Masachika E, Kanno T, Nakano T, et al.
Naftopidil induces apoptosis in malignant mesothelioma cell lines independently of α1-adrenoceptor blocking.
Anticancer Res. 2013; 33(3):887-94 [PubMed]

BACKGROUND: Naftopidil, an α1-adrenoceptor blocker, has been clinically used for the treatment of benign prostate hyperplasia and hypertension. Emerging evidence has shown that naftopidil exhibits an antitumor effect on a variety of cancer types including prostate cancer. The aim of the present study was to investigate naftopidil-induced apoptosis in human malignant mesothelioma cells and to shed light on the underlying mechanism.
MATERIALS AND METHODS: 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining, western blotting, and enzymatic assay of caspase-3, -8, and -9 activities were carried out on human malignant mesothelioma cell lines NCI-H28, NCI-H2052, NCI-H2452, and MSTO-211H cells. To knock-down α1D-adrenoceptor, siRNA to silence human α1D-adrenoceptor-targeted gene was constructed and transfected into cells.
RESULTS: Naftopidil induced apoptosis in all the investigated malignant mesothelioma cells, and a similar effect was obtained with prazosin, another α1-adrenoceptor blocker. α1-Adrenoceptor is linked to Gq/11 protein involving activation of protein kinase C (PKC). Naftopidil-induced reduction in cell viability was inhibited by GF109203X, while prazosin-induced in cell viability was less affected. Knocking-down α1D-adrenoceptor promoted malignant mesothelioma cell proliferation. Both naftopidil and prazosin activated caspase-3 and -8 in all the investigated malignant mesothelioma cells.
CONCLUSION: Naftopidil, as well as prazosin, has the potential to induce apoptosis in malignant mesothelioma cells by activating caspase-8 and the effector caspase-3, regardless of α1-adrenoceptor blocking.

Kobayashi M, Huang CL, Sonobe M, et al.
Snail expression is associated with a poor prognosis in malignant pleural mesotheliomas.
Ann Thorac Surg. 2013; 95(4):1181-8 [PubMed]

BACKGROUND: Malignant pleural mesotheliomas (MPMs) are aggressive tumors with a poor prognosis. We aimed to clarify the mechanisms of epithelial-to-mesenchymal transition (EMT) in MPMs by analyzing the expressions of EMT-associated transcription factors and E-cadherin in relation to tumor proliferation rates and patient survival.
METHODS: One hundred nine patients with MPMs were investigated. Among these patients, there were 61 epithelioid tumors, 21 sarcomatoid tumors, 20 biphasic tumors, and 7 desmoplastic tumors. Immunohistochemical analyses were performed to evaluate the expressions of Snail, ZEB1, Twist, E-cadherin, and the Ki-67 proliferation index.
RESULTS: The expressions of Snail and ZEB1 were significantly higher in the nonepithelioid tumors than in the epithelioid tumors (p<0.0001 and p=0.0051, respectively). Furthermore, the E-cadherin expression was significantly lower in the Snail-high tumors than in the Snail-low tumors (p=0.0423). The E-cadherin expression was significantly lower in the nonepithelioid tumors than in the epithelioid tumors (p=0.0126). The Ki-67 proliferation index was significantly higher in the nonepithelioid tumors than in the epithelioid tumors (p=0.025). Patient survival was significantly lower in patients with Snail-high MPMs than in those with Snail-low MPMs (p=0.0016), especially in patients with nonepithelioid tumors (p=0.0089). The multivariate analysis also demonstrated that nuclear Snail expression was a significant predictor of poor prognosis in patients with MPMs (p=0.0142).
CONCLUSIONS: The Snail expression is associated with EMT and a poor prognosis in MPMs. Snail could be a potential molecular target for the treatment of patients with MPMs.

Sugarbaker DJ, Gill RR, Yeap BY, et al.
Hyperthermic intraoperative pleural cisplatin chemotherapy extends interval to recurrence and survival among low-risk patients with malignant pleural mesothelioma undergoing surgical macroscopic complete resection.
J Thorac Cardiovasc Surg. 2013; 145(4):955-63 [PubMed]

OBJECTIVE: Local recurrence limits long-term survival in patients with malignant pleural mesothelioma. We investigated whether hyperthermic intraoperative cisplatin chemotherapy lavage affects the interval to recurrence and overall survival among patients with favorable prognostic factors.
METHODS: Using a preoperative risk assessment algorithm we had previously developed and validated, we retrospectively identified a cohort of patients treated with cytoreductive surgery from 2001 to 2009. The patients had epithelial histologic findings on biopsy and were characterized as having a low risk of early recurrence and death (ie, tumor volume ≤ 500 cm(3) and were either men with a hemoglobin level of ≥ 13 g/dL or were women). Those patients who had received hyperthermic intraoperative cisplatin chemotherapy were compared with a comparison group of those who had not. Fisher's exact test was used to determine the balance of prognostic factors. The Kaplan-Meier method and log-rank tests were used to estimate and compare the interval to recurrence and overall survival. Cox proportional hazards regression was used for multivariate analysis.
RESULTS: The cohort criteria identified 103 patients: 72 who received hyperthermic intraoperative cisplatin chemotherapy and 31 who did not. The groups were balanced for prognostic factors, except for the use of neoadjuvant chemotherapy (more common in the comparison group). The hyperthermic intraoperative cisplatin chemotherapy group exhibited a significantly longer interval to recurrence (27.1 vs 12.8 months) and overall survival (35.3 vs 22.8 months) than the comparison group. The improved interval to recurrence and overall survival for the hyperthermic intraoperative cisplatin chemotherapy group were particularly evident among the subgroups of patients who had not received hemithoracic radiotherapy and who had pathologic stage N1 or N2 lymph node metastases.
CONCLUSIONS: A favorable outcome and minimal incremental morbidity support the incorporation of hyperthermic intraoperative cisplatin chemotherapy into multimodality treatment strategies for patients with low-risk epithelial malignant pleural mesothelioma.

Mineo TC, Ambrogi V
Malignant pleural mesothelioma: factors influencing the prognosis.
Oncology (Williston Park). 2012; 26(12):1164-75 [PubMed]

Malignant pleural mesothelioma (MPM) is a highly severe primary tumor of the pleura mainly related to exposure to asbestos fibers. The median survival after symptom onset is less than 12 months. Conventional medical and surgical therapies--either as single lines or combined--are not wholly effective. No universally accepted guidelines have yet been established for patient selection and the use of therapeutic strategies. In addition, retrospective staging systems have proved inadequate at improving therapeutic outcomes. Therapy is currently guided by gross tumor characteristics and patient features; however, these seem less accurate than the biological fingerprint of the tumor. A number of clinical prognostic factors have been considered in large multicenter series and independently validated. A series of novel biomarkers can predict the evolution of the disease. Here we summarize the principal and novel factors that influence prognosis and are thus potentially useful for selecting patients for targeted therapy.

Haas AR, Sterman DH
Malignant pleural mesothelioma: update on treatment options with a focus on novel therapies.
Clin Chest Med. 2013; 34(1):99-111 [PubMed] Article available free on PMC after 01/03/2014

There is evidence that improved treatments of malignant pleural mesothelioma are increasing the quality and quantity of life for patients with mesothelioma. Multimodality treatment programs that combine maximal surgical cytoreduction with novel forms of radiation therapy and more effective chemotherapy combinations may offer significant increases in survival for certain subgroups of patients with mesothelioma. Lung-sparing surgery may allow improvements in pulmonary function after surgery-based multimodality therapy, and potential longer overall survival than that seen with extrapleural pneumonectomy. Experimental treatments provide hope for all patients with mesothelioma, and in the future may be combined with standard therapy in multimodality protocols.

Gibb H, Fulcher K, Nagarajan S, et al.
Analyses of radiation and mesothelioma in the US Transuranium and Uranium Registries.
Am J Public Health. 2013; 103(4):710-6 [PubMed]

OBJECTIVES: We examined the relationship between radiation and excess deaths from mesothelioma among deceased nuclear workers who were part of the US Transuranium and Uranium Registries.
METHODS: We performed univariate analysis with SAS Version 9.1 software. We conducted proportionate mortality ratio (PMR) and proportionate cancer mortality ratio (PCMR) analyses using the National Institute for Occupational Safety and Health Life Table Analysis System with the referent group being all deaths in the United States.
RESULTS: We found a PMR of 62.40 (P < .05) and a PCMR of 46.92 (P < .05) for mesothelioma. PMRs for the 4 cumulative external radiation dose quartiles were 61.83, 57.43, 74.46, and 83.31. PCMRs were 36.16, 47.07, 51.35, and 67.73. The PMR and PCMR for trachea, bronchus, and lung cancer were not significantly elevated.
CONCLUSIONS: The relationship between cumulative external radiation dose and the PMR and PCMR for mesothelioma suggests that external radiation at nuclear facilities is associated with an increased risk of mesothelioma. The lack of a significantly elevated PMR and PCMR for trachea, bronchus, and lung cancer suggests that asbestos did not confound this relationship.

Pinato DJ, Mauri FA, Lloyd T, et al.
The expression of Axl receptor tyrosine kinase influences the tumour phenotype and clinical outcome of patients with malignant pleural mesothelioma.
Br J Cancer. 2013; 108(3):621-8 [PubMed] Article available free on PMC after 19/02/2014

BACKGROUND: Recent preclinical studies identified Axl, a tyrosine kinase receptor implicated in tumour progression and epithelial-to-mesenchymal transition, as a putative therapeutic target in malignant pleural mesothelioma (MPM), an invariably fatal malignancy with limited treatment options. Here, we studied the expression of Axl and its ligand Gas-6 (growth arrest signal-6) in primary specimens of MPM, correlating their expression levels with tumour phenotype and clinical outcomes.
METHODS: Two independent cohorts of consecutive patients diagnosed with MPM were studied: a derivation cohort composed of 63 cases and a validation set of 35 cases. Clinical variables including patients' demographics, tumour stage, histotype, performance status (PS), Axl and Gas-6 staining were tested for predicting overall survival (OS) using univariate and multivariate analyses.
RESULTS: In the derivation cohort, Axl (P=0.001) but not Gas-6 overexpression (P=0.35) emerged as a univariate prognostic factor for OS, together with stage (P=0.05), PS (P<0.001) hypoalbuminaemia (P<0.001) and anaemia (P<0.001). Multivariate analyses confirmed Axl overexpression (P=0.01), PS (P=0.01), hypoalbuminaemia (P<0.001) and anaemia (P=0.04) as independent predictors of OS. The prognostic role of Axl overexpression was externally validated in an independent cohort (P=0.03).
CONCLUSION: Overexpression of Axl is found in the majority of MPM specimens and influences patient's survival independently from other established prognostic factors. Such information may support patient selection for future trials.

Hmeljak J, Erčulj N, Dolžan V, et al.
Is survivin expression prognostic or predictive in malignant pleural mesothelioma?
Virchows Arch. 2013; 462(3):315-21 [PubMed]

Malignant pleural mesothelioma is an incurable cancer strongly associated with asbestos exposure and characterised by poor response to treatment. The inhibitor-of-apoptosis protein family member survivin is involved in apoptosis and proliferation and is expressed in cancer cells only. The aims of the present study were to elucidate whether survivin expression is associated with tumour cell apoptosis and proliferation and to assess the prognostic and predictive value of survivin expression in malignant pleural mesothelioma. Archival pleural mesothelioma tissue samples from 101 patients were immunohistochemically analysed for nuclear expression of survivin, for proliferation with the use of Ki-67 as marker and for apoptosis using active caspase-3 as a marker. Staining results and clinical data were included in a survival analysis. Survivin was highly expressed in tumour cell nuclei in all samples and this correlated positively with both apoptosis and proliferation, but did not have a significant prognostic value. We found significantly higher survivin expression in patients who responded to chemotherapy compared to patients with progressive disease. Survivin expression might contribute to treatment response prediction, but survivin expression in malignant pleural mesothelioma did not have prognostic significance.

Pairon JC, Laurent F, Rinaldo M, et al.
Pleural plaques and the risk of pleural mesothelioma.
J Natl Cancer Inst. 2013; 105(4):293-301 [PubMed]

BACKGROUND: The association between pleural plaques and pleural mesothelioma remains controversial. The present study was designed to examine the association between pleural plaques on computed tomography (CT) scan and the risk of pleural mesothelioma in a follow-up study of asbestos-exposed workers.
METHODS: Retired or unemployed workers previously occupationally exposed to asbestos were invited to participate in a screening program for asbestos-related diseases, including CT scan, organized between October 2003 and December 2005 in four regions in France. Randomized, independent, double reading of CT scans by a panel of seven chest radiologists focused on benign asbestos-related abnormalities. A 7-year follow-up study was conducted in the 5287 male subjects for whom chest CT scan was available. Annual determination of the number of subjects eligible for free medical care because of pleural mesothelioma was carried out. Diagnosis certification was obtained from the French mesothelioma panel of pathologists. Survival regression based on the Cox model was used to estimate the risk of pleural mesothelioma associated with pleural plaques, with age as the main time variable and time-varying exposure variables, namely duration of exposure, time since first exposure, and cumulative exposure index to asbestos. All statistical tests were two-sided.
RESULTS: A total of 17 incident cases of pleural mesothelioma were diagnosed. A statistically significant association was observed between mesothelioma and pleural plaques (unadjusted hazard ratio (HR) = 8.9, 95% confidence interval [CI] = 3.0 to 26.5; adjusted HR = 6.8, 95% CI = 2.2 to 21.4 after adjustment for time since first exposure and cumulative exposure index to asbestos).
CONCLUSION: The presence of pleural plaques may be an independent risk factor for pleural mesothelioma.

Gong YS, Rong YT, Han WC, Zhang YC
Peripheral lymphadenopathy as the initial manifestation of malignant mesothelioma in a child.
Hum Pathol. 2013; 44(4):664-9 [PubMed]

Peripheral lymphadenopathy is a rare presentation in malignant mesothelioma. We describe a unique case of malignant mesothelioma arising in an 11-year-old boy, for whom peripheral lymphadenopathy was the initial manifestation of the disease. The final diagnosis was confirmed by a broad panel of immunohistochemical markers. Literature review disclosed only 2 cases in childhood that initially presented with peripheral lymphadenopathy. Pathologists should be aware of this rare biologic behavior of malignant mesothelioma to reach the correct and prompt diagnosis.

Jagirdar R, Solenov EI, Hatzoglou C, et al.
Gene expression profile of aquaporin 1 and associated interactors in malignant pleural mesothelioma.
Gene. 2013; 517(1):99-105 [PubMed]

Overexpression of AQP1 has recently been shown to be an independent prognostic factor in pleural mesothelioma favoring survival. This paper presents a data mining and bioinformatics approach towards the evaluation of the gene expression profile of AQP1 in malignant pleural mesothelioma and of AQP1 associated markers in the context of mesothelioma disease phenotype, CDKN2A gene deletion, sex and asbestos exposure. The data generated were thus again subjected to differential expression profile analysis. Here we report that AQP1 is overexpressed in epithelioid mesothelioma and identify TRIP6 and EFEMP2 as candidate genes for further investigation in mesothelioma.

Wu D, Hiroshima K, Matsumoto S, et al.
Diagnostic usefulness of p16/CDKN2A FISH in distinguishing between sarcomatoid mesothelioma and fibrous pleuritis.
Am J Clin Pathol. 2013; 139(1):39-46 [PubMed]

The distinction between sarcomatoid mesothelioma and fibrous pleuritis is difficult based on histology, especially when the amount of tumor tissue examined via biopsy is small and immunohistochemical examination is inconclusive. We studied the usefulness of deletion of p16 with fluorescence in situ hybridization (FISH) and p16 hypermethylation with polymerase chain reaction for the diagnosis and prognosis of malignant pleural mesothelioma (MPM). We analyzed 50 MPMs, including 22 sarcomatoid mesothelioma cases and 10 fibrous pleuritis cases. We set the cutoff value of homozygous deletion pattern as 14.4% based on FISH signaling patterns using samples of fibrous pleuritis. The percentage of homozygous deletion pattern was higher than 14.4% in 55.6% of the epithelioid mesotheliomas (10/18) and in all of the sarcomatoid mesotheliomas (22/22). Methylation of p16 was observed in 7 (20.6%) of 34 informative cases. p16 FISH analysis can be a reliable test for distinguishing between sarcomatoid mesothelioma and fibrous pleuritis and a prognostic factor for MPM.

Yonemura Y, Ishibashi H, Canbay E, et al.
Treatment results of diffuse malignant peritoneal mesothelioma.
Gan To Kagaku Ryoho. 2012; 39(12):2416-9 [PubMed]

During the last 7 years, 21 patients with DMPM were treated. Histologic types were epitheloid type in 18 patients, biphasic type in 2 patients and sarcomatoid type in 1 patient. Preoperative systemic chemotherapy, hyperthermic intraperitoneal chemotherapy(HIPEC) by laparoscopy(LHIPEC), and intraperitoneal(IP) chemotherapy were done in 14, 3 and 1 patients, respectively. Cytoreductive surgery(CRS) was done in 13 patients. Ten patients received HIPEC after CRS. Partial responses were experienced in 4 of 13 patients treated with preoperative systemic chemotherapy. One of three patients treated by LHIPEC showed complete response. Among 13 patients received laparotomy, complete removal of PC was done in 4(31%) patients. The other 9 patients who received incomplete cytoreduction had diffuse involvement on the small bowel and its mesentery. All over 5-year survival was 17%. Patients treated with HIPEC survived significantly longer than non-HIPEC group. Neoadjuvant laparoscopic HIPEC may have a great role in the preoperative control of small PC on the surface of small bowel.

Pinto C, Novello S, Torri V, et al.
Second Italian consensus conference on malignant pleural mesothelioma: state of the art and recommendations.
Cancer Treat Rev. 2013; 39(4):328-39 [PubMed]

Malignant pleural mesothelioma (MPM) is a relevant public health issue. A large amount of data indicate a relationship between mesothelioma and asbestos exposure. MPM incidence has considerably and constantly increased over the past two decades in industrialized countries and is expected to peak in 2010-2020. In Italy, the standardized incidence rate in 2008 was 3.6 and 1.3 per 100,000 in men and women respectively, with wide differences from one region to another. The approach to this disease remains difficult and complex in terms of pathogenic mechanism, diagnosis, staging and treatment thus an optimal strategy has not yet been clearly defined. The Second Italian Multidisciplinary Consensus Conference on Malignant Pleural Mesothelioma was held in Turin (Italy) on November 24-25, 2011: recommendations on MPM management for public health institutions, clinicians and patients are presented in this report.

Agarwal V, Campbell A, Beaumont KL, et al.
PTEN protein expression in malignant pleural mesothelioma.
Tumour Biol. 2013; 34(2):847-51 [PubMed]

Malignant pleural mesothelioma is associated with poor prognosis and despite recent advances in chemotherapy, the median survival is still approximately 12 months. Loss of phosphatase and tensin homolog (PTEN) protein expression may lead to constitutive activation of AKT resulting in cell survival and proliferation. Small studies reported that PTEN protein expression is rarely lost in mesothelioma whilst a larger study demonstrated prognostic significance of PTEN protein expression status with absence in 62 % of cases. We aimed to analyse PTEN protein expression in mesothelioma. Immunohistochemical analysis was performed in 86 archival mesothelioma samples to determine the PTEN protein expression status and statistical analysis was performed to identify any prognostic significance. Mesothelial cells in normal pleura demonstrated positive staining for PTEN protein and served as a positive reference. For mesothelioma samples, the expression of PTEN protein was scored as 0 (negative), 1 (intensity less than that of positive normal pleura reference slide) and 2 (intensity equal to or greater than positive normal pleura reference slide). A total of 23/86 (26.7 %) scored 0, 23/86 (26.7 %) scored 1 and 40/86 (46.5 %) scored 2 for PTEN expression. Univariate analysis demonstrated that lack of PTEN expression was not associated with survival. PTEN protein expression was undetectable in 26.7 % of mesothelioma samples; however, no prognostic significance was identified. Absence of PTEN protein may result in activation of the PI3K/AKT/MTOR pathway. Targeting this pathway with inhibitors further downstream of PTEN may provide a potential therapeutic target in selected patients.

Pasello G, Marulli G, Polo V, et al.
Pemetrexed plus carboplatin or cisplatin as neoadjuvant treatment of operable malignant pleural mesothelioma (MPM).
Anticancer Res. 2012; 32(12):5393-9 [PubMed]

AIM: The objective of this study was the retrospective evaluation of tolerability and activity of pemetrexed with carboplatin (AC) or cisplatin (AP) as neoadjuvant chemotherapy in a consecutive series of patients with malignant pleural mesothelioma (MPM).
PATIENTS AND METHODS: Patients with operable MPM received three cycles of AC or AP followed by surgery and radiotherapy.
RESULTS: Since 2005, 51 patients have been treated with AC (27) and AP (24). We observed higher incidence of grade 3 anaemia, cumulative grade 2-3 asthenia and worsening of performance status in the AP group. Response to AC and AP were; complete: 4% vs. 0%, partial: 18% vs. 17%, stable disease: 74% vs. 79%, progressive disease: 4%; the resection rate was 81% vs. 79%.
CONCLUSION: AC and AP are active and feasible neoadjuvant regimens. Progression-free survival, response, disease control and resection rate were similar in the two treatment groups. The lower tolerability to AP treatment could impair the clinical condition of patients undergoing surgery.

Zhang J, Qiu S, Zhang Y, et al.
Loss of mesothelin expression by mesothelioma cells grown in vitro determines sensitivity to anti-mesothelin immunotoxin SS1P.
Anticancer Res. 2012; 32(12):5151-8 [PubMed]

BACKGROUND/AIM: To determine if early passage tumor cells obtained from patients with mesothelioma continue to express the tumor differentiation antigen mesothelin and their sensitivity to the anti-mesothelin immunotoxin SS1P.
MATERIALS AND METHODS: Cell cultures were established from ascites or pleural effusion of 6 peritoneal and 3 pleural mesothelioma patients, respectively. These cells were evaluated for mesothelin expression by immunohistochemistry and flow cytometry.
RESULTS: Although mesothelin was highly expressed in tumor biopsies of all patients, only 3 out of 9 malignant effusions from these patients when grown in short-term culture showed strong mesothelin positivity by IHC. By flow cytometry, the number of mesothelin sites per cell was variable ranging from 580 to 210,000 sites/cell. Cells with strong mesothelin expression by IHC and increased number of mesothelin sites/cell were sensitive to SS1P.
CONCLUSIONS: Most mesothelioma tumors loose mesothelin when grown in vitro and the sensitivity of these cells to SS1P is dependent on the number of mesothelin sites/cell.

Yanagawa J, Rusch V
Surgical management of malignant pleural mesothelioma.
Thorac Surg Clin. 2013; 23(1):73-87, vi [PubMed]

The uniquely diffuse nature of malignant pleural mesothelioma (MPM) makes it difficult to diagnose, stage, and treat. In addition, it is a relatively uncommon disease, making adequate prospective trials difficult to perform and leading to several controversies regarding the best management of MPM. Perhaps the greatest area of dispute is whether extrapleural pneumonectomy or pleurectomy/decortication is the most appropriate curative operation for patients who are physiologically candidates for both. Although median survival remains poor, important strides have been made in the treatment of MPM, mainly in the form of multimodality therapeutic regimens.

Mogi A, Koga K, Aoki M, et al.
Expression and role of GLUT-1, MCT-1, and MCT-4 in malignant pleural mesothelioma.
Virchows Arch. 2013; 462(1):83-93 [PubMed]

Malignant cells supply their energy needs through increased glucose consumption, producing large quantities of lactic acid via glycolysis. Glucose transporters (GLUTs) and monocarboxylate transporters (MCTs) are therefore commonly up-regulated in human malignancies to mediate glucose influx and lactic acid efflux, respectively. However, their roles in malignant pleural mesothelioma (MPM) have not been fully elucidated. Here, we evaluated GLUT-1, MCT-1, and MCT-4 expression in human MPM and reactive mesothelial hyperplasia (RMH) and elucidated their biological role in vitro. GLUT-1, MCT-1, and MCT-4 expression was determined in human MPM (n = 35) and RMH (n = 20) specimens by immunohistochemistry and in frozen tissue, and MPM cell lines, by real-time reverse transcription-polymerase chain reaction and western blot analysis. GLUT-1, MCT-1, and MCT-4 functions in MPM were evaluated by transfection with small interfering RNA. Immunohistochemical analysis revealed higher levels of GLUT-1, MCT-1, and MCT-4 in MPM than in RMH. Additionally, GLUT-1, MCT-1, and MCT-4 mRNA levels were higher in MPM than in non-neoplastic mesothelial cell lines. The siRNA-mediated knockdown of GLUT-1 or MCT-1 significantly suppressed tumor cell proliferation, and MCT-1 silencing inhibited invasion and induced apoptosis. Taken together, these results indicate that combined application of GLUT-1, MCT-1, and MCT-4 immunohistochemistry might be useful in differentiating MPM from RMH and suggest that MCT-1plays an important biological role.

Dunder I, Baykal C, Turkmen I, et al.
Malignant primary peritoneal mesothelioma: report of two cases and review of literature.
Eur J Gynaecol Oncol. 2012; 33(5):549-51 [PubMed]

INTRODUCTION: Malignant primary peritoneal mesothelioma is a rare and highly aggressive tumor. This tumor can be misdiagnosed as ovarian carcinoma.
CASE: Two cases of malignant primary peritoneal mesothelioma that were misdiagnosed as ovarian carcinoma were operated in our instutition. Patients were 74 and 45 years-old at admittance.
CONCLUSION: Malignant primary peritoneal mesothelioma is being a problem for gynecologic oncologists because of the close similarity with epithelial ovarian cancer. Diagnosis and treatment of these patients are still under debate.

Cameron RB, Hou D
Intraoperative hyperthermic chemotherapy perfusion for malignant pleural mesothelioma: an in vitro evaluation.
J Thorac Cardiovasc Surg. 2013; 145(2):496-504 [PubMed]

OBJECTIVES: Hyperthermic chemotherapy perfusion has been used in the treatment of both pleural and peritoneal mesothelioma without an extensive basic science foundation. Clinical data are limited with no prospective randomized trials to support the use of this potentially toxic therapy. We sought to generate basic scientific support for this clinical practice and to define the optimal conditions for use in future clinical trials.
METHODS: Growth of a variety of in vitro established cell lines, including a hyperthermia-sensitive Chinese hamster ovary (CHO)-K1 cell line, a normal lung fibroblast line (MRC-5), a lung cancer line (A549), and 3 human mesothelioma cell lines (NCI-H28, NCI-H2052, and MSTO-211H), was assessed using a novel tetrazolium compound (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt [MTS]) and an electron coupling reagent (phenazine methosulfate), which measures the absorbance at 490 nm of a formazan product reduced from MTS by living cells (MTS metabolic assay), or a standard dilution clonogenic assay, which enumerates colony-forming units of more than 50 cells. Each cell line was plated into flasks and then exposed to varying combinations of chemotherapy agents and hyperthermia (37°C-45°C). The cells then were harvested and assessed in either assay. The role of chemotherapeutic agents currently most commonly used in clinical practice, including cisplatin, gemcitabine, and pemetrexed, was assessed with and without simultaneous heat exposure.
RESULTS: Conditions initially were explored using hyperthermia alone in CHO-K1, A549, and NCI-H28 cell lines using temperatures of 37°C, 42°C, and 45°C for 20, 40, and 60 minutes, respectively. This showed a reproducible dose-response curve in CHO-K1 cells with increasing temperature producing lower survival to only 1.5% of the control at 45°C for 60 minutes (P < .01). The A549 cells also showed a response but only at the highest temperature, and the NCI-H28 cells showed a more modest reduction to 65% at 45°C for 60 minutes (P < .01). When the 2 assays were directly compared, the MTS assay failed to detect differences between groups and therefore was discontinued from the remainder of these experiments. Next, hyperthermia was limited to the physiologic limit of 42°C, and the addition of chemotherapy was assessed. Doses were chosen on the basis of prior pharmacokinetic data from studies showing a maximum tissue/blood level of 200 ng/mL for cisplatin pleural instillation and were thought to more accurately reflect actual tumor levels. Cisplatin alone modestly reduced the clonogenic potential to 26%, 16.4%, and 13.6% at 42°C, respectively, for 60 minutes (P < .01); however, this was only a further reduction of 29.6%, 33.8%, and 34.2%, respectively, from the cisplatin alone control. Therefore, most of the reduction was attributable to chemotherapy and not hyperthermia. With combinations of cisplatin/gemcitabine and cisplatin/pemetrexed, the effect was larger, with reduction to 9.6%, 0%, and 0%, respectively (P < .01) (incremental reduction of 16.5%, 0%, and 0%, respectively, due to hyperthermia). Cisplatin/pemetrexed produced essentially identical results.
CONCLUSIONS: Intrapleural chemotherapy seems to be most effective when using 2 drug combinations. All mesothelioma cell lines showed no particular sensitivity to heat. The use of hyperthermia alone or with chemotherapy produces at best only a modest effect and does not necessarily support its current clinical use.

Hoda MA, Münzker J, Ghanim B, et al.
Suppression of activin A signals inhibits growth of malignant pleural mesothelioma cells.
Br J Cancer. 2012; 107(12):1978-86 [PubMed] Article available free on PMC after 04/12/2013

BACKGROUND: Activins control the growth of several tumour types including thoracic malignancies. In the present study, we investigated their expression and function in malignant pleural mesothelioma (MPM).
METHODS: The expression of activins and activin receptors was analysed by quantitative PCR in a panel of MPM cell lines. Activin A expression was further analysed by immunohistochemistry in MPM tissue specimens (N=53). Subsequently, MPM cells were treated with activin A, activin receptor inhibitors or activin-targeting siRNA and the impact on cell viability, proliferation, migration and signalling was assessed.
RESULTS: Concomitant expression of activin subunits and receptors was found in all cell lines, and activin A was overexpressed in most cell lines compared with non-malignant mesothelial cells. Similarly, immunohistochemistry demonstrated intense staining of tumour cells for activin A in a subset of patients. Treatment with activin A induced SMAD2 phosphorylation and stimulated clonogenic growth of mesothelioma cells. In contrast, treatment with kinase inhibitors of activin receptors (SB-431542, A-8301) inhibited MPM cell viability, clonogenicity and migration. Silencing of activin A expression by siRNA oligonucleotides further confirmed these results and led to reduced cyclin D1/3 expression.
CONCLUSION: Our study suggests that activin A contributes to the malignant phenotype of MPM cells via regulation of cyclin D and may represent a valuable candidate for therapeutic interference.

Maki Y, Asano H, Toyooka S, et al.
MicroRNA miR-34b/c enhances cellular radiosensitivity of malignant pleural mesothelioma cells.
Anticancer Res. 2012; 32(11):4871-5 [PubMed]

BACKGROUND: We previously reported that epigenetic silencing of microRNA-34b/c (miR-34b/c) plays an important role in the pathogenesis of malignant pleural mesothelioma (MPM). We examined the impact of miR-34b/c restoration on the radiosensitivity of MPM cells.
MATERIALS AND METHODS: We established stable miR-34b/c and scramble transfectants of two MPM cell lines, H2052 and H28. We examined these transfectants by clonogenic survival assay, phosphorylated histone H2AX (γH2AX) foci assay, cell-cycle analysis, and western blotting.
RESULTS: The clonogenic survival assay revealed that miR-34b/c radiosensitized MPM cells. γH2AX foci assay showed that DNA double-strand break repair was delayed in miR-34b/c transfectants. The proportion of sub-G(1) phase cells was increased in miR-34b/c transfectants after irradiation. miR-34b/c inhibited expression of cyclin-D1, cyclin-dependent kinase 4/6, B-cell lymphoma-2 (BCL-2) and increased cleaved poly (ADP-ribose) polymerase (cPARP) and cleaved caspase-3 after irradiation.
CONCLUSION: Our results indicate that miR-34b/c enhances radiosensitivity by promoting radiation-induced apoptosis and suggested that miR-34b/c might be a useful therapeutic molecule to enhance radiotherapy in MPM.

Minatel E, Trovo M, Polesel J, et al.
Tomotherapy after pleurectomy/decortication or biopsy for malignant pleural mesothelioma allows the delivery of high dose of radiation in patients with intact lung.
J Thorac Oncol. 2012; 7(12):1862-6 [PubMed]

INTRODUCTION: This study aimed to assess the safety of high doses of radiation delivered with tomotherapy to the intact lung after radical pleurectomy/decortication or biopsy for malignant pleural mesothelioma (MPM).
METHODS: Twenty-eight patients were enrolled in this prospective study and underwent adjuvant or definitive tomotherapy after radical pleurectomy/decortication (n = 20) or pleural biopsy (n = 8) for MPM. The dose prescribed to the planning target volume, defined as the entire hemithorax, including chest-wall incisions and drain sites and excluding the intact lung, was 50 Gy delivered in 25 fractions. All patients underwent fluorodeoxyglucose-positron emission tomography for staging after surgery. Any fluorodeoxyglucose-avid areas or regions of particular concern for residual disease were given a simultaneous boost of radiotherapy to 60 Gy. Specific lung dosimetric parameters were reported. Toxicity was graded using the modified Common Toxicity Criteria version 3.0.
RESULTS: The median follow-up was of 19 months (range, 6-29 months). Five patients (17.8%) experienced severe respiratory symptoms corresponding to grade 2 pneumonitis in three cases, and grade 3 pneumonitis in two cases. No fatal respiratory toxicity was reported. Controlateral lung V5 was strongly correlated with the risk of pneumonitis. Patients who developed grade 2 and 3 pneumonitis had a higher controlateral lung V5 (mean V5=32%) than those without pneumonitis (mean V5=17%) (p=0.002). Other two grade 3 toxicities were registered: one severe pain to the chest wall, and one severe thrombocytopenia.
CONCLUSIONS: Tomotherapy allows the safe delivery of high dose of radiation to the hemithorax of MPM patients with intact lung.

Helland Å, Solberg S, Brustugun OT
Incidence and survival of malignant pleural mesothelioma in norway: a population-based study of 1686 cases.
J Thorac Oncol. 2012; 7(12):1858-61 [PubMed]

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

Yamanaka M, Tada Y, Kawamura K, et al.
E1B-55 kDa-defective adenoviruses activate p53 in mesothelioma and enhance cytotoxicity of anticancer agents.
J Thorac Oncol. 2012; 7(12):1850-7 [PubMed]

INTRODUCTION: Genetic characterization of malignant mesothelioma shows a homozygous deletion of the INK4A/ARF locus, which results in inactivation of the p53 pathways.
METHODS: We examined possible antitumor effects of adenoviruses with a deletion of the E1B-55kD gene (Ad-delE1B55) on mesothelioma and investigated combinatory actions with the first-line chemotherapeutic agents.
RESULTS: Ad-delE1B55 produced cytotoxicity on mesothelioma cells, which was associated with p53 phosphorylation, pRb dephosphorylation, and cleavage of caspases. Ad-delE1B55-infected cells displayed hyperploidy at the cell-cycle analysis and showed enlarged nuclear configurations. Combination of Ad-delE1B55 plus cisplatin or pemetrexed produced antitumor effects in vitro. Furthermore, Ad-delE1B55 and cisplatin showed combinatory effects in an orthotopic animal model.
CONCLUSIONS: Cell death caused by Ad-delE1B55 is attributable to cell-cycle arrest at M-phase checkpoint followed by activated apoptotic pathways, and combination of the first-line chemotherapeutic agents and the oncolytic adenovirus is a potential therapeutic for mesothelioma.

Vogl TJ, Lindemayr S, Naguib NN, et al.
Nonselective transarterial chemoperfusion: a palliative treatment for malignant pleural mesothelioma.
Radiology. 2013; 266(2):649-56 [PubMed]

PURPOSE: To evaluate tumor response by means of volumetric assessment, survival, and changes in patient symptoms after the treatment of unresectable and/or recurrent pleural mesothelioma by using regional nonselective transarterial chemoperfusion as a palliative treatment option.
MATERIALS AND METHODS: This retrospective study was approved by the hospital ethical committee, and all patients signed an informed consent prior to treatment. Thirty-nine patients (mean age, 64.0 years; 10 women and 29 men) with unresectable pleural mesothelioma were treated with repetitive transarterial chemoperfusion between March 2007 and March 2010, with a mean of 2.9 sessions per patient at 4-week intervals. Transarterial chemoperfusion was performed by using mitomycin C, cisplatin, and gemcitabine. Computed tomography findings and patient symptoms were evaluated. Tumor response was evaluated by using Response Evaluation Criteria in Solid Tumors guidelines, and survival was assessed with the Kaplan-Meier method. The change in volume for the partial-response group was tested by using the Wilcoxon signed-rank test.
RESULTS: In 36% of treated tumors (14 of 39), partial response was achieved, and tumor volume decreased from a mean value ± standard deviation of 839.6 mL ± 590.3 (range, 3.9-1972.2 mL) to 137 mL ± 399.8 (range, 0.88-1131.4; P = .00012). In 49% of tumors (19 of 39), stable disease was noted. In 15% of tumors (six of 39), progressive disease was seen. Mean specific growth rate of the tumor was 0.00158% per day. The mean survival time was 14.2 months (range, 2.1-33.1 months) from the start of treatment. For patients with tumors that responded to treatment, mean survival time was 15 months (range, 4.5-33.1 months). Mean time to disease progression was 2.6 months for all tumors, 1.5 months for stable disease, and 1.3 months for progressive disease.
CONCLUSION: Transarterial chemoperfusion may have the potential to yield positive results and response in the treatment of recurrent and/or unresectable pleural mesothelioma. © RSNA, 2012.

Cornelissen R, Lievense LA, Heuvers ME, et al.
Dendritic cell-based immunotherapy in mesothelioma.
Immunotherapy. 2012; 4(10):1011-22 [PubMed]

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

Mortensen C, Bhatnagar R, Edey AJ
Imaging the pleura.
Br J Hosp Med (Lond). 2012; 73(11):626-32 [PubMed]

Pleural disease is now recognized as an important subspecialty of pulmonary medicine, with increasing provision being made for specialist services and procedures. In response, the field of pleural imaging has advanced in recent years, especially with regard to ultrasound. Salient multimodality imaging techniques are discussed.

Subhannachart P, Dumavibhat N, Siriruttanapruk S
Asbestos-related diseases in Thailand and review literature.
J Med Assoc Thai. 2012; 95 Suppl 8:S71-6 [PubMed]

Asbestos is a harmful substance that can cause both malignancy and non-malignancy in humans. Although it has been used in Thailand for several years, few cases of asbestos-related diseases were reported. Concerning about high consumption and long exposure of asbestos in the country, the incurable but preventable diseases caused by asbestos will be the health problem in the near future. The authors presented 2 cases with asbestos-related diseases, one diagnosed as malignant mesothelioma and the other as asbestosis.