, Trond; Heyerdahl, Helen; Peng, Qian; Hoie, J.; Normann, E.; Solheim, O.; Moan, Johan; Giercksky, Karl-Erik

    1995-03-01

    Nine patients with malignant pleural mesothelioma underwent extensive surgery followed by intra-operative photodynamic therapy. Two mg/kg Photofrin was given 48 hours prior to surgery. The thoracic cavity and eventual remaining lung were exposed to 15 - 30 Joules/cm2 of 630 nm laser light. Tumor tissue was analyzed by microscopic photometrical techniques. Five patients with mixed or epithelioid tumors with fluorescence intensity > 100 gray level/pixel seemed to benefit from the given therapy. One patient was free of disease 18 months after treatment. Two patients were treated for metastasis after 12 months with no sign of intrathoracic recurrence. Both are still alive, one without further sign of disease 32 months after initial treatment. Two patients presented generalized disease after 9 and 13 months and intrathoracic recurrence several months later. Two patients with poorly differentiated tumors and 2 patients with moderate to highly differentiated tumors, but with fluorescence intensity < 100 gray level/pixel, presented recurrences after 4 months. PDT-efficiency seems to be predicted by the intensity and distribution of drug-induced fluorescence in tumor tissue. PDT may enhance the possibility to achieve complete local tumor control after excision. Multimodal therapeutic approach of local and systemic disease seems mandatory to further improve survival.

  19. Staging algorithm for diffuse malignant pleural mesothelioma.

    PubMed

    Zielinski, Marcin; Hauer, Jolanta; Hauer, Lukasz; Pankowski, Juliusz; Nabialek, Tomasz; Szlubowski, Artur

    2010-02-01

    An algorithm of preoperative mediastinal nodal staging with endobronchial/endoesophageal ultrasonography (EBUS/EUS) and transcervical extended mediastinal lymphadenectomy (TEMLA) combined with laparoscopy/peritoneal lavage and cytology was analyzed to establish the realistic criteria for radical multimodality treatment of malignant pleural mesothelioma (MPM). The algorithm included computed tomography (CT), thoracoscopy with multiple pleural biopsies and talc pleurodesis, EBUS/EUS and one-stage TEMLA and laparoscopy/peritoneal lavage and cytology of the fluid. Forty-two patients were diagnosed from 1 January 2004 to 31 December 2008. There were 16 women and 26 men in ages ranging from 43 to 77 years (mean 57.8); 31 epithelioid, 2 sarcomatoid and 9 biphasic type MPM. 21/42 patients were considered possible candidates for multimodality treatment. Three patients who received neoadjuvant chemotherapy were excluded from this study. EBUS/EUS was performed to stage the mediastinal nodes. In 3/18 patients metastatic nodes were discovered. In the rest of the 15 patients simultaneous TEMLA and laparoscopy/peritoneal lavage and cytology of the fluid were performed. In three patients TEMLA was positive, in six patients laparoscopy was positive and in two patients both TEMLA and laparoscopy were positive. Finally, 4/42 (9.5%) patients underwent thoracotomy with one exploration (chest wall infiltration) and three pleuropneumonectomies with the subsequent chemo- and radiotherapy. The proposed algorithm of preoperative staging spared the majority of MPM patients from futile surgery. PMID:19843550

  20. 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

  1. Diffuse malignant pleural mesothelioma and asbestos exposure

    PubMed Central

    Whitwell, F.; Rawcliffe, Rachel M.

    1971-01-01

    Pleural mesothelioma has been diagnosed in 52 patients in three hospitals on Merseyside between 1955 and 1970, 60% being diagnosed from operation specimens and the rest from postmortem tissues. Necropsies eventually held on nearly half the operation cases confirmed the diagnosis, giving a necropsy rate of 70% for the series. The morbid anatomy conformed to earlier descriptions except that widespread metastases were much commoner than has usually been described. Histological findings agreed with previous accounts of the tumour, except that, in our hands, special acid mucopolysaccharide staining was less reliable than Southgate's mucicarmine, which was of value in differential diagnosis. Association with asbestos was confirmed from industrial histories in 80% of cases, the commonest industries involved being shipbuilding and repairing in men and sackware repairing in women. Lungs of industrial mesothelioma cases showed basal asbestosis in 17% and excessive asbestos bodies in almost all the rest. Quantitative comparison of asbestos bodies in lung smears from mesothelioma cases compared with lung smears from other Merseyside adults showed much higher counts in the mesothelioma cases. The interval from first exposure to asbestos until appearance of mesothelioma ranged between 13 and 63 years, with a mean of 42 years. We think the incidence of mesothelioma will continue to rise with the increased use of asbestos until about 40 years after adequate protective measures have been taken. Images PMID:5101273

  2. 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

  3. Alveolar-filling growth pattern of sarcomatoid malignant pleural mesothelioma.

    PubMed

    Hayakawa, Takamitsu; Tajima, Shogo; Takanashi, Yusuke; Takahashi, Tsuyoshi; Neyatani, Hiroshi; Funai, Kazuhito

    2016-09-01

    A case of sarcomatoid malignant pleural mesothelioma showing extremely rare growth pattern is described. A 63-year-old man presented to our hospital with left pleural effusion. A computed tomography (CT) scan of the chest showed diffusely thickened left visceral and parietal pleura associated with intermingled pulmonary infiltrative shadowing. Biopsy of the pleura under general anaesthesia confirmed the diagnosis of sarcomatoid malignant pleural mesothelioma. The patient underwent left extra-pleural pneumonectomy. Histopathologically, the sarcomatoid spindle tumour cells changed their morphology to polygonal cells in the pulmonary parenchyma and grew upwards, filling the alveolar space without the destruction of its septa, showing an alveolar-filling growth pattern. The current report indicates a case of sarcomatoid pleural mesothelioma that shows an alveolar-filling growth pattern, despite having not been thoroughly categorized in the World Health Organization (WHO) classification. PMID:27516891

  4. Asbestos-related lung cancer and malignant mesothelioma of the pleura: selected current issues.

    PubMed

    Markowitz, Steven

    2015-06-01

    Asbestos-related diseases persist, because millions of workers have had prior exposure and many industrializing countries continue to use asbestos. Globally, an estimated 107,000 people die annually from lung cancer, malignant mesothelioma, and asbestosis due to occupational asbestos exposure. Malignant mesothelioma and lung cancer are caused by all major types of asbestos. Asbestos causes more lung cancer deaths than malignant mesothelioma of the pleura; most cases of the latter are due to asbestos exposure. The cancer risk increases with cumulative asbestos exposure, with increased risk even at low levels of exposure to asbestos. Based on empirical studies, an estimated cumulative occupational exposure to asbestos of 1 fiber/mL-year substantially raises malignant mesothelioma risk. No safe threshold for asbestos exposure has been established for lung cancer and mesothelioma. The validity of fiber-type risk assessments depends critically on the quality of exposure assessments, which vary considerably, leading to a high degree of uncertainty. Asbestos exposure without asbestosis and smoking increases the risk of lung cancer. The joint effect of asbestos and smoking is supra-additive, which may depend in part on the presence of asbestosis. Asbestos workers who cease smoking experience a dramatic drop in lung cancer risk, which approaches that of nonsmokers after 30 years. Studies to date show that longer, thinner fibers have a stronger association with lung cancer than shorter, less thin fibers, but the latter nonetheless also show an association with lung cancer and mesothelioma. Low-dose chest computed tomographic scanning offers an unprecedented opportunity to detect early-stage lung cancers in asbestos-exposed workers. PMID:26024342

  5. 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

  6. [Malignant peritoneal mesothelioma. Case report and review of the literature].

    PubMed

    Ruiz-Tirado, María Luisa; Olvera-Rodríguez, Arturo; Díaz-Barranco, Irma; Ruiz-Romano, Agueda; Castillo-Ruiz, Natalia; Olvera-Quiroz, Silvia Eurydice

    2011-01-01

    A woman 88 years old with a clinical picture initiated eight days before characterized by asthenia, adynamia, hyporexia, increase of the abdominal perimeter, pain and constipation. Her husband worked at the automotive industry for more than 30 years (brakes specialist). She had a history of hypertension; abdominal ultrasound showed a metastatic liver of unknown origin and ascites. An ascites sample was gotten. Malignant cells matching with malignant peritoneal mesothelioma were observed. The patient died 30 days after the diagnosis. The peritoneal mesothelioma is a rare form of cancer that can be benign or malignant. Incidence rate increases with age. It is more frequent in men and over 60 years with a survival from five to twelve months after diagnosis. The most important risk factor is the chronic labor exposition to asbestos that includes the family. The diagnosis is difficult even for experts. Additionally, we present a brief review of the literature. PMID:21513666

  7. 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

  8. 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

  9. 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

  10. 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

  11. [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

  12. ¹⁸F-FDG-PET/CT in malignant mesothelioma.

    PubMed

    Fuccio, Chiara; Spinapolice, Elena Giulia; Ferretti, Alice; Castellucci, Paolo; Marzola, Maria Cristina; Trifirò, Giuseppe; Rubello, Domenico

    2013-07-01

    It is well known the useful role of ¹⁸F-FDG-PET/CT for differential diagnosis between benign and malignant disease, for staging, for monitoring response and for prognosis regarding mesothelioma. Recently, literature was enriched with new interesting studies regarding the potential applications of ¹⁸F-FDG-PET/CT in this field. The purpose of this review is to evaluate articles published on line (PubMed) from January 2011 until October 2012 in order to obtain an overview of recent progress of molecular imaging in malignant mesothelioma. The main topics concern the use of ¹⁸F-FDG-PET/CT in radiation therapy planning, monitoring of treatment (surgery/chemotherapy) response and prognosis assessment. PMID:23583476

  13. Prognostic significance of DNA aneuploidy in diffuse malignant mesothelioma

    SciTech Connect

    Isobe, Hiroshi; Sridhar, K.S.; Doria, R.

    1995-01-01

    DNA ploidy of pepsin digested preparations of 48 paraffin-embedded specimens from 19 patients with histologically confirmed malignant mesothelioma was determined by laser flow cytometry. Eight of the 19 tumors (42%) were diploid and 11 (58%) were aneuploid. Of the aneuploid tumors, only one showed multiploidy. The median survival time of the patients with diploid tumors was 19, 16, and 14 months from the onset of symptoms, diagnosis, and treatment, respectively. The median survival in patients with aneuploid tumors was 8, 7, and 7 months from the onset of first symptoms, diagnosis, and treatment. Thus, patients with diploid tumors lived longer than patients with aneuploid tumors. These results suggest that DNA ploidy analysis may be of prognostic value in malignant mesothelioma. 31 refs., 2 figs., 3 tabs.

  14. 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

  15. 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

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

    PubMed

    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 Ca(2+) and cell viability in mesothelioma cells. Effects of the oleuropein-enriched fraction on Ca(2+) 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 Ca(2+) concentration ([Ca(2+)]i). Application of standard oleuropein and hydroxytyrosol, and of the inhibitor of low-voltage T-type Ca(2+) channels NNC-55-0396, suggested that the effect is mainly due to oleuropein acting through its hydroxytyrosol moiety on T-type Ca(2+) 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 Ca(2+) channels and thereby dysregulating intracellular Ca(2+) dynamics. PMID:26693247

  17. 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

  18. 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

  19. 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

  20. [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

  1. Occurrence of malignant peritoneal mesothelioma after surgery and irradiation for cervical cancer

    SciTech Connect

    Beier, K.M.; Gallup, D.G.; Burgess, R.; Stock, R.J.

    1984-03-01

    Mesothelioma of the peritoneal cavity after irradiation is rare, and the diagnosis is sometimes difficult to establish. The following case is a report of a mesothelioma occurring 9 years after radiation therapy for carcinoma of the cervix. In this patient, who had a hysterectomy and bilateral oophorectomy 7 years prior to the mesothelioma diagnosis, the histologic, histochemical, and ultrastructural findings were all consistent with a diagnosis of malignant peritoneal mesothelioma. It is believed that this case is one of the first well-documented cases of peritoneal mesothelioma in a female who was treated by pelvic irradiation for another neoplasm.

  2. 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

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

    SciTech Connect

    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.

  4. 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

  5. Clinical and prognostic features of erionite-induced malignant mesothelioma.

    PubMed

    Demirer, Ersin; Ghattas, Christian F; Radwan, Mohamed O; Elamin, Elamin M

    2015-03-01

    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

  6. 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

  7. 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

  8. Detection of Malignant Mesothelioma Using Nuclear Structure of Mesothelial Cells in Effusion Cytology Specimens

    PubMed Central

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

    2015-01-01

    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

  9. 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

  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

    PubMed Central

    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

    2015-01-01

    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

  12. 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.

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

    DOE PAGESBeta

    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

  14. Peritoneal Malignant Mesothelioma with Epithelioid Type, Demonstrating High Serum and Ascitic KL-6 Levels: Immunohistochemical Analyses

    PubMed Central

    Nahar, Saifun; Nakamoto, Manabu; Hokama, Akira; Kobashigawa, Chiharu; Kaida, Masatoshi; Kinjo, Tetsu; Hirata, Tetsuo; Kinjo, Nagisa; Saio, Masanao; Yoshimi, Naoki; Ohtsuki, Yuji; Fujita, Jiro

    2015-01-01

    We report a case of KL-6 producing peritoneal malignant mesothelioma. A 56-year-old woman was referred to our hospital on November 2005 with severe abdominal distention. Peritoneal malignant mesothelioma with epithelioid type was diagnosed by clinical symptoms, laboratory investigations, imaging studies, and immunohistochemical examination of known tumor markers. In addition, high serum and ascitic KL-6 levels were observed and the immunostaining of the tumor for KL-6 was evident. We thus consider KL-6 to be a potential novel marker for peritoneal malignant mesothelioma with epithelioid type. PMID:26500734

  15. Peritoneal Malignant Mesothelioma with Epithelioid Type, Demonstrating High Serum and Ascitic KL-6 Levels: Immunohistochemical Analyses.

    PubMed

    Nahar, Saifun; Nakamoto, Manabu; Hokama, Akira; Kobashigawa, Chiharu; Kaida, Masatoshi; Kinjo, Tetsu; Hirata, Tetsuo; Kinjo, Nagisa; Saio, Masanao; Yoshimi, Naoki; Ohtsuki, Yuji; Fujita, Jiro

    2015-09-01

    We report a case of KL-6 producing peritoneal malignant mesothelioma. A 56-year-old woman was referred to our hospital on November 2005 with severe abdominal distention. Peritoneal malignant mesothelioma with epithelioid type was diagnosed by clinical symptoms, laboratory investigations, imaging studies, and immunohistochemical examination of known tumor markers. In addition, high serum and ascitic KL-6 levels were observed and the immunostaining of the tumor for KL-6 was evident. We thus consider KL-6 to be a potential novel marker for peritoneal malignant mesothelioma with epithelioid type. PMID:26500734

  16. 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

  17. Tenascin-X is a novel diagnostic marker of malignant mesothelioma.

    PubMed

    Yuan, Yuan; Nymoen, Dag André; Stavnes, Helene Tuft; Rosnes, Anne Katrine; Bjørang, Ola; Wu, Chuanyue; Nesland, Jahn M; Davidson, Ben

    2009-11-01

    Tenascin XB (TNXB) was previously identified as a gene that is more highly expressed in malignant mesothelioma compared with ovarian/peritoneal serous carcinoma based on gene expression array analysis. The objective of this study was to validate this finding at the mRNA and protein levels. Effusions (n = 91; 71 ovarian carcinomas, 10 breast carcinomas, and 10 malignant mesotheliomas) were assayed for TNXB mRNA expression using quantitative polymerase chain reaction. Tenascin-X protein expression was studied in 183 effusions (137 carcinomas of different origin, 37 mesotheliomas, and 9 reactive effusions) and 178 solid lesions (122 ovarian/peritoneal carcinomas and 56 mesotheliomas) using immunohistochemistry. Quantitative polymerase chain reaction analysis showed significantly higher TNXB mRNA level in mesotheliomas compared with ovarian and breast carcinomas (P < 0.001). By immunohistochemistry, tenascin-X protein expression was significantly higher in malignant mesothelioma compared with metastatic carcinoma in effusions (34 of 37 vs. 31 of 137 positive cases; sensitivity = 92% and specificity = 77%; P < 0.001). Reactive mesothelial cells had focal or no tenascin-X expression. Tenascin-X protein was detected in 41 of 56 mesothelioma biopsy specimens and was uniformly absent from all 122 ovarian carcinomas (sensitivity = 73% and specificity = 100%; P < 0.001). Our data suggest that tenascin-X may be a new diagnostic marker of malignant mesothelioma in the differential diagnosis of cancers involving the serosal cavities, particularly in the differential diagnosis between this tumor and ovarian/peritoneal serous carcinoma. PMID:19738457

  18. [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. PMID:15303546

  19. Mesothelioma of tunica vaginalis of "uncertain malignant potential" - an evolving concept: case report and review of the literature

    PubMed Central

    2011-01-01

    Mesothelioma of tunica vaginalis is a rare neoplasm, typically demonstrating frankly malignant morphology and aggressive behavior. Rare cases of well-differentiated papillary mesotheliomas have also been reported, which, in contrast, demonstrate indolent behavior. There are, however, cases which do not fit into the well-differentiated or diffuse malignant mesothelioma categories and can be considered mesothelioma of tunica vaginalis of "uncertain malignant potential", which is an emerging diagnostic category. A 57-year-old man presented with a neoplasm in a hydrocele sac. The neoplasm was non-invasive, but showed focal complex and solid growth and it was difficult to categorize either as well-differentiated papillary mesotheliomas or malignant mesothelioma. After the initial limited resection, the patient underwent radical orchiectomy with hemiscrotectomy and is alive and without disease progression after 6 years. Documentation of these rare tumors will allow their distinction from true malignant mesotheliomas and will facilitate the development of specific treatment recommendations. PMID:21867523

  20. Downregulation of TBXAS1 in an iron-induced malignant mesothelioma model

    PubMed Central

    Minami, Daisuke; Takigawa, Nagio; Kato, Yuka; Kudo, Kenichiro; Isozaki, Hideko; Hashida, Shinsuke; Harada, Daijiro; Ochi, Nobuaki; Fujii, Masanori; Kubo, Toshio; Ohashi, Kadoaki; Sato, Akiko; Tanaka, Takehiro; Hotta, Katsuyuki; Tabata, Masahiro; Toyooka, Shinichi; Tanimoto, Mitsune; Kiura, Katsuyuki

    2015-01-01

    Malignant mesothelioma is an aggressive and therapy-resistant neoplasm arising from mesothelial cells. Evidence suggests that the major pathology associated with asbestos-induced mesothelioma is local iron overload. In the present study, we induced iron-induced mesothelioma in rats based on previous reports. Ten Wistar rats were given ferric saccharate and nitrilotriacetate i.p. for 5 days a week. Five of the ten rats exhibited widespread mesotheliomas in the peritoneum and tunica vaginalis. The tumor cells showed positive immunostaining for calretinin, wilms tumor-1, podoplanin and the oxidative DNA marker 8-hydroxy-2′-deoxyguanosine. In three of the five rats with mesothelioma, array-based comparative genomic hybridization analysis identified a common chromosomal deletion mapped to the chromosomal 4q31 locus, which encompasses the TBXAS1 gene. Downregulation of the TBXAS1 gene was confirmed using quantitative PCR. TBXAS1 gene expression was also reduced in three of four human malignant pleural mesothelioma cell lines compared with normal bronchial epithelial cells. Immunohistochemistry revealed that TBXAS1 expression was weakly positive and positive in five and three out of eight human malignant mesothelioma samples, respectively. In conclusion, TBXAS1 gene expression was downregulated in rats with iron-induced mesothelioma. The relationship between iron overload and TBXAS1 downregulation should be pursued further. PMID:26211743

  1. Downregulation of TBXAS1 in an iron-induced malignant mesothelioma model.

    PubMed

    Minami, Daisuke; Takigawa, Nagio; Kato, Yuka; Kudo, Kenichiro; Isozaki, Hideko; Hashida, Shinsuke; Harada, Daijiro; Ochi, Nobuaki; Fujii, Masanori; Kubo, Toshio; Ohashi, Kadoaki; Sato, Akiko; Tanaka, Takehiro; Hotta, Katsuyuki; Tabata, Masahiro; Toyooka, Shinichi; Tanimoto, Mitsune; Kiura, Katsuyuki

    2015-10-01

    Malignant mesothelioma is an aggressive and therapy-resistant neoplasm arising from mesothelial cells. Evidence suggests that the major pathology associated with asbestos-induced mesothelioma is local iron overload. In the present study, we induced iron-induced mesothelioma in rats based on previous reports. Ten Wistar rats were given ferric saccharate and nitrilotriacetate i.p. for 5 days a week. Five of the ten rats exhibited widespread mesotheliomas in the peritoneum and tunica vaginalis. The tumor cells showed positive immunostaining for calretinin, wilms tumor-1, podoplanin and the oxidative DNA marker 8-hydroxy-2'-deoxyguanosine. In three of the five rats with mesothelioma, array-based comparative genomic hybridization analysis identified a common chromosomal deletion mapped to the chromosomal 4q31 locus, which encompasses the TBXAS1 gene. Downregulation of the TBXAS1 gene was confirmed using quantitative PCR. TBXAS1 gene expression was also reduced in three of four human malignant pleural mesothelioma cell lines compared with normal bronchial epithelial cells. Immunohistochemistry revealed that TBXAS1 expression was weakly positive and positive in five and three out of eight human malignant mesothelioma samples, respectively. In conclusion, TBXAS1 gene expression was downregulated in rats with iron-induced mesothelioma. The relationship between iron overload and TBXAS1 downregulation should be pursued further. PMID:26211743

  2. Photodynamic therapy for lung cancer and malignant pleural mesothelioma.

    PubMed

    Simone, Charles B; Cengel, Keith A

    2014-12-01

    Photodynamic therapy (PDT) is a form of non-ionizing radiation therapy that uses a drug, called a photosensitizer, combined with light to produce singlet oxygen ((1)O2) that can exert anti-cancer activity through apoptotic, necrotic, or autophagic tumor cell death. PDT is increasingly being used to treat thoracic malignancies. For early-stage non-small cell lung cancer (NSCLC), PDT is primarily employed as an endobronchial therapy to definitively treat endobronchial or roentgenographically occult tumors. Similarly, patients with multiple primary lung cancers may be definitively treated with PDT. For advanced or metastatic NSCLC and small cell lung cancer (SCLC), PDT is primarily employed to palliate symptoms from obstructing endobronchial lesions causing airway compromise or hemoptysis. PDT can be used in advanced NSCLC to attempt to increase operability or to reduce the extent of operation intervention required, and selectively to treat pleural dissemination intraoperatively following macroscopically complete surgical resection. Intraoperative PDT can be safely combined with macroscopically complete surgical resection and other treatment modalities for malignant pleural mesothelioma (MPM) to improve local control and prolong survival. This report reviews the mechanism of and rationale for using PDT to treat thoracic malignancies, details prospective and major retrospectives studies of PDT to treat NSCLC, SCLC, and MPM, and describes improvements in and future roles and directions of PDT. PMID:25499640

  3. A case report of metastasis of malignant mesothelioma to the oral gingiva

    PubMed Central

    2011-01-01

    Introduction Metastatic mesothelioma to the oral cavity arises from the pleura or peritoneum and distant hematogenous metastases are seen in more than half of cases but only a few cases are reported to the oral cavity. Case A 75 year old male suffering from metastatic mesothelioma presents an hyperplasia of the attached gingiva. Malignant mesothelioma is a rare tumour arising from pleura, pericardium or peritoneum. Conclusion This article highlights the importance of biopsy and histopathological diagnosis of oral lesions especially in case of a malignant history. PMID:21513537

  4. 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. PMID:17634686

  5. 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

  6. Malignant mesothelioma of the pleura in Barrow-in-Furness.

    PubMed Central

    Edge, J R; Choudhury, S L

    1978-01-01

    Ffty cases of malignant pleural mesothelioma (47 men and 3 women) have been diagnosed during the period 1966-76 in Barrow-in-Furness, all of them histologically proved and accepted by the Pneumoconiosis Panel. At the time of writing only three survive. There was a history of industrial exposure to asbestos in all 47 men, who had worked in various trades in the shipyard, as had one of the women. One of the women was married to a shipyard plumber, who may have brought home asbestos dust on his clothes. Only one patient, a housewife, aged 28 at diagnosis, had no known asbestos contact. The asbestos content of the lungs has been measured in the last 20 cases, in 18 of whom it was found to be substantially greater than the accepted levels for the general population. In a small number studied by electron microscopy, the predominant fibre was crocidolite. A positive histological diagnosis was achieved in 39 subjects during life in the expectation of securing industrial compensation, but, in spite of this, less than half of the dependants are currently receiving payments. Metastases, though never clinically apparent, were frequent at necropsy. PMID:644536

  7. Vinca alkaloids in the therapeutic management of malignant pleural mesothelioma.

    PubMed

    Ceresoli, Giovanni Luca; Zucali, Paolo Andrea

    2015-12-01

    Therapeutic options for malignant pleural mesothelioma (MPM) are limited. Most patients are treated with chemotherapy during the course of their disease. The combination of pemetrexed with a platinum compound is the standard of care in the first-line setting, while no established treatment exists in the second and beyond-line setting. Vinca alkaloids are chemotherapeutic agents that have demonstrated clinical efficacy both as single agents and in combination in a broad spectrum of cancers, including MPM. Vinorelbine has shown activity in MPM patients as neoadjuvant therapy, first-line treatment, and in the second and third-line setting. Vinflunine is a derivative of vinorelbine that has been studied in MPM as first-line agent. While the role of vinca alkaloids in the first-line treatment of MPM seems marginal, treatment with vinorelbine remains a reasonable option for pemetrexed-pretreated patients in clinical practice, based on an acceptable rate of stable disease, confirmed by several trials. Ongoing studies on predictive biomarkers for vinorelbine will hopefully be able to individualize treatment, increasing response rates and survival outcomes. PMID:26526504

  8. Rapidly progressive sarcomatoid malignant mesothelioma of the pleura mimicking pulmonary empyema.

    PubMed

    Fujita, Kohei; Kim, Young Hak; Nakatani, Koichi; Mio, Tadashi

    2015-10-01

    Refractory empyema occasionally reflects hidden malignant disease. We presented a rare case of rapidly progressive malignant mesothelioma of the pleura (MPM) mimicking empyema. Physicians should be aware of MPM when patients with empyema are refractory to the standard treatment, and PET-CT may be helpful in establishing a precise diagnosis in such cases. PMID:26509028

  9. Distinctive clinical characteristics of malignant mesothelioma in young patients

    PubMed Central

    Yu, Tinghui; Gill, Ammara; Prasad, Vinay

    2015-01-01

    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. PMID:26202904

  10. 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. PMID:26202904

  11. 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

  12. 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

  13. 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.

  14. 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. PMID:26004138

  15. 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

  16. Microdissection, mRNA amplification and microarray: a study of pleural mesothelial and malignant mesothelioma cells.

    PubMed

    Mohr, Steve; Bottin, Marie-Claire; Lannes, Béatrice; Neuville, Agnès; Bellocq, Jean-Pierre; Keith, Gérard; Rihn, Bertrand Henri

    2004-01-01

    The studies of molecular alterations in tumor cells with microarrays are often hampered by inherent tissue heterogeneity. The emergence of Laser Capture Microdissection (LCM) allowed us to overcome this challenge since it gives selective access to cancer cells that are isolated from their native tissue environment. In this report, we microdissected mesothelial cells and malignant mesothelioma cells of ex vivo resected specimens using LCM. Amplified RNA from mesothelial and mesothelioma microdissected cells allowed us to measure global gene expression with 10 K-microarrays in four independent experiments. We screened 9850 annotated human genes, 1275 of which have satisfied our data analysis requirements. They included 302 overexpressed genes and 160 downregulated genes in mesothelioma microdissected cells as compared to mesothelial microdissected cells. Among them, the expression levels of eight genes, namely BF, FTL, IGFBP7, RARRES1, RARRES2, RBP1, SAT, and TXN according to HUGO nomenclature, were increased, whereas six: ALOX5AP, CLNS1A, EIF4A2, ELK3, REQ and SYPL, were found to be underexpressed in mesothelioma microdissected cells. The ferritin light polypeptide (FTL) gene overexpression was confirmed by real time quantitative PCR. Our approach allowed a comprehensive in situ examination of mesothelioma and provided an accurate way to find new marker genes that may be useful for diagnosis and treatment of malignant pleural mesothelioma. PMID:14987796

  17. Human malignant mesothelioma is recapitulated in immunocompetent BALB/c mice injected with murine AB cells.

    PubMed

    Mezzapelle, Rosanna; Rrapaj, Eltjona; Gatti, Elena; Ceriotti, Chiara; Marchis, Francesco De; Preti, Alessandro; Spinelli, Antonello E; Perani, Laura; Venturini, Massimo; Valtorta, Silvia; Moresco, Rosa Maria; Pecciarini, Lorenza; Doglioni, Claudio; Frenquelli, Michela; Crippa, Luca; Recordati, Camilla; Scanziani, Eugenio; de Vries, Hilda; Berns, Anton; Frapolli, Roberta; Boldorini, Renzo; D'Incalci, Maurizio; Bianchi, Marco E; Crippa, Massimo P

    2016-01-01

    Malignant Mesothelioma is a highly aggressive cancer, which is difficult to diagnose and treat. Here we describe the molecular, cellular and morphological characterization of a syngeneic system consisting of murine AB1, AB12 and AB22 mesothelioma cells injected in immunocompetent BALB/c mice, which allows the study of the interplay of tumor cells with the immune system. Murine mesothelioma cells, like human ones, respond to exogenous High Mobility Group Box 1 protein, a Damage-Associated Molecular Pattern that acts as a chemoattractant for leukocytes and as a proinflammatory mediator. The tumors derived from AB cells are morphologically and histologically similar to human MM tumors, and respond to treatments used for MM patients. Our system largely recapitulates human mesothelioma, and we advocate its use for the study of MM development and treatment. PMID:26961782

  18. Human malignant mesothelioma is recapitulated in immunocompetent BALB/c mice injected with murine AB cells

    PubMed Central

    Mezzapelle, Rosanna; Rrapaj, Eltjona; Gatti, Elena; Ceriotti, Chiara; Marchis, Francesco De; Preti, Alessandro; Spinelli, Antonello E.; Perani, Laura; Venturini, Massimo; Valtorta, Silvia; Moresco, Rosa Maria; Pecciarini, Lorenza; Doglioni, Claudio; Frenquelli, Michela; Crippa, Luca; Recordati, Camilla; Scanziani, Eugenio; de Vries, Hilda; Berns, Anton; Frapolli, Roberta; Boldorini, Renzo; D’Incalci, Maurizio; Bianchi, Marco E.; Crippa, Massimo P.

    2016-01-01

    Malignant Mesothelioma is a highly aggressive cancer, which is difficult to diagnose and treat. Here we describe the molecular, cellular and morphological characterization of a syngeneic system consisting of murine AB1, AB12 and AB22 mesothelioma cells injected in immunocompetent BALB/c mice, which allows the study of the interplay of tumor cells with the immune system. Murine mesothelioma cells, like human ones, respond to exogenous High Mobility Group Box 1 protein, a Damage-Associated Molecular Pattern that acts as a chemoattractant for leukocytes and as a proinflammatory mediator. The tumors derived from AB cells are morphologically and histologically similar to human MM tumors, and respond to treatments used for MM patients. Our system largely recapitulates human mesothelioma, and we advocate its use for the study of MM development and treatment. PMID:26961782

  19. [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. PMID:18050854

  20. [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. PMID:17575406

  1. Cyberknife radiosurgery for focal paravertebral recurrence after radical pleurectomy/decortication in malignant pleural mesothelioma.

    PubMed

    Lang-Lazdunski, Loïc; Barrington, Sally; Bille, Andrea; Bondiau, Pierre-Yves

    2012-06-01

    We present a case of malignant pleural mesothelioma with focal relapse in the Azygos arch region after radical pleurectomy/decortication and adjuvant chemotherapy. Tumour recurrence was successfully treated by Cyberknife radiosurgery (70 Gy in five fractions). Patient remains disease-free at 40 months without any other treatment. PMID:22290898

  2. 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). PMID:17980576

  3. 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

  4. 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

  5. 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

  6. Asymptomatic localized pleural amyloidosis mimicking malignant pleural mesothelioma: report of a case

    PubMed Central

    Nakano, Tomoyuki; Tetsuka, Kenji; Fukushima, Noriyoshi

    2016-01-01

    We herein report an asymptomatic 65-year-old male with localized pleural amyloidosis mimicking malignant pleural mesothelioma. He had a history of exposure to asbestos and was admitted for investigation of an abnormal pleural thickness detected by chest radiography. Positron emission tomography showed elevation of standardized uptake value corresponding to the pleural thickness. Partial pleurectomy including the tumor was performed for the purpose of diagnosis and local disease control. The pathological examination showed that the tumor was pleural amyloidosis. The tumor was diagnosed as localized primary amyloidosis, because serum monoclonal protein concentration did not increase. Pleural amyloidosis should be considered as a differential diagnosis from pleural mesothelioma. PMID:26904248

  7. 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

  8. Malignant mesothelioma of the greater omentum mimicking omental infarction: A case report

    PubMed Central

    Shin, Min-Kee; Lee, Ok-Jae; Ha, Chang-Yoon; Min, Hyun-Joo; Kim, Tae-Hyo

    2009-01-01

    Mesothelioma develops most commonly in the pleura, and less frequently in the peritoneum. Usually, it manifests as diffuse peritoneal thickening and multiple nodules, and rarely as a solitary mass. We report a rare case of primary malignant mesothelioma of the greater omentum, which mimicked omental infarct. A 54-year-old Korean man was admitted because of severe abdominal pain of sudden onset. A tender mass with indistinct margins was palpated in the upper abdomen. Abdominal ultrasound and computed tomography showed an ill-defined mass in the greater omentum and little ascites in the peri-hepatic space, and neutrophil-dominant exudates were documented on paracentesis. Intravenous antibiotics and analgesics were given for omental infarction with superimposed infection, which resulted in symptomatic improvement. The imaging studies after a week revealed a growing mass and ascites. Laparoscopic surgery was performed and an 8 cm × 3.3 cm greater omental mass was found, with multiple small nodules on the peritoneum, diaphragm, and pelvic cavity wall. Histological examination showed proliferating malignant epithelioid cells that stained strongly for calretinin, which was compatible with malignant mesothelioma. We recommend that primary omental mesothelioma should be included in the differential diagnosis of patients with omental infarction, despite its rarity. PMID:19824125

  9. In vivo imaging of human malignant mesothelioma grown orthotopically in the peritoneal cavity of nude mice.

    PubMed

    Feng, Mingqian; Zhang, Jingli; Anver, Miriam; Hassan, Raffit; Ho, Mitchell

    2011-01-01

    Malignant mesothelioma (MM) causes significant morbidity and mortality in patients. With increasing efforts devoted to developing therapeutics targeting mesothelioma, a xenograft mouse model with in vivo tumor imaging is especially desired for evaluating anti-tumor therapies. In the present study, we fluorescently labeled the NCI-H226 human mesothelioma cell line by a lentiviral vector harboring a luciferase-GFP (Luc/GFP) fusion gene driven by the RNA polymerase II promoter. After single-cell cloning by flow cytometry, a clone (named LMB-H226-GL) that stably expresses high levels of Luc/GFP was obtained. The in vivo tumorigenicity of Luc/GFP-labeled LMB-H226-GL was determined by using intraperitoneal injections of the cells in nude mice. LMB-H226-GL was found to be able to consistently form solid tumors in the peritoneum of mice. Tumor growth and aggressive progression could be quantitated via in vivo bioluminescence imaging. The model exhibited the pathological hallmarks consistent with the clinical progression of MM in terms of tumor growth and spread inside the peritoneal cavity. To evaluate the in vivo efficacy of drugs targeting mesothelioma, we treated mice with SS1P, a recombinant immunotoxin currently evaluated in Phase II clinical trials for treatment of mesothelioma. All the tumor-bearing mice had a significant response to SS1P treatment. Our results showed that this is a well-suited model for mesothelioma, and may be useful for evaluating other novel agents for mesothelioma treatment in vivo. PMID:21479131

  10. In Vivo Imaging of Human Malignant Mesothelioma Grown Orthotopically in the Peritoneal Cavity of Nude Mice

    PubMed Central

    Feng, Mingqian; Zhang, Jingli; Anver, Miriam; Hassan, Raffit; Ho, Mitchell

    2011-01-01

    Malignant mesothelioma (MM) causes significant morbidity and mortality in patients. With increasing efforts devoted to developing therapeutics targeting mesothelioma, a xenograft mouse model with in vivo tumor imaging is especially desired for evaluating anti-tumor therapies. In the present study, we fluorescently labeled the NCI-H226 human mesothelioma cell line by a lentiviral vector harboring a luciferase-GFP (Luc/GFP) fusion gene driven by the RNA polymerase II promoter. After single-cell cloning by flow cytometry, a clone (named LMB-H226-GL) that stably expresses high levels of Luc/GFP was obtained. The in vivo tumorigenicity of Luc/GFP-labeled LMB-H226-GL was determined by using intraperitoneal injections of the cells in nude mice. LMB-H226-GL was found to be able to consistently form solid tumors in the peritoneum of mice. Tumor growth and aggressive progression could be quantitated via in vivo bioluminescence imaging. The model exhibited the pathological hallmarks consistent with the clinical progression of MM in terms of tumor growth and spread inside the peritoneal cavity. To evaluate the in vivo efficacy of drugs targeting mesothelioma, we treated mice with SS1P, a recombinant immunotoxin currently evaluated in Phase II clinical trials for treatment of mesothelioma. All the tumor-bearing mice had a significant response to SS1P treatment. Our results showed that this is a well-suited model for mesothelioma, and may be useful for evaluating other novel agents for mesothelioma treatment in vivo. PMID:21479131

  11. Pegylated liposomal doxorubicin in malignant pleural mesothelioma: a possible guardian for long-term survival

    PubMed Central

    Zarogoulidis, Paul; Mavroudi, Maria; Porpodis, Konstantinos; Domvri, Kalliopi; Sakkas, Antonios; Machairiotis, Nikolaos; Stylianaki, Aikaterini; Tsiotsios, Anastasios; Courcoutsakis, Nikolaos; Zarogoulidis, Konstantinos

    2012-01-01

    Malignant pleural mesothelioma is a rare and aggressive malignancy of the pleura correlated with exposure to asbestos, with a medium survival of 11–12 months after diagnosis. A case of a 67-year-old male who had previously worked in the asbestos industry and is a current smoker is reported. The computed tomography evaluation revealed a right pleural mass with pleural thickening, and the pleural biopsy confirmed a diagnosis of malignant pleural mesothelioma. He was treated with chemotherapy consisting of etoposide, paclitaxel, and pegylated liposomal doxorubicin hydrochloride. After completion of chemotherapy, radiologic evaluation confirmed a reduction of pleural thickening and improvement in his symptoms. A complete presentation of each drug formulation and characteristics are also included in this paper. The patient’s follow-up is continuing, and computed tomography reveals stable disease 9 years after initial examination. PMID:23055748

  12. Genomic copy number alterations in 33 malignant peritoneal mesothelioma analyzed by comparative genomic hybridization array.

    PubMed

    Chirac, Pierre; Maillet, Denis; Leprêtre, Frédéric; Isaac, Sylvie; Glehen, Olivier; Figeac, Martin; Villeneuve, Laurent; Péron, Julien; Gibson, Fernando; Galateau-Sallé, Françoise; Gilly, François-Noël; Brevet, Marie

    2016-09-01

    Malignant peritoneal mesotheliomas (MPM) are rare, accounting for approximately 8% of cases of mesothelioma in France. We performed comparative genomic hybridization (CGH) on frozen MPM samples using the Agilent Human Genome CGH 180 K array. Samples were taken from a total of 33 French patients, comprising 20 men and 13 women with a mean (range) age of 58.4 (17-76) years. Asbestos exposure was reported in 8 patients (24.2%). Median (range) overall survival (OS) was 39 (0-119) months. CGH analysis demonstrated the presence of chromosomal instability in patients with MPM, with a genomic pattern that was similar to that described for pleural mesothelioma, including the loss of chromosomal regions 3p21, 9p21, and 22q12. In addition, novel genomic copy number alterations were identified, including the 15q26.2 region and the 8p11.22 region. Median OS was associated with a low peritoneal cancer index (P=.011), epithelioid subtype (P=.038), and a low number of genomic aberrations (P=.015), all of which constitute good prognostic factors for MPM. Our results provide new insights into the genetic and genomic background of MPM. Although pleural and peritoneal mesotheliomas have different risk factors, different therapeutics, and different prognosis; these data provide support to combine pleural and peritoneal mesothelioma in same clinical assays. PMID:27184482

  13. Malignant pleural mesothelioma: history, controversy and future of a manmade epidemic.

    PubMed

    Røe, Oluf Dimitri; Stella, Giulia Maria

    2015-03-01

    Asbestos is the term for a family of naturally occurring minerals that have been used on a small scale since ancient times. Industrialisation demanded increased mining and refining in the 20th century, and in 1960, Wagner, Sleggs and Marchand from South Africa linked asbestos to mesothelioma, paving the way to the current knowledge of the aetiology, epidemiology and biology of malignant pleural mesothelioma. Pleural mesothelioma is one of the most lethal cancers, with increasing incidence worldwide. This review will give some snapshots of the history of pleural mesothelioma discovery, and the body of epidemiological and biological research, including some of the controversies and unresolved questions. Translational research is currently unravelling novel circulating biomarkers for earlier diagnosis and novel treatment targets. Current breakthrough discoveries of clinically promising noninvasive biomarkers, such as the 13-protein signature, microRNAs and the BAP1 mesothelioma/cancer syndrome, are highlighted. The asbestos history is a lesson to not be repeated, but here we also review recent in vivo and in vitro studies showing that manmade carbon nanofibres could pose a similar danger to human health. This should be taken seriously by regulatory bodies to ensure thorough testing of novel materials before release in the society. PMID:25726562

  14. Inflammation-Related IL1β/IL1R Signaling Promotes the Development of Asbestos-Induced Malignant Mesothelioma.

    PubMed

    Kadariya, Yuwaraj; Menges, Craig W; Talarchek, Jacqueline; Cai, Kathy Q; Klein-Szanto, Andres J; Pietrofesa, Ralph A; Christofidou-Solomidou, Melpo; Cheung, Mitchell; Mossman, Brooke T; Shukla, Arti; Testa, Joseph R

    2016-05-01

    Exposure to asbestos is causally associated with the development of malignant mesothelioma, a cancer of cells lining the internal body cavities. Malignant mesothelioma is an aggressive cancer resistant to all current therapies. Once inhaled or ingested, asbestos causes inflammation in and around tissues that come in contact with these carcinogenic fibers. Recent studies suggest that inflammation is a major contributing factor in the development of many types of cancer, including malignant mesothelioma. The NALP3/NLRP3 inflammasome, including the component ASC, is thought to be an important mediator of inflammation in cells that sense extracellular insults, such as asbestos, and activate a signaling cascade resulting in release of mature IL1β and recruitment of inflammatory cells. To determine if inflammasome-mediated inflammation contributes to asbestos-induced malignant mesothelioma, we chronically exposed Asc-deficient mice and wild-type littermates to asbestos and evaluated differences in tumor incidence and latency. The Asc-deficient mice showed significantly delayed tumor onset and reduced malignant mesothelioma incidence compared with wild-type animals. We also tested whether inflammation-related release of IL1β contributes to tumor development in an accelerated mouse model of asbestos-induced malignant mesothelioma. Nf2(+/-);Cdkn2a(+/-) mice exposed to asbestos in the presence of anakinra, an IL1 receptor (IL1R) antagonist, showed a marked delay in the median time of malignant mesothelioma onset compared with similarly exposed mice given vehicle control (33.1 weeks vs. 22.6 weeks, respectively). Collectively, these studies provide evidence for a link between inflammation-related IL1β/IL1R signaling and the development of asbestos-induced malignant mesothelioma. Furthermore, these findings provide rationale for chemoprevention strategies targeting IL1β/IL1R signaling in high-risk, asbestos-exposed populations. Cancer Prev Res; 9(5); 406-14. ©2016 AACR

  15. Surgical cytoreduction restores the antitumor efficacy of a Listeria monocytogenes vaccine in malignant pleural mesothelioma.

    PubMed

    Kennedy, Gregory T; Judy, Brendan F; Bhojnagarwala, Pratik; Moon, Edmund K; Fridlender, Zvi G; Albelda, Steven M; Singhal, Sunil

    2015-07-01

    Recent studies suggest that immunotherapy may offer a promising treatment strategy for early-stage malignant pleural mesothelioma (MPM), but advanced tumor burden may limit the efficacy of immunotherapy. Therefore, we hypothesized that surgical cytoreduction could restore the efficacy of vaccine-based immunotherapy for MPM. We developed a murine model of MPM through transduction of a mesothelioma cell line with mesothelin. We used this model to evaluate the efficacy of a Listeria monocytogenes vaccine expressing mesothelin. Tumor growth was significantly inhibited at four weeks in animals vaccinated two weeks prior to tumor cell inoculation as compared to those given an empty vector control (1371 ± 420 mm(3) versus 405 ± 139 mm(3); p < 0.01). Mice vaccinated one week prior to tumor challenge also displayed significant reduction in tumor volume (1227 ± 406 mm(3) versus 309 ± 173 mm(3); p < 0.01). The vaccine had no effect when administered concurrently with tumor challenge, or after tumors were established. Flow cytometry showed reduced mesothelin expression in large tumors, as well as tumor-associated immunosuppression due to increased myeloid derived suppressor cells (MDSCs). These factors may have limited vaccine efficacy for advanced disease. Surgical cytoreduction of established tumors restored the antitumor potency of the therapeutic vaccine, with significantly reduced tumor burden at post-operative day 18 (397 ± 103 mm(3) versus 1047 ± 258 mm(3); p < 0.01). We found that surgery reduced MDSCs to levels comparable to those in tumor-naïve mice. This study demonstrates that cytoreduction surgery restores the efficacy of cancer vaccines for MPM by reducing tumor-related immunosuppression that impairs immunotherapy. PMID:25999306

  16. 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

  17. Malignant Mesothelioma Versus Metastatic Carcinoma of the Pleura: A CT Challenge

    PubMed Central

    Bakhshayesh Karam, Mehrdad; Karimi, Shirin; Mosadegh, Leila; Chaibakhsh, Samira

    2016-01-01

    Background: Malignant pleural mesothelioma (MPM) is a rare malignant neoplasm of the pleura that typically affects individuals occupationally exposed to asbestos through a variety of industries. MPM presents with several CT features similar to more common pleural diseases such as metastatic pleural malignancy. Objectives: The aim of this study is to differentiate malignant pleural mesothelioma from metastatic carcinoma of the pleura by pathological and radiological assessment in order to investigate accuracy of CT scan in this regard and to compare CT features of these two malignancies. Patients and Methods: Chest CT scans of 55 pleural malignancy patients including MPM and metastatic pleural malignancy were evaluated in this retrospective study. The pathologist made the definite diagnosis based on immunohistochemistry. A chest radiologist unaware of the pathology diagnosis observed all CT scans. Several parameters including pleural thickening, pleural effusion, thickening of inter lobar fissure, contralateral extension, contraction of involved hemithorax, parenchymal involvement (infiltration, nodules, fibrosis), pleural mediastinal involvement, lymphadenopathy, extrapleural invasion (hepatic, chest wall, diaphragm, intraperitoneal), and pericardial involvement were checked. Data analysis was carried out using SPSS version 16, and the ability of CT scan to differentiate malignant pleural mesothelioma and metastatic pleural diseases was investigated. Results: Totally 29 males and 26 females were assessed in this study. Based on pathology, 17 MPM and 38 metastatic pleural malignancies were diagnosed. According to CT study, about 82% of the patients with MPM and about 79% of the patients with metastatic pleural diseases were correctly diagnosed by a radiologist. The most common findings suggestive of MPM were pleural thickening (88.2%), loculated effusion (58.8%), and thickening of the interlobar fissure (47.1%). Whereas free pleural effusion (71.7%), parenchymal

  18. 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.

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

    PubMed Central

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

    2014-01-01

    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. PMID:24754309

  20. Malignant mesothelioma: clustering in a family producing asbestos cement in their home.

    PubMed Central

    Otte, K E; Sigsgaard, T I; Kjaerulff, J

    1990-01-01

    In a family with a remarkable aggregation of malignant mesothelioma the father, mother, and a son all died of the condition, whereas two other sons and a daughter were unaffected. From 1944 to 1961 the family produced a material that was used to fix screws in drilled holes and consisted of amosite, gypsum, and sand. It was produced in the basement of their villa and was described as being a dusty job. The father died in 1984 aged 74, the son in 1985 aged 45, and the mother in 1987 aged 79. It is concluded that there is a high risk of malignant mesothelioma after massive exposure to amosite and the risk and latency period are independent of age during the exposure. Images PMID:2155646

  1. 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

  2. Management of recurrence after initial surgery for malignant pleural mesothelioma: a mini-review.

    PubMed

    Halezeroğlu, Semih; Migliore, Marcello

    2015-01-01

    Recurrence after surgery in the multimodality therapy for malignant pleural mesothelioma is a common problem. As the majority of patients experience not only local but also distant metastases, a systemic treatment strategy in addition to local control measures remains necessary. Nevertheless, none of the chemotherapy regimens have achieved clinical success. Local management modalities such as stereotaxic treatments, cryoablation and redo surgery on the other hand have promising results, but provide palliative outcomes. PMID:26638919

  3. Soluble Mesothelin-Related Peptides Levels in Patients with Malignant Mesothelioma

    PubMed Central

    Franko, Alenka; Dolzan, Vita; Kovac, Viljem; Arneric, Niko; Dodic-Fikfak, Metoda

    2012-01-01

    Soluble mesothelin-related peptides (SMRP) are a potential tumor marker for malignant mesothelioma. The aim of this study was to determine the differences in SMRP levels in patients with malignant mesothelioma before treatment and in various responses to treatment and to investigate whether SMRP level could be useful in evaluating tumor response to treatment. The study included patients with malignant mesothelioma treated at the Institute of Oncology Ljubljana between March 2007 and December 2009. Blood samples were collected before treatment and/or in various responses to treatment. SMRP levels were determined using ELISA assay based upon a combination of two monoclonal antibodies. Mann-Whitney test was used to determine the differences in SMRP levels in various responses to treatment. Median SMRP was 2.80 nmol/L (range 0.00–34.80) before treatment, 0.00 nmol/L (range 0.00–0.00) in complete response, 0.48 nmol/L (range 0.00–4.40) in partial response, 1.65 nmol/L (range 0.00–20.71) in stable disease and 7.15 nmol/L (range 0.44–31.56) in progressive disease. Pre-treatment SMRP levels were significantly higher than in stable disease, partial response and complete response (p=0.006), as were SMRP levels in progressive disease compared to stable disease, partial response and complete response (p = 0.006), as were SMRP levels in progressive disease compared to stable disease, partial response and complete response (p < 0.001). Our findings suggest that SMRP may be a useful tumor marker for detecting the progression of malignant mesothelioma and evaluating tumor response to treatment. PMID:22377706

  4. Non-Amplified FGFR1 is a Growth Driver in Malignant Pleural Mesothelioma

    PubMed Central

    Marek, Lindsay A.; Hinz, Trista K.; von Mässenhause, Anne; Olszewski, Kyle A.; Kleczko, Emily K.; Böhm, Diana; Weiser-Evans, Mary C.; Nemenoff, Raphael A.; Hoffmann, Hans; Warth, Arne; Gozgit, Joseph M.; Perner, Sven; Heasley, Lynn E.

    2014-01-01

    Malignant pleural mesothelioma (MPM) is associated with asbestos exposure and is a cancer that has not been significantly impacted by small molecule-based targeted therapeutics. Previously, we demonstrated the existence of functional subsets of lung cancer and head and neck squamous cell carcinoma (HNSCC) cell lines in which fibroblast growth factor receptor (FGFR) autocrine signaling functions as a non-mutated growth pathway. In a panel of pleural mesothelioma cell lines, FGFR1 and FGF2 were co-expressed in 3 of 7 cell lines and were significantly associated with sensitivity to the FGFR-active tyrosine kinase inhibitor (TKI), ponatinib, both in vitro and in vivo using orthotopically propagated xenografts. Furthermore, RNAi-mediated silencing confirmed the requirement for FGFR1 in specific mesothelioma cells and sensitivity to the FGF ligand trap, FP-1039, validated the requirement for autocrine FGFs. None of the FGFR1-dependent mesothelioma cells exhibited increased FGFR1 gene copy number, based on a FISH assay, indicating that increased FGFR1 transcript and protein expression were not mediated by gene amplification. Elevated FGFR1 mRNA was detected in a subset of primary MPM clinical specimens and like MPM cells, none harbored increased FGFR1 gene copy number. These results indicate that autocrine signaling through FGFR1 represents a targetable therapeutic pathway in MPM and that biomarkers distinct from increased FGFR1 gene copy number such as FGFR1 mRNA would be required to identify MPM patients bearing tumors driven by FGFR1 activity. Implications FGFR1 is a viable therapeutic target in a subset of malignant pleural mesotheliomas, but FGFR TKI-responsive tumors will need to be selected by a biomarker distinct from increased FGFR1 gene copy number, possibly FGFR1 mRNA or protein levels. PMID:24966347

  5. [Causation in the court: the complex case of malignant mesothelioma].

    PubMed

    Lageard, Giovanni

    2011-01-01

    The aim of this paper is to carry out an analysis of the legal evolution in Italy of the assessment of causation i.e. cause and effect, in oncological diseases, a question taken into consideration by the High Court almost exclusively with reference to pleural mesothelioma. The most debated question when defining the causal association between asbestos exposure and mesothelioma is the possible role that any multiple potentially causative exposures could assume in the induction and development of the disease, and in particular the role of any asbestos exposure over the successive employment periods. Indeed, this is a subject on which, to date, no agreement has yet been reached in scientific doctrine: these divergences bear important practical significance from a legal point of view, since sustaining one thesis or another may constitute determining factors when ascertaining responsibility for individuals who, in the past, had decisional statuses in the workplace. Jurisprudence in the High Court took on an oscillating position on this question as from the early 2000s, which was divided into those who sustained the thesis of the relevance of any asbestos exposure over the successive employment periods and those who were of a different opinion, i.e. only the first exposure period has relevant causative effect. The point under discussion concerns, in particular, the adequacy of a probabilistic law only governing such a question. An important turning point was made in the year 2010 when two sentences were announced in the High Court, reiterating, in strict compliance with the principles affirmed by the United Sections in 2002, that a judge cannot, and must not, be satisfied with a general causation, but must rather reach a judgment on the basis of an individual causation. In particular, not only did the second of these two sentences recognise the multifactorial nature of mesothelioma, something which had almost always been denied in jurisprudence in the past, but it also

  6. Expression and activity of eIF6 trigger Malignant Pleural Mesothelioma growth in vivo

    PubMed Central

    Pesce, Elisa; Mutti, Luciano; Murer, Bruno; Grosso, Stefano; Ricciardi, Sara; Brina, Daniela; Biffo, Stefano

    2015-01-01

    eIF6 is an antiassociation factor that regulates the availability of active 80S. Its activation is driven by the RACK1/PKCβ axis, in a mTORc1 independent manner. We previously described that eIF6 haploinsufficiency causes a striking survival in the Eμ-Myc mouse lymphoma model, with lifespans extended up to 18 months. Here we screen for eIF6 expression in human cancers. We show that Malignant Pleural Mesothelioma tumors (MPM) and a MPM cell line (REN cells) contain high levels of hyperphosphorylated eIF6. Enzastaurin is a PKC beta inhibitor used in clinical trials. We prove that Enzastaurin treatment decreases eIF6 phosphorylation rate, but not eIF6 protein stability. The growth of REN, in vivo, and metastasis are reduced by either Enzastaurin treatment or eIF6 shRNA. Molecular analysis reveals that eIF6 manipulation affects the metabolic status of malignant mesothelioma cells. Less glycolysis and less ATP content are evident in REN cells depleted for eIF6 or treated with Enzastaurin (Anti-Warburg effect). We propose that eIF6 is necessary for malignant mesothelioma growth, in vivo, and can be targeted by kinase inhibitors. PMID:26462016

  7. 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

  8. 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

  9. Biologic therapy and gene therapy in the multimodality treatment of malignant pleural mesothelioma.

    PubMed

    Viti, Andrea; Bertolaccini, Luca; Terzi, Alberto

    2015-10-01

    The last years have witnessed an abrupt paradigm shift in cancer treatment owing to the discoveries concerning the relationships between the immune system and neoplastic cells. In the field of malignant mesothelioma, which, despite painstaking efforts, remains an incurable form of cancer, the researchers' attention has been seized by a variety of new biologic approaches, including both viral gene therapy and active immunotherapy. The former is meant to induce programmed cell death by introducing a specific gene in the target cell, this gene encoding a specific protein with anticancer activity. Active immunotherapy, on the other hand, tires to induce an active response of the immune system, whose surveillance may be easily dodged by cancer cells. In fact, this mechanism seems to play an important role in the development, growth and diffusion of malignant mesothelioma which easily manages to hinder the immune response. A thorough understanding of the relationships existing between mesothelioma and immune system is the basis for the success of those immune therapies, which are showing promising results in the preclinical setting, especially when combined with other approaches, such as cytoreductive surgery. PMID:26605294

  10. 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

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

    PubMed

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

    2014-10-01

    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

  12. 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

  13. A nuclear grading system is a strong predictor of survival in epitheloid diffuse malignant pleural mesothelioma.

    PubMed

    Kadota, Kyuichi; Suzuki, Kei; Colovos, Christos; Sima, Camelia S; Rusch, Valerie W; Travis, William D; Adusumilli, Prasad S

    2012-02-01

    Epithelioid mesothelioma is the most prevalent subtype of diffuse malignant pleural mesothelioma in which only staging is prognostic for survival. In this study of epithelioid diffuse malignant pleural mesothelioma, we investigate the prognostic utility of nuclear features. The slides of 232 epithelioid diffuse malignant pleural mesothelioma patients (14 stage I, 54 stage II, 130 stage III, and 34 stage IV) from a single institution were reviewed for the following seven nuclear features: nuclear atypia, nuclear/cytoplasmic ratio, chromatin pattern, intranuclear inclusions, prominence of nucleoli, mitotic count, and atypical mitoses. MIB-1 immunohistochemistry was performed using tissue microarray, and MIB-1 labeling index was recorded as the percentage of positive tumor cells. Median overall survival of all patients was 16 months and correlated with nuclear atypia (P<0.001), chromatin pattern (P=0.031), prominence of nucleoli (P<0.001), mitotic count (P<0.001), and atypical mitoses (P<0.001) by univariate analysis. Multivariate analysis revealed nuclear atypia (P=0.012) and mitotic count (P<0.001) as independent prognostic factors, and these two factors were utilized to create a three-tier nuclear grade score. The resulting nuclear grade stratified patients into three distinct prognostic groups: grade I (n=107, median overall survival=28 months), grade II (n=91, 14 months), and grade III (n=34, 5 months). Not only was nuclear grade an independent predictor of overall survival (P<0.001), but it was also a stronger discriminator of survival than all currently available factors. Furthermore, nuclear grade was associated with time to recurrence (P=0.004) in patients who underwent complete surgical resection (n=159). MIB-1 labeling index correlated with mitotic count (P<0.001) and nuclear atypia (P=0.037) and stratified overall survival (P<0.001) and time to recurrence (P=0.048), confirming the prognostic value of the nuclear grade. Nuclear grading in epithelioid

  14. microRNAs are differentially regulated between MDM2-positive and negative malignant pleural mesothelioma

    PubMed Central

    Walter, Robert Fred Henry; Vollbrecht, Claudia; Werner, Robert; Wohlschlaeger, Jeremias; Christoph, Daniel Christian; Schmid, Kurt Werner; Mairinger, Fabian Dominik

    2016-01-01

    Background Malignant pleural mesothelioma (MPM) is a highly aggressive tumour first-line treated with a combination of cisplatin and pemetrexed. MDM2 and P14/ARF (CDKN2A) are upstream regulators of TP53 and may contribute to its inactivation. In the present study, we now aimed to define the impact of miRNA expression on this mechanism. Material and Methods 24 formalin-fixed paraffin-embedded (FFPE) tumour specimens were used for miRNA expression analysis of the 800 most important miRNAs using the nCounter technique (NanoString). Significantly deregulated miRNAs were identified before a KEGG-pathway analysis was performed. Results 17 miRNAs regulating TP53, 18 miRNAs regulating MDM2, and 11 miRNAs directly regulating CDKN2A are significantly downregulated in MDM2-expressing mesotheliomas. TP53 is downregulated in MDM2-negative tumours through miRNAs with a miSVR prediction score of 11.67, RB1 with a prediction score of 8.02, MDM2 with a prediction score of 4.50 and CDKN2A with a prediction score of 1.27. Conclusion MDM2 expression seems to impact miRNA expression levels in MPM. Especially, miRNAs involved in TP53-signaling are strongly decreased in MDM2-positive mesotheliomas. A better understanding of its tumour biology may open the chance for new therapeutic approaches and thereby augment patients' outcome. PMID:26918730

  15. 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.

  16. 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

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

    PubMed

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

    2013-04-01

    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

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

    PubMed

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

    2016-09-01

    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

  19. Pleural epitheliod hemangioendothelioma: What started as a liver fluke and ended up being almost mistaken for malignant mesothelioma

    PubMed Central

    Jamy, Omer H.; Huber, Bryan; Giri, Smith

    2015-01-01

    Epitheliod hemangioendothelioma (EHE) is a rare tumor of vascular origin. The pleural variant has only been reported around 20 times in English literature. It commonly occurs in older men and carries a poor prognosis with average survival lasting from a few weeks to months. Pleural EHE (PEHE) can be a diagnostic challenge due to its rarity as well as similarities to other pleural and vascular tumors. There is currently no standard treatment for EHE. Due to the rarity of this disease, reaching a final diagnosis is challenging. It's clinical, radiological, and pathological resemblance to malignant mesothelioma can cause a delay in diagnosis. Special stains such as CD31, CD34, and factor VIII related antigen can help differentiate between the two. Ordering appropriate stains in a timely manner can help avoid misdiagnosing PEHE. PMID:26664569

  20. 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

  1. [Expanded access program in the United States and Alimta program for malignant mesothelioma patients].

    PubMed

    Nambu, Yoshihiro

    2007-02-01

    In the United States, Expanded Access Program is allowed by FDA to facilitate the availability of promising new drugs to desperately ill patients as early in the drug development process as possible, before marketing begins, and to obtain additional data on the drug's safety and effectiveness. Eli Lilly conducted Alimta Expanded Access Programs for 1200 malignant mesothelioma patients with free of charge and obtained clinical efficacy and severe adverse events. The system development for Expanded Access Program should be discussed for future Japanese participation to this program. PMID:17301544

  2. 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.

  3. Pooled analysis of NAT2 genotypes as risk factors for asbestos-related malignant mesothelioma.

    PubMed

    Betti, Marta; Neri, Monica; Ferrante, Daniela; Landi, Stefano; Biava, Alessandra; Gemignani, Federica; Bertolotti, Marinella; Mirabelli, Dario; Padoan, Marina; Ugolini, Donatella; Botta, Mario; Bonassi, Stefano; Magnani, Corrado; Dianzani, Irma

    2009-05-01

    Malignant mesothelioma (MM) is a rare and aggressive tumor of the pleura. The most important causal factor for the development of MM is occupational exposure to asbestos. Different lines of evidence suggest a role of genetic background in MM development, as for other cancers. Two published studies observed an association between MM and N-acetyl-transferase 2 (NAT2) polymorphisms. First, a Finnish study observed that the NAT2 slow acetylator phenotype was associated with an increased risk of MM. Conversely, MM risk was higher in Italian subjects carrying the NAT2 fast acetylator genotypes. The conflicting results obtained in Finland and Italy could be ascribed to random chance, considering the small panel of patients and controls in the two studies, but also ethnic or other differences may have been important. To ascertain the role of NAT2 genotype, we performed a study on 252 MM patients and 262 controls recruited in two Northern Italy areas that were characterized by high asbestos exposure, due to intense industrial activities (an asbestos cement factory in Casale Monferrato, mainly shipyards and refineries in Liguria). Unconditional multivariate logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). NAT2 fast acetylator genotypes showed an increased OR, although not statistically significant, both in asbestos-exposed subjects (OR=1.47; 95% CI=0.96-2.26) and in the entire population (OR=1.38; 95% CI=0.93-2.04). These results suggest that NAT2 polymorphisms do not exert a strong effect on individual susceptibility to MM. PMID:18838334

  4. Liposomal pemetrexed: formulation, characterization and in vitro cytotoxicity studies for effective management of malignant pleural mesothelioma.

    PubMed

    Essam Eldin, Noha; Elnahas, Hanan Mohamed; Mahdy, Mahmoud Abd-Elghany; Ishida, Tatsuhiro

    2015-01-01

    Pemetrexed (PMX) is a newly developed multi-targeted anti-folate with promising clinical activity in many solid tumors including malignant pleural mesothelioma (MPM). However, PMX does not show sufficient anti-tumor activity in vivo when used alone either due to inefficient delivery of adequate concentrations to tumor tissue or dose-limiting side effects. In order to overcome these problems and to achieve potent anti-tumor activity, PMX was encapsulated into a liposomal delivery system. In the present study, various formulations of liposomal PMX were prepared. The effect of formulation parameters on the encapsulation efficiency of PMX within liposomes was evaluated. In addition, the influence of drug release rate on the in vitro cytotoxicity was investigated. Encapsulation of PMX within liposomes was remarkably increased by the incorporation of cholesterol within liposomal membranes and by increasing the total lipid concentration. Encapsulation efficiency was found to be unaffected by the type of phospholipid used or the inclusion of a cation lipid, DC-6-14. Interestingly, encapsulation of PMX within "fluid" liposomes was found to allow efficient release of PMX from liposomes resulting in a potent in vitro cytotoxicity against MPM MSTO-211H cell line. On the other hand, entrapment of PMX within "solid" liposomes substantially hindered PMX release from liposomes, and thus PMX failed to exert any in vitro cytotoxicity. These results suggest that encapsulation of PMX within "fluid" liposomes might represent a novel strategy to enhance the therapeutic efficacy of PMX while minimizing the side effect encountered by the non selective delivery of free PMX to various body tissues. PMID:25757929

  5. 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.

  6. KAT5 (Tip60) is a potential therapeutic target in malignant pleural mesothelioma.

    PubMed

    Cregan, Sian; McDonagh, Lauran; Gao, Yun; Barr, Martin P; O'Byrne, Kenneth J; Finn, Stephen P; Cuffe, Sinead; Gray, Steven G

    2016-03-01

    Malignant pleural mesothelioma (MPM) is a rare aggressive cancer of the pleura. Asbestos exposure (through inhalation) is the most well established risk factor for mesothelioma. The current standard of care for patients suffering from MPM is a combination of cisplatin and pemetrexed (or alternatively cisplatin and raltitrexed). Most patients, however, die within 24 months of diagnosis. New therapies are therefore urgently required for this disease. Lysine acetyltransferases (KATs) including KAT5 have been linked with the development of cisplatin resistance. This gene may therefore be altered in MPM and could represent a novel candidate target for intervention. Using RT-PCR screening the expression of all known KAT5 variants was found to be markedly increased in malignant tumors compared to benign pleura. When separated according to histological subtype, KAT5 was significantly overexpressed in both the sarcomatoid and biphasic subgroups for all transcript variants. A panel of MPM cell lines including the normal pleural cells LP9 and Met5A was screened for expression of KAT5 variants. Treatment of cells with a small molecule inhibitor of KAT5 (MG-149) caused significant inhibition of cellular proliferation (p<0.0001), induction of apoptosis and was accompanied by significant induction of pro-inflammatory cytokines/chemokines. PMID:26780987

  7. 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 ther-apy (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

  8. Malignant Peritoneal Mesothelioma in an Adolescent Male With BAP1 Deletion.

    PubMed

    Taylor, Steve; Carpentieri, David; Williams, James; Acosta, Juan; Southard, Richard

    2015-07-01

    Diffuse malignant peritoneal mesotheliomas in children are uncommon, aggressive tumors with a grave prognosis. We herein report the clinical, radiologic, and pathologic findings of a 16-year-old male. The adolescent presented with a history of abdominal pain, nausea and daily, nonbilious, nonbloody emesis for 3 weeks. Radiographic imaging suggested small bowel obstruction. The diagnostic work-up and differential diagnoses are discussed. Histologically, the tumor was composed of epithelioid cells with a papillary and glandular architectural pattern. A few glands appeared to produce mucinous material. Histochemistry revealed PAS diastase resistant mucin, an inconspicuous finding in diffuse malignant peritoneal mesothelioma. An extensive immunohistochemistry panel (calretinin, WT-1, D2-40, CK 7, CAM 5.2, CK 5/6, CEA, B72.3, CK 20, CD10, CD30, CD15, CD117, PLAP, S100, TFE3, and EMA) confirmed the diagnosis. Of special interest, BAP1 staining was cytoplasmic and consistent with 3p deletion detected by conventional cytogenetics. The ultrastructural analysis demonstrated long microvilli, desmosomes, and intercellular junctions which further supported the diagnosis. PMID:25222065

  9. 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

  10. Overexpression and potential targeting of the oncofoetal antigen 5T4 in malignant pleural mesothelioma.

    PubMed

    Al-Taei, Saly; Salimu, Josephine; Lester, Jason F; Linnane, Seamus; Goonewardena, Madusha; Harrop, Richard; Mason, Malcolm D; Tabi, Zsuzsanna

    2012-08-01

    Malignant pleural mesothelioma (MPM) is resistant to conventional treatments. Novel, targeted treatments are hampered by the relative lack of MPM-associated tumour antigens. The aim of this study was to evaluate the level of expression and the relevance of 5T4 as a tumour-associated antigen in MPM. 5T4 expression was assessed by Western blotting, flow cytometry, immuno-cytochemistry and -histochemistry in 11 mesothelioma cell lines, 21 tumour biopsies, and ex vivo tumour cells obtained from the pleural fluid (PF) of 10 patients. 5T4 antibody levels were also determined in the plasma of patients and healthy donors. The susceptibility of MPM cells to 5T4-specific T-cell-mediated killing was determined using an HLA-A2(+), CD8(+) T-cell line, developed against the 5T4(17-25) peptide. We report here that cell surface 5T4 expression was detected in all mesothelioma cell lines and PF cell samples. Mesothelin and CD200, a suggested mesothelioma marker, were co-expressed with 5T4 on tumour cells in PF. Immunohistochemistry confirmed overexpression of 5T4, similar to mesothelin, on tumour cells but not on reactive stroma in all tissue sections tested. Median 5T4 antibody levels were 46% higher in patient than in healthy donor plasma, indicating immune recognition. Importantly, 5T4-specific CD8(+) T-cells were able to kill four out of six HLA-A2(+) MPM cell lines but not an HLA-A2(-) cell line, demonstrating immune recognition of MPM-associated 5T4 antigen at the effector T-cell level. We conclude that 5T4 is a potential new antigen for targeted therapies such as immunotherapy in MPM, as it is overexpressed on mesothelioma cells and recognised by 5T4-specific cytotoxic T-cells. Our findings have been translated into a Phase II clinical trial applying 5T4-targeted therapies in MPM patients. PMID:22498111

  11. A 26-year-old male with mesothelioma due to asbestos exposure.

    PubMed

    Zarogoulidis, P; Orfanidis, M; Constadinidis, T C; Eleutheriadou, E; Kontakiotis, T; Kerenidi, T; Sakkas, L; Courcoutsakis, N; Zarogoulidis, K

    2011-01-01

    Mesothelioma is a malignancy with poor prognosis, with an average 5-year survival rate being less than 9%. This type of cancer is almost exclusively caused by exposure to asbestos. A long exposure can cause mesothelioma and so can short ones, as each exposure is cumulative. We report a case of a 26-year-old male who was exposed to asbestos during his primary school years from the age of 6 to 12. Although the tumor mainly affects older men who in their youth were occupationally exposed to asbestos, malignant mesothelioma can also occur in young adults. A medical history was carefully taken and asbestos exposure was immediately mentioned by the patient. We conducted biopsy on the right supraclavicular lymph node. The patient was not a candidate for surgery, and chemotherapy treatment was initiated. While patient's chemotherapy is still ongoing, no other similar cases of students or teachers have been traced up to date from his school. The school building was demolished in January 2009. PMID:21776278

  12. A 26-Year-Old Male with Mesothelioma Due to Asbestos Exposure

    PubMed Central

    Zarogoulidis, P.; Orfanidis, M.; Constadinidis, T. C.; Eleutheriadou, E.; Kontakiotis, T.; Kerenidi, T.; Sakkas, L.; Courcoutsakis, N.; Zarogoulidis, K.

    2011-01-01

    Mesothelioma is a malignancy with poor prognosis, with an average 5-year survival rate being less than 9%. This type of cancer is almost exclusively caused by exposure to asbestos. A long exposure can cause mesothelioma and so can short ones, as each exposure is cumulative. We report a case of a 26-year-old male who was exposed to asbestos during his primary school years from the age of 6 to 12. Although the tumor mainly affects older men who in their youth were occupationally exposed to asbestos, malignant mesothelioma can also occur in young adults. A medical history was carefully taken and asbestos exposure was immediately mentioned by the patient. We conducted biopsy on the right supraclavicular lymph node. The patient was not a candidate for surgery, and chemotherapy treatment was initiated. While patient's chemotherapy is still ongoing, no other similar cases of students or teachers have been traced up to date from his school. The school building was demolished in January 2009. PMID:21776278

  13. 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.

  14. Pleural malignant mesothelioma and non-occupational exposure to asbestos in Casale Monferrato, Italy.

    PubMed Central

    Magnani, C; Terracini, B; Ivaldi, C; Botta, M; Mancini, A; Andrion, A

    1995-01-01

    OBJECTIVES--To assess and quantify the occurrence of pleural malignant mesotheliomas in people who neither experienced occupational exposure to asbestos nor were married to (or known to live with) workers exposed to asbestos in the workplace. The study was conducted in the area of the local health authority of Casale Monferrato, in north western Italy, where a large factory that produced asbestos cement was active up to 1985. No other major activities related to asbestos have ever been present in the area. METHODS--A retrospective survey covering the period 1980 to 1991 identified 126 incident pleural malignant mesotheliomas histologically diagnosed among residents in the local health authority (population at the 1981 census 98,000). Submission of 83 of 95 cases diagnosed during 1980-9 for revision by a panel of five expert pathologists led to the exclusion of 21. The 31 cases diagnosed in 1990-1 were not submitted for revision. For 64 of the 105 retained cases, information derived from different sources (rosters of the employees in the asbestos cement factory dated back to 1907, list of their spouses, clinical records) did not suggest occupational or paraoccupational exposure to asbestos. RESULTS--Incidence excludes cases for which there was some suggestion of occupational or paraoccupational exposure to asbestos. Incidence of histologically confirmed malignant mesothelioma among residents in the local health authority (annual x 100,000; age adjusted) was 4.2 in men and 2.3 in women (based on 26 and 18 cases respectively). In both sexes, rates in 1985-9 were higher than in the previous quinquennium. Corresponding estimates for 1990-1 (based on unrevised diagnoses) suggest similar rates in men and women. CONCLUSION--Rate ratios which are four to six times those measured by conventional Italian cancer registries can hardly be totally explained by bias produced by lack of recognition of occupational or paraoccupational exposure. The problem of proving this type of

  15. 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

  16. 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

  17. 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

  18. 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

  19. Malignant mesothelioma caused by childhood exposure to long-fiber low aspect ratio tremolite.

    PubMed

    Magee, F; Wright, J L; Chan, N; Lawson, L; Churg, A

    1986-01-01

    A 41-year-old man was found to have a malignant mesothelioma of the pleura. During childhood in Corsica, he had been exposed at home to chrysotile ore from the Canari mine. Analysis of lung mineral content revealed background levels of chrysotile but an elevated level of tremolite and actinolite asbestos. The latter had a geometric mean length of 3.7 microns, a value considerably longer than we have found for tremolite and actinolite from Quebec chrysotile miners but roughly the same as the mean length of amosite and crocidolite in workers with occupational amphibole exposure. No tremolite or actinolite fibers of length greater than 8 microns microns and width less than 0.25 micron were observed. The mean aspect ratio of the tremolite and actinolite fibers was 7, a value similar to that found in chrysotile miners with mesothelioma but considerably less than the mean aspect ratio of amosite and crocidolite from those with occupational exposure. These data suggest that long-fiber tremolite is a potential mesothelial carcinogen in humans, and that fiber length is more important than fiber aspect ratio in this regard. PMID:3017103

  20. 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

  1. Positive response of a primary malignant pericardial mesothelioma to pemetrexed plus cisplatin followed by pemetrexed maintenance chemotherapy: A case report

    PubMed Central

    CHUNG, SANG MI; CHOI, SEONG JI; KIM, MIN JUNG; CHOI, JUNG YOON; KIM, HONG JUN; LEE, SUK-YOUNG; KANG, EUN JOO

    2016-01-01

    Primary malignant pericardial mesothelioma (PMPM) is a rare tumor with poor prognosis. Surgery is the treatment of choice, but numerous cases are inoperable. For the treatment of inoperable or metastatic cases, systemic chemotherapy is required. However, a standard chemotherapeutic regimen for the treatment of pericardial mesothelioma has not yet been established. Chemotherapy involving pemetrexed and cisplatin has been actively used in the treatment of pleural or peritoneal mesothelioma, and may be considered for the treatment of PMPM. The present study reports the case of a patient with PMPM with lung metastasis who demonstrated a positive response to treatment with pemetrexed and cisplatin followed by pemetrexed maintenance chemotherapy, leading to prolonged progression-free survival for 21 months. PMID:27347127

  2. Repetitive responses to nanoparticle albumin-bound paclitaxel and carboplatin in malignant pleural mesothelioma.

    PubMed

    Kanai, Osamu; Fujita, Kohei; Nakatani, Koichi; Mio, Tadashi

    2016-03-01

    Malignant pleural mesothelioma (MPM) is a rare tumor with a poor prognosis. Although cisplatin plus pemetrexed is the standard chemotherapy for patients with unresectable MPM, few agents are available for MPM patients who do not tolerate pemetrexed. Here, we report the first case of an MPM patient for whom the combination of nanoparticle albumin-bound paclitaxel and carboplatin (nabPC) repetitively achieved tumor regression. A 76-year-old man was diagnosed with epithelioid MPM. One cycle of carboplatin plus pemetrexed and two cycles of gemcitabine were administered but failed to inhibit tumor progression. By contrast, four cycles of nabPC resulted in a good response. Upon disease progression, four cycles of nabPC were performed again and resulted in a modest response. In conclusion, based on the present case, nabPC is a potential alternative chemotherapeutic agent for MPM, especially for MPM patients who do not tolerate pemetrexed. PMID:26839699

  3. Comprehensive treatment of malignant mesothelioma patients after the failure of systemic chemotherapy.

    PubMed

    Chen, Jibing; Liang, Bing; Yuan, Yuanying; Liu, Chunyan; Li, Li; Li, Haibo; Mu, Feng; Zuo, Jiansheng; Xu, Kecheng

    2012-12-01

    Malignant mesothelioma (MM) is an aggressive neoplasm usually arising from the mesothelial surfaces of the pleural or peritoneal cavity. Currently, no standard therapy is available. The most commonly used therapy is cytoreductive surgery combined with systematic chemotherapy, but the median overall survival (OS) is less than 12 months; moreover, treatments are lacking for patients in whom chemotherapy has failed and/or who cannot withstand surgery. We investigated multiple minimally invasive therapies (cryosurgery, photodynamic therapy and intracavity chemotherapy) for the treatment of MM patients in whom systemic chemotherapy had failed. Twenty-seven patients were divided into comprehensive (combination of the three therapies) and palliative (intracavity chemotherapy only) treatment groups. The OS of patients who received comprehensive treatment was significantly longer than that of those who received palliative treatment (median OS: 64 vs. 9 months, P<0.001). This interesting result was not associated with treatment timing, but was closely associated with repeated treatments. PMID:22939880

  4. G-CSF-producing malignant pleural mesothelioma: an autopsy case report with literature review.

    PubMed

    Oka, Kuniyuki; Sarashina, Gen; Yonekawa, Nobuo; Watanabe, Osamu; Miyao, Yoshiko; Hashimoto, Toshio; Yatabe, Yasushi

    2012-06-01

    This study reports a 54-year-old man who was a carpenter by occupation. He suffered from left chest and back pain and left pleural effusion. Peripheral blood showed granulocytosis and high serum titers of granulocyte-colony stimulating factor (G-CSF) and CYFRA. He died 20 months later. At autopsy, a pleural tumor located around the left lung and thickening of the pericardium, diaphragm, and esophagus by tumor infiltration was seen. The tumor proliferated in papillary and solid alveolar patterns by neoplastic cells. They were positive for calretinin, D2-40, CK5/6, HBME-1, G-CSF, CK19, and E-cadherin. He was diagnosed with G-CSF-producing epithelioid malignant pleural mesothelioma. PMID:21911431

  5. Inhibition of hedgehog signaling reduces the side population in human malignant mesothelioma cell lines

    PubMed Central

    Kim, H-A; Kim, M-C; Kim, N-Y; Kim, Y

    2015-01-01

    Deregulation of crucial embryonic pathways, including hedgehog signaling, has been frequently implicated in a variety of human cancers and is emerging as an important target for anticancer therapy. This study evaluated the potential anticancer effects of cyclopamine, a chemical inhibitor of hedgehog signaling, in human malignant mesothelioma (HMM) cell lines. Cyclopamine treatment significantly decreased the proliferation of HMM cells by promoting apoptosis and shifting the cell cycle toward dormant phase. The clonogenicity and mobility of HMM cells were significantly decreased by cyclopamine treatment. Treatment of HMM cells with cyclopamine significantly reduced the abundance of side population cells, which were measured using an assay composed of Hoechst 33342 dye staining and subsequent flow cytometry. Furthermore, the expression levels of stemness-related genes were significantly affected by cyclopamine treatment. Taken together, the present study showed that targeting hedgehog signaling could reduce a more aggressive subpopulation of the cancer cells, suggesting an alternative approach for HMM therapy. PMID:26206198

  6. Immune response profiling of malignant pleural mesothelioma for diagnostic and prognostic biomarkers.

    PubMed

    Creaney, Jenette; Dick, Ian M; Musk, A W Bill; Olsen, Nola J; Robinson, Bruce W S

    2016-09-01

    The asbestos induced cancer malignant mesothelioma (MM) is difficult to diagnose and has a poor prognosis. MM is an immunological cancer, therefore autoantibodies may be suitable biomarkers and associated with prognosis. We used Protoarray(®) microarrays to determine immune responses to 8798 antigens in 10 MM and 10 asbestos exposed controls and developed diagnostic panels using 17 antigens from this. The AUC of these panels were independently tested in these 10 MM patients and controls and in a validation group of 36 controls and 35 MM patients using luminex assays; none of the antigens identified were validated. Immune responses to RAB38 were associated with a better prognosis. PMID:27009350

  7. 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.

  8. Serum HMGB1 as a prognostic marker for malignant pleural mesothelioma

    PubMed Central

    2013-01-01

    Background Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor of mesothelial origin that shows a limited response to conventional chemotherapy and radiotherapy. Therefore, diagnosing MPM early is very important. Some researchers have previously reported that high-mobility group box 1 (HMGB1) was correlated with pulmonary fibrosis. MPM involves the malignant transformation of mesothelial cells, which originate from mesenchymal cells similar to lung fibroblasts. Here, we investigated serum levels of HMGB1 in patients with MPM and compared them with those of a population that had been exposed to asbestos without developing MPM. Methods HMGB1 production from MPM cell lines was measured using ELISA. Serum HMGB1 levels were also examined in 61 MPM patients and 45 individuals with benign asbestos-related diseases. Results HMGB1 concentrations of 2 out of 4 MPM cell lines were higher than that of normal mesothelial cell line, Met-5A. We demonstrated that patients with MPM had significantly higher serum levels of HMGB1 than the population who had been exposed to asbestos but had not developed MPM. The difference in overall survival between groups with serum HMGB1 levels that were lower and higher than assumed cut-off values was significant. Conclusions Our data suggest that serum HMGB1 concentration is a useful prognostic factor for MPM. PMID:23617783

  9. Transforming growth factor-beta 1 (TGF-beta 1)- and beta 2-like activities in malignant pleural effusions caused by malignant mesothelioma or primary lung cancer.

    PubMed Central

    Maeda, J; Ueki, N; Ohkawa, T; Iwahashi, N; Nakano, T; Hada, T; Higashino, K

    1994-01-01

    We investigated the levels of TGF-beta in malignant pleural effusions (MPE) caused by malignant mesothelioma (MESO) or primary lung cancer. TGF-beta levels in MPE caused by MESO were 283.9 +/- 219.2 pm (mean +/- s.d.) and were three to six times higher than those due to primary lung cancers (P < 0.01 or P < 0.05). We also evaluated TGF-beta 1- and beta 2-like activities in MPE using specific polyclonal antibodies. Although TGF-beta 1-like activity could be detected in all cases, TGF-beta 2-like activities were detected in five of seven in MESO and in a few cases with primary lung cancer. These results demonstrate that the levels of total TGF-beta and TGF-beta 2-like activity may be clinically useful to differentiate MESO from primary lung cancer. Our data also suggest that TGF-beta may help further characterize the clinical features of MESO. PMID:7955539

  10. Peroxiredoxin 3 Is a Redox-Dependent Target of Thiostrepton in Malignant Mesothelioma Cells

    PubMed Central

    Newick, Kheng; Cunniff, Brian; Preston, Kelsey; Held, Paul; Arbiser, Jack; Pass, Harvey; Mossman, Brooke; Shukla, Arti; Heintz, Nicholas

    2012-01-01

    Thiostrepton (TS) is a thiazole antibiotic that inhibits expression of FOXM1, an oncogenic transcription factor required for cell cycle progression and resistance to oncogene-induced oxidative stress. The mechanism of action of TS is unclear and strategies that enhance TS activity will improve its therapeutic potential. Analysis of human tumor specimens showed FOXM1 is broadly expressed in malignant mesothelioma (MM), an intractable tumor associated with asbestos exposure. The mechanism of action of TS was investigated in a cell culture model of human MM. As for other tumor cell types, TS inhibited expression of FOXM1 in MM cells in a dose-dependent manner. Suppression of FOXM1 expression and coincidental activation of ERK1/2 by TS were abrogated by pre-incubation of cells with the antioxidant N-acetyl-L-cysteine (NAC), indicating its mechanism of action in MM cells is redox-dependent. Examination of the mitochondrial thioredoxin reductase 2 (TR2)-thioredoxin 2 (TRX2)-peroxiredoxin 3 (PRX3) antioxidant network revealed that TS modifies the electrophoretic mobility of PRX3. Incubation of recombinant human PRX3 with TS in vitro also resulted in PRX3 with altered electrophoretic mobility. The cellular and recombinant species of modified PRX3 were resistant to dithiothreitol and SDS and suppressed by NAC, indicating that TS covalently adducts cysteine residues in PRX3. Reduction of endogenous mitochondrial TRX2 levels by the cationic triphenylmethane gentian violet (GV) promoted modification of PRX3 by TS and significantly enhanced its cytotoxic activity. Our results indicate TS covalently adducts PRX3, thereby disabling a major mitochondrial antioxidant network that counters chronic mitochondrial oxidative stress. Redox-active compounds like GV that modify the TR2/TRX2 network may significantly enhance the efficacy of TS, thereby providing a combinatorial approach for exploiting redox-dependent perturbations in mitochondrial function as a therapeutic approach in

  11. 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

  12. Wnt7A is a putative prognostic and chemosensitivity marker in human malignant pleural mesothelioma

    PubMed Central

    HIRATA, TOMOMI; ZHENG, QINGFENG; CHEN, ZHAO; KINOSHITA, HIROYASU; OKAMOTO, JUNICHI; KRATZ, JOHANNES; LI, HUI; LUI, NATALIE; DO, HANH; CHENG, TIFFANY; TSENG, HSIN-HUI KATTY; KOIZUMI, KIYOSHI; SHIMIZU, KAZUO; ZHOU, HAI-MENG; JABLONS, DAVID; HE, BIAO

    2015-01-01

    Malignant pleural mesothelioma (MPM) is a highly aggressive tumor that has a poor prognosis, limited treatment options, and a worldwide incidence that is expected to increase in the next decade. We evaluated Wnt7A expression in 50 surgically resected tumor specimens using quantitative PCR. The expression values, were assessed by clinicopathological factors and K-M and Cox’s regression with OS. The mean level of Wnt7A expression had a significant correlation with International Mesothelioma Interest Group (IMIG) stage (P<0.034), gender, smoking history and ethnicity, respectively (P=0.020, P=0.014, P=0.039). In the univariate analysis, low Wnt7A expression was a significant negative factor for overall survival (P=0.043, HR=2.30). However, multivariate Cox’s regression revealed no significant factors for overall survival (low Wnt7A: P=0.051, HR=2.283; non-epithelioid subtype: P=0.050, HR=2.898). In patients with epithelioid tumors, those with low Wnt7A expression had significantly worse prognosis (P=0.019, HR=2.98). In patients with epithelioid tumors, females had significantly better prognosis than males (P=0.035). In patients who did not have neoadjuvant chemotherapy, prognosis was significantly more favorable for patients with high Wnt7A expression than for those with low Wnt7A expression (P=0.031). Among the patients with low Wnt7A-expressing tumors, those who received neoadjuvant chemotherapy had better prognosis than those who did not (P=0.024). The results of our study suggest that Wnt7A expression is a putative prognostic factor and a predictor of chemosensitivity. PMID:25632963

  13. Genetic variants associated with increased risk of malignant pleural mesothelioma: a genome-wide association study.

    PubMed

    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

  14. 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

  15. Assessment of immunological competence and SV40 specific recall immunity in malignant pleural mesothelioma.

    PubMed

    Jasani, Bharat; Coleman, Sharon; Butchart, Eric; Evans, Eve M-L; Adams, Malcolm; Mason, Malcolm; Gibbs, Allen; Tabi, Zsuzsanna

    2005-03-18

    Diffuse malignant pleural mesothelioma (MPM) is the third most common lung malignancy showing rising incidence with 250,000 deaths expected from it in Western Europe over the next 35 year. The tumour is generally resistant to conventional treatment and there is urgent need for novel preventative and therapeutic measures to combat this growing public threat. Finding of SV40 DNA sequences in a high proportion (40-90%) of several series of MPM cases, and suggestion of its potential co-carcinogen role provide a rationale for the development of novel anti-MPM vaccines incorporating SV40 gene sequences or antigenic determinants. As a prelude to adopting this approach, general T cell function was examined in relatively early cases of MPM presenting for biopsy or debulking surgery. CD8+ T cell responses were studied using antigenic epitopes of common viral antigens covering a broad range of haplotypes. 74.1% (20/27) of MPM patients and 80% (8/10) of the control subjects showed T cell responsiveness to the viral peptides mix, whilst a small proportion showed SV40 specific recall immunity. PMID:15755635

  16. Inhibition of PAI-1 Limits Tumor Angiogenesis Regardless of Angiogenic Stimuli in Malignant Pleural Mesothelioma.

    PubMed

    Takayama, Yusuke; Hattori, Noboru; Hamada, Hironobu; Masuda, Takeshi; Omori, Keitaro; Akita, Shin; Iwamoto, Hiroshi; Fujitaka, Kazunori; Kohno, Nobuoki

    2016-06-01

    Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor that secretes various angiogenic factors. The main inhibitor of plasminogen activators, PAI-1 (SERPINE1), has been implicated in tumor progression and angiogenesis, and high PAI-1 expression has been associated with poor prognosis in MPM patients. In this study, we examined the antiangiogenic effects of PAI-1 inhibition in MPM. We administered the PAI-1 inhibitor, SK-216, to orthotopic mouse models in which MPM cells expressing high levels of VEGF (VEGFA) or bFGF (FGF2) were intrapleurally transplanted. SK-216 administration reduced tumor weights and the degree of angiogenesis in intrapleural tumors, irrespective of their angiogenic expression profiles. In addition, a combination of SK-216 and the chemotherapeutic agent cisplatin significantly reduced tumor weights compared with monotherapy, prolonging the survival of animals compared with cisplatin treatment alone. Furthermore, SK-216 inhibited migration and tube formation of cultured human umbilical vein endothelial cells induced by various angiogenic factors known to be secreted by MPM. These findings suggest that PAI-1 inactivation by SK-216 may represent a general strategy for inhibiting angiogenesis, including for the treatment of MPM. Cancer Res; 76(11); 3285-94. ©2016 AACR. PMID:27197170

  17. 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

  18. An Autopsied Case of Malignant Sarcomatoid Pleural Mesothelioma in Which Chest Pain Developed Several Months Earlier without Abnormality on Imaging

    PubMed Central

    Yaguchi, Daizo; Ichikawa, Motoshi; Inoue, Noriko; Kobayashi, Daisuke; Matsuura, Akinobu; Shizu, Masato; Imai, Naoyuki; Watanabe, Kazuko

    2015-01-01

    The patient experienced chest pain for about 7 months, but a diagnosis could not be made until after death. He was diagnosed with malignant sarcomatoid pleural mesothelioma on autopsy. In this case report, difficult aspects of the diagnosis are discussed. The 70-year-old Japanese man was a driver who transported ceramic-related products. Right chest pain developed in July 2013, but no abnormality was detected on a chest computed tomography (CT) performed in September 2013, and the pain was managed as right intercostal neuralgia. A chest CT performed in late October 2013 revealed a right pleural effusion, and the patient was referred to our hospital in early November 2013. Thoracentesis was performed, but the cytology was negative, and no diagnosis could be made. Close examination was postponed because the patient developed a subarachnoid hemorrhage. He underwent 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) after discharge from the neurosurgery department, and extensive right pleural thickening and 18F-FDG accumulation in this region were observed. Based on these findings, malignant pleural mesothelioma was suspected, and a thoracoscopy was performed under local anesthesia in early December 2013, but no definite diagnosis could be made. The patient selected best supportive care and died about 7 months after the initial development of right chest pain. The disease was definitively diagnosed as malignant sarcomatoid pleural mesothelioma by a pathological autopsy. When chronic chest pain of unknown cause is observed and past exposure to asbestos is suspected, actions to prevent delay in diagnosis should be taken, including testing for suspicion of malignant pleural mesothelioma. PMID:26600776

  19. 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

  20. An Autopsied Case of Malignant Sarcomatoid Pleural Mesothelioma in Which Chest Pain Developed Several Months Earlier without Abnormality on Imaging.

    PubMed

    Yaguchi, Daizo; Ichikawa, Motoshi; Inoue, Noriko; Kobayashi, Daisuke; Matsuura, Akinobu; Shizu, Masato; Imai, Naoyuki; Watanabe, Kazuko

    2015-01-01

    The patient experienced chest pain for about 7 months, but a diagnosis could not be made until after death. He was diagnosed with malignant sarcomatoid pleural mesothelioma on autopsy. In this case report, difficult aspects of the diagnosis are discussed. The 70-year-old Japanese man was a driver who transported ceramic-related products. Right chest pain developed in July 2013, but no abnormality was detected on a chest computed tomography (CT) performed in September 2013, and the pain was managed as right intercostal neuralgia. A chest CT performed in late October 2013 revealed a right pleural effusion, and the patient was referred to our hospital in early November 2013. Thoracentesis was performed, but the cytology was negative, and no diagnosis could be made. Close examination was postponed because the patient developed a subarachnoid hemorrhage. He underwent (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) after discharge from the neurosurgery department, and extensive right pleural thickening and (18)F-FDG accumulation in this region were observed. Based on these findings, malignant pleural mesothelioma was suspected, and a thoracoscopy was performed under local anesthesia in early December 2013, but no definite diagnosis could be made. The patient selected best supportive care and died about 7 months after the initial development of right chest pain. The disease was definitively diagnosed as malignant sarcomatoid pleural mesothelioma by a pathological autopsy. When chronic chest pain of unknown cause is observed and past exposure to asbestos is suspected, actions to prevent delay in diagnosis should be taken, including testing for suspicion of malignant pleural mesothelioma. PMID:26600776

  1. 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

  2. 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.

  3. Inhibition of autophagy sensitizes malignant pleural mesothelioma cells to dual PI3K/mTOR inhibitors

    PubMed Central

    Echeverry, N; Ziltener, G; Barbone, D; Weder, W; Stahel, R A; Broaddus, V C; Felley-Bosco, E

    2015-01-01

    Malignant pleural mesothelioma (MPM) originates in most of the cases from chronic inflammation of the mesothelium due to exposure to asbestos fibers. Given the limited effect of chemotherapy, a big effort is being made to find new treatment options. The PI3K/mTOR pathway was reported to be upregulated in MPM. We tested the cell growth inhibition properties of two dual PI3K/mTOR inhibitors NVP-BEZ235 and GDC-0980 on 19 MPM cell lines. We could identify resistant and sensitive lines; however, there was no correlation to the downregulation of PI3K/mTOR activity markers. As a result of mTOR inhibition, both drugs efficiently induced long-term autophagy but not cell death. Autophagy blockade by chloroquine in combination with the dual PI3K/mTOR inhibitors significantly induced caspase-independent cell death involving RIP1 in the sensitive cell line SPC212. Cell death in the resistant cell line Mero-82 was less pronounced, and it was not induced via RIP1-dependent mechanism, suggesting the involvement of RIP1 downstream effectors. Cell death induction was confirmed in 3D systems. Based on these results, we identify autophagy as one of the main mechanisms of cell death resistance against dual PI3K/mTOR inhibitors in MPM. As PI3K/mTOR inhibitors are under investigation in clinical trials, these results may help interpreting their outcome and suggest ways for intervention. PMID:25950487

  4. CREST biorepository for translational studies on malignant mesothelioma, lung cancer and other respiratory tract diseases: Informatics infrastructure and standardized annotation

    PubMed Central

    UGOLINI, DONATELLA; NERI, MONICA; BENNATI, LUCA; CANESSA, PIER ALDO; CASANOVA, GEORGIA; LANDO, CECILIA; LEONCINI, GIACOMO; MARRONI, PAOLA; PARODI, BARBARA; SIMONASSI, CLAUDIO; BONASSI, STEFANO

    2012-01-01

    Advances in molecular epidemiology and translational research have led to the need for biospecimen collection. The Cancer of the Respiratory Tract (CREST) biorepository is concerned with pleural malignant mesothelioma (MM) and lung cancer (LC). The biorepository staff has collected demographic and epidemiological data directly from consenting subjects using a structured questionnaire, in agreement with The Public Population Project in Genomics (P3G). Clinical and follow-up data were collected. Sample data were also recorded. The architecture is based on a database designed with Microsoft Access. Data standardization was carried out to conform with established conventions or procedures. As from January 31, 2011, the overall number of recruited subjects was 1,857 (454 LC, 245 MM, 130 other cancers and 1,028 controls). Due to its infrastructure, CREST was able to join international projects, sharing samples and/or data with other research groups in the field. The data management system allows CREST to be involved, through a minimum data set, in the national project for the construction of the Italian network of Oncologic BioBanks (RIBBO), and in the infrastructure of a pan-European biobank network (BBMRI). The CREST biorepository is a valuable tool for translational studies on respiratory tract diseases, because of its simple and efficient infrastructure. PMID:22969926

  5. Estrogen receptor β activation impairs mitochondrial oxidative metabolism and affects malignant mesothelioma cell growth in vitro and in vivo

    PubMed Central

    Manente, A G; Valenti, D; Pinton, G; Jithesh, P V; Daga, A; Rossi, L; Gray, S G; O'Byrne, K J; Fennell, D A; Vacca, R A; Nilsson, S; Mutti, L; Moro, L

    2013-01-01

    Estrogen receptor (ER)-β has been shown to possess a tumor suppressive effect, and is a potential target for cancer therapy. Using gene-expression meta-analysis of human malignant pleural mesothelioma, we identified an ESR2 (ERβ coding gene) signature. High ESR2 expression was strongly associated with low succinate dehydrogenase B (SDHB) (which encodes a mitochondrial respiratory chain complex II subunit) expression. We demonstrate that SDHB loss induced ESR2 expression, and that activated ERβ, by over-expression or by selective agonist stimulation, negatively affected oxidative phosphorylation compromising mitochondrial complex II and IV activity. This resulted in reduced mitochondrial ATP production, increased glycolysis dependence and impaired cell proliferation. The observed in vitro effects were phenocopied in vivo using a selective ERβ agonist in a mesothelioma mouse model. On the whole, our data highlight an unforeseen interaction between ERβ-mediated tumor suppression and energy metabolism that may be exploited to improve on the therapy for clinical management of malignant mesothelioma. PMID:24061575

  6. Resveratrol contributes to chemosensitivity of malignant mesothelioma cells with activation of p53.

    PubMed

    Lee, Yoon-Jin; Park, Ihl-Sung; Lee, Yong-Jin; Shim, Jung-Hyun; Cho, Moon-Kyun; Nam, Hae-Seon; Park, Ji Woong; Oh, Myung-Ho; Lee, Sang-Han

    2014-01-01

    Resveratrol is a naturally occurring polyphenolic phytoalexin with chemopreventive properties. We previously reported a synergistic anti-proliferative effect of resveratrol and clofarabine against malignant mesothelioma (MM) cells. Here, we further investigated molecular mechanisms involved in the synergistic interaction of these compounds in MM MSTO-211H cells. Resveratrol, in combination with clofarabine, time-dependently induced a strong cytotoxic effect with the nuclear accumulation of phospho-p53 (p-p53) in MSTO-211H cells, but not in normal mesothelial MeT-5A cells. Combination treatment up-regulated the levels of p-p53, cleaved caspase-3, and cleaved PARP proteins. Gene silencing with p53-targeting siRNA attenuated the sensitivity of cells to the combined treatment of two compounds. Analyses of p53 DNA binding assay, p53 reporter gene assay, and RTP-CR toward p53-regulated genes, including Bax, PUMA, Noxa and p21, demonstrated that induced p-p53 is transcriptionally active. These results were further confirmed by the siRNA-mediated knockdown of p53 gene. Combination treatment significantly caused the accumulation of cells at G1 phase with the increases in the sub-G0/G1 peak, DNA ladder, nuclear fragmentation, and caspase-3/7 activity. Taken together, these results demonstrate that resveratrol and clofarabine synergistically elicit apoptotic signal via a p53-dependent pathway, and provide a scientific rationale for clinical evaluation of resveratrol as a promising chemopotentiator in MM. PMID:24239893

  7. Risk of second primary cancers after malignant mesothelioma and vice versa.

    PubMed

    Chen, Tianhui; Kharazmi, Elham; Lou, Jianlin; Zhang, Xing; Sundquist, Kristina; Hemminki, Kari

    2016-08-28

    We aimed at investigating risk of specific second primary cancers (SPCs) after malignant mesothelioma (MM) and vice versa, which has not been reported. Among survivors of 3672 pleural MM and 895 peritoneal MM, overall 113 and 28 SPCs were recorded, respectively, while reverse analyses included overall 431 pleural and 88 peritoneal MMs after any first cancers. We found a bidirectional association of pleural MM with kidney cancer for overall [for second kidney cancer after pleural MM: standardized incidence ratios (SIRs) = 4.4, 95% confidence intervals (CIs): 2.0-8.3; for second pleural MM after kidney cancer: 2.3 (1.3-3.9)] and for <1 year follow-up [5.4 (2.0-12) and 4.9 (2.0-10), respectively, according to the 2-way analyses]. In contrast, a bidirectional association of pleural MM with unknown primary cancer was found only for follow-up ≥1 year [3.9 (1.1-10) and 2.8 (1.3-5.1), respectively]. We found a bidirectional association of pleural MM with kidney cancer for overall and for <1 year follow-up, suggesting the involvement of germline BAP1 mutations and increased medical surveillance, while the bidirectional association of pleural MM with unknown primary cancer suggests shared genetic or environmental risk factors. PMID:27260871

  8. SIRT1 at the crossroads of AKT1 and ERβ in malignant pleural mesothelioma cells.

    PubMed

    Pinton, Giulia; Zonca, Sara; Manente, Arcangela G; Cavaletto, Maria; Borroni, Ester; Daga, Antonio; Jithesh, Puthen V; Fennell, Dean; Nilsson, Stefan; Moro, Laura

    2016-03-22

    In this report, we show that malignant pleural mesothelioma (MPM) patients whose tumors express high levels of AKT1 exhibit a significantly worse prognosis, whereas no significant correlation with AKT3 expression is observed. We provide data that establish a phosphorylation independent role of AKT1 in affecting MPM cell shape and anchorage independent cell growth in vitro and highlight the AKT1 isoform-specific nature of these effects.We describe that AKT1 activity is inhibited by the loss of SIRT1-mediated deacetylation and identify, by mass spectrometry, 11 unique proteins that interact with acetylated AKT1.Our data demonstrate a role of the AKT1/SIRT1/FOXM1 axis in the expression of the tumor suppressor ERβ. We further demonstrate an inhibitory feedback loop by ERβ, activated by the selective agonist KB9520, on this axis both in vitro and in vivo.Our data broaden the current knowledge of ERβ and AKT isoform-specific functions that could be valuable in the design of novel and effective therapeutic strategies for MPM. PMID:26885609

  9. SIRT1 at the crossroads of AKT1 and ERβ in malignant pleural mesothelioma cells

    PubMed Central

    Pinton, Giulia; Zonca, Sara; Manente, Arcangela G.; Cavaletto, Maria; Borroni, Ester; Daga, Antonio; Jithesh, Puthen V.; Fennell, Dean; Nilsson, Stefan; Moro, Laura

    2016-01-01

    In this report, we show that malignant pleural mesothelioma (MPM) patients whose tumors express high levels of AKT1 exhibit a significantly worse prognosis, whereas no significant correlation with AKT3 expression is observed. We provide data that establish a phosphorylation independent role of AKT1 in affecting MPM cell shape and anchorage independent cell growth in vitro and highlight the AKT1 isoform-specific nature of these effects. We describe that AKT1 activity is inhibited by the loss of SIRT1-mediated deacetylation and identify, by mass spectrometry, 11 unique proteins that interact with acetylated AKT1. Our data demonstrate a role of the AKT1/SIRT1/FOXM1 axis in the expression of the tumor suppressor ERβ. We further demonstrate an inhibitory feedback loop by ERβ, activated by the selective agonist KB9520, on this axis both in vitro and in vivo. Our data broaden the current knowledge of ERβ and AKT isoform-specific functions that could be valuable in the design of novel and effective therapeutic strategies for MPM. PMID:26885609

  10. 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

  11. miR-193a-3p is a potential tumor suppressor in malignant pleural mesothelioma

    PubMed Central

    Cheng, Yuen Yee; Hanh, Jacky; Weiss, Jocelyn; Mugridge, Nancy; Wright, Casey M.; Linton, Anthony; Kao, Steven C.; Edelman, J. James B.; Vallely, Michael P.; McCaughan, Brian C.; Cooper, Wendy; Klebe, Sonja; Lin, Ruby C.Y.; Brahmbhatt, Himanshu; MacDiarmid, Jennifer; van Zandwijk, Nico; Reid, Glen

    2015-01-01

    Malignant pleural mesothelioma (MPM) is an asbestos-induced cancer with poor prognosis that displays characteristic alterations in microRNA expression. Recently it was reported that the expression of a subset of microRNAs can distinguish between MPM and adenocarcinoma of the lung. However, the functional importance of these changes has yet to be investigated. We compared expression of miR-192, miR-193a-3p and the miR-200 family in normal pleura and MPM tumor specimens and found a statistically significant reduction in the levels of miR-193a-3p (3.1-fold) and miR-192 (2.8-fold) in MPM. Transfection of MPM cells with a miR-193a-3p mimic resulted in inhibition of growth and an induction of apoptosis and necrosis in vitro. The growth inhibitory effects of miR-193a-3p were associated with a decrease in MCL1 expression and were recapitulated by RNAi-mediated MCL1 silencing. Targeted delivery of miR-193a-3p mimic using EDV minicells inhibited MPM xenograft tumour growth, and was associated with increased apoptosis. In conclusion, miR-193a-3p appears to have importance in the biology of MPM and may represent a target for therapeutic intervention. PMID:26125439

  12. Overexpression of SOCS3 exhibits preclinical antitumor activity against malignant pleural mesothelioma.

    PubMed

    Iwahori, Kota; Serada, Satoshi; Fujimoto, Minoru; Nomura, Shintaro; Osaki, Tadashi; Lee, Chun Man; Mizuguchi, Hiroyuki; Takahashi, Tsuyoshi; Ripley, Barry; Okumura, Meinoshin; Kawase, Ichiro; Kishimoto, Tadamitsu; Naka, Tetsuji

    2011-08-15

    Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis for which an effective therapy remains to be established. Our study investigated the therapeutic potential of the suppressor of cytokine signaling 3 (SOCS3), an endogenous inhibitor of intracellular signaling pathways, for treatment of MPM. We infected MPM cells (H226, EHMES-1, MESO-1 and MESO-4) with an adenovirus-expressing SOCS3 (AdSOCS3) to examine the effect of SOCS3 overexpression on MPM cells. SOCS3 overexpression reduced MPM proliferation and induced apoptosis and partial G0/G1 arrest. SOCS3 also inhibited the proliferation of MPM cells via multiple signaling pathways including Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3), extracellular signal-regulated kinase (ERK), focal adhesion kinase (FAK) and p53 pathways. Notably, AdSOCS3 treatment inhibited tumor growth in an MPM pleural xenograft model. These findings demonstrate that overexpression of SOCS3 has a potent antitumor effect against MPM both in vitro and in vivo and indicate the potential for clinical use of SOCS3 for MPM treatment. PMID:20949562

  13. Clinicopathologic and Survival Characteristics of Malignant Pleural Mesothelioma Registered in Hospital Cancer Registry

    PubMed Central

    Najmi, Kosar; Khosravi, Adnan; Seifi, Sharare; Chaibakhsh, Samira; Radmand, Golnar; Khodadad, Kian

    2014-01-01

    Background Malignant pleural mesothelioma (MPM) is a rare but fatal thoracic tumor, which in the majority of patients is caused by prolonged exposure to asbestos fibers. We aimed at presenting clinicopathological and treatment outcomes of 60 patients of MPM registered in our hospital cancer registry. Materials and Methods Demographic characteristics of patients, exposure to asbestos, smoking habit, their clinicopathologic characteristics and survival analysis were described. Results Sixty patients had MPM. Forty patients (66.7%) were men. The mean age of patients was 55.8±11 years. Chest pain and dyspnea were the most prevalent symptoms (31.7%, and 30%, respectively). Thirty-six (61.7%) patients reported asbestos exposure. The median survival and Progression free survival (PFS) were 10.5 months (0.95CI=9.22-11.78) and 7.57 months (0.95CI=5.68-9.45), respectively. In multivariate analysis, exposure to asbestos and epithelioid subtype significantly extended the survival time. Bilateral involvement, high blood level of LDH and platelet count ≥400,000 significantly shortened the overall survival. Conclusion MPM is still an important health problem in Iran. Given the aforementioned results, developing a national program to eliminate asbestos-related diseases according to the world health organization (WHO) recommendation is necessary. PMID:25506370

  14. Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations.

    PubMed

    Bueno, Raphael; Stawiski, Eric W; Goldstein, Leonard D; Durinck, Steffen; De Rienzo, Assunta; Modrusan, Zora; Gnad, Florian; Nguyen, Thong T; Jaiswal, Bijay S; Chirieac, Lucian R; Sciaranghella, Daniele; Dao, Nhien; Gustafson, Corinne E; Munir, Kiara J; Hackney, Jason A; Chaudhuri, Amitabha; Gupta, Ravi; Guillory, Joseph; Toy, Karen; Ha, Connie; Chen, Ying-Jiun; Stinson, Jeremy; Chaudhuri, Subhra; Zhang, Na; Wu, Thomas D; Sugarbaker, David J; de Sauvage, Frederic J; Richards, William G; Seshagiri, Somasekar

    2016-04-01

    We analyzed transcriptomes (n = 211), whole exomes (n = 99) and targeted exomes (n = 103) from 216 malignant pleural mesothelioma (MPM) tumors. Using RNA-seq data, we identified four distinct molecular subtypes: sarcomatoid, epithelioid, biphasic-epithelioid (biphasic-E) and biphasic-sarcomatoid (biphasic-S). Through exome analysis, we found BAP1, NF2, TP53, SETD2, DDX3X, ULK2, RYR2, CFAP45, SETDB1 and DDX51 to be significantly mutated (q-score ≥ 0.8) in MPMs. We identified recurrent mutations in several genes, including SF3B1 (∼2%; 4/216) and TRAF7 (∼2%; 5/216). SF3B1-mutant samples showed a splicing profile distinct from that of wild-type tumors. TRAF7 alterations occurred primarily in the WD40 domain and were, except in one case, mutually exclusive with NF2 alterations. We found recurrent gene fusions and splice alterations to be frequent mechanisms for inactivation of NF2, BAP1 and SETD2. Through integrated analyses, we identified alterations in Hippo, mTOR, histone methylation, RNA helicase and p53 signaling pathways in MPMs. PMID:26928227

  15. 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

  16. 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

  17. 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

  18. 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

  19. miR-1 Induces Growth Arrest and Apoptosis in Malignant Mesothelioma

    PubMed Central

    Xu, Yue; Zheng, Ming; Merritt, Robert E.; Shrager, Joseph B.; Wakelee, Heather A.; Kratzke, Robert A.

    2013-01-01

    Background: We investigated microRNA expression profiles of malignant pleural mesothelioma (MPM) specimens to identify novel microRNA that are potentially involved in the oncogenic transformation of human pleural cells. Methods: microRNA microarray transcriptional profiling studies of 25 MPM primary tumors were performed. We used normal pleural tissue from an unmatched patient cohort as normal comparators. To confirm microarray data, we used real-time quantitative polymerase chain reaction. Representative cell lines H513 and H2052 were used in functional analyses of miR-1. Results: In addition to several novel MPM-associated microRNAs, we observed that the expression level of miR-1 was significantly lower in tumors as compared with normal pleural specimens. Subsequently, pre-miR of miR-1 was introduced into MPM cell lines to overexpress this microRNA. Phenotypic changes of these altered cells were assayed. The cellular proliferation rate was significantly inhibited after overexpression of miR-1. Early and late apoptosis was increased markedly in miR-1-transfected cell lines. Taken together, these data suggested that overexpression of miR-1 induced apoptosis in these MPM cell lines, acting as a tumor suppressor. We confirmed our observations by assessing in the transduced MPM cells cell cycle-related, proapoptotic, and antiapoptotic genes, which all showed coordinated, significant changes characteristic of the apoptotic phenotype. Conclusions: Further investigation and validation of our microRNA database of MPM may elucidate previously unrecognized molecular pathways and/or mechanisms by identifying novel microRNAs that are involved in malignant transformation. Our study has now found miR-1 to be one of these MPM-associated microRNAs, with potential pathogenic and therapeutic significance. PMID:23828229

  20. 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

  1. 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

  2. Fibulin-3 as a biomarker of response to treatment in malignant mesothelioma

    PubMed Central

    Kovac, Viljem; Dodic-Fikfak, Metoda; Arneric, Niko; Dolzan, Vita; Franko, Alenka

    2015-01-01

    Background Fibulin-3 is a new potential biomarker for malignant mesothelioma (MM). This study evaluated the potential applicability of fibulin-3 plasma levels as a biomarker of response to treatment and its prognostic value for progressive disease within 18 months. The potential applicability of fibulin-3 in comparison with or in addition to soluble mesothelin-related peptides (SMRP) was also assessed. Patients and methods. The study included 78 MM patients treated at the Institute of Oncology Ljubljana between 2007 and 2011. Fibulin-3 levels in plasma samples obtained before treatment and in various responses to treatment were measured with the enzyme-linked immunosorbent assay. Results In patients evaluated before the treatment, fibulin-3 levels were not influenced by histopathological sub-types, tumour stages or the presence of metastatic disease. Significantly higher fibulin-3 levels were found in progressive disease as compared to the levels before treatment (Mann-Whitney [U] test = 472.50, p = 0.003), in complete response to treatment (U = 42.00, p = 0.010), and in stable disease (U = 542.00, p = 0.001). Patients with fibulin-3 levels exceeding 34.25 ng/ml before treatment had more than four times higher probability for developing progressive disease within 18 months (odds ratio [OR] = 4.35, 95% confidence interval [CI] 1.56–12.13). Additionally, patients with fibulin-3 levels above 34.25 ng/ml after treatment with complete response or stable disease had increased odds for progressive disease within 18 months (OR = 6.94, 95% CI 0.99–48.55 and OR = 4.39, 95% CI 1.63–11.81, respectively). Conclusions Our findings suggest that in addition to SMRP fibulin-3 could also be helpful in detecting the progression of MM. PMID:26401134

  3. Clinical experience of volumetric modulated arc therapy for malignant pleural mesothelioma after extrapleural pneumonectomy

    PubMed Central

    Kimura, Tomoki; Doi, Yoshiko; Nakashima, Takeo; Imano, Nobuki; Katsuta, Tsuyoshi; Takahashi, Shigeo; Kenjo, Masahiro; Ozawa, Shuichi; Murakami, Yuji; Nagata, Yasushi

    2015-01-01

    The purpose of this study was to evaluate the efficacy and safety of volumetric modulated arc therapy (VMAT) after extrapleural pneumonectomy (EPP) in patients with malignant pleural mesothelioma (MPM). A total of 15 patients who received VMAT after EPP were enrolled. All patients were males, and the median age was 67 years (Stage IB in two, II in six, and III in seven patients). The clinical target volume (CTV) included the entire preoperative ipsilateral hemithorax and involved nodal stations. The CTV was generally expanded by 10–15 mm beyond the planning target volume (PTV). The dose prescription was designed to cover 95% of the PTV with 54 Gy in 30 fractions. The median follow-up period was 11 months. Treatment-related toxicities were evaluated by Common Terminology Criteria for Adverse Events (CTCAE) ver. 4. One-year local control, disease-free survival, and overall survival rates were 55.7% [95% confidence interval (CI): 25.6–85.8%], 29.3% (95% CI: 5.3–53.3%), and 43.1% (95% CI: 17.1–69.0%), respectively. According to the histological analysis, the one-year LC rate was significantly worse in patients with non-epithelial type (biphasic and sarcomatoid types) than in patients with epithelial type [epithelial type: 83.3% (95% CI, 53.5–100%), non-epithelial type: 0% (95% CI, 0%), P = 0.0011]. Grade 3 pneumonitis after VMAT was observed in three patients (20.0%); however, no patients died of pulmonary toxicity. VMAT appears to be relatively safe for patients with MPM after EPP because of the low pulmonary dose. PMID:25599996

  4. Therapeutic activity of glycoengineered anti-GM2 antibodies against malignant pleural mesothelioma

    PubMed Central

    Li, Qi; Wang, Wei; Machino, Yusuke; Yamada, Tadaaki; Kita, Kenji; Oshima, Masanobu; Sekido, Yoshitaka; Tsuchiya, Mami; Suzuki, Yui; Nan-ya, Ken-ichiro; Iida, Shigeru; Nakamura, Kazuyasu; Iwakiri, Shotaro; Itoi, Kazumi; Yano, Seiji

    2015-01-01

    Malignant pleural mesothelioma (MPM) is a rare and highly aggressive neoplasm that arises from the pleural, pericardial, or peritoneal lining. Although surgery, chemotherapy, radiotherapy, and combinations of these therapies are used to treat MPM, the median survival of such patients is dismal. Therefore, there is a compelling need to develop novel therapeutics with different modes of action. Ganglioside GM2 is a glycolipid that has been shown to be overexpressed in various types of cancer. However, there are no published reports regarding the use of GM2 as a potential therapeutic target in cases of MPM. In this study, we evaluated the efficacy of the anti-GM2 antibody BIW-8962 as an anti-MPM therapeutic using in vitro and in vivo assays. Consequently, the GM2 expression in the MPM cell lines was confirmed using flow cytometry. In addition, eight of 11 cell lines were GM2-positive (73%), although the GM2 expression was variable. BIW-8962 showed a significant antibody-dependent cellular cytotoxicity activity against the GM2-expressing MPM cell line MSTO-211H, the effect of which depended on the antibody concentration and effector/target ratio. In an in vivo orthotropic mouse model using MSTO-211H cells, BIW-8962 significantly decreased the incidence and size of tumors. Additionally, the GM2 expression was confirmed in the MPM clinical specimens. Fifty-eight percent of the MPM tumors were positive for GM2, with individual variation in the intensity and frequency of staining. These data suggest that anti-GM2 antibodies may become a therapeutic option for MPM patients. PMID:25421609

  5. Antitumor effect and antiangiogenic potential of the mTOR inhibitor temsirolimus against malignant pleural mesothelioma.

    PubMed

    Moriya, Makio; Yamada, Tadaaki; Tamura, Masaya; Ishikawa, Daisuke; Hoda, Mir Alireza; Matsumoto, Isao; Klepetko, Walter; Oda, Makoto; Yano, Seiji; Watanabe, Go

    2014-03-01

    The mTOR inhibitor temsirolimus has antitumor and antiangiogenic activity against several carcinomas, yet few reports document the efficacy of temsirolimus against malignant pleural mesothelioma (MPM). Therefore, we evaluated the efficacy of temsirolimus and the antiangiogenic effect of temsirolimus in the treatment of MPM. We examined the efficacy of temsirolimus alone and the efficacy of the combination of temsirolimus and cisplatin or pemetrexed against four MPM cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The effect of temsirolimus on the production of proangiogenic cytokines by MPM cell lines was examined by enzyme-linked immunosorbent assay (ELISA). Expression of mTOR and proangiogenic cytokines in clinical specimens from MPM patients was determined by immunohistochemistry. Temsirolimus inhibited cell viability and suppressed cell proliferation of all MPM cell lines. Combined treatment with temsirolimus and cisplatin inhibited the viability of all MPM cell lines more effectively than temsirolimus alone. Temsirolimus strongly inhibited the phosphorylation of p70s6k, a downstream molecule of mTOR, in all MPM cell lines and led to an increase in the levels of cleaved caspase-3 in the H226 and Y-meso14 cells. Temsirolimus also inhibited the production of vascular endothelial growth factor (VEGF) and platelet-derived growth factor-AA (PDGF-AA). Phosphorylated mTOR and high expression of VEGF and PDGF were detected in 2 and 3, respectively, out of the 5 MPM specimens. These results suggest that temsirolimus has activity against MPM cells by inhibition of cell proliferation and angiogenesis, and may be beneficial for a subset of MPM patients with high mTOR expression. PMID:24378576

  6. Disulfiram Suppresses Growth of the Malignant Pleural Mesothelioma Cells in Part by Inducing Apoptosis

    PubMed Central

    Muthu, Magesh; Jamal, Shazia; Chen, Di; Yang, Huanjie; Polin, Lisa A.; Tarca, Adi L.; Pass, Harvey I.; Dou, Q. Ping; Sharma, Sunita; Wali, Anil; Rishi, Arun K.

    2014-01-01

    Dithiocarbamate compound Disulfiram (DSF) that binds with copper and functions as an inhibitor of aldehyde dehydrogenase is a Food and Drug Administration approved agent for treatment of alcoholism. Copper complexed DSF (DSF-Cu) also possesses anti-tumor and chemosensitizing properties; however, its molecular mechanisms of action remain unclear. Here we investigated malignant pleural mesothelioma (MPM) suppressive effects of DSF-Cu and the molecular mechanisms involved. DSF-Cu inhibited growth of the murine as well as human MPM cells in part by increasing levels of ubiquitinated proteins. DSF-Cu exposure stimulated apoptosis in MPM cells that involved activation of stress-activated protein kinases (SAPKs) p38 and JNK1/2, caspase-3, and cleavage of poly-(ADP-ribose)-polymerase, as well as increased expression of sulfatase 1 and apoptosis transducing CARP-1/CCAR1 protein. Gene-array based analyses revealed that DSF-Cu suppressed cell growth and metastasis-promoting genes including matrix metallopeptidase 3 and 10. DSF inhibited MPM cell growth and survival by upregulating cell cycle inhibitor p27Kip1, IGFBP7, and inhibitors of NF-κB such as ABIN 1 and 2 and Inhibitory κB (IκB)α and β proteins. DSF-Cu promoted cleavage of vimentin, as well as serine-phosphorylation and lysine-63 linked ubiquitination of podoplanin. Administration of 50 mg/kg DSF-Cu by daily i.p injections inhibited growth of murine MPM cell-derived tumors in vivo. Although podoplanin expression often correlates with metastatic disease and poor prognosis, phosphorylation of serines in cytoplasmic domain of podoplanin has recently been shown to interfere with cellular motility and migration signaling. Post-translational modification of podoplanin and cleavage of vimentin by DSF-Cu underscore a metastasis inhibitory property of this agent and together with our in vivo studies underscore its potential as an anti-MPM agent. PMID:24690739

  7. Immune biomarkers PD-1/PD-L1 and TLR3 in malignant pleural mesotheliomas.

    PubMed

    Combaz-Lair, Christelle; Galateau-Sallé, Françoise; McLeer-Florin, Anne; Le Stang, Nolwenn; David-Boudet, Laurence; Duruisseaux, Mickael; Ferretti, Gilbert R; Brambilla, Elisabeth; Lebecque, Serge; Lantuejoul, Sylvie

    2016-06-01

    Malignant pleural mesothelioma (MPM) is an aggressive tumor with no effective therapy. However PD-L1/PD-1 immunity checkpoint therapies gave encouraging results; TLR3 is a programmed death factor, which triggering up-regulates PD-L1. As PD-1/PD-L1 blocking antibodies could restore antitumor immune responses alone or in combination with TLR3 agonists, we investigated PD-L1/PD-1 and TLR3 expressions in MPM to select patients for immunotherapy. Sixty-eight pleural surgical specimens, including 58 MPM (epithelioid, n = 34; biphasic, n = 11; sarcomatoid, n = 13) and 10 benign lesions, were studied. PD-L1 expression was assessed using E1L3N and SP142 clones in tumor cells (TCs) and in tumor-infiltrating lymphocytes (TILs) (positivity threshold of 1%), and compared with overall survival. PD-1, CD3 and CD8 expression by TILs, and TLR3 expression by TCs were analyzed concomitantly. PD-L1 was more expressed by sarcomatoid subtype than by other MPM (62% versus 23% and 9% for E1L3N; 38% versus 11% for SP142) (P = .01 and .04, respectively). Specificity and sensitivity of E1L3N and SP142 were of 53% and 98%, and 90% and 86%, respectively. PD-L1 expression by TILs and TCs correlated for SP142 (P = .023), and PD-L1 SP142 expression by TCs was associated with shorter overall survival (P = .016). TLR3 was expressed in most MPM, but weakly in sarcomatoid MPM. We confirm by comparing two commercially available antibodies that PD-L1 expression is higher in sarcomatoid MPM and correlates with a shorter survival. Whereas TLR3 agonists could be tested in MPM expressing TLR3, the sarcomatoid subtype could benefit from anti-PD-L1/PD-1 therapies alone or in combination. PMID:26980049

  8. 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

  9. Diagnostic Accuracy of Calretinin for Malignant Mesothelioma in Serous Effusions: a Meta-analysis

    PubMed Central

    Li, Diandian; Wang, Bo; Long, Hongyu; Wen, Fuqiang

    2015-01-01

    Numerous studies have investigated the utility of calretinin in differentiating malignant mesothelioma (MM) from metastatic carcinoma (MC) in serous effusions. However, the results remain controversial. The aim of this study is to determine the overall accuracy of calretinin in serous effusions for MM through a meta-analysis of published studies. Publications addressing the accuracy of calretinin in the diagnosis of MM were selected from the Medline (Ovid), PubMed, the Cochrane Library Database and the Web of Science. Data from selected studies were pooled to yield summary sensitivity, specificity, positive and negative likelihood ratio (LR), diagnostic odds ratio (DOR), and receiver operating characteristic (SROC) curve. Statistical analysis was performed by Meta-Disc 1.4 and STATA 12.0 softwares. 18 studies met the inclusion criteria and the summary estimating for calretinin in the diagnosis of MM were: sensitivity 0.91 (95%CI: 0.87–0.94), specificity 0.96 (95%CI: 0.95–0.96), positive likelihood ratio (PLR) 14.42 (95%CI: 7.92–26.26), negative likelihood ratio (NLR) 0.1 (95%CI: 0.05–0.2) and diagnostic odds ratio 163.03 (95%CI: 54.62–486.63). The SROC curve indicated that the maximum joint sensitivity and specificity (Q-value) was 0.92; the area under the curve was 0.97. Our findings suggest that calretinin may be a useful diagnostic tool for confirming MM in serous effusions. PMID:25821016

  10. c-Met expression and MET amplification in malignant pleural mesothelioma.

    PubMed

    Bois, Melanie C; Mansfield, Aaron S; Sukov, William R; Jenkins, Sarah M; Moser, Justin C; Sattler, Christopher A; Smith, Carin Y; Molina, Julian R; Peikert, Tobias; Roden, Anja C

    2016-08-01

    c-Met is a receptor tyrosine kinase shown to be overexpressed in malignant pleural mesothelioma (MPM). Whereas MET mutations have been identified in 3%-16% of MPMs, MET amplification has recently been reported in a single epithelioid MPM. We studied c-Met expression and MET amplification in a large MPM cohort and correlated results with morphologic and clinical features. We report the first case of MET amplification in sarcomatoid MPM. MPMs from surgical pathology files (1989-2014) were reviewed. c-Met immunohistochemistry was performed. Staining intensity and distribution were multiplied (H-score). Staining localization (cytoplasmic and/or membranous) was noted. Fluorescence in situ hybridization was performed using probes for MET and centromere 7. One hundred forty-nine patients (median age, 68.0years; interquartile range, 61-75) had epithelioid (n=97), biphasic (n=18), or sarcomatoid (n=34) MPM. Median follow-up was 10.1months (range, 0.1-222.5). One hundred thirty patients died of disease; 2 were alive with disease. c-Met was expressed in 147 MPMs. c-Met staining intensity, distribution, and H-score differed among the histologic subtypes (P=.015; P=.0001, and P=.0005, respectively), but none were predictive of survival. Epithelioid subtype had greater c-Met expression. MET amplification was identified in 1 sarcomatoid MPM and MET duplication in 1 epithelioid MPM; both had poor outcomes. Chromosome 7 aneusomy was observed in 54 of 144 (37.5%) MPMs and associated with decreased overall survival in sarcomatoid MPMs (hazard ratio=2.81; 95% confidence interval, 1.21-6.51; P=.01). In conclusion, c-Met is expressed in MPM, with significant differences in expression among histologic subtypes. MET amplification is a rare event in MPM, making it an unlikely common pathogenesis for c-Met expression. PMID:27402216

  11. 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. PMID:24366282

  12. 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.

  13. Variation in Drug Sensitivity of Malignant Mesothelioma Cell Lines with Substantial Effects of Selenite and Bortezomib, Highlights Need for Individualized Therapy

    PubMed Central

    Szulkin, Adam; Nilsonne, Gustav; Mundt, Filip; Wasik, Agata M.; Souri, Pega; Hjerpe, Anders; Dobra, Katalin

    2013-01-01

    Background Malignant mesothelioma cells have an epithelioid or sarcomatoid morphology, both of which may be present in the same tumor. The sarcomatoid phenotype is associated with worse prognosis and heterogeneity of mesothelioma cells may contribute to therapy resistance, which is often seen in mesothelioma. This study aimed to investigate differences in sensitivity between mesothelioma cell lines to anti-cancer drugs. We studied two novel drugs, selenite and bortezomib and compared their effect to four conventional drugs. We also investigated the immunoreactivity of potential predictive markers for drug sensitivity; Pgp, MRP-1, ERCC1, RRM1, TS, xCT and proteasome 20S subunit. Materials and methods We treated six mesothelioma cell lines with selenite, bortezomib, carboplatin, pemetrexed, doxorubicin or gemcitabine as single agents and in combinations. Viability was measured after 24 and 48 hours. Immunocytochemistry was used to detect predictive markers. Results As a single agent, selenite was effective on four out of six cell lines, and in combination with bortezomib yielded the greatest response in the studied mesothelioma cell lines. Cells with an epithelioid phenotype were generally more sensitive to the different drugs than the sarcomatoid cells. Extensive S-phase arrest was seen in pemetrexed-sensitive cell lines. MRP-1 predicted sensitivity of cell lines to treatment with carboplatin and xCT predicted pemetrexed effect. Conclusions The observed heterogeneity in sensitivity of mesothelioma cell lines with different morphology highlights the need for more individualized therapy, requiring development of methods to predict drug sensitivity of individual tumors. Selenite and bortezomib showed a superior effect compared to conventional drugs, motivating clinical testing of these agents as future treatment regime components for patients with malignant mesothelioma. PMID:23840376

  14. 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

  15. Pleuroscopic punch biopsy using insulated-tip diathermic knife-2 for the diagnosis of desmoplastic malignant mesothelioma.

    PubMed

    Masai, Kyohei; Sasada, Shinji; Izumo, Takehiro; Taniyama, Tomoko; Nakamura, Yukiko; Chavez, Christine; Sakurai, Hiroyuki; Tsuta, Koji; Tsuchida, Takaaki

    2013-10-01

    Desmoplastic malignant mesothelioma (DMM) is a rare subtype of malignant pleural mesothelioma (MPM) and is often difficult to distinguish from pleural fibrosis and reactive mesothelial hyperplasia, especially if the biopsy samples are small. We performed full-thickness pleural biopsy on a lesion suspected to be DMM using an insulated-tip diathermic knife-2 (IT knife-2) during flex-rigid pleuroscopy. IT knife-2 is a novel electrosurgical device for endoscopic submucosal dissection in the early gastrointestinal cancer. It consists of a needle knife with 3 short blades at the distal end attached to an insulated ceramic tip. A 54-year-old man presenting with chest wall mass and thickened pleura, in whom a computed tomography-guided percutaneous needle aspiration had remained negative, underwent flex-rigid pleuroscopy for definitive diagnosis. While applying electric current, we used the IT knife-2 to incise the pleura in a circular shape just above the endothoracic fascia. The incised pleura was removed by forceps and examined pathologically. The microscopic examination was compatible with DMM. We discovered that pleuroscopic punch biopsy using IT knife-2 can diagnose DMM. Use of IT knife-2 during flex-rigid pleuroscopy can obtain sufficient samples from densely thickened pleura, which is difficult to diagnose with small biopsies. PMID:24162121

  16. Comparison of fibre types and size distributions in lung tissues of paraoccupational and occupational cases of malignant mesothelioma.

    PubMed Central

    Gibbs, A R; Griffiths, D M; Pooley, F D; Jones, J S

    1990-01-01

    The results of analysis of mineral fibres in lung tissues from 10 paraoccupational cases of malignant mesothelioma were compared with analysis obtained from seven cases of malignant mesotheliomas that had developed in gas mask workers. Nine of the paraoccupational cases were considered to have developed their tumours because of exposure to asbestos on their husbands' working clothes and one cancer developed in the daughter of a man who had died of asbestosis. The gas mask workers had direct exposure to asbestos while working in a factory that produced military gas masks. The results of mineral fibre analysis in the paraoccupational cases were variable; six showed high crocidolite concentrations, seven raised amosite concentrations and two normal concentrations of all types of asbestos fibre measured. Chrysotile was raised in one case but crocidolite and amosite were also increased. The gas mask workers showed a consistent pattern with high crocidolite concentrations and normal or low concentrations of chrysotile and amosite. Fibre lengths for chrysotile were similar in both groups and predominantly less than 5 microns. Crocidolite fibres tended to be longer in the gas mask workers than in the paraoccupational group and longer than chrysotile in both groups. Amosite fibres tended to be more variable in width than those of chrysotile or crocidolite. PMID:2207033

  17. Expression of the tumor suppressor gene, p53, during the development of murine malignant mesotheliomas induced by asbestos fibers

    SciTech Connect

    Cora, E.; Kane, A. )

    1991-03-15

    Malignant mesotheliomas are rare tumors arising from the pleural or peritoneal lining after exposure to asbestos fibers. As a model system for human occupational exposure, C57B1/6 mice received weekly intraperitoneal injections of 200 {mu}g of crocidolite asbestos fibers. Tumors developed in 30-40% of mice after 30-60 weeks. Discrete morphologic stages in the development of malignant mesotheliomas have been identified: reactive mesothelial cells after 1-6 wks., dysplastic cells after 12-22 wks., neoplastic cells after 30-40 wks., and metastasizing cells after 40-50 wks. Cell lines have been established corresponding to each of these morphologic stages and probed for altered expression of oncogenes and tumor suppressor genes. Using Northern blot analysis, four cell lines derived from neoplastic and invasive tumors showed absent or reduced expression of p53 mRNA in contrast to nontumorigenic cell lines derived from reactive mesothelial cells. Southern blot analysis revealed no rearrangement of the p53 gene after digestion with the restriction enzyme BamHI. It is hypothesized that point mutations in the p53 gene are correlated with neoplastic progression in this model system.

  18. 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. PMID:26588871

  19. Failure Patterns After Hemithoracic Pleural Intensity Modulated Radiation Therapy for Malignant Pleural Mesothelioma

    SciTech Connect

    Rimner, Andreas; Spratt, Daniel E.; Zauderer, Marjorie G.; Rosenzweig, Kenneth E.; Wu, Abraham J.; Foster, Amanda; Yorke, Ellen D.; Adusumilli, Prasad; Rusch, Valerie W.; Krug, Lee M.

    2014-10-01

    Purpose: We previously reported our technique for delivering intensity modulated radiation therapy (IMRT) to the entire pleura while attempting to spare the lung in patients with malignant pleural mesothelioma (MPM). Herein, we report a detailed pattern-of-failure analysis in patients with MPM who were unresectable or underwent pleurectomy/decortication (P/D), uniformly treated with hemithoracic pleural IMRT. Methods and Materials: Sixty-seven patients with MPM were treated with definitive or adjuvant hemithoracic pleural IMRT between November 2004 and May 2013. Pretreatment imaging, treatment plans, and posttreatment imaging were retrospectively reviewed to determine failure location(s). Failures were categorized as in-field (within the 90% isodose line), marginal (<90% and ≥50% isodose lines), out-of-field (outside the 50% isodose line), or distant. Results: The median follow-up was 24 months from diagnosis and the median time to in-field local failure from the end of RT was 10 months. Forty-three in-field local failures (64%) were found with a 1- and 2-year actuarial failure rate of 56% and 74%, respectively. For patients who underwent P/D versus those who received a partial pleurectomy or were deemed unresectable, the median time to in-field local failure was 14 months versus 6 months, respectively, with 1- and 2-year actuarial in-field local failure rates of 43% and 60% versus 66% and 83%, respectively (P=.03). There were 13 marginal failures (19%). Five of the marginal failures (38%) were located within the costomediastinal recess. Marginal failures decreased with increasing institutional experience (P=.04). Twenty-five patients (37%) had out-of-field failures. Distant failures occurred in 32 patients (48%). Conclusions: After hemithoracic pleural IMRT, local failure remains the dominant form of failure pattern. Patients treated with adjuvant hemithoracic pleural IMRT after P/D experience a significantly longer time to local and distant failure than

  20. Massive localized malignant pleural mesothelioma (LMPM): manifestations on computed tomography in 6 cases

    PubMed Central

    Yao, Weigen; Yang, Hanqing; Huang, Guolai; Yan, Yang; Wang, Honglin; Sun, Dongfang

    2015-01-01

    Objective: Our study analyzed the clinical symptoms and computed tomography (CT) manifestations of massive localized malignant pleural mesothelioma (LMPM) patients to improve the knowledge and diagnosis of this disease. Methods: Our study collected 6 massive LMPM patients pathologically confirmed by CT in the department of Radiology of the People’s Hospital of Yuyao, Zhejiang Province, from January, 2007 to June, 2013; data of patients were also collected. The clinical symptoms, clinicopathological characteristics, CT manifestations, treatments and prognosis of enrolled patients were analyzed. Results: Our study enrolled 6 LMPM patients (2 males; 4 females) classified to epitheliated type (n = 4) and sarcomatous type (n = 2) with mean age of 62.7 ± 7.4, and 5 of them had a history of asbestos exposure. CT manifestations revealed that large soft-tissue mass close to pleura, which was smooth and lobulated, was discovered in all patients with maximum diameter of 10~15 cm and mean diameter of 13.67 ± 1.15 cm; The mean value of CT was 36.29 ± 2.62 HU; after enhancement, the mean value was increased to 76.36 ± 7.73 HU; patients showed zones of small patchy necrosis and large patchy necrosis. The following presentations were founded: enlargement of tumor vessel which showed arborization (2 patients), mass wrap around the descending aorta in left lower chest (1 patient), strips of fat density in mediastinum superior (1 patient), pleural tail sign (3 patients). Among 6 patients, pleural effusion (n = 4), mediastinal lymph node enlargement (n = 3), invasion and destruction of local ribs (n = 2). Median survival time of patients were 20 months (2 cases conducted operation), 24 (2 cases chose combined radiotherapy and chemotherapy) and less than 6 months (2 cases underwent chemotherapy). Conclusion: To sum up, CT showed important diagnostic values on massive LMPM patients; patients with a history of asbestos exposure, large soft-tissue mass of pleura with an abundant

  1. 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

  2. Elevated PDGFRB gene copy number gain is prognostic for improved survival outcomes in resected malignant pleural mesothelioma.

    PubMed

    Tsao, Anne S; Harun, Nusrat; Fujimoto, Junya; Devito, Vikki; Lee, J Jack; Kuhn, Elisabetta; Mehran, Reza; Rice, David; Moran, Cesar; Hong, Waun Ki; Shen, Li; Suraokar, Milind; Wistuba, Ignacio

    2014-06-01

    PDGF/PDGFR pathway has been implicated in malignant pleural mesothelioma (MPM) carcinogenesis, and evidence suggests autocrine mechanisms of proliferation. We sought to evaluate the incidence of PDGFRB gene copy number gain (CNG) by fluorescence in situ hybridization and PDGFR pathway protein expression by immunohistochemistry (IHC) and correlate it to patient clinical outcome. Eighty-eight archived tumor blocks from resected MPM with full clinical information were used to perform IHC biomarkers (PDGFRα, PDGFRβ, p-PDGFRβ) and fluorescence in situ hybridization analysis of PDGFRB gene CNG. Spearman rank correlation, Wilcoxon rank-sum test, Kruskal-Wallis test, BLiP plots, and Kaplan-Meier method were used to analyze the biomarkers and correlation to clinical outcome. Several correlations between the IHC biomarkers were seen; however, none correlated to clinically relevant patient demographics or histology. In the CNG analysis, PDGFRB gene CNG in >10% of tumor cells had lower cytoplasmic p-PDGFRβ (P=.029), while PDGFRB gene CNG in >40% of tumor cells had a higher cytoplasmic PDGFRβ (P=.04). PDGFRB gene CNG status did not associate with patient demographics or tumor characteristics. PDGFR pathway IHC biomarkers did not associate with survival outcomes. However, patients with PDGFRB CNG >40% of tumor cells had improved relapse-free survival (HR 0.25 [95% CI 0.09-0.72], P=.0096) and improved overall survival (HR 0.32 [95% CI 0.11-0.89], P=.029). PDGFRB CNG >40% of MPM tumor cells is a potential prognostic biomarker for surgery and may identify a unique population of mesothelioma patients. Future validation of this biomarker in prospective trials is needed. From a retrospective review of archived tissue specimens from patients with resected malignant pleural mesothelioma tumors, we show that patients with PDGFRB CNG >40% of tumor cells had improved relapse-free survival (HR 0.25 [95% CI 0.09-0.72], P=.0096) and improved overall survival (HR 0.32 [95% CI 0

  3. 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

  4. [The epidemiologic surveillance of malignant mesothelioma in the Lower Iseo Lake area].

    PubMed

    Barbieri, Pietro Gino; Somigliana, Anna; Caironi, Massimo; Migliori, Maurizio

    2007-01-01

    Starting from an hospital observation of the mesotheliomas cluster in women living in a lakeside area (Iseo lake, Northern Italy), an epidemiological surveillance of this tumour was performed by the local occupational health service. This cluster wasn't notified, in spite of the relevant number of factories producing asbestos textile materials in this area. From 1977 to august 2006, 45 cases of mesothelioma were detected among the workers of 3 textile industries located in 3 little villages: 14 cases occurred working crocidolite and chrysotile rope and gasket; 20 cases in a textile factory producing cotton garments, that was adjacent to and polluted by the farmer and were asbestos insulation and blankets used for fireproofing are present; 11 cases occurred among women working in silk factories. The mesothelioma cases occurred in the same period in this area, which constituted the recruitment area of the people working in the 3 textile plants (11 villages, about 43,000 inhabitants), are 55.93% of which had been occupationally exposed to asbestos. Out of the dockyard and the asbestos-cement industries, this frequency of occupational exposed workers is the highest never observed in Italy. The majority of the cases (66%) occurred among women working in the textile factories. In a women, producing asbestos textile materials and suffered form peritoneal mesothelioma and pleural plaques, the analysis (by SEM) of asbestos fibre lung burden show 286 million fibres x gr. of dry tissue. Between the 42 mesothelioma cases occurring in the population of the 3 villages where the textile plants was located, we observed only one case with possible environmental exposure to asbestos: a gardener of the village where the manufacturing asbestos ropes and gasket plant is present. In the silk factories, asbestos exposure was probable because of the presence of asbestos insulated pipes. The female pleural mesothelioma standard incidence observed in this area (6.8 x 100,000, 1977-2005) is

  5. Genes Associated With Prognosis After Surgery For Malignant Pleural Mesothelioma Promote Tumor Cell Survival In Vitro

    PubMed Central

    2011-01-01

    Background Mesothelioma is an aggressive neoplasm with few effective treatments, one being cytoreductive surgery. We previously described a test, based on differential expression levels of four genes, to predict clinical outcome in prospectively consented mesothelioma patients after surgery. In this study, we determined whether any of these four genes could be linked to a cancer relevant phenotype. Methods We conducted a high-throughput RNA inhibition screen to knockdown gene expression levels of the four genes comprising the test (ARHGDIA, COBLL1, PKM2, TM4SF1) in both a human lung-derived normal and a tumor cell line using three different small inhibitory RNA molecules per gene. Successful knockdown was confirmed using quantitative RT-PCR. Detection of statistically significant changes in apoptosis and mitosis was performed using immunological assays and quantified using video-assisted microscopy at a single time-point. Changes in nuclear shape, size, and numbers were used to provide additional support of initial findings. Each experiment was conducted in triplicate. Specificity was assured by requiring that at least 2 different siRNAs produced the observed change in each cell line/time-point/gene/assay combination. Results Knockdown of ARHGDIA, COBLL1, and TM4SF1 resulted in 2- to 4-fold increased levels of apoptosis in normal cells (ARHGDIA only) and tumor cells (all three genes). No statistically significant changes were observed in apoptosis after knockdown of PKM2 or for mitosis after knockdown of any gene. Conclusions We provide evidence that ARHGDIA, COBLL1, and TM4SF1 are negative regulators of apoptosis in cultured tumor cells. These genes, and their related intracellular signaling pathways, may represent potential therapeutic targets in mesothelioma. PMID:21569526

  6. 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

  7. Novel Genes and Pathways Modulated by Syndecan-1: Implications for the Proliferation and Cell-Cycle Regulation of Malignant Mesothelioma Cells

    PubMed Central

    Szatmári, Tünde; Mundt, Filip; Heidari-Hamedani, Ghazal; Zong, Fang; Ferolla, Elena; Alexeyenko, Andrey; Hjerpe, Anders; Dobra, Katalin

    2012-01-01

    Malignant pleural mesothelioma is a highly malignant tumor, originating from mesothelial cells of the serous cavities. In mesothelioma the expression of syndecan-1 correlates to epithelioid morphology and inhibition of growth and migration. Our previous data suggest a complex role of syndecan-1 in mesothelioma cell proliferation although the exact underlying molecular mechanisms are not completely elucidated. The aim of this study is therefore to disclose critical genes and pathways affected by syndecan-1 in mesothelioma; in order to better understand its importance for tumor cell growth and proliferation. We modulated the expression of syndecan-1 in a human mesothelioma cell line via both overexpression and silencing, and followed the transcriptomic responses with microarray analysis. To project the transcriptome analysis on the full-dimensional picture of cellular regulation, we applied pathway analysis using Ingenuity Pathway Analysis (IPA) and a novel method of network enrichment analysis (NEA) which elucidated signaling relations between differentially expressed genes and pathways acting via various molecular mechanisms. Syndecan-1 overexpression had profound effects on genes involved in regulation of cell growth, cell cycle progression, adhesion, migration and extracellular matrix organization. In particular, expression of several growth factors, interleukins, and enzymes of importance for heparan sulfate sulfation pattern, extracellular matrix proteins and proteoglycans were significantly altered. Syndecan-1 silencing had less powerful effect on the transcriptome compared to overexpression, which can be explained by the already low initial syndecan-1 level of these cells. Nevertheless, 14 genes showed response to both up- and downregulation of syndecan-1. The “cytokine – cytokine-receptor interaction”, the TGF-β, EGF, VEGF and ERK/MAPK pathways were enriched in both experimental settings. Most strikingly, nearly all analyzed pathways related to cell

  8. 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

  9. Association of MiR-126 with Soluble Mesothelin-Related Peptides, a Marker for Malignant Mesothelioma

    PubMed Central

    Santarelli, Lory; Strafella, Elisabetta; Staffolani, Sara; Amati, Monica; Emanuelli, Monica; Sartini, Davide; Pozzi, Valentina; Carbonari, Damiano; Bracci, Massimo; Pignotti, Elettra; Mazzanti, Paola; Sabbatini, Armando; Ranaldi, Renzo; Gasparini, Stefano; Neuzil, Jiri; Tomasetti, Marco

    2011-01-01

    Background Improved detection methods for diagnosis of malignant pleural mesothelioma (MPM) are essential for early and reliable detection as well as treatment. Since recent data point to abnormal levels of microRNAs (miRNAs) in tumors, we hypothesized that a profile of deregulated miRNAs may be a marker of MPM and that the levels of specific miRNAs may be used for monitoring its progress. Methods and Results miRNAs isolated from fresh-frozen biopsies of MPM patients were tested for the expression of 88 types of miRNA involved in cancerogenesis. Most of the tested miRNAs were downregulated in the malignant tissues compared with the normal tissues. Of eight significantly downregulated, three miRNAs were assayed in cancerous tissue and adjacent non-cancerous tissue sample pairs collected from 27 formalin-fixed, paraffin-embedded MPM tissues by quantitative RT-PCR. Among the miRNAs tested, only miR-126 significantly remained downregulated in the malignant tissues. Furthermore, the performance of the selected miR-126 as biomarker was evaluated in serum samples of asbestos-exposed subjects and MPM patients and compared with controls. MiR-126 was not affected by asbestos exposure, whereas it was found strongly associated with VEGF serum levels. Levels of miR-126 in serum, and its levels in patients' serum in association with a specific marker of MPM, SMRPs, correlate with subjects at high risk to develop MPM. Conclusions and Significance We propose miR-126, in association with SMRPs, as a marker for early detection of MPM. The identification of tumor biomarkers used alone or, in particular, in combination could greatly facilitate the surveillance procedure for cohorts of subjects exposed to asbestos. PMID:21483773

  10. Management of ascites due to gastrointestinal malignancy

    PubMed Central

    Saif, Muhammad W.; Siddiqui, Imran A. P.; Sohail, Muhammad A.

    2009-01-01

    Ascites is the pathological accumulation of fluid within the abdominal cavity. The most common cancers associated with ascites are adenocarcinomas of the ovary, breast, colon, stomach and pancreas. Symptoms include abdominal distension, nausea, vomiting, early satiety, dyspnea, lower extremity edema, weight gain and reduced mobility. There are many potential causes of ascites in cancer patients, including peritoneal carcinomatosis, malignant obstruction of draining lymphatics, portal vein thrombosis, elevated portal venous pressure from cirrhosis, congestive heart failure, constrictive pericarditis, nephrotic syndrome and peritoneal infections. Depending on the clinical presentation and expected survival, a diagnostic evaluation is usually indicated as it will impact both prognosis and the treatment approach. Key tests include serum albumin and protein and a simultaneous diagnostic paracentesis, checking ascitic fluid, WBCs, albumin, protein and cytology. Median survival after diagnosis of malignant ascites is in the range of 1 to 4 months; survival is apt to be longer for ovarian and breast cancers if systemic anti-cancer treatments are available. PMID:19700895

  11. 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

    2016-08-15

    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

  12. Pleural malignant mesothelioma epidemic: incidence, modalities of asbestos exposure and occupations involved from the Italian National Register.

    PubMed

    Marinaccio, Alessandro; Binazzi, Alessandra; Marzio, Davide Di; Scarselli, Alberto; Verardo, Marina; Mirabelli, Dario; Gennaro, Valerio; Mensi, Carolina; Riboldi, Luciano; Merler, Enzo; Zotti, Renata De; Romanelli, Antonio; Chellini, Elisabetta; Silvestri, Stefano; Pascucci, Cristiana; Romeo, Elisa; Menegozzo, Simona; Musti, Marina; Cavone, Domenica; Cauzillo, Gabriella; Tumino, Rosario; Nicita, Carmela; Melis, Massimo; Iavicoli, Sergio

    2012-05-01

    Due to the large scale use of asbestos (more than 3.5 million tons produced or imported until its definitive banning in 1992), a specific national surveillance system of mesothelioma incident cases is active in Italy, with direct and individual anamnestic etiological investigation. In the period between 1993 and 2004, a case-list of 8,868 pleural MM was recorded by the Italian National Register (ReNaM) and the modalities of exposure to asbestos fibres have been investigated for 6,603 of them. Standardized incidence rates are 3.49 (per 100,000 inhabitants) for men and 1.25 for women, with a wide regional variability. Occupational asbestos exposure was in 69.3% of interviewed subjects (N = 4,577 cases), while 4.4% was due to cohabitation with someone (generally, the husband) occupationally exposed, 4.7% by environmental exposure from living near a contamination source and 1.6% during a leisure activity. In the male group, 81.5% of interviewed subjects exhibit an occupational exposure. In the exposed workers, the median year of first exposure was 1957, and mean latency was 43.7 years. The analysis of exposures by industrial sector focuses on a decreasing trend for those traditionally signaled as "at risk" (asbestos-cement industry, shipbuilding and repair and railway carriages maintenance) and an increasing trend for the building construction sector. The systematic mesothelioma surveillance system is relevant for the prevention of the disease and for supporting an efficient compensation system. The existing experience on all-too-predictable asbestos effects should be transferred to developing countries where asbestos use is spreading. PMID:21647880

  13. 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. PMID:22532243

  14. 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

  15. 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

  16. FDG PET/CT Response Evaluation in Malignant Pleural Mesothelioma Patients Treated with Talc Pleurodesis and Chemotherapy

    PubMed Central

    Genestreti, Giovenzio; Moretti, Andrea; Piciucchi, Sara; Giovannini, Noemi; Galassi, Riccardo; Scarpi, Emanuela; Burgio, Marco Angelo; Amadori, Dino; Sanna, Stefano; Poletti, Venerino; Matteucci, Federica; Gavelli, Giampaolo

    2012-01-01

    Purpose: Talc pleurodesis (TP) is employed worldwide for the management of persistent pneumothorax or pleural effusion, particularly of malignant origin. However, there are very little available data on 18F-fluorodeoxyglucose positron-emission tomography/computed tomography (18F FDG PET/CT) response evaluation in malignant pleural mesothelioma (MPM) patients treated with TP and chemotherapy. Methods: Patients with histologically confirmed MPM underwent TP and FDG PET/CT staging and restaging after 3-4 courses of chemotherapy. All patients fasted and received a dose of 5.18 MBq 18F-FDG per kilogram of body weight. Whole-body emission scans were acquired with and without Ordered Subset Expectation Maximization (OSEM) iterative reconstruction algorithm. Results: From January 2004 to March 2010, 8 patients with biopsy confirmed MPM (7 epithelial, 1 biphasic), with a median age of 65 years (range: 54-77), were evaluated. Median follow-up was 31 months (range: 4-44). After TP treatment, there was a mean interval of 14 days (range: 9-22) and 125 days (range: 76-162) between FDG PET/CT staging and restaging. According to modified RECIST and EORTC criteria, there was a concordance between the radiologic and metabolic SUVmean and SUVmax responses in 6 (75%) and 3 (37.5%) patients, respectively. Conclusion: TP produces an increased FDG PET uptake which may interfere with the post-chemotherapy disease evaluation. In our case series, the metabolic response measured by SUVmean seems to be in better agreement with the radiologic response compared to the SUVmax. PMID:22670158

  17. 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

  18. 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.

  19. 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

  20. Which type of surgery should become the preferred procedure for malignant pleural mesothelioma: extrapleural pneumonectomy or extended pleurectomy?

    PubMed Central

    Cansever, Levent; Demir, Adalet; Ceyhan, Süleyman; Akın, Hasan; Ürer, Halide Nur; Ölçmen, Aysun; Kocatürk, Celalettin; Dinçer, İbrahim

    2013-01-01

    Purposes Since radiation and chemotherapy have limitations as therapies for malignant pleural mesothelioma (MPM). The type of surgery [extrapleural pneumonectomy (EPP), extended pleurectomy (E/P), and pleurectomy/decortication (P/D)] remains controversial. Methods This study involves 76 consecutive patients. 58 of the cases were males (76%) with a median age of 53.17±10.93 years. EPP, E/P, and P/D were performed in 31, 20, and 25 cases, respectively. Results The median survival time was 20 months in all patients. Overall, five-year survival rate was 14.3%. The survival rate was significantly better in epithelioid mesothelioma (P=0.049). For EPP cases, the median survival rate was 17 months, and the three-to-five year survival rates were 21% and 17%, respectively. For E/P cases, the median survival rate was 27 months and the three-year and four-year survival rates were 34% and 30%, respectively. For P/D cases, the median survival rate was 15 months and the three-to-five year survival rate was 13% and 0%. There were no statistically significant differences between the three surgical techniques (P=0.088). A comparative analysis indicates only a statistically significant difference in the E/P and P/D comparison (P=0.032). Hospital mortality showed a higher trend in EPP group (EPP: 12.9%, E/P: 0% and P/D: 4%, P=0.145). N2 cases, there were no cases of two-year survival. The survival rate in N2 was comparatively much lower, which was statistically significant (P=0.005). In multivariate analysis, only P/D (OR 0.3, 95% CI: 0.1-0.9, P=0.049) and N2 (OR 1.6, 95% CI: 0.9-2.6, P=0.090) were found to be poor prognostic factors. Conclusions E/P could be encouraged to EPP with lower mortality rate and better survival trend in MPM. N2 diseases were negative prognostic factors in MPM. PMID:23991301

  1. 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

  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

    2016-01-01

    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

  3. HER1-Targeted 86Y-Panitumumab Possesses Superior Targeting Characteristics than 86Y-Cetuximab for PET Imaging of Human Malignant Mesothelioma Tumors Xenografts

    PubMed Central

    Nayak, Tapan K.; Garmestani, Kayhan; Milenic, Diane E.; Baidoo, Kwamena E.; Brechbiel, Martin W.

    2011-01-01

    Malignant mesothelioma (MM), a rare form of cancer is often associated with previous exposure to fibrous minerals, such as asbestos. Asbestos exposure increases HER1-activity and expression in pre-clinical models. Additionally, HER1 over-expression is observed in the majority of MM cases. In this study, the utility of HER1-targeted chimeric IgG1, cetuximab, and a human IgG2, panitumumab, radiolabeled with 86Y, were evaluated for PET imaging to detect MM non-invasively in vivo, and to select an antibody candidate for radioimmunotherapy (RIT). Methods Radioimmunoconjugates (RICs) of cetuximab and panitumumab were prepared by conjugation with CHX-A’’-DTPA followed by radiolabeling with 86Y. The HER1 expression of NCI-H226, NCI-H2052, NCI-H2452 and MSTO-211H human mesothelioma cells was characterized by flow cytometry. In vivo biodistribution, pharmacokinetic analysis, and PET imaging were performed in tumor bearing athymic mice. Results In vivo studies demonstrated high HER1 tumor uptake of both RICs. Significant reduction in tumor uptake was observed in mice co-injected with excess mAb (0.1 mg), demonstrating that uptake in the tumor was receptor specific. Significant differences were observed in the in vivo characteristics of the RICs. The blood clearance T½α of 86Y-cetuximab (0.9–1.1 h) was faster than 86Y-panitumumab (2.6–3.1 h). Also, the tumor area under the curve (AUC) to liver AUC ratios of 86Y-panitumumab were 1.5 to 2.5 times greater than 86Y-cetuximab as observed by the differences in PET tumor to background ratios, which could be critical when imaging orthotopic tumors and concerns regarding radiation doses to normal organs such as the liver. Conclusion This study demonstrates the more favorable HER1-targeting characteristics of 86Y-panitumumab than 86Y-cetuximab for non-invasive assessment of the HER1 status of MM by PET imaging. Due to lower liver uptake, panitumumab based immunoconjugates may fare better in therapy than corresponding cetuximab

  4. 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

  5. Quality of life and personality traits in patients with malignant pleural mesothelioma and their first-degree caregivers.

    PubMed

    Granieri, Antonella; Tamburello, Stella; Tamburello, Antonino; Casale, Silvia; Cont, Chiara; Guglielmucci, Fanny; Innamorati, Marco

    2013-01-01

    Asbestos exposure causes significant pleural diseases, including malignant pleural mesothelioma (MPM). Taking into account the impact of MPM on emotional functioning and wellbeing, this study aimed to evaluate the quality of life and personality traits in patients with MPM and their first-degree caregivers through the World Health Organization Quality of Life-BREF (WHOQOL-BREF) and the Minnesota Multiphasic Personality Inventory-2 Restructured Form (MMPI-2-RF). The sample was composed of 27 MPM patients, 55 first-degree relatives enrolled in Casale Monferrato and Monfalcone (Italy), and 40 healthy controls (HC). Patients and relatives reported poorer physical health than the HC. Patients had a higher overall sense of physical debilitation and poorer health than relatives and the HC, more numerous complaints of memory problems and difficulties in concentrating, and a greater belief that goals cannot be reached or problems solved, while often claiming that they were more indecisive and inefficacious than the HC. First-degree relatives reported lower opinions of others, a greater belief that goals cannot be reached or problems solved, support for the notion that they are indecisive and inefficacious, and were more likely to suffer from fear that significantly inhibited normal activities than were HC. In multinomial regression analyses, partial models indicated that sex, physical comorbidities, and the True Response Inconsistency (TRIN-r), Malaise (MLS), and Behavior-Restricting Fears (BRF) dimensions of the MMPI-2-RF had significant effects on group differences. In conclusion, health care providers should assess the ongoing adjustment and emotional wellbeing of people with MPM and their relatives, and provide support to reduce emotional distress. PMID:23983468

  6. 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. PMID:27235332

  7. Resistance to caspase-8 and -9 fragments in a malignant pleural mesothelioma cell line with acquired cisplatin-resistance

    PubMed Central

    Janson, V; Johansson, A; Grankvist, K

    2010-01-01

    Apoptotic cysteine–aspartate proteases (caspases) are essential for the progression and execution of apoptosis, and detection of caspase fragmentation or activity is often used as markers of apoptosis. Cisplatin (cis-diamminedichloroplatinum (II)) is a chemotherapeutic drug that is clinically used for the treatment of solid tumours. We compared a cisplatin-resistant pleural malignant mesothelioma cell line (P31res1.2) with its parental cell line (P31) regarding the consequences of in vitro acquired cisplatin-resistance on basal and cisplatin-induced (equitoxic and equiapoptotic cisplatin concentrations) caspase-3, -8 and -9 fragmentation and proteolytic activity. Acquisition of cisplatin-resistance resulted in basal fragmentation of caspase-8 and -9 without a concomitant increase in proteolytic activity, and there was an increased basal caspase-3/7 activity. Similarly, cisplatin-resistant non-small-cell lung cancer cells, H1299res, had increased caspase-3 and -9 content compared with the parental H1299 cells. In P31 cells, cisplatin exposure resulted in caspase-9-mediated caspase-3/7 activation, but in P31res1.2 cells the cisplatin-induced caspase-3/7 activation occurred before caspase-8 or -9 activation. We therefore concluded that in vitro acquisition of cisplatin-resistance rendered P31res1.2 cells resistant to caspase-8 and caspase-9 fragments and that cisplatin-induced, initiator-caspase independent caspase-3/7 activation was necessary to overcome this resistance. Finally, the results demonstrated that detection of cleaved caspase fragments alone might be insufficient as a marker of caspase activity and ensuing apoptosis induction. PMID:21364680

  8. 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

  9. 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.

  10. 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