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Purpose: Both extrapleural pneumonectomy (EPP) and pleurectomy/decortication (P/D) are used for the surgical treatment of malignant pleural mesothelioma (MPM). This study aimed to compare the operative and clinical outcomes and survival between EPP and P/D., Methods: We performed a retrospective analysis of the surgical and clinical data of 40 patients who underwent either EPP (n = 18) or P/D (n = 22) for MPM at our institution between January 2000 and December 2018., Results: In comparison to EPP, P/D was associated with a higher intraoperative bleeding volume (1175 vs 1805 ml, p = 0.0020) and greater duration of postoperative thoracic drainage (3 vs 16 days, p < 0.0001). Adjuvant chemotherapy was more common after P/D (81.8%) than after EPP (33.3%; p = 0.0024). For epithelioid-type MPM, overall survival (OS) and recurrence-free survival (RFS) were significantly better in patients who underwent P/D in comparison to those who underwent EPP (p = 0.040 and p = 0.015, respectively), with no difference for the biphasic and sarcomatoid types of MPM. A Cox proportional hazards regression model identified P/D as a significant favorable prognostic factor for OS [hazard ratio (HR), 0.391; 95% confidence interval (CI), 0.175-0.871; p = 0.022] and RFS (HR, 0.418; 95% CI, 0.190-0.920; p = 0.030)., Conclusions: Based on our findings, P/D may be superior to EPP for improving the prognosis of patients with resectable epithelioid-type MPM., (© 2022. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Purpose: Despite becoming the preferred surgical technique for malignant pleural mesothelioma, pleurectomy/decortication has received few prospective clinical trials. Therefore, the Japan Mesothelioma Interest Group conducted a prospective multi-institutional study to evaluate the feasibility of neoadjuvant chemotherapy followed by pleurectomy/decortication., Methods: Patients with histologically confirmed, resectable malignant pleural mesothelioma underwent neoadjuvant chemotherapy comprising pemetrexed 500 mg/m 2 plus cisplatin 75 mg/m 2 for 3 cycles, followed by pleurectomy/decortication. The primary end point was macroscopic complete resection rate regardless of the surgical technique used., Results: Among the 24 patients enrolled, 20 received neoadjuvant chemotherapy and 18 proceeded to surgery, all of whom achieved macroscopic complete resection. Pleurectomy/decortication was performed in 15 patients. The trial satisfied the primary end point, with a macroscopic complete resection rate of 90% (18/20, 95% confidence interval, 68.3-98.8). No treatment-related 30- and 90-day mortality occurred. The overall survival after 1 and 2 years and median overall survival after registration were 95.0% (95% confidence interval, 69.5-99.3), 70.0% (95% confidence interval, 45.1-85.3), and 3.45 years (95% confidence interval, 1.64 to not available), respectively. The cumulative incidence of progression after 1 and 2 years and median time to progression were 33.3% (95% confidence interval, 17.3-64.1), 61.1% (95% confidence interval, 42.3-88.3), and 1.71 years (95% confidence interval, 1.00-2.99), respectively. The best postoperative value for forced expiratory volume was 78.0% of preoperative values., Conclusions: Neoadjuvant chemotherapy followed by pleurectomy/decortication was feasible with acceptable survival and mortality/morbidity. Postoperative pulmonary function was approximately 80% of the preoperative pulmonary function., (Copyright © 2021. Published by Elsevier Inc.)

Objective: Pleurectomy/decortication has been preferably employed as a curative-intent surgery for malignant pleural mesothelioma. However, visceral pleurectomy during pleurectomy/decortication provides technical challenges. For visceral pleurectomy, pleural incisions are commonly made to create a dissection plane between the visceral pleura and the lung parenchyma, which may cause tumor dissemination and may not allow en bloc complete resection of the entire pleura. To overcome such potential disadvantages, we have developed a novel surgical technique without any pleural incision (non-incisional pleurectomy/decortication) to achieve en bloc removal of the entire pleura., Methods: A total of 36 consecutive patients who underwent non-incisional pleurectomy/decortication for malignant pleural mesothelioma from January 2017 through December 2020 in our institute were retrospectively reviewed to assess the feasibility., Results: Macroscopic complete resection was achieved in 31 patients (86.1%) with non-incisional pleurectomy/decortication. In the majority of patients (n = 29), en bloc complete resection of the entire pleura was achieved (without pleural laceration in 10 and with some pleural laceration in 19 patients). The total operation time and the duration of visceral pleurectomy were significantly shorter as compared with those for conventional pleurectomy/decortication (median, 350 versus 506 min [P = 0.011], and 43 versus 97 min [P < 0.001], respectively). Among 36 patients who underwent non-incisional pleurectomy/decortication, postoperative complications developed in 13 patients (36.1%), and one patient died on the postoperative day 95 caused by aggressive tumor progression of residual tumor., Conclusions: Non-incisional pleurectomy/decortication is a fast and feasible technique to achieve en bloc macroscopic complete resection for malignant pleural mesothelioma., (© 2021. The Japanese Association for Thoracic Surgery.)

We report the case of a 56-year-old woman who underwent pleural biopsy to identify the cause of the right pleural effusion. The pathological diagnosis was epithelial malignant pleural mesothelioma. The patient worked as a junior high school teacher and strongly hoped for continuing work. Thus, we performed pleurectomy/decortication (P/D) as a curative surgery. The operative findings showed pleural thickening that in the lower lobe of the lung. Thus, peeling of the lower lobe was performed. Pleural biopsy was only performed on the upper and middle lobes. As a result, the operation was limited P/D. The pathological findings showed a small number of mesothelioma cells in the upper and middle lobes. The patient received four courses of cisplatin plus pemetrexed systemic chemotherapy after surgery. Continuous maintenance chemotherapy using pemetrexed has been performed until the time of writing. At present, she has continued her work for 6 years after the operation and has extended her retirement age without recurrence.

Complete resection is the mainstay of treatment for thymoma. Even for advanced-stage thymoma with pleural dissemination, complete resection with extrapleural pneumonectomy may provide a favorable prognosis. Pleurectomy decortication, a lung-sparing surgery, has been preferably employed in recent years as an alternative surgical procedure for malignant pleural mesothelioma. However, little has been reported about pleurectomy decortication for other malignant tumors with pleural dissemination. Here, we present the first case of thymoma with pleural dissemination for which complete en bloc resection was achieved with extended pleurectomy decortication.

Detection of rare tumor cells circulating in the blood (CTCs) presents technical challenges. CellSearch, the only approved system for clinical use, fails to capture epithelial cell adhesion molecule-negative CTCs such as malignant pleural mesothelioma (MPM). We have developed a novel microfluidic device (CTC-chip) in which any Ab to capture CTCs is conjugated. The CTC-chip was coated with an Ab against podoplanin that is abundantly expressed on MPM. Circulating tumor cell-detection performance was evaluated in experimental models in which MPM cells were spiked in blood sampled from a healthy volunteer and in clinical samples drawn from MPM patients. The CTC-chip showed superior CTC-detection performance over CellSearch in experimental models (sensitivity, 63.3%-64.5% vs 0%-1.1%; P < .001) and in clinical samples (CTC-positivity, 68.8% vs 6.3%; P < .001). A receiver operating characteristic (ROC) analysis showed that the CTC test provided a significant diagnostic performance in discrimination of unresectable disease from resectable disease (area under the ROC curve, 0.851; P = .003). The higher CTC count (≥2 cells/mL) was significantly associated with a poor prognosis (P = .030). The novel CTC-chip enabled sensitive detection of CTCs, which provided significant diagnostic and prognostic information in MPM., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Pleurectomy-decortication (P/D) is lung-sparing surgery with curative intent for malignant pleural mesothelioma (MPM). Visceral pleurectomy is the most challenging step in this procedure. At the beginning of pleurectomy, a sharp pleural incision through the tumor is usually made to create the dissection plane between the visceral pleura and the lung parenchyma, which may cause the spread of tumor cells into the operation field. Here, we describe a sophisticated surgical technique of P/D without any pleural incision ("non-incisional P/D") to achieve en bloc removal of the entire pleura and tumor, which may improve postoperative survival by preventing tumor spread.

Background: Mesothelioma is increasingly recognised as a global health issue and the assessment of its global burden is warranted., Objectives: To descriptively analyse national mortality data and to use reported and estimated data to calculate the global burden of mesothelioma deaths., Methods: For the study period of 1994 to 2014, we grouped 230 countries into 59 countries with quality mesothelioma mortality data suitable to be used for reference rates, 45 countries with poor quality data and 126 countries with no data, based on the availability of data in the WHO Mortality Database. To estimate global deaths, we extrapolated the gender-specific and age-specific mortality rates of the countries with quality data to all other countries., Results: The global numbers and rates of mesothelioma deaths have increased over time. The 59 countries with quality data recorded 15 011 mesothelioma deaths per year over the 3 most recent years with available data (equivalent to 9.9 deaths per million per year). From these reference data, we extrapolated the global mesothelioma deaths to be 38 400 per year, based on extrapolations for asbestos use., Conclusions: Although the validity of our extrapolation method depends on the adequate identification of quality mesothelioma data and appropriate adjustment for other variables, our estimates can be updated, refined and verified because they are based on commonly accessible data and are derived using a straightforward algorithm. Our estimates are within the range of previously reported values but higher than the most recently reported values., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Purpose: We conducted a prospective multi-institutional study to determine the feasibility of trimodality therapy (TMT) comprising induction chemotherapy followed by extrapleural pneumonectomy (EPP) and radiation therapy in Japanese patients with malignant pleural mesothelioma (MPM)., Methods: Major eligibility criteria were histologically confirmed diagnosis of MPM, including clinical subtypes T0-3, N0-2, M0 disease; no prior treatment for the disease; age 20-75 years; Eastern Cooperative Oncology Group performance status 0 or 1; predicted postoperative forced expiratory volume >1000 ml in 1 s; written informed consent. Treatment methods comprised induction chemotherapy using pemetrexed (500 mg/m(2)) plus cisplatin (60 mg/m(2)) for three cycles, followed by EPP and postoperative hemithoracic radiation therapy (54 Gy). Primary endpoints were macroscopic complete resection (MCR) rate for EPP and treatment-related mortality for TMT., Results: Forty-two eligible patients were enrolled: median age 64.5 (range 43-74) years; M:F = 39:3, clinical stage I:II:III = 14:13:15; histological type epithelioid were sarcomatoid; biphasic; others = 28:1:9:4. Of 42 patients, 30 completed EPP with MCR and 17 completed TMT. The trial met the primary endpoints, with an MCR rate of 71 % (30/42) and treatment-related mortality of 9.5 % (4/42). Overall median survival time and 2-year survival rate for 42 registered patients were 19.9 months and 42.9 %, respectively. Two-year relapse-free survival rate of 30 patients who completed EPP with MCR was 37.0 %., Conclusion: This phase II study met the predefined primary endpoints, but its risk/benefit ratio was not satisfactory.

Purpose: To investigate the diagnostic and prognostic value of circulating tumor cells (CTCs), a potential surrogate of micrometastasis, in malignant pleural mesothelioma (MPM)., Methods: We prospectively evaluated CTCs in 7.5 mL of peripheral blood sampled from patients with a suspicion of MPM. A semiautomated system was used to capture CTCs with an antibody against the epithelial cell adhesion molecule., Results: Of 136 eligible patients, 32 were finally diagnosed with nonmalignant diseases (NM), and 104 had MPM. CTCs were detected in 32.7 % (34 of 104) of MPM patients but in only 9.4 % (3 of 32) of NM patients (P = 0.011). The CTC count was significantly higher in MPM patients than in NM patients (P = 0.007), and a receiver operating characteristic (ROC) curve analysis showed an insufficient capability of the CTC test in discrimination between MPM and NM, with an area under ROC curve of 0.623 (95 % confidence interval, 0.523-0.723; P = 0.036). Among MPM patients, CTCs were more frequently detected in patients with epithelioid subtype (39.7 %, 31 of 78) than in those with nonepithelioid subtypes (11.5 %, 3 of 26; P = 0.016). Positive CTCs (CTC count ≥ 1) were a significant factor to predict a poor prognosis among epithelioid patients (median overall survival, 22.3 months for positive CTCs vs. 12.6 months for negative CTCs; P = 0.004) and not in nonepithelioid patients (P = 0.649). A multivariate analysis showed that positive CTCs were a significant and independent factor to predict a poor prognosis (hazard ratio, 2.904; 95 % confidence interval, 1.530-5.511; P = 0.001) for epithelioid MPM patients., Conclusions: CTC was a promising marker in diagnosis and prediction of prognosis in MPM, especially in epithelioid MPM.

Epithelioid tumors with aggressive behavior have been reported; however, the epithelioid type of malignant pleural mesothelioma (MPM) has a less aggressive behavior. Few studies have evaluated the prognostic value of epithelial-mesenchymal transition (EMT) markers in MPM. We hypothesized that mesenchymal characteristics might predominate in the tumors. Tumor specimens were collected from 33 consecutive patients. We analyzed the EMT expression levels in tumor samples by an immunohistochemical analysis. Positive expression of E-cadherin, γ-catenin, vimentin, fibronectin, Twist and YB-1 was observed in 25, 14, 21, 1, 19 and 18 patients, respectively. No significant association between these markers and the clinicopathological characteristics was found. γ-Catenin demonstrated a trend towards decreased expression in sarcomatoid tumors compared to epithelioid tumors. On the other hand, a trend was noted towards higher expression of vimentin, Twist and YB-1 in sarcomatoid tumors. The survival curves demonstrated that the patients with negative γ-catenin and positive Twist staining had a tendency to have a worse prognosis. Although the individual proteins might not significantly affect the progression of MPM, the combination of γ-catenin and Twist staining can predict the prognosis of patients with MPM., (© 2014 S. Karger AG, Basel.)

A prospective multi-institutional study has been initiated in Japan to evaluate the feasibility of induction chemotherapy using pemetrexed plus cisplatin, followed by pleurectomy/decortication aimed at macroscopic complete resection in patients with resectable malignant pleural mesothelioma. The study was initiated on September 2012, for which 24 patients will be recruited over a period of 2 years. The primary endpoint is the macroscopic complete resection rate, regardless of the surgical technique employed (i.e. pleurectomy/decortication or extrapleural pneumonectomy). The secondary endpoints are the pleurectomy/decortication rate, macroscopic complete resection rate by pleurectomy/decortication, pulmonary function at 3 months after surgery, adverse events, treatment-related mortality, response rate to chemotherapy and 3-year overall survival rate.

Hyaluronic acid (HA) has been proposed as a biochemical marker of malignant pleural mesothelioma (MPM). The present study focused on the implications of HA and CD44 interaction in the proliferation and invasiveness of MPM. The proliferation and invasive activity was evaluated in two human mesothelioma cell lines, ACC-MESO-1 and K921MSO, by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and the transwell chamber model. The knockdown of CD44 gene expression was accomplished by transfection of the cells with small interfering RNA. Flow cytometry revealed that both the ACC-MESO-1 and K921MSO cell lines highly expressed CD44. Treatment with HA enhanced the proliferation in both mesothelioma cell lines in comparison to cells without HA treatment. The treatment with HA (25 μg/ml) also significantly upregulated the invasion of both types of cells. The silencing of CD44 significantly abrogated the effect of HA treatment on the proliferation of ACC-MESO-1 cells and significantly suppressed the proliferation of K921MSO cells. HA-CD44 binding is important for the migration and proliferation of mesothelioma cells. Therefore, the HA-CD44 interaction is a potentially useful therapeutic target in MPM.

Background: The purpose of this study was to investigate the diagnostic and prognostic value of circulating endothelial cell (CEC), a potential surrogate of tumor angiogenesis, in malignant pleural mesothelioma (MPM)., Methods: We prospectively evaluated CEC count in 4.0 mL of peripheral blood sampled from patients with a suspicion of MPM. An automated system was used to capture CECs with an anti-CD146 antibody., Results: Of 109 eligible patients, 30 were finally diagnosed with non-malignant diseases, and 79 were with MPM. CEC count was significantly higher in MPM patients than in NM patients (mean CEC count, 120.3 and 39.9, respectively; P = 0.001), and a receiver operating characteristic (ROC) curve analysis showed that CEC provided a significant diagnostic performance in discrimination between MPM and nonmalignant diseases with an area under curve (AUC-ROC) of 0.700 (95 % confidence interval [95 % CI], 0.595-0.806; P = 0.001). Among MPM patients, CEC count was positively correlated with intratumoral microvessel density (MVD), a measurement of tumor angiogenesis (Spearman correlation coefficiency [r] = 0.444; P = 0.001). Higher CEC count (>50) was significantly associated with a poor prognosis (median overall survival, 11.4 months [95 % CI, 7.6-15.2] for higher CEC count patients versus 20.1 months [95 % CI, 16.0-24.2] for lower CEC count patients; P = 0.028). A multivariate analysis showed that higher CEC count was a significant and independent factor to predict a poor prognosis (hazard ratio [HR], 2.24, [95 % CI, 1.24-4.43]; P = 0.009)., Conclusions: CEC, as a surrogate of tumor angiogenesis, was a promising marker in diagnosis and prediction of prognosis in MPM.

In the present study, we analyzed genomic alterations of BRCA1-associated protein 1 (BAP1) in 23 malignant mesotheliomas (MMs), 16 epithelioid and seven non-epithelioid, consisting of 18 clinical specimens and five established cell lines. In examining these samples for homozygous deletions and sequence-level mutations, we found biallelic BAP1 gene alterations in 14 of 23 MMs (61%). Seven of these 14 MMs had homozygous deletions of the partial or entire BAP1 gene, another five had sequence-level mutations, including small deletions, a nonsense mutation, and missense mutations with additional monoallelic deletions, and the remaining two had homozygous mutations without allelic loss. All but one of the 14 BAP1 gene mutations were found in the epithelioid-type MMs; BAP1 mutations were found in 13 of 16 epithelioid-type MMs, but in only one of seven non-epithelioid-type MMs (13/16 vs 1/7; P = 0.005). There was no BAP1 mRNA expression in MMs with biallelic deletion and repressed expression was confirmed in MM specimens with deletion/mutation as compared with Met5a, SV40-transformed normal mesothelial cells. Western blot showed that seven of eight epithelioid MMs analyzed were BAP1 negative. Immunostaining with anti-BAP1 antibody in normal lung tissues revealed clear nuclear staining of normal mesothelial cells. No nuclear staining was observed among BAP1 mutation-positive MM tumors, whereas nuclear staining was observed among BAP1 mutation-negative MM tumors. These results suggest that the lack of the tumor suppressor BAP1 may be more specifically involved in the pathogenesis of epithelioid MM rather than non-epithelioid MM, and would be useful for diagnosis of epithelioid-type MM., (© 2012 Japanese Cancer Association.)

Array-based comparative genomic hybridization analysis was performed on 21 malignant mesothelioma (MM) samples (16 primary cell cultures and 5 cell lines) and two reactive mesothelial hyperplasia (RM) primary cell cultures. The RM samples did not have any genomic losses or gains. In MM samples, deletions in 1p, 3p21, 4q, 9p21, 16p13 and 22q were detected frequently. We focused on 3p21 because this deletion was specific to the epithelioid type. Especially, a deletion in 3p21.1 region carrying seven genes including SEMA3G was found in 52% of MM samples (11 of 14 epithelioid samples). The allele loss of 3p21.1 might be a good marker for the epithelioid MM. A homozygous deletion in this region was detected in two MM primary cell cultures. A heterozygous deletion detected in nine samples contained the 3p21.1 region and 3p21.31 one carrying the candidate tumor suppressor genes such as semaphorin 3F (SEMA3F), SEMA3B and Ras association (RalGDS/AF-6) domain family member 1 (RASSF1A). SEMA3B, 3F and 3G are class 3 semaphorins and inhibit growth by competing with vascular endothelial growth factor (VEGF) through binding to neuropilin. All MM samples downregulated the expression of more than one gene for SEMA3B, 3F and 3G when compared with Met5a, a normal pleura-derived cell line. Moreover, in 12 of 14 epithelioid MM samples the expression level of SEMA3A was lower than that in Met5a and the two RM samples. An augmented expression of VEGFA was detected in half of the MM samples. The expression ratio of VEGFA/SEMA3A was significantly higher in the epithelioid MMs than in Met5a, RMs and the non-epithelioid MMs. Our data suggest that the downregulated expression of SEMA3A and several SEMA3s results in a loss of inhibitory activities in tumor angiogenesis and tumor growth of VEGFA; therefore, it may play an important role on the pathogenesis of the epithelioid type of MM.

The research project entitled "Comprehensive approach on asbestos-related diseases" supported by the "Special Coordination Funds for Promoting Science and Technology (H18-1-3-3-1)" began in 2006 and was completed at the end of the Japanese fiscal year of 2010. This project included four parts; (1) malignant mesothelioma (MM) cases and specimen registration, (2) development of procedures for the early diagnosis of MM, (3) commencement of clinical investigations including multimodal approaches, and (4) basic research comprising three components; (i) cellular and molecular characterization of mesothelioma cells, (ii) immunological effects of asbestos, and (iii) elucidation of asbestos-induced carcinogenesis using animal models. In this special issue of the Japanese Journal of Hygiene, we briefly introduce the achievements of our project. The second and third parts and the third component of the fourth part are described in other manuscripts written by Professors Fukuoka, Hasegawa, and Toyokuni. In this manuscript, we introduce a brief summary of the first part "MM cases and specimen registration", the first component of the fourth part "Cellular and molecular characterization of mesothelioma cells" and the second component of the fourth part "Immunological effects of asbestos". In addition, a previous special issue presented by the Study Group of Fibrous and Particulate Substances (SGFPS) (chaired by Professor Otsuki, Kawasaki Medical School, Japan) for the Japanese Society of Hygiene and published in Environmental Health and Preventive Medicine Volume 13, 2008, included reviews of the aforementioned first component of the fourth part of the project. Taken together, our project led medical investigations regarding asbestos and MM progress and contributed towards the care and examination of patients with asbestos-related diseases during these five years. Further investigations are required to facilitate the development of preventive measures and the cure of asbestos-related diseases, particularly in Japan, where asbestos-related diseases are predicted to increase in the next 10 to 20 years.

The feasibility and efficacy of trimodality therapy for malignant pleural mesothelioma (MPM) are still controversial mainly due to the lack of clinical evidence. Although three major clinical trials on this therapy have been recently reported from North America and Europe, it remains unclear whether results in Caucasian populations may be directly applicable to Asian populations. In this context, as a project of the "Comprehensive approach on asbestos-related diseases" supported by the "Special Coordination Fund for Promoting Science and Technology of MEXT, Japan", a prospective multi-institutional study has been planned to evaluate the feasibility of induction chemotherapy using pemetrexed plus cisplatin, followed by extrapleural pneumonectomy (EPP) and postoperative hemithoracic radiation in patients with resectable MPM. Primary endpoints are macroscopic complete resection rate by EPP and treatment-related mortality for trimodality therapy. The study was initiated in May 2008 and patient enrollment was finished in November 2010.

Malignant mesothelioma (MM) is a highly aggressive, incurable neoplasm associated with asbestos exposure. Early detection of MM is not easy and radiological surveillance is imperfect. The use of blood-based biomarkers might solve this difficulty and allow detection of MM at an early stage when combined treatment involving surgery, chemotherapy and radiotherapy might be effective. In the research project entitled "Comprehensive approach on asbestos-related diseases" supported by the "Special Coordination Funds for Promoting Science and Technology (H18-1-3-3-1)", we conducted an exploratory study on the detection of markers for diagnosing early-stage MM. In this study, we have shown that serum soluble mesothelin-related peptide (SMRP) is a highly specific and moderately sensitive biomarker for diagnosing MM. SMRP levels in pleural effusion were elevated not only in advanced-stage malignant pleural mesothelioma (MPM), but also in early-stage disease. SMRP in pleural effusion can be an MPM-specific biomarker with greater sensitivity than in serum, especially for the early stage of the disease. Circulating tumor cells (CTCs) and circulating endothelial cells (CECs) were considered to be useful surrogate markers of disease progression in MPM, although the lack of sensitivity for early-stage disease remains to be improved. Cytological analysis with gene expression profiling has been more effective in detecting early-stage MPM with pleural effusion. In conclusion, blood or effusion-based biomarkers, possibly in combination with other new modalities, such as a thoracoscopy combined with the advanced imaging systems consisting of autofluorescence imaging (AFI) and narrow band imaging (NBI), will show some promise for curing MPM if the disease is detected at an early stage.

Well-differentiated papillary mesothelioma (WDPM) is an uncommon tumor with a papillary architecture, bland cytologic features, a tendency toward superficial spread without invasion, and good prognosis with prolonged survival. WDPM occurs primarily in the peritoneum of women, but also rarely in the pleura. We here report a case of 48-year-old woman who developed WDPM in the pleura with no history of asbestos exposure. Tumors were multifocal and widespread with a velvety appearance on the surface of parietal and visceral pleurae resected by extrapleural pneumonectomy (EPP). Tumors showed papillary structures with fibrovascular cores and lined by epithelioid cells. Immunohistochemically, these epithelioid tumor cells were positive for epithelial membrane antigen (EMA), a marker of malignant mesothelioma, with more than 50% positive for p53. Tumor cells microinvaded into subpleural parenchyma of the lung and minimally spread to adipose tissues of the mediastinal lesion. In addition, tumor cells invaded into the chest wall with a trabecular or glandular architecture. Based on these findings, this case is pathologically considered as WDPM of the pleura with malignant potential., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

A prospective multi-institutional study has been commenced in Japan to evaluate the feasibility of induction chemotherapy using pemetrexed plus cisplatin, followed by extrapleural pneumonectomy (EPP) and postoperative hemithoracic radiation in patients with resectable malignant pleural mesothelioma. The study was initiated on May 2008 and 40 patients will be recruited over 3 years. Primary endpoints are macroscopic complete resection rate by EPP and treatment-related mortality for trimodality therapy. Secondary endpoints include treatment completion rate, adverse events, response rate by chemotherapy and 2-year overall and relapse-free survival.

Malignant pleural mesothelioma (MPM) is associated with a poor prognosis; and to make things worse, its incidence is increasing throughout the world. Surgical management of MPM is comprised of two aspects: diagnosis and resection. Surgical biopsy with thoracoscopy provides a higher yield but a higher rate of tumor cell seeding than blind biopsy. In some surgical cases, extended surgical staging with mediastinoscopy, laparoscopy, and contralateral thoracoscopy is required for the preoperative evaluation for resectablity. There are two types of surgical resection for MPM. Pleurectomy/decortication (P/D) involves removal of as much of the visceral, parietal, and pericardial pleura and the tumor as possible without removing the underlying lung. Because P/D is less radical but less invasive compared to extrapleural pneumonectomy (EPP), it can be tolerated by poor-risk patients. EPP comprises en bloc resection of visceral, parietal, and pericardial pleura and adjacent components such as ipsilateral lung, pericardium, and diaphragm, without opening the pleural cavity. EPP was considered a highly dangerous procedure with a surgical mortality of more than 30% decades ago, but its current operative mortality/morbidity rates are 4%-9% and 60%, respectively. As macroscopic complete resection is the primary goal of surgery for MPM because of its diffuse intrapleural growth, surgical resection alone is associated with poor survival. In this context, combination therapy with surgery plus chemotherapy and/or radiotherapy is currently considered the standard treatment for patients with respectable MPM. A national survey of EPP was conducted recently in Japan, and a few multicenter clinical trials will start soon.

Background: Pemetrexed, a multi-targeted antifolate (MTA), is a promising agent in the treatment of malignant pleural mesothelioma (MPM) and non-small cell lung cancer (NSCLC). With the aim of finding an optimal schedule for the combination therapy of MTA and gemcitabine (GEM), we investigated their interaction against an MPM cell line, 211H, and the NSCLC cell lines A549 and H1299., Methods: Combination index analysis was used in 3 different schedules. Cell cycle analysis by flow cytometry and real-time RT-PCR analysis of thymidylate synthase (TS), folylpolyglutamate synthetase (FPGS) and reduced folate carrier 1 (RFC1) genes were performed to understand the biological consequences of their interaction., Results: MTA showed potent cytotoxicity against 211H cells (IC(50), 67 nM for 48 h exposure), compared to NSCLC cell lines. Significantly higher expression of FPGS and RFC1 mRNAs in 211H cells were associated with MTA sensitivity. Simultaneous exposure of MTA and GEM was antagonistic in all cell lines tested. Strong synergism was observed in 211H cells when MTA preceded GEM, but the inverted sequence showed antagonism. Similar results were exhibited in H1299 cells, whereas a moderately synergistic effect was observed in A549 cells when GEM preceded MTA. S phase accumulation by MTA treatment partly supported these results., Conclusion: Sequential administration of MTA and GEM is active, and the schedule of MTA followed by GEM is recommended for treating MPM., ((c) 2008 S. Karger AG, Basel.)

Background: Curative intent surgery may be indicated for some patients with resectable early stage malignant pleural mesothelioma (MPM). However, sarcomatoid MPM is a highly aggressive subtype for which curative intent surgery is generally not recommended. Case presentation: We present the case of a 63-year-old man who presented with dyspnea and chest tightness. Computed tomography revealed pleural thickening and nodular lesions. A pleural biopsy confirmed lymphohistiocytoid MPM (cT1N0M0, stage IA), prompting surgical intervention. The patient underwent left extrapleural pneumonectomy (EPP), and the final diagnosis was sarcomatoid MPM (pT2N0M0, stage IB). Although post-operative chemotherapy was planned, the patient refused additional treatment, because of the introduction of home oxygen therapy, and has remained recurrence-free for 10 years after the surgery. Conclusions: This case presents a noteworthy instance of achieving long-term recurrence-free survival solely through curative intent surgery for sarcomatoid MPM. It highlights the potential efficacy of surgical intervention in managing this aggressive subtype, offering a glimmer of hope for improved outcomes. Further research is warranted to better define the role of surgery in the treatment of sarcomatoid MPM. [ABSTRACT FROM AUTHOR]

Background: Pleural mesothelioma is an aggressive malignant tumor and has a poor prognosis. In particular, biphasic pleural mesothelioma is a less common histologic type, and successful outcomes are rare. Case presentation: A 60-year-old man was referred to our associated hospital because of dyspnea. Massive right pleural effusion and thickening of the entire right parietal pleura were revealed by radiological examination. After pleural biopsy, we diagnosed the patient's tumor as biphasic pleural mesothelioma. The patient was admitted to our hospital for multimodal treatment. Two cycles of chemotherapy were initially administered with dramatic effects. Therefore, we decided to perform surgery and achieved a macroscopic complete resection. Postoperative chemotherapy was administered with no adverse events. No recurrence has been observed 11 months post-operation. Conclusions: We encountered a case of biphasic pleural mesothelioma that responded well to chemotherapy, enabling macroscopic complete resection. [ABSTRACT FROM AUTHOR]

Malignant mesothelioma (MM) is a highly aggressive malignant tumor, predominantly associated with job-related exposure to asbestos. Development of effective and non-invasive modalities for diagnosis is an important issue in occupational medicine. Circulating tumor cells (CTCs), which are tumor cells that are shed from primary tumors and circulate in the peripheral blood, may be detected at an earlier stage than malignant tumors, and detection of CTCs may provide a novel insight into the diagnosis of MM. In a previous study evaluating clinical utility of CTCs, detected with a widely used system 'CellSearch', the authors indicated a significant however insufficient capability in the diagnosis of MM, suggesting need for a more sensitive system. Accordingly, the authors developed a novel microfluidic system to capture CTCs (CTC-chip), and demonstrated that the CTC-chip effectively captured MM cells (ACC-MESO-4) spiked in the blood by conjugating an anti-podoplanin antibody. The results of the present study demonstrated that the CTC-chip coated with the anti-podoplanin antibody captured another MM cell (ACC-MESO-1). However, the capture efficiencies were lower than those for ACC-MESO-4. In addition, an anti-mesothelin antibody was used to capture CTCs, however the CTC-chip coated with the anti-mesothelin antibody failed to effectively capture MM cells, possibly due to low mesothelin expression. Overall, the CTC-chip may capture specific types of CTCs by conjugating any antibody against an antigen expressed on CTCs, and may be a useful system for the diagnosis of malignant tumors, including MM. [ABSTRACT FROM AUTHOR]

In our previous study, a microfluidic system was developed based on podoplanin detection for capturing circulating tumor cells (CTCs), derived from malignant pleural mesothelioma (MPM). However, non-epithelioid MPM shows low podoplanin protein expression compared with that in epithelioid MPM; thus, some CTC populations may be missed. To overcome this limitation, a new CTC-detection chip was developed by combining the conventional podoplanin antibody (clone: NZ-1.2) with an epidermal growth factor receptor (EGFR)-targeted antibody (cetuximab). The cell-capture efficiency of the Cocktail-chip reached 100% in all the histological MPM cell lines. The median CTC-counts from 19 patients with MPM (epithelioid/non-epithelioid: 10/9) with the NZ-1.2- and Cocktail-chips were 1 and 3 (P=0.311) in 1 ml peripheral blood, 1.5 and 2 (P=0.332) in epithelioid MPM, and 1 and 3 (P=0.106) in non-epithelioid MPM, respectively. Overall, the Cocktail-chip showed an improved ability to detect more CTCs in patients with non-epithelioid MPM compared with that in the conventional NZ-1.2-chip, showing non-significant, but higher CTC detection. Furthermore, CTC-counts, determined using the Cocktail-chip were significantly correlated with the clinical stage of non-epithelioid MPM. In epithelioid MPM, the Cocktail-chip achieved a CTC-detection efficiency equivalent to that in the conventional NZ-1.2-chip. The Cocktail-chip enabled sensitive CTC detection of all histological MPM, including the non-epithelioid subtype, which may provide a foundation for the diagnosis, treatment, and prognosis of MPM progression. [ABSTRACT FROM AUTHOR]

Circulating tumor cell (CTC) is a potentially useful surrogate of micro-metastasis, but detection of rare tumor cells contaminated in a vast majority of normal hematologic cells remains technical challenges. To achieve effective detection of a variety of CTCs, we have developed a novel microfluidic system (CTC-chip) in which any antibody to capture CTCs is easily conjugated. In previous studies, we employed an antibody (clone E-1) against podoplanin that was strongly expressed on mesothelioma cells. The CTC-chip coated by the E-1 antibody (E1-chip) provided a modest sensitivity in detection of CTCs in malignant pleural mesothelioma (MPM). Here, to achieve a higher sensitivity, we employed a novel anti-podoplanin antibody (clone NZ-1.2). In an experimental model, MPM cells with high podoplanin expression were effectively captured with the CTC-chip coated by the NZ-1.2 antibody (NZ1.2-chip). Next, we evaluated CTCs in the peripheral blood sampled from 22 MPM patients using the NZ1.2-chip and the E1-chip. One or more CTCs were detected in 15 patients (68.2%) with the NZ1.2-chip, whereas only in 10 patients (45.5%) with the E1-chip. Of noted, in most (92.3%, 12/13) patients with epithelioid MPM subtype, CTCs were positive with the NZ1.2-chip. The CTC-count detected with the NZ1.2-chip was significantly higher than that with the E1-chip (p = 0.034). The clinical implications of CTCs detected with the NZ1.2-chip will be examined in a future study. [ABSTRACT FROM AUTHOR]