Malignant pleural mesothelioma:The disdained member of thoracic oncology!

Pleural mesothelioma is a very aggressive malignancy that arises from the pleural mesothelial cell lining and is linked strongly to prior asbestos exposure.The ban on asbestos has helped to lower the incidence,but in developing countries like India,it is expected to rise.It has an extended latency period usually progressing over decades and presents with nonspecific symptoms.It has a median survival ranging between 10-22 months.The diagnosis of malignant pleural mesothelioma is challenging and is done using computed tomography(CT),magnetic resonance imaging,or positron emission tomography-CT,with the last two predicting the resectability of the tumor better than CT alone.A pleural biopsy along with an array of immunohistochemical markers,such as p16,BRCA1 associated protein 1,and claudin-4,are required for a definitive diagnosis.Several genetic alterations have prognostic significance as well.The current histological subtype identification is indispensable for decision making because of the new therapeutic avenues being explored.The combination of nivolumab and ipilimumab-based immunotherapy outperformed platinum and pemetrexed-based chemotherapy in terms of survival benefit and improved quality of life especially for non-epithelioid subtypes.However,the latter continues to be a robust treatment option for patients with the epithelioid subtype.Surgery is recommended for resectable cases with radiotherapy being indicated in neoadjuvant,adjuvant,and palliative settings along with systemic treatment.This review article provides an overview of epidemiology,etiology,clinical manifestations,diagnostic approaches(including immunohistochemical and genetic markers),staging,and multidisciplinary approaches to current treatment for malignant pleural mesothelioma using surgery,chemotherapy,immunotherapy,and radiotherapy.It also sheds light on some recent studies(EMPHACIS,CALGB30901,Checkmate-743,etc.)that have led to significant developments in recent years with clinically meaningful results.

Clinical Value of Vascular Endothelial Growth Factor Combined with Interferon-γ in Diagnosing Malignant Pleural Effusion and Tuberculous Pleural Effusion

In order to investigate the clinical value of vascular endothelial growth factor （VEGF） combined with interferon-γ （IFN-γ） in diagnosing malignant pleural effusion and tuberculous pleural effusion, 42 cases of malignant pleural effusion and 45 cases of tuberculous pleural effusion in Tongji Hospital, from March 2004 to May 2005, were included, The carcinoembryonic antigen （CEA）, VEGF and IFN-γ levels of pleural effusion were detected by using ELISA, and adenosine deaminase （ADA） activity was determined by using enzyme kinetic analytical method. The sensitivity, specificity, accuracy and area under the curve （AUCR^ROC） of CEA and VEGF, VEGF/IFN-γ ratio, ADA and IFN-γ were measured by receiver operating characteristic curve （ROC）, The results showed that CEA, VEGF levels and VEGF/IFN-γ ratio were significantly higher and the ADA and IFN-γ levels were significantly lower in malignant group than those in tuberculous group （P〈0,01）, The sensitivity, specificity, accuracy and AUCR^ROC of VEGF/IFN-γ ratio （88,7%, 99,8%, 94,4%, 0.96 respectively） were higher than those of CEA （67.8%, 96.1%, 82,4%, 0.78 respectively） and VEGF （81,5%, 84,3%, 82.9%, 0.79 respectively）. The sensitivity, specificity, accuracy and AUCR^ROC of IFN-γ （85.7%, 96,4%, 90.9%, 0.94 respectively） were higher than those of ADA （80,2%, 87,6%, 83.8%, 0,81 respectively）. It was concluded that VEGF/IFN-γ ratio and IFN-γ could be used as valuable parameters for the differential diagnosis of malignant pleural effusion and tuberculous pleural effusion.

GOECP/SEOR clinical guidelines on radiotherapy for malignant pleural mesothelioma

Malignant pleural mesothelioma(MPM)is a rare tumor with poor prognosis and rising incidence.Palliative care is common in MPM as radical treatment with curative intent is often not possible due to metastasis or extensive locoregional involvement.Numerous therapeutic advances have been made in recent years,including the use of less aggressive surgical techniques associated with lower morbidity and mortality(e.g.,pleurectomy/decortication),technological advancements in the field of radiotherapy(intensity-modulated radiotherapy,image-guided radiotherapy,stereotactic body radiotherapy,proton therapy),and developments in systemic therapies(chemotherapy and immunotherapy).These improvements have had as yet only a modest effect on local control and survival.Advances in the management of MPM and standardization of care are hampered by the evidence to date,limited by high heterogeneity among studies and small sample sizes.In this clinical guideline prepared by the oncological group for the study of lung cancer of the Spanish Society of Radiation Oncology,we review clinical,histologic,and therapeutic aspects of MPM,with a particular focus on all aspects relating to radiotherapy,including the current evidence base,associations with chemotherapy and surgery,treatment volumes and planning,technological advances,and reradiation.

Th17/Treg Imbalance in Malignant Pleural Effusion

Both T helper IL-17-producing cells （Thl7 cells） and regulatory T cells （Tregs） have been found to be increased in malignant pleural effusion （MPE）. However, the possible imbalance between Thl7 cells and Tregs, as well as the association of.Thl7/Treg and Thl/Th2 cells in MPE remains to be elucidated. The objective of the present study was to investigate the distribution of Th 17 cells in relation to Tregs, as well as Thl/Th2 balance in MPE. The number ofThl7, Tregs, Thl, and Th2 cells in MPE and peripheral blood was determined by using flow cytometry. The relationship among the number of Thl7, Tregs, Thl, and Th2 cells was explored. It was found that the number of Thl7, Tregs, Thl, and Th2 cells was all increased in MPE as compared with the corresponding peripheral blood. The number of Thl7 cells was correlated negatively with Tregs in MPE, but not in blood. Thl7 cells and Thl7/Treg ratio were positively, and Tregs were negatively, correlated with Thl cells, but not with either Th2 cells or Th1/Th2 ratio in MPE. This study supports earlier data that both Thl7 cells and Treg are present at higher frequencies in MPE than in the autologous blood. For the first time, we show that Thl7/Treg imbalance exists in MPE.

Multiple bowel intussusceptions from metastatic localized malignant pleural mesothelioma:A case report

Localized malignant pleural mesothelioma (LMPM) is a rare occurrence, and gastrointestinal intra-luminal metastases have not previously been reported. Herein, we report a patient with LMPM who presented with a local recurrence 10 mo after initial en bloc surgical resection. Abdominal computed tomography was performed for intractable, vague abdominal pain with episodic vomiting, which showed a "target sign" over the left lower quadrant. Laparotomy revealed several intra-luminal metastatic tumors in the small intestine and colon and a segmental resection of metastatic lesions was performed. Unfortunately, the patient died of sepsis despite successful surgical intervention. Though local recurrence is more frequent in LMPM, the possibility of distant metastasis should not be ignored in patients with non-specifi c abdominal pain.

Malignant pleural mesothelioma mimics thoracic empyema: A case report

BACKGROUND Thoracic empyema and malignant pleural mesothelioma(MPM)are distinct medical conditions with similar symptoms,including cough,chest pain,and breathing difficulty.We present a rare MPM case mimicking thoracic empyema.Physicians must consider MPM risks for patients exposed to building material who exhibit lobulated pleural effusions,indicating thoracic empyema.CASE SUMMARY A 68-year-old retired male construction worker suffered from shortness of breath and chest tightness over 10 d,particularly during physical activity.A poor appetite and 4 kg weight loss over the past 3 wk were also reported.Chest images and laboratory data concluded a tentative impression of empyema thoracis(right).Video-assisted thoracic surgery with decortication and delobulation(right)was conducted.The pathological report yielded an MPM diagnosis.Refractory pleural bilateral effusions and respiratory failure developed postoperatively,and the patient died three weeks after the operation.CONCLUSION Thoracic empyema and MPM are distinct medical conditions that can present similar symptoms,and video-assisted thoracic surgery facilitates an accurate diagnosis.Empyema-mimicking presentations and postoperative refractory pleural effusion may indicate a poor MPM outcome.

Regional hyperthermia combined with intrapleural chemotherapy in patients with malignant pleural effusion

Objective: The aim of our study was to assess the efficacy of regional hyperthermia combined with intrapleural chemotherapy and to evaluate the effect on the immunologic cells and vascular endothelial growth factor (VEGF) in patients with malignant pleural effusion. Methods: The 102 patients with malignant pleural effusion were included in this study: 52 patients undergoing regional hyperthermia with intrapleural chemotherapy (HICT), and 50 patients treated with intrapleural chemotherapy (ICT). Chemotherapy was administered into the thoracic cavity weekly through a tube with CDDP (dose = 40 mg/m2), and hyperthermia was performed twice a week for 60 minutes following the ICT. We evaluated the response rates and side-effects after 4 weeks. Before and after the treatment, T cell subsets and NK cells were detected by flow cytometry and VEGF was measured with ELISA kits. Results: Compared HICT to ICT, the overall response rates of the whole group, breast cancers and lung cancers were 80.8% vs 54% (P < 0.01), 86.7% vs 56.3% (P > 0.05) and 78.4% vs 52.9% (P < 0.05) respectively. The ratios of CD4+, CD4+/CD8+ and NK cells increased and the concentration of VEGF decreased more significantly after HICT. Conclusion: We concluded that combined regional hyperthermia with intrapleural chemotherapy could control the malignant pleural effusion effectively with mild toxicity. The levels of the T cell subset, NK cells and VEGF in both blood and effusion changed obviously.

Results of flexible 3D-conformal radiotherapy for patients with diffuse malignant pleural mesothelioma and comparative study of this technique with conventional radiotherapy

Objective： To observe the effects of the new technique of flexible 3D-conformal radiotherapy with combination of photon and electron （3DCRT） in the treatment of the patients with diffuse malignant pleural mesothelioma （MPM）, and carry out the comparative study between flexible 3DCRT and hemithoracic conventional radiotherapy （CRT）. Methods： From January 2004 to October 2007, 8 patients with MPM were treated with flexible 3DCRT. 5 patients had received cycles of chemotherapy before radiation. New technique of flexible 3DCRT with combination of photon and electron was used in our study, and DT 32.2-64 Gy with conventional split were delivered. CRT technique was mimicked to compare with 3DCRT technique to predict the possibility of lung damage in two methods. Results： One patient reached CR and other 7 patients got PR after radiation. Two patients died during the follow-up. The median survival time （MST） was 15.4 months and it was 18.8 months for sequential chemotherapy and radiotherapy group and 9.7 months for radiotherapy alone group. The V20, V30, and ipsilateral and contralateral median lung dosage （MLD） were 20.5%, 15.6%, 18.8 Gy and 2.2 Gy respectively when the flexible 3DCRT technique was used, whereas they were 36.8%, 27.9%, 31.1 Gy and 1.2 Gy respectively when the CRT technique was used. They were statistically different for the lung V20, V30 and ipsilateral MLD between the two techniques （P 〈 0.01）, whereas there was no different for the contralateral MLD （P = 0.08）. All patients received radiation were found to have lung fibrosis and classified as grades 1-2 radiation pneumonitis. The quality of life was increased from score 2.83 to 3.76 and it was significantly different （P 〈 0.01）. Conclusion： MPM is moderately sensitive to radiation. The flexible 3DCRT technique is feasible in the treatment of MPM and lung damage is reduced apparently comparing with the CRT technique. The quality of life of patients with MPM is improved after irradiation.

Complex Target Volume Delineation and Treatment Planning in Radiotherapy for Malignant Pleural Mesothelioma (MPM)

Introduction: Radiotherapy alone or combined with surgery and/or chemotherapy is being investigated in the treatment of malignant pleural mesothelioma (MPM). This study aimed to simulate a Volumetric Modulated Arc Therapy (VMAT) treatment of a patient with MPM. Materials and Methods: CT images from a patient with intact lungs were imported via DICOM into the Pinnacle3 treatment planning (TP) system (TPS) and used as a model for MPM to delineate organs at risk (OAR) and both clinical and planning target volumes (CTV and PTV) with a margin of 5 mm. Elekta Synergy with 6 MV photons and 80 leafs MLCi2 was employed. VMAT plans were generated using two coplanar arcs with gantry rotation angles of 178° - 182°, the collimator angles of each arc were set to 90°, Octavius® 4D 729 was employed for quality assurance while the calculated and measured doses were compared using VeriSoft. Results: A TP was achieved. The Gamma volume analysis with criteria of 3 mm distance to agreement and 3% dose difference yielded the gamma passing rate = 99.9%. The reference isodose was 42.75 Gy with the coverage constraints for the PTV D95 and V95 = 95.0% of 45 Gy. The remaining dosimetric parameters met the recommendations from the clinically acceptable guidelines for the radiotherapy of MPM. Conclusion: Using well-defined TV and VMAT, a consistent TP compared to similar ones from publications was achieved. We obtained a high agreement between the 3D dose reconstructed and the dose calculated.

Intrathoracic latissimus dorsi muscle transposition: a reliable technique for prevention of bronchopleural fistula developing after extrapleural pneumonectomy and external beam radiotherapy in malignant pleural mesothelioma

Objective: Bronchopleural fistula (BPF) is a life threatening complication after pneumonectomy. Extra thoracic skeletal muscle transposition especially latissimus dorsi muscle flap (LDMF) had been used to prevent this complication. The aim of this study was to assess the effectiveness of LDMF in preventing BPF developing after extrapleural pneumonectomy (EPP) and external radiation therapy in malignant pleural mesothelioma (MPM). Methods: Between May 1999 and Dec. 2008, 37 patients with MPM were operated upon by EPP using LDMF prophylactically to reinforce the bronchial stump, and then received external radiation therapy with or without postoperative chemotherapy. Results: The mean age of all patients was 46.7 (range 26-57) years. Twenty five patients were males and 12 patients were females. Twenty three patients had MPM of the right side and 14 patients had MPM of the left side. The peri-operative mortality was 2.7% and only few flap related postoperative morbidity were reported in the form of minor seroma and subcutaneous surgical emphysema. The median follow up was 17 (range 9-43) months. All cases completed their postoperative external radiation therapy with no reported cases of early or late BPF. Conclusion: Intrathoracic pedicled LDMF transposition is proved to be effective in prevention of BPF developing after EPP and external radiation therapy in MPM and it is advised to be a routine step in EPP in these cases and to use more sophisticated technique of postoperative external beam radiotherapy (3D conformal or IMRT) to minimize this complication.

Extra-pleural pneumonectomy in the setting of tri-modality therapy for patients with malignant pleural mesothelioma

Although declining in the US due to restrictions of asbestos exposure, malignant pleura/mesothelioma （MPP） remains a very serious thoracic malignancy that is rising in incidence worldwide （1）. Trirnodality therapy with chemotherapy and radiotherapy combined with extrapleural pneumonectomy （EPP） has gained acceptance given the acceptable mortality rate （〈5%） and long term survival reported in patients with epithelial histology, negative margins, and no extrapleural lymph node involvement after trimodalitv treatment （2）.

Study on the Correlation between Syndrome Differentiation of Malignant Pleural Effusion Treated by External Treatment of Traditional Chinese Medicine and Immunohistochemistry of Biopsy Tissue Based on Medical Video-assisted Thoracoscope

Objective:Guided by the theory of syndrome differentiation of yin and yang in traditional Chinese medicine surgery,through visual observation of internal medicine thoracoscope,comprehensive observation of pleural cavity and immunohistochemistry of biopsy tissue,to classify malignant pleural effusion according to syndrome differentiation,and to explore the scientific nature of its theory.Methods:From March 1,2014 to February 28,2015,40 cases of malignant pleural effusion were treated in Beijing Chaoyang Hospital affiliated to Capital Medical University.According to the proposed TCM diagnostic criteria for yin and yang syndrome differentiation,and collect age,gender,course of disease,clinical symptoms,tumor primary focus,histomorphological manifestations and immunohistochemical results and other related information,and carry out statistical data processing.Results:The positive syndrome was mainly metastatic lung adenocarcinoma,which accounted for the majority of all MPE cases,up to 75%.The immunohistochemical results of biopsy tissues were mainly CEA and TTF-1 positive;While pleural effusion caused by pleural mesothelioma was the main type of yin syndrome,and the results of immunohistochemistry combined with biopsy were mainly positive for D2-40,Calretinin,WT-1 and CK5/6.Conclusion:TCM syndrome differentiation of MPE based on internal thoracoscopy combined with biopsy immunohistochemical results has sufficient theoretical basis and certain scientific nature,and further clinical research is needed to verify its effectiveness and practicability in the future.

Immune Regulation of Interleukin-27 in Malignant Pleural Effusion

Background： lnterlcukin （IL）-27 has been reported to have anti-proliferate and anti-angiogenic activities on cancer cells. However, the involvement of IL-27 in malignant pleural effusion （MPE） remains unknown. Thus, in this research, we compared the immune functions of IL-27, interferon （IFN）-γ, and IL-17 on lung cancer cells and revealed the regulatory mechanism of IL-27 in MPE. Methods： The distribution ofl L-27 in both MPE and blood was evaluated by enzyme-linked immunosorbent assay and flow cytometry. The expressions otcytokine receptors and the levels of the phosphorylated signal transducer and activator of transcription （STAT） signalings were detected by flow cytometry. As well as the effects of proliferation, apoptosis, migration, and adherent activity of IL-27, IFN-γ, and IL-17 on lung cancer cells were also explored. Results： The expression of IL-27 was increased in M PE when compared with blood （ 147.3 ± 25. 1 pg/ml vs. 100.3 ± 13.9 pg/ml, P = 0.04）. IL-27 was noted to suppress both proliferation （18.33 ±0.21 vs. 27.77 ±0.88, P = 0.0005） and migration （1.82 ±0.44 vs. 3.13 ±0.07, P = 0.04） of A549 cells, but obviously prornoted apoptosis of A549 cells （9.47 ±1.14 vs. 4.96 ±0.17, P = 0.02） by activating STAT1 signaling. Interestingly, IL-27 played totally opposite effects on A549 cells by activating STAT3 pathway. Moreover, IL-27 exerted different intercellular adherent activities ofA549 cells to pleural mesothelial cell monolayer by activating different STAT signalings. Conelusions： IL-27 might exert an important immune regulation on lung cancer cells in human pleural malignant environment.

Interleukin-17 inhibits development of malignant pleural effusion via interleukin-9-dependent mechanism

Th17 and Th9 cells have been demonstrated to possess immune regulatory functions in malignant pleural effusion （MPE）. However, whether IL-17 can affect differentiation and function of Th9 cells in MPE remains unknown. The objective of the present study was to explore the impact of IL-17 on the in vivo differentiation of Th9 cells in relation to Th2 cells in a murine model of MPE, and to explore whether IL-17 inhibits MPE formation via IL-9-dependent mechanism. It was found that Th9 and Th2 cells were decreased in MPE from 1L-17-/- mice as compared with wild type mice. IL-17 deficiency inhibited Th9 and Th2 cell differentiation via suppressing transcription faclLors IRF4 and GATA-3, respectively. IL-17 deficiency enhanced MPE formation by promoting angiogenesis and proliferation of pleurai tumors, and thus accelerated the death of mice bearing MPE. The in vivo administration of anti-IL-9 neutralizing mAb accelerated the death of WT mice; whereas administration of exoge- nous IL-9 improved the survival of IL-17-/- mice. Our data provide the first definitive evidence that IL-17 promotes the differ- entiation of Th9 and Th2 cells in MPE. Our findings also demonstrate that IL-17 inhibits the formation of MPE and improves the survival of mice bearing MPE via an IL-9-dependent mechanism.

Clinical Observation on the Efficacy of Xiaoshui Decoction (消水方) Combined with Intrapleural Perfusion of Cisplatin in Treating Malignant Pleural Effusion

Objective： To observe the clinical efficacy of Xiaoshui decoction （XSD,消水方） combined with intrapleural perfusion of cisplatin in the treatment of malignant pleural effusion. Methods： Fifty-one patients with malignant pleural effusion were randomly assigned to two groups. The treated group patients） received oral administration of XSD combined with intrapleural perfusion of cisplatin, and control group （25 patients） was only treated with intrapleural perfusion of cisplatin. The effects of 26 he he short-term efficacy, quality of life scores and clinical symptom scores of malignant pleural effusion were evaluated. Results： The short-term efficacy in the treated group and the control group was 72.0% and 58.3%, respectively, and no significant difference was found （P〉0.05）. In contrast, the quality of life in the treated group was significantly improved compared to that of the control group （P〈0.05）, and so was the symptom remission （P〈0.05）. Conclusions： The combined therapy of XSD and intrapleural perfusion of cisplatin did not show obvious improvement in short-term efficacy, but the therapy remarkably alleviated the symptoms and improved the quality of life of patients.

Soluble CD40 in plasma and malignant pleural effusion with non-small cell lung cancer:A potential marker of prognosis

Objective: Soluble CD40 (sCD40) is a potential modulator for both antitumor responses and CD40-based immunotherapy;however the levels and significance of sCD40 in non-small cell lung cancer (NSCLC) patients with malignant pleural effusion are unknown. Methods: Forty-eight patients with lung cancer were treated in our institutions from January 2008 to January 2010. Peripheral blood and pleural effusion samples were collected from each subject. sCD40 levels in plasma and malignant pleural effusions supernatant were measured. The CD40L expression on CD3t T-cells was confirmed by flow cytometric direct immunofluorescence analysis. All patients were followed up after the study ended on January 1, 2010. Results: Patients with malignant pleural effusion of NSCLC had elevated circulating and pleural effusion levels of sCD40, and these elevated sCD40 levels were associated with advanced diseases and a poor prognosis. Conclusions: These findings indicate that elevated sCD40 may have a role in modulating antitumor responses and may also be a useful prognostic marker. Copyright ? 2015, Chinese Medical Association Production. Production and hosting by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

mprovement of Malignant Pleural Mesothelioma Prognosis： Early Diagnosis and Multimodality Treatment

Malignant pleural mesothelioma （MPM） is the most common primary malignancy of the pleura. The occurrence of malignant mesothelioma is typically related to exposure to mineral fibers such as asbestos and erionite.Reports suggest that genetic factors may also play a role in MPM.141 Moreover, latency periods that are the period of time between the first exposure to asbestos and a disease diagnosis range from 20 to 50 years. The mortality burden from asbestos-related diseases （ARD） is heavy andARD accounts for 92,250 deaths per year globally. To improve survival of MPM patients, effective strategy of early diagnosis and effective treatment strategies are highly needed.

A STUDY OF THE CYTOTOXICITY OF MALIGNANT PLEURAL EFFUSION LYMPHOCYTES AND LAK CELLS AGAINST AUTOLOGOUS TUMOR CELLS

The cytotoxicity of malignant pleural effusion lymphocytes (MPEL) against autologous tumor cells (ATC) were compared with that of peripheral blood lymphocytes (PBL). It was demonstracted that the cytotoxicity of PBL was higher than that of MPEL (P< 0.001), but the cytotoxicity and expansion of MPEL-activated by rIL-2 was much higher than that of PBL activated by rIL-2 (LAK cells) (P< 0.001). This shows that local immune reaction of the pleural cavity of patients with malignant pleural effusion was in the state of suppression. MPEL activated are better effector cells than LAK cells in tumor adoptive immunotherapy.

Cancer-directed surgery in malignant pleural mesothelioma: extrapleural pneumonectomy and pleurectomy/decortication

Malignant pleural mesothelioma(MPM)is a primary solid malignancy related to inhalational asbestos exposure.Despite advances in therapy,MPM remains challenging to treat with a post-treatment survival of only 15%at 5-year.In recent years,extra-pleural pneumonectomy has decreased in popularity due to a high morbidity rate and mortality compared to pleurectomy/decortication and other therapeutic alternatives.In this review,we will discuss both procedures,outcomes,ongoing studies,and the roles of surgery in the future treatment of this disease.

Tumour suppressor microRNAs contribute to drug resistance in malignant pleural mesothelioma by targeting anti-apoptotic pathways

Aim:Aberrant microRNA expression is a common event in cancer drug resistance,however its involvement in malignant pleural mesothelioma(MPM)drug resistance is largely unexplored.We aimed to investigate the contribution of microRNAs to the resistance to drugs commonly used in the treatment of MPM.Methods:Drug resistant MPM cell lines were generated by treatment with cisplatin,gemcitabine or vinorelbine.Expression of microRNAs was quantified using RT-qPCR.Apoptosis and drug sensitivity assays were carried out following transfection with microRNA mimics or BCL2 siRNAs combined with drugs.Results:Expression of miR-15a,miR-16 and miR-34a was downregulated in MPM cells with acquired drug resistance.Transfection with miR-15a or miR-16 mimics reversed the resistance to cisplatin,gemcitabine or vinorelbine,whereas miR-34a reversed cisplatin and vinorelbine resistance only.Similarly,in parental cell lines,miR-15a or miR-16 mimics sensitised cells to all drugs,whereas miR-34a increased response to cisplatin and vinorelbine.Increased microRNA expression increased drug-induced apoptosis and caused BCL2 mRNA and protein reduction.RNAi-mediated knockdown of BCL2 partly recapitulated the increase in drug sensitivity in cisplatin and vinorelbine treated cells.Conclusion:Drug-resistant MPM cell lines exhibited reduced expression of tumour suppressor microRNAs.Increasing tumour suppressor of microRNA expression sensitised both drug resistant and parental cell lines to chemotherapeutic agents,in part through targeting of BCL2.Taken together,these data suggest that miR-15a,miR-16 and miR-34a are involved in the acquired and intrinsic drug resistance phenotype of MPM cells.