Treatment Of Malignant Pleural Mesothelioma Research Articles

Medical Treatment of Mesothelioma: Anything New?

In the present report, we review the current standard and investigational treatments of malignant pleural mesothelioma (MPM). Several studies have reported the use of gemcitabine and cisplatin as an induction chemotherapy in combination with extrapleural pneumonectomy (EPP) and thoracic radiation in a combined-modality approach for resectable MPM. Since the combination of cisplatin with pemetrexed was applied as the standard first-line regimen for unresectable MPM, the combination as an induction chemotherapy regimen has been proven effective in phase 2 trials. In addition, intensity-modulated radiation therapy and proton therapy have been introduced as new radiation methods into the combined modality. Hyperthermic intraoperative chemotherapy following EPP appears effective with acceptable toxicity. In addition, clinical studies that include molecular targeting agents, immunotherapy, and gene therapy have all been conducted. Thus, although there are numerous hopeful treatments for MPM, the benefits of these regimens remain to be proven in a randomized clinical setting.

Abstract 5041: Thymidylate synthase (TS) in malignant pleural mesothelioma (MPM): Correlation with clinical outcome and pharmacological role in the synergistic interaction of vandetanib with pemetrexed/carboplatin combination

Abstract Pemetrexed improves the effect of platinum-compounds against MPM, but biomarkers of response and novel effective combinations are warranted. The present study evaluated the 1) correlation between expression and polymorphisms of pemetrexed's key target TS and outcome of MPM patients treated upfront with carboplatin/pemetrexed, and 2) pharmacological interaction of new targeted compounds (gefitinib, erlotinib, sorafenib, vandetanib, and enzastaurin) with carboplatin-pemetrexed in MPM cell lines. Analysis of TS TSER-2R/3R, mRNA and protein expression was performed by PCR and immunohistochemistry (using H-score) in tumors from 99 patients. The role of TS and other molecular determinants in the interaction of carboplatin, pemetrexed with new targeted compounds was investigated in the H2052, H2452, H28 and MSTO-211H cells. Drug interaction was studied using MTT and SRB assays and evaluated with combination index method. EGFR, Akt and Erk phosphorylation, as well as VEGF secretion, were analyzed with ELISA, whereas RT-PCR and western blot were performed to assess modulation of the expression of TS, E2F-1 and genes involved in DNA repair (ERCC1 and XPD). A significant correlation between low TS protein expression and response (odd ratio, 4.2; p=0.023), longer PFS (8vs6 months; hazard ratio [HR]:0.60: p=0.023), or OS (18vs9 months; HR:0.59; p=0.029) was found when patients were categorized according to median H-score. Similarly, patients with TS mRNA below the median had longer PFS and OS (p<0.001). The higher tertile of TS mRNA expression also correlated with higher risk of progressive disease (OR:2.5; p=0.044). At multivariate analysis, TS mRNA level and H-score confirmed their independent prognostic role for PFS and OS. No correlations were observed for TSER polymorphisms. Vandetanib emerged as the targeted compound with the most potent cell growth inhibitory effects, and interacted synergistically with carboplatin and pemetrexed in all cell lines, increasing apoptotic indices. Pemetrexed enhanced EGFR phosphorylation, but reduced Akt phosphorylation and ERCC1 and XPD expression. Conversely, vandetanib significantly downregulated EGFR, Erk and Akt phosphorylation, as well as E2F-1 and TS expression (eg, H28 cells had 4.8-fold TS mRNA decrease). In conclusion, low TS protein and mRNA levels were associated to response, longer PFS and OS. Furthermore, vandetanib improved pemetrexed-carboplatin activity against MPM cells, through modulation of critical molecular mechanisms, such as EGFR-Akt phosphorylation and TS expression. These data support further prospective trials for the validation of the prognostic/predictive role of TS in patients treated with pemetrexed-based regimens, as well as future studies on the integration of vandetanib in the treatment of MPM. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5041. doi:10.1158/1538-7445.AM2011-5041

Thymidylate Synthase and Excision Repair Cross-Complementing Group-1 as Predictors of Responsiveness in Mesothelioma Patients Treated with Pemetrexed/Carboplatin

The pemetrexed/platinum agent combination represents the standard of care in first-line treatment for malignant pleural mesothelioma (MPM). However, there are no established indicators of responsiveness that can be used to optimize the treatment. This retrospective study aimed to assess the role of excision repair cross-complementing group-1 (ERCC1) and thymidylate synthase (TS) in tumors, and correlate expression levels and polymorphisms of these key determinants of drug activity with the outcome of MPM patients treated with carboplatin/pemetrexed in first-line setting. Analysis of TS and ERCC1 polymorphisms, mRNA and protein expression was done by PCR and immunohistochemistry [with the H-score (histologic score)] in tumor specimens from 126 MPM patients, including 99 carboplatin-/pemetrexed-treated patients. A significant correlation between low TS protein expression and disease control (DC) to carboplatin/pemetrexed therapy (P = 0.027), longer progression-free survival (PFS; P = 0.017), and longer overall survival (OS; P = 0.022) was found when patients were categorized according to median H-score. However, patients with the higher tertile of TS mRNA expression correlated with higher risk of developing progressive disease (P = 0.022), shorter PFS (P < 0.001), and shorter OS (P < 0.001). At multivariate analysis, the higher tertile of TS mRNA level and TS H-score confirmed their independent prognostic role for DC, PFS, and OS. No significant associations were found among ERCC1 protein expression, TS and ERCC1 polymorphisms, and clinical outcome. In our series of carboplatin-/pemetrexed-treated MPM patients, low TS protein and mRNA levels were significantly associated to DC, improved PFS, and OS. Prospective trials for the validation of the prognostic/predictive role of TS in MPM patients treated with pemetrexed-based regimens are warranted.

Surgical Treatment of Malignant Pleural Mesothelioma

Malignant Pleural Mesothelioma (MPM) remains a rare and lethal disease that is directly related to asbestos exposure in the vast majority of cases. While the total number of cases remains low compared to other malignancies, the worldwide incidence is expected to increase over the next twenty years. Currently, survival rates remain dismal and there is no standard therapy or consensus regarding treatment. However, over the last fifteen years there have been substantial improvements in the diagnosis and treatment of MPM, including easier and more accurate diagnostic techniques, improved methods of staging, more effective systemic therapy, a remarkable decrease in operative mortality, marked improvements in local control with adjuvant therapy, and perhaps most important, an emphasis on multidisciplinary care and multimodality clinical trials. Despite these advances, optimal therapy for these patients remains highly controversial and the role of surgery is actively debated. Most controversy centers on whether surgery increases survival and whether a survival benefit is best achieved with extrapleural pneumonectomy or pleurectomy/decortication within a multimodal regimen. To date, trimodality therapy that includes surgery, chemotherapy, and radiation offers the best survival advantage. It is generally accepted that the main goals of surgery, within the framework of a multimodality approach, is not only complete resection if possible, but more realistically, the resection of all macroscopic disease as an adjunct to the delivery of chemotherapy and radiation. The surgical options available to obtain this goal include extrapleural pneumonectomy (EPP) and pleurectomy/decortication (P/D). There are no randomized trials directly comparing EPP and P/D and the level of evidence supporting either technique remains low. Ultimately, the choice of operation depends on multiple factors including: disease stage, the patient's cardiopulmonary reserve, surgeon experience and philosophy, and the extent of planned adjuvant therapy. Yet, despite the inherent biases in most studies, the data thus far illustrates significant survival advantages with both P/D and EPP and surgeons should consider these approaches in select patients.

Intérêt de la tomothérapie après pleuro-pneumonectomie extrapleurale dans le mésothéliome pleural malin : premiers résultats cliniques

There is little clinical data about the place of helicoidal tomotherapy (HT) in the treatment of malignant pleural mesothelioma (MPM). This new form of intensity modulated radiotherapy (IMRT) has great theoretical advantages in large and complex volumes when compared to "traditional" forms of radiotherapy.Fourteen patients diagnosed with MPM received adjuvant radiotherapy by HT. The patients were treated at the Curie Institute and the René Gauducheau Centre, starting in August 12007. All patients had a complete initial staging, an extrapleural pneumonectomy (EPP), and a minimum follow-up of six months. The median dose prescribed to the surgical cavity was 50 Gy (48-54 Gy) in 2 Gy (1.80-2.07) fractions. High dose regions received concomitant 57 Gy (54-69 Gy) in 2.16 Gy (2.00-2.30 Gy) fractions.Median follow-up was 12.6 months after ending HT. Seven patients received neoadjuvant chemotherapy (cisplatin or carboplatin, and pemetrexed). Eight patients were staged pT3 and five were staged pN1-2. HT was well tolerated. Two patients had suspected G5 radiation pneumonitis within 6 months of ending HT. Of the 12 patients who survived treatment, six relapsed (in average 5.1 months after HT): distant. Four relapses were distant; two relapses were both local and distant. Three patients died after their initial relapse. After initial diagnosis, the median survival was 18.4 months. A learning curve was observed in the optimization of the dosimetric parameters.Helicoidal tomotherapy is a reliable, quite well tolerated, and efficient way of treating MPM patients after an EPP.

Malignant pleural mesothelioma: when is radiation therapy indicated?

Malignant pleural mesothelioma is an aggressive tumor of serosal surfaces resistant to many current treatment options. This article will provide a comprehensive discussion of the latest developments in the treatment of malignant pleural mesothelioma, with a focus on radiation therapy. We will discuss the role of radiotherapy as a prophylactic, palliative and potentially curative treatment of malignant pleural mesothelioma. An update will be provided of the latest clinical trials including new treatment.

Extrapleural pneumonectomy or supportive care: treatment of malignant pleural mesothelioma?

A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was whether extrapleural pneumonectomy (EPP) is superior to supportive care in the treatment of patients with malignant pleural mesothelioma (MPM). Overall, 110 papers were found using the reported search, of which 14 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results are tabulated. We conclude that EPP confers no advantage to chemotherapy and palliative treatment in terms of survival and symptom improvement. Ten studies evaluated the role of EPP in the management of MPM. The median survival was 13 months and perioperative and 30-day mortality rates were 5.7% and 9.1%, respectively. There was a high morbidity rate of 37% including atrial fibrillation, empyema and supraventricular arrhythmias. Disease recurred in 73% of patients at a median time of 10 months. Median hospital stay was 13 days and intensive care unit stay was 1.5 days. At three months postsurgery, improvement in symptoms was achieved in 68% of patients. Significant advantages were observed in patients with epithelial MPM (19 vs. 8 months, P<0.01) compared to non-epithelial MPM and with N2 disease (19 vs. 10 months) compared to N1 or N0 disease, respectively. Two studies reported outcomes after chemotherapy in patients with MPM. The median survival was 13 months and symptoms improved in 50% of patients. Response rate of 21% was achieved and the median time to disease progression was 7.2 months. Postoperative haematological toxicity was common and included neutropenia (25%), anaemia (5%) and thrombocytopenia (7.4%). Two studies analysed palliative treatment in mesothelioma and reported a median survival of seven months and improvement in symptoms in 25% of patients at one-year post-treatment. The 30-day mortality rate was 7.8% and complications included prolonged air leak (9.8%) and empyema (4%). Median hospital stay was seven days. Overall, EPP shows no benefit in terms of survival or symptom improvement which is compounded by its high operative mortality and recurrence rate.

Targeted therapies in malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis, whose exposure to asbestos fibers is the main etiology. The incidence of MPM is anticipated to increase worldwide during the first half of this century. MPM is notoriously refractory to most treatments, and the only standard of care is cisplatin and antifolate first-line chemotherapy. The urgent need for additional therapeutic agents, in parallel with advances in the knowledge of the molecular events of oncogenesis, has resulted in the development of the so-called 'targeted agents' that specifically inhibit critical pathways in malignant cells and in their microenvironment. We carried out a comprehensive review of the literature from January 2000 to May 2010 on studies that assessed targeted agents for the systemic treatment of MPM. Although tyrosine kinase inhibitors directed against the epidermal growth factor and the platelet-derived growth factor receptors did not show significant clinical activity in phase II studies, some other targeted therapies seemed promising, notably histone deacetylase inhibitors and antiangiogenic agents. However, none of these has yet reached daily practice. That is the reason why efforts must continue in the area of clinical and translational research for MPM.

Is pleurectomy and decortication superior to palliative care in the treatment of malignant pleural mesothelioma?

A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was whether pleurectomy/decortication (P/D) is superior to palliative care in the treatment of patients with malignant pleural mesothelioma (MPM). Overall 80 papers were found using the reported search, of which 11 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results are tabulated. We conclude that P/D may lead to superior survival rates but at the expense of higher morbidity rates to palliative treatment. Six studies reported patient outcomes after use of radical P/D to treat patients with MPM. Radical P/D leads to a higher median survival than supportive care (14.5 vs. 4.5 months) and non-radical decortication (15.3 vs. 7.1 months, P < 0.000). However, radical P/D had a complication rate of 30%, hospital stay of 12 days with an operative mortality rate of 9.1%. One-year survival rate was 65% but this fell to 0-24% at three years. Three studies highlighted the use of palliative chemotherapy to manage patients with MPM. Median survival (14 vs. 10 months) was higher in patients who received chemotherapy early compared to those on a delayed protocol. Early chemotherapy had a longer time to disease progression (25 vs. 11 weeks, P = 0.1) and greater one-year survival (66% vs. 36%) than the delayed group. Active symptom control (ASC) alone had lower symptom control rates than the combination of ASC plus MVP (mitomycin+vinblastine+cisplatin) (7% vs. 11%, P = 0.0017) and ASC plus vinorelbine (4% vs. 7%, P = 0.047). Three studies reported results of palliative surgery in patients with known MPM. Median survival period was 213 days with a 30-day mortality rate of 7.8%. Survival rates reduced from 70.6% at three months to 25.5% at one-year post-surgery. Prolonged air-leak and postoperative empyema complicated 9.8% and 4% of patients, respectively. P/D is a morbid operation that is associated with significant perioperative mortality and complication rates. Although a number of retrospective studies have shown a small benefit in survival with P/D, the heavily documented similarity in patient outcomes between P/D and extrapleural pneumonectomy along with the results of the Mesothelioma and Radical Surgery trial, should induce the surgical community to consider the use of P/D only in patients with malignant mesothelioma enrolled in prospective trials.

Onconase mediated NFKβ downregulation in malignant pleural mesothelioma

PurposeTreatment of malignant pleural mesothelioma (MPM) with Ranpirnase (Onconase) results in disruption of protein translation and cell apoptosis. We hypothesize that Onconase acts via down regulation of nuclear factor kappa B (NFKβ) by specific microRNAs (miRNA) and that interference of this pathway could have implications for MPM resistance to chemotherapy.Experimental DesignThree immortalized MPM cell lines (H2959, H2373, and H2591) were exposed to Onconase at 0–20 µg/mL. Cell counts were measured at 48 and 72 hours. Gene expression in miRNA-enriched RNA was validated by RT-PCR. The functional implications of miRNA expression were evaluated by transfecting miRNA mimics or inhibitors into MPM cell lines, and performing Matrigel™ invasion, cell proliferation, soft agar colony formation, and scratch closure assays. Effects on NFKβ expression and downstream targets including ABC transporters, BCL-xl, and IAP were assessed by RT-PCR and Western Blotting.ResultsTreatment with 20µg/mL of Onconase significantly decreased cell count and invasion. Hsa-miR-17* was significantly upregulated and hsa-miR-30c significantly down-regulated by Onconase treatment in all cell lines. Forced expression of hsa-miR-17* mimic and hsa-miR-30c inhibitor each significantly decreased functional activity of Onconase in all assays. NFKB1(p50) expression and downstream targets were also decreased with Onconase treatment as well as with forced expression miRNA mimic and inhibitors.ConclusionsOnconase treatment caused a significant decrease in cell proliferation, invasion, and in expression of certain miRNAs. Recapitulation of the resultant miRNA expression pattern with hsa-miR-17* mimic and hsa-miR-30c inhibitor resulted in downregulation of NFKB1 and reduced malignant behavior in functional assays. Thus, Onconase likely exerts its anti-tumor effect through these miRNAs.

Staging of patients after extrapleural pneumonectomy for malignant pleural mesothelioma - institutional review and current update

Extrapleural pneumonectomy (EPP) has been established as a viable surgical option in the treatment of malignant pleural mesothelioma (MPM) for selected patients. A number of pathological staging systems have been developed to prognosticate survival outcomes. We assessed 91 patients with MPM who underwent EPP in our institution and evaluated the applicability of the most updated staging systems in the current literature. After a mean follow-up of 20 months, the median overall survival was 27.6 months. Postoperative pathological staging according to the International Mesothelioma Interest Group criteria (P = 0.026) and the Brigham and Women's Hospital criteria (P = 0.039) were both found to be significant prognostic factors. Adjuvant chemotherapy (P = 0.022) and radiotherapy (P = 0.008) were associated with improved survival outcomes. These findings are consistent with previous reports that demonstrated the usefulness of pathological staging systems as a prognostic tool in patients with MPM after undergoing EPP. However, preoperative clinical staging systems need to be developed to facilitate the patient selection process prior to surgery.

Platinum-based doublet chemotherapy in pre-treated malignant pleural mesothelioma (MPM) patients: A mono-institutional experience

BackgroundThe major clinical problems of MPM management are the short duration of response and the early relapse. Currently, after the first-line standard pemetrexed/platinum combination there is not a defined regimen for the second line treatment of MPM, and the clinical benefits in fit patients are uncertain. We analyzed the feasibility of gemcitabine/platinum chemotherapy in pretreated MPM patients. MethodsEligible patients should have relapsed after first-line chemotherapy with pemetrexed plus cisplatin (24%) or carboplatin (76%); 53% of the patients had previously received trimodality treatment, 18% neoadjuvant chemotherapy followed by pleurectomy/decortication, 29% were inoperable. Patients had to have PS=0–2, adequate organ function, measurable disease.Chemotherapy was gemcitabine 1000mg/m2 days 1, 8 associated to the alternative platinum compound respect to 1st line, i.e. cisplatin 75mg/m2 or carboplatin AUC 5 day 1 every 3 weeks, for 3–6 cycles. Baseline staging and reassessment after cycles 3 and 6 were performed with CT-scan. ResultsSince 2006 17 relapsed MPM patients were referred to our centre. Patients were 12 males and 5 females; median age: 61 years (range 47–74); histology: 12 epithelial, 4 sarcomatoid and 1 biphasic. PS 1–2 (15:2).The combination of gemcitabine with carboplatin/cisplatin was administered as second line treatment in 13 (76%) patients, as third line in 4 (24%) patients. Two patients were lost to follow-up without re-evaluation, therefore radiologic and clinical response was assessable in 15 (88%) patients. Among evaluable patients 10 (67%) showed stable disease and 5 (33%) progressive disease. Symptoms improved in 8 (53%) cases. In the intent-to-treat population median survival was 28 weeks (range 13–168) and median time-to-treatment failure 15 weeks (range 3–75).Toxicity profile showed 2 (13%) grade 4 and 6 (40%) grade 3 thrombocytopenia, 4 (27%) grade 3 leucopenia, 3 (20%) grade 3 anaemia and 6 (40%) of grade 3 neutropenia. Grade 3 non haematological toxicities were nausea (14%) and asthenia (21%). ConclusionGemcitabine-platinum regimens are able to control symptoms and disease progression with a modest toxicity profile. The present results from a small series of patients should be confirmed by a prospective trial in a larger cohort of patients.

Phase II Study of Gemcitabine Plus Docetaxel as Second-Line Treatment in Malignant Pleural Mesothelioma

The combinations of cisplatin-pemetrexed and cisplatin-gemcitabine are considered the standard systemic therapy for malignant pleural mesothelioma (MPM), which is a rapidly progressive tumor. The purpose of the present study is to evaluate the efficacy, safety, and clinical benefit of the gemcitabine plus docetaxel regimen in the second-line treatment of this disease. A total of 37 patients with MPM were treated with the combination of docetaxel (80 mg/m) and gemcitabine (1000 mg/m) on day 1 and 14 of a 28-day cycle. The regimen was repeated for a maximum of 6 cycles or until disease progression or unacceptable toxicity. There was partial response of the disease in 7 patients (18.9%), whereas it remained stable in 23 patients (62.2%) and progressed in 7 patients (18.9%). The median time to disease progression was 7 months (range: 5.8-8.2 months) with a mean survival of 16.2 months (range: 13-19.3 months). The biweekly administration of docetaxel and gemcitabine, along with granulocyte colony-stimulating factor support, constitutes a safe, tolerable, and convenient regimen for the treatment of MPM, suggesting that this combination may be a viable option, especially in previously treated patients.

Investigational approaches for mesothelioma.

Malignant pleural mesothelioma (MPM) is a rare, aggressive tumor with a poor prognosis. In view of the poor survival benefit from first-line chemotherapy and the lack of subsequent effective treatment options, there is a strong need for the development of more effective treatment approaches for patients with MPM. This review will provide a comprehensive state of the art of new investigational approaches for mesothelioma. In an introductory section, the etiology, epidemiology, natural history, and standard of care treatment for MPM will be discussed. This review provide an update of the major clinical trials that impact mesothelioma treatment, discuss the impact of novel therapeutics, and provide perspective on where the clinical research in mesothelioma is moving. The evidence was collected by a systematic analysis of the literature (2000–2011) using the databases Medline (National Library of Medicine, USA), Embase (Elsevier, Netherlands), Cochrane Library (Great Britain), National Guideline Clearinghouse (USA), HTA Database (International Network of Agencies for Health Technology Assessment – INAHTA), NIH database (USA), International Pleural Mesothelioma Program – WHOLIS (WHO Database), with the following keywords and filters: mesothelioma, guidelines, treatment, surgery, chemotherapy, radiotherapy, review, investigational, drugs. Currently different targeted therapies and biologicals are under investigation for MPM. It is important that the molecular biologic research should first focus on mesothelioma-specific pathways and biomarkers in order to have more effective treatment options for this disease. The use of array technology will be certainly an implicit gain in the identification of new potential prognostic or biomarkers or important pathways in the MPM pathogenesis. Probably a central mesothelioma virtual tissue bank may contribute to the ultimate goal to identify druggable targets and to develop personalized treatment for the MPM patients.

Computerized segmentation and measurement of malignant pleural mesothelioma.

The current linear method to track tumor progression and evaluate treatment efficacy is insufficient for malignant pleural mesothelioma (MPM). A volumetric method for tumor measurement could improve the evaluation of novel treatments, but a fully manual implementation of volume measurement is too tedious and time-consuming. This manuscript presents a computerized method for the three-dimensional segmentation and volumetric analysis of MPM. The computerized MPM segmentation method segments the lung parenchyma and hemithoracic cavities to define the pleural space. Nonlinear diffusion and a k-means classifier are then implemented to identify MPM in the pleural space. A database of 31 computed tomography scans from 31 patients with pathologically confirmed MPM was retrospectively collected. Three observers independently outlined five randomly selected sections in each scan. The Jaccard similarity coefficient (J) between each of the observers and between the observer-defined and computer-defined segmentations was calculated. The computer-defined and the observer-defined segmentation areas (averaged over all observers) were both calculated for each axial section and compared using Bland-Altman plots. The median J value among observers averaged over all sections was 0.517. The median J between the computer-defined and manual segmentations was 0.484. The difference between these values was not statistically significant. The area delineated by the computerized method demonstrated variability and bias comparable to the tumor area calculated from manual delineations. A computerized method for segmentation and measurement of MPM was developed. This method requires minimal initialization by the user and demonstrated good agreement with manually drawn outlines and area measurements. This method will allow volumetric tracking of tumor progression and may improve the evaluation of novel MPM treatments.

Overexpression of SOCS3 exhibits preclinical antitumor activity against malignant pleural mesothelioma

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

European guidelines for the management of malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is nearly invariably lethal tumor of the pleura. Significant therapeutic nihilism exists among health professionals. Recent progress has reshaped the clinical landscape in the treatment of MPM. Two European guidelines have been published, one from the task force of the European Respiratory Society and the European Society of Thoracic Surgery, and the other from the European Society of Medical Oncology. With these guidelines and recommendations as a guidepost, this review discusses the major changes and their impact on the management of MPM.

S37 Comparison of dynamic contrast enhanced MRI (DCE-MRI) parameters with integrated PET-CT and serum mesothelin in the baseline assessment of malignant pleural mesothelioma

Integrated PET-CT scans and serum mesothelin measurement have shown early promise in predicting prognosis and evaluating treatment response in malignant pleural mesothelioma (MPM) but may be less reliable with sarcomatoid...

Extrapleural pneumonectomy, photodynamic therapy and intensity modulated radiation therapy for the treatment of malignant pleural mesothelioma

Intensity modulated radiation therapy (IMRT) has recently been proposed for the treatment of malignant pleural mesothelioma (MPM). Here, we describe our experience with a multimodality approach for the treatment of mesothelioma, incorporating extrapleural pneumonectomy, intraoperative photodynamic therapy and postoperative hemithoracic IMRT. From 2004-2007, we treated 11 MPM patients with hemithoracic IMRT, 7 of whom had undergone porfimer sodium-mediated PDT as an intraoperative adjuvant to surgical debulking. The median radiation dose to the planning treatment volume (PTV) ranged from 45.4-54.5Gy. For the contralateral lung, V20 ranged from 1.4 - 28.5%, V5 from 42 - 100%, and MLD from 6.8 - 16.5Gy. In our series, 1 patient experienced respiratory failure secondary to radiation pneumonitis that did not require mechanical ventilation. Multimodality therapy combining surgery with increased doses of radiation using IMRT, and newer treatment modalities such as PDT, appears safe. Future prospective analysis will be needed to demonstrate efficacy of this approach in the treatment of malignant mesothelioma. Efforts to reduce lung toxicity and improve dose delivery are needed and provide the promise of improved local control and quality of life in a carefully chosen multidisciplinary approach.

Inhibition of Met/HGF receptor and angiogenesis by NK4 leads to suppression of tumor growth and migration in malignant pleural mesothelioma

NK4 exhibits two distinct biological actions: antagonistic inhibition of hepatocyte growth factor (HGF) through binding to the Met/HGF receptor, and antiangiogenic action through binding to perlecan. Here, the anti-tumor effect of NK4 on malignant pleural mesothelioma was investigated. Of the 7 human malignant mesothelioma cell lines (ACC-Meso-1, ACC-Meso-4, EHMES-1, EHMES-10, H28, H2052 and JMN-1B), only EHMES-10 cells formed subcutaneous tumors when implanted into mice. For EHMES-10 cells, HGF facilitated invasion of the cells in collagen gel, whereas NK4 and neutralizing anti-HGF antibody suppressed the HGF-induced invasion. In addition, NK4 but not anti-HGF antibody suppressed proliferation of EHMES-10 cells in collagen, suggesting that the suppression by NK4 was independent of the HGF-Met pathway. In the subcutaneous tumor model, recombinant adenovirus-mediated intratumoral expression of NK4 inhibited tumor growth, while the invasive characteristic of tumor cells was not observed. Analysis of Met receptor tyrosine phosphorylation, proliferation, apoptosis and blood vessels in the tumor tissues indicated that the inhibitory effect of NK4 expression might be primarily caused by the inhibition of tumor angiogenesis. In all the 7 mesothelioma lines, HGF stimulated Met tyrosine phosphorylation, and this was associated with enhanced cell migration. HGF-dependent Met activation and migration were inhibited by NK4. Since malignant pleural mesothelioma represents an aggressive neoplasm characterized by extensive invasive growth, suppression of invasive growth has therapeutic value. Thus, the simultaneous inhibition of the HGF-Met pathway and angiogenesis by NK4 for treatment of malignant pleural mesothelioma is significant, particularly to attenuate migration and invasive growth.