Malignant pleural mesothelioma continues to be a clinical challenge. The disease is associated with asbestos exposure; its incidence will continue to increase in regions even though the commercial use of asbestos has been banned, and is certain to continue to contribute to cancer mortality in regions of the word lacking worker protection and persisting with its commercial use. It will depend on political actions and the will of governments to change this situation [1]. Once diagnosed with pleural mesothelioma, patients nearly invariably die of the disease. Advances have been made in the immunohistochemical diagnosis of the disease allowing a firm diagnosis in most patients. While some benefit of chemotherapy for advanced disease has been established, many other aspects of treatment continue to be controversial, in particular in regard to surgery and radiotherapy. However, the best survival data are reported from groups using multimodality treatment including neo- or adjuvant chemotherapy and extrapleural pneumonectomy (EPP). Over the past few years several review articles have dealt with pleural mesothelioma [2–5] and recently the new European Respiratory Society/European Society of Thoracic Surgeons guidelines have been published [6].

epidemiology

In Europe, where commercial use of asbestos has been banned for many years, a first analysis predicted that male mesothelioma deaths will to continue to increase and peak in the year 2020 [7]. More recent models indicate that the increase may already be levelling off and the peak should occur earlier at around 2015 [8, 9]. These estimates have taken into consideration a certain latency period and the ban on commercial asbestos exposure in the early 1990s. However, recent data from the Italian Mesothelioma Registry demonstrated an even longer median latency than expected. The median latency was 44.6 years and increasing over time in a linear fashion [10]. Environmental asbestos exposure is common in some villages in Turkey. Here the rate of mesothelioma mortality can be >100-fold higher than in control villages [11].

molecular pathology

Although mesothelioma development is linked to asbestos fibers such as crocidolite, amosite and tremolite, the exact mechanism of mesothelioma development is unclear. The pleura is the target for the carcinogenic activity of asbestos probably because asbestos can translocate from the lung to the pleural space and then concentrate in the parietal pleura at the sites of lymphatic drainage [12].

To get insight on genes relevant to pathology, chromosomal aberrations have been investigated. Cytogenetic studies have revealed highly complex karyotypic changes involving all chromosomes with chromosomal losses more frequent than chromosomal gain [13]. A number of recurrent abnormalities have been found, among those deletion of 9p21 and 22q12. The single most consistent numerical chromosomal change concerns chromosome 22. The tumor suppressor merlin is encoded by the neurofibromatosis type 2 gene (NF2), which is located on chromosome 22q12, and mutations in this gene have been found in 40% of mesotheliomas [14–16]. Re-expression of NF2 inhibits invasiveness of mesothelioma cells [17]. Mesotheliomas develop at higher frequency in mice with only one NF2 allele compared with the wild type when experimentally exposed to asbestos fibers [18]. In addition, in asbestos-induced tumors the remaining NF2 allele is lost, indicating that the NF2 gene has a key role as ‘gatekeeper’ in asbestos-induced mesothelioma [18]. Additional characterization of this model led to the discovery that loss of the remaining allele was accompanied by loss of INK4a/ARF [19]. The INK4a/ARF locus is located at the 9p21 region and encodes two distinct proteins translated from alternatively spliced mRNA: p16 and ARF. p16 inhibits cyclin-dependent kinase-4/6, thereby controlling retinoblastoma phosphorylation, hence cell cycle arrest in G1. ARF promotes MDM2 degradation preventing MDM2-mediated degradation of p53. Mesotheliomas lack expression of both p16 and ARF proteins [20, 21] due to gene deletion [22–24] or methylation [25–27]. In experimental animal models, targeted inactivation of NF2 by adeno-Cre infection of the mesothelial cells lining the thoracic cavity rarely results in mesothelioma. However, concomitant loss of INK4a/ARF strongly accelerates mesothelioma development [28], indicating that functional inactivation of NF2 leads to tumor development in a ‘permissive’ (INK4a/ARF deficient) background. If this animal model is representative of key pathways for mesothelioma development in humans, one may ask the question why mutations in this gene have been found ‘only’ in 40% of mesothelioma [14–16]. One of the reasons could be that NF2 might be inactivated by other ways than deletion.

The human NF2 gene consists of 17 exons and spans ∼95 kb of DNA. NF2 transcripts undergo alternative splicing, generating multiple isoforms [29]. Isoform I, missing exon 16, and isoform II, containing all 17 exons, are the two predominant species. As the result of alternative splicing, isoform I encodes a 595-amino-acid protein. Isoform II differs from isoform I only at the C terminus. Insertion of exon 16 into the mRNA provides a new stop codon, resulting in a 590-amino-acid protein that is identical to isoform I over the first 579 residues. Other less abundant variants such as delE2, missing exon 2, delE3, missing exon 3, and delE2/3, missing exons 2 and 3, have been described [29–32]. Only isoform I functions as a tumor suppressor and this activity is phosphorylation dependent [33, 34]. Phosphorylation of Ser518 by PKA or PAK inactivates merlin by disrupting the intramolecular self-association. Myosin phosphatase MYPT1-PP1δ dephosphorylates Ser518 and thereby activates merlin. PP1δ docks on merlin through binding of its targeting subunit, MYPT1 and a missense mutation (L339F) found in brain tumors ablates its binding to MYPT1, indicating that disruption of NF2 function indeed happens also by avoiding dephosphorylation [35]. This is further supported by the observation that protein kinase C-potentiated phosphatase inhibitor of 17 kDa (CPI-17), a cellular inhibitor of MYPT1, induces neoplastic transformation in vitro by inactivating NF2/merlin [36].

No data are available yet on NF2 isoforms expressed in mesothelioma and their phosphorylation status, but the recent findings of NF2/merlin inactivation in DU145 prostate cancer cells by PAK-mediated constitutive phosphorylation [37] indicate that this possibility might have clinical relevance. Phosphorylation of residues other than Ser518 inhibits NF2/merlin function in a different way. Indeed, Akt-driven phosphorylation on Thr230 and Ser515 leads to NF2/merlin ubiquitination and degradation [38]. This indicates that in tumors expressing an intact NF2/merlin, an active PI3K pathway would also result in NF2 functional inactivation. Malignant mesothelioma tumor specimens demonstrate high levels of phosphorylated Akt expression [39] and this may be linked to overexpression of autocrine growth factors such as hepatocyte growth factor and its receptor c-Met [39, 40]. Activated PI3K generates a lipid second messenger, which is essential for translocation of Akt to the plasma membrane, where it is phosphorylated and activated by phosphoinositide-dependent kinase 1. Phosphorylated Akt then conveys downstream signals, promoting cellular proliferation and survival over apoptosis. Activity of the PI3K/Akt pathway is negatively regulated by the phosphatase and tensin analogue (PTEN) tumor suppressor gene, and overexpression of PTEN in mesothelioma cells induced hypophosphorylation of Akt and apoptosis [41]. In addition poor survival of malignant pleural mesothelioma patients lacking PTEN expression has been observed [42].

If inactivation of NF2 in an INK4a/ARF-deficient background triggers the development of malignant mesothelioma one could ask how and why these genes could act as ‘gatekeeper’ and ‘caretaker’. The answers to these questions can be inferred from the fact that NF2/merlin is required for the assembly but not the maintenance of apico-lateral junctional complexes [43], which means that NF2 loss will be mostly important when it occurs in dividing cells, e.g. during tissue repair. This might be one of the reasons why it is disrupted in mesothelioma, which is thought to result from chronic mesothelium injury by asbestos fibers [44]. Cells that cannot form apico-lateral junctional complexes will be unable to form a well-organized tissue and will be resistant to contact-dependent growth arrest. Chronic injury stimulates tissue repair by activating stem cells [45] and mesothelioma carcinogenesis could proceed by misappropriating homeostatic mechanisms that govern tissue repair and stem cell self-renewal. This concept is supported by the observation that the Wnt-dependent stem cell signaling pathway is dysregulated in mesothelioma. Indeed, there is a significant transcriptional downregulation of the secreted frizzled-related proteins (sFRPs) in malignant pleural mesothelioma primary tissues and cell lines [46]. sFRPs, a family of five secreted glycoproteins, have been identified as possible dominant-negative modulators of the Wnt signal transduction pathway. Transfection of the SFRP gene construct into MPM cell lines lacking sFRP expression resulted in apoptosis and growth suppression [46].

The idea of mesothelioma as one of the chronic inflammation-related cancers is reinforced by the recent observation that inflammation-associated transcription factor NF-κB is constitutively active in various mesothelioma cell lines [47]. This results in activation of anti-apoptotic mechanisms as frequently observed in mesothelioma [48].

As mentioned in the Diagnosis section below, during mesothelioma development epithelial cells undergo epithelial to mesenchymal transition and another gene, p15, also located in the 9p21 locus, seems to be involved. Indeed on the one hand, p15 is often silenced by methylation in mesothelioma [27] and on the other hand, in an experimental animal model, combined deficiency of p16 and p15 results in a different type of soft tissue sarcoma composed of mixed cell types and showing biphasic differentiation [49].

diagnosis

Morphologically, pleural mesothelioma presents most often as epithelioid and less commonly as mixed disease or especially as a pure sarcomatoid form. Even less common is the well-differentiated papillary mesothelioma of the pleura. This disease was initially described in the peritoneum of young women without a history of asbestos exposure. A case series from France described the pleural variant of this disease, which is characterized by lack of deep invasion and association with a more indolent course; however, in some cases with evaluation to pleural mesothelioma. It occurs equally in men and women and a history of asbestos exposure has been identified in half of the cases [50].

The morphological diagnosis of pleural mesothelioma is generally made by a pleural biopsy, preferentially by thoracoscopy. Immunohistochemical staining has a central role in the diagnostic process. Markers indicative of the diagnosis of mesothelioma are calretinin, D2-40, WT1, cytokeratin 5/6 and podoplanin, while epithelial membrane antigen (EMA), carcino-embryonic antigen (CEA) and thyroid transcription factor 1 (TTF1-1) are indicative of the diagnosis of adenocarcinoma, the latter in particular of adenocarcinoma of lung origin [51–53]. In contrast to these markers, staining for mesothelin is less useful for the diagnosis of mesothelioma [54]. The distinction between sarcomatous mesothelioma and true sarcoma or the rare sarcomatoid carcinoma of the lung can also be a challenge. Here, a recent publication recommended the use of cytokeratin antibodies together with WT1 [55].

The identification of mesothelin-related proteins as serum markers of mesothelioma has raised great hopes of their potential to monitor the disease under therapy and their investigation for the screening of individuals exposed to asbestos [56]. Since, several investigators have examined the potential clinical role of mesothelin. Mesothelin serum levels were found to be elevated in patients with mesothelioma and ovarian cancer [57]. Serum levels were higher in patients with mesothelioma than in patients with lung cancer and in one study differed significantly between stage I and higher stages of mesothelioma [58, 59]. The discriminating power to distinguish between non-small-cell lung cancer and mesothelioma was increased by combining serum CEA and mesothelin measurements [60].

surgery

The role of surgery in pleural mesothelioma continues to be a matter of debate. The procedures used for the treatment of mesothelioma are thoracoscopy and pleurodesis for diagnosis and pleural effusion control, pleurectomy with tumor decortication of the lungs for debulking and major cytoreduction and especially EPP as the most radical resection. A systematic review based on the literature from 1985 to 2004 could not determine whether the use of EPP improves survival or effectively palliates symptoms of pleural mesothelioma [61]. Some centers advise pleurectomy and decortication for patients with compromised cardiac or pulmonary function, advanced age or certain disease distributions, in particular with early disease, in order to remove the bulk of the tumor while sparing lung function. When comparing their results with EPP with video-assisted thoracoscopic pleurectomy and decortication in patients >65 years of age, the group in Leicester (UK) documented a reduced 30-day mortality with the VATS procedure with a similar survival outcome (11.5 months for EPP and 14 months for pleurectomy and decortication) [62]. In some series the outcome after EPP was worse in patients with N2 disease [63, 64] as investigated in a case–control study comparing the outcome in patients with N2 disease between EPP and open radical pleurectomy and decortication. The two groups did not differ in stage, but differed in age with older patients undergoing pleurectomy and decortication. With 15 and 16 months, there was no difference in survival [65]. Combing the experience of three large centers in the United States, the outcome of 663 patients treated between 1990 and 2006 was analyzed retrospectively [66]. The median survival for the entire group was 14 months with a small advantage for pleurectomy and decortication. Operative mortality was 7% for EPP and 4% for pleurectomy and decortication. A multivariate analysis demonstrated a hazard ratio for EPP of 1.4. A difference was noted in the site of first recurrence. Local recurrence occurred in 33% versus 65%, distant recurrence in 66% versus 35% in patients undergoing EPP versus pleurectomy and decortication. However, because of biases in patient selection for a certain procedure and the retrospective nature of the analysis, no firm conclusions can be made until the question is addressed in a controlled prospective trial.

multimodality therapy including neoadjuvant chemotherapy and EPP

The largest published experience with EPP in conjunction with adjuvant chemotherapy and radiotherapy was published from the Boston group. An update from this group included 183 patients intended for the trimodality approach [63]. Median survival in the 176 patients alive after surgery was 19 months. The availability of more effective chemotherapy regimens and the experience of neoadjuvant chemotherapy in stage IIIA non-small-cell lung cancer prompted us to explore the role of neoadjuvant chemotherapy and EPP in pleural mesothelioma. In a pilot study on 19 patients treated at the University Hospital of Zürich, the response to neoadjuvant cisplatin and gemcitabine was 31%, and 16 patients underwent EPP with no perioperative mortality. The median survival of all patients was 23 months, and two of these patients remained disease free for 6 years after surgery [67]. These results were confirmed in a prospective multicenter phase II trial in Switzerland. Sixty-one patients with T1–localized T3 and N01–N2 disease and including all histologies received three cycles of neoadjuvant cisplatin and gemcitabine [68]. Extrapleural pneumonectomy was performed in 45 (74%) and complete resection was felt to be achieved in 37 (61%) patients. Operative mortality was 2.2%. The median survival by intent to treat was 19.8 months, the median survival for patients undergoing EPP was 23 months. Quality of life measurements were performed. Psychological distress showed only minor variation over time with distress above the cut-off score indicating no morbidity in 82% at baseline and 76% at 3 months after surgery. These results compare favourably with the series from Boston with a median survival after EPP of 19 months [69], a series from the Mayo Clinic with a median survival after EPP of 12 months [70] and a series from the MD Anderson Cancer Center with a median survival after EPP and intensity-modulated radiotherapy of 10.2 months [71].

Based on the results of a landmark trial [72] demonstrating the survival benefit of a combination chemotherapy of cisplatin with pemetrexed over cisplatin alone this combination has been adopted for a neoadjuvant approach by most centers. While the published results and reviews [73] so far are indicative that radical surgery may indeed be associated with longer survival than chemotherapy alone, final proof of this concept will only come from a randomized study. These data will hopefully be forthcoming from the MARS (mesothelioma and radical surgery) trial initiated in the UK.

While the rate of operative mortality after EPP is now <5% in experienced centers, EPP is associated with significant operative morbidity requiring the attention of a dedicated team. Three recent series have analyzed their operative complications. The group in Boston reported minor and major complications in 60% of patients operated on and overall mortality was 3.4% [74]. The group from Leicester reported significant morbidity in 63% and an overall mortality of 6.7% [75]. Risk factors for perioperative morbidity were induction chemotherapy for acute lung injury and symptomatic mediastinal shift, right-sided procedures and prolonged operations for technical complications such as dehiscence of the diaphragmatic patch, chylothorax or fistulae. Our group in Zürich reported postoperative complications in 62% and mortality in 3.1% [76]. Most frequent complications included postoperative empyema in 16%, bronchopulmonary fistula in 10%, chylothorax in 8% and patch failure in 6%. All could be successfully managed.

radiotherapy

Radiotherapy can be effective for local palliation and has been suggested to be of benefit for the prevention of malignant seeding after invasive procedures [77, 78]; however, this has recently been thrown into doubt by other reports and is no longer recommended [79, 80].

After EPP most patients have tumor recurrence in the ipsilateral chest. The rate of local relapse reported from the Boston group was 35.% [81]. A phase II trial from the Memorial Sloan-Kettering Cancer Center indicated a reduced rate (6%) of local failure after EPP with high-dose postoperative radiotherapy [82]. This was confirmed in a study of intensity-modulated radiation therapy from the MD Anderson Cancer Center, demonstrating local failure in 13% with distant failure of 54% [71]. Intensity-modulated radiotherapy after extrapleural pneumotectomy can be associated with severe or lethal pulmonary toxicity. A series of 13 patients treated in Boston reported the development of fatal pneumonitis in six patients, the most likely explanation being dose–volume effects on the contralateral lung [83]. The author suggested specific metric techniques to avoid this toxicity [84]. The rate of lethal pulmonary toxicity was much lower in patients of the MD Anderson Cancer Center series where in a retrospective analysis the importance of low V20 was emphazised [85]. The impact of high-dose hemithoracic radiation on toxicity and local failure after neoadjuvant chemotherapy and extrapleural pneumonecty is the subject of an ongoing prospective randomized study of the Swiss Group for Clinical Cancer Research.

imaging

The role of imaging in pleural mesothelioma has been examined in two recent reviews [86, 87]. The role of 2-[fluorine-18]fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) and PET–CT for staging and selection of patients for surgery has been investigated in smaller series. A first report on PET demonstrated increased uptake of pleural mesothelioma in 62 of 63 patients and identification of six patients with N3 or M1 disease subsequently confirmed by other means. However, the sensitivity of PET in identifying the 21 patients with surgical T4 status was only 19% and the nine patients with surgical N2 only 11% [88]. Using integrated PET–CT for the staging of potentially resectable pleural mesothelioma, extrathoracic disease that was not identified by conventional staging was found in 7 of 29 patients, but tumor stage was correctly identified in only 15 of 24 and nodal stage only in 6 of 17 [89]. Thus, based on these studies, the major role of PET and PET–CT lies in the identification of extrathoracic disease and not in the determination of T and N stage. FDG-PET cannot be used for assessment of local disease in patients who underwent talc pleurodesis, since this procedure can lead to persistant pleural FDG uptake [90].

Response assessment in malignant mesothelioma remains difficult; however, the adoption of modified RECIST criteria by most investigators has improved the situation somewhat. They were developed because of the nature of pleural mesothelioma to grow as a rind and are reported as the difference in the sum of two measurements perpendicular to the chest wall at three different levels. Response according to these criteria predicted for survival and forced vital capacity [91]. While modified RECIST is the standard currently used in assessing response in pleural mesothelioma, more sophisticated methods such as computerized analysis of CT scans [92] and total glycolytic volume determined in PET–CT have been developed and await clinical validation. FDG-PET might have a role in the assessment of tumor response. A study on a group of 22 patients reported an association of early metabolic response with time to progression, while no such association was found using CT-based criteria [93]. A second study on 23 patients found an association of an early reduction in the total glycolytic volume with survival [94].

systemic chemotherapy

The palliative effect of combination chemotherapy for patients with pleural mesothelioma has been documented in a study from the UK. An update of the experience from the Royal Marsden Hospital focused on the palliative benefits of mitomycin C, vinblastine and cisplatin. While the rate of objective response was only 13.5% and the median survival only 7 months, 69% of patients reported an improvement of symptoms. The symptoms best responding to treatment were pain in 71%, cough in 62% and dyspnoea in 50% [95].

Two large randomized trials have proved the benefit of the addition of a folate antagonist to cisplatin. A large prospective trial including 456 patients comparing cisplatin alone with cisplatin and pemetrexed demonstrated a significantly better response (17% versus 41%) and median survival (9.3 months versus 12.1 months) with the cisplatin–pemetrexed combination over cisplatin alone [72]. A post-study analysis on the use of second-line chemotherapy supports the assumption that this survival effect is not the result of second-line chemotherapy [96]. The EORTC study, which included 250 patients to examine the addition of raltitrexed to cisplatin, also proved superioritiy of the combination chemotherapy for response (14% versus 24%) and median survival (8.8 months versus 11.1 months) [97]. Based on the registration of pemetrexed and the trial results, the combination of cisplatin and pemetrexed has since become the preferred chemotherapy regimen for patients with pleural mesothelioma.

Pemetrexed in combination with carboplatin has been explored in two large phase II studies. They reported response rates of 19% and 21% and median survival of 12.7 and 14 months. Non-hematological toxicity was negligible and febrile neutropenia occurred in only one study at a rate of 1% of patients [98, 99]. Based on the activity of both agents in mesothelioma, the combination of pemetrexed and gemcitabine has been investigated in a phase II study. The authors concluded that the efficacy was not better than expected with pemetrexed alone and inferior to the platin–pemetrexed combinations [100].

The effect of early or delayed chemotherapy in symptomatically stable patients was explored in a small randomized trial also using mitomycin C, vinblastine and cisplatin chemotherapy [101]. Twenty were in the early chemotherapy group and 22 in the delayed chemotherapy group, of which 17 eventually received chemotherapy. The median time to symptomatic progression was significantly better in the early chemotherapy group as compared with the late chemotherapy group with 25 weeks as compared with 11 weeks. There was a trend to better survival in the early chemotherapy group with 14 as compared with 10 months.

The role of second-line chemotherapy in pleural mesothelioma needs to be defined. Pemetrexed alone or in combination with carboplatin has yielded objective responses of ∼20% in a small series of patients with disease progression after cisplatin chemotherapy [102]. Recently a prospective randomized phase III study enrolling 243 patients examined the role of pemetrexed versus best supportive care [103]. This study demonstrated a better disease control rate for the pemetrexed arm (59% versus 19%); however, there was no significant survival benefit. The survival results might have been influenced by post-discontinuation chemotherapy, which was given to 28% of patients in the pemetrexed group and 51% of patients in the best supportive care group. The question of how to treat patients with progression after cisplatin and pemetrexed is unanswered. Vinorelbine has demonstrated activity when used in first-line therapy and might be a reasonable choice [104]. Vinflunine, a new microtubule inhibitor, has recently been demonstrated to have clinical activity when used in first line [105].

new approaches

Despite the expression of epidermal growth factor receptor in pleural mesothelioma and promising preclinical data, single-agent gefitinib and erlotinib were found to have no significant clinical activity [106, 107]. Because platelet-derived growth factor was thought to be an important factor in the pathogenesis of mesothelioma and c-kit expression was reported to be present in one-third of mesotheliomas in one small series, the activity of single-agent imatinib has been examined in two phase II studies. No objective responses were seen [108, 109]. In contrast, clinical signals with objective responses were reported in abstract form with multitargeted tyrosine kinase inhibitors vatalanib and sorafenib, both including vascular endothelial growth factor (VEGF)-2 as target [110, 111], prompting further clinical studies with this group of agents.

The potential role of the anti-VEGF antibody bevacizumab in mesothelioma has been explored in a large randomized phase II study in combination with cisplatin and gemcitabine. The result has been presented and failed to show a survival benefit for bevacizumab in this combination [112]. A first report on the potential of thalidomide demonstrated disease stabilization in 27% of 40 patients [113], a firm conclusion, however, can only be drawn after the completion of a prospective phase III trial on thalidomide maintenance that is currently being conducted in the Netherlands.

Preclinical studies with the proteosome inhibitor bortezomib have demonstrated activity and synergy with cisplatin in mesothelioma cell lines and clinical phase II studies with this agent in pleural mesothelioma have been initiated [114]. Histone deacetylase inhibitors are also under investigation. In a phase I study with the suberoylanilide hydroxamic acid in advanced cancer unconfirmed responses have been reported in 3 of 13 patients with mesothelioma, prompting further investigations into this disease in a prospective randomized phase III study in second line [115]. As reviewed by Fenell [5] other histone deacetylase inhibitors being explored in early clinical trials in mesothelioma are belonistat [116] and desipeptide in combination with flavopiridol, the latter combination having demonstrated cytotoxicity in mesothelioma cells [116]. The potential dependence of mesothelioma cells on external arginine because of loss of expression of argininosuccinate has led to the investigation of a pegylated form of arginine deiminase [117, 118].

Mesothelin might not only serve as diagnostic marker in serum or tissue, but also represent a target for therapy of mesothelioma [119]. Patients with mesothelioma and other tumors expressing mesothelin have been treated in a phase I study with a recombinant anti-mesothelin immunotoxin. Despite transient pleuritis as dose-limiting toxicity, treatment was otherwise well tolerated and clinical activity has been observed [120]. A chimeric anti-mesothelin antibody has been developed, which is now undergoing clinical testing [121].

Other targeted strategies have been elucidated in preclinical studies that might lead to new therapeutic approaches. These include targeting the apoptotic pathway with antisense oligonucleotides to survivin or inducing apoptosis with the TRAIL antibodies mapatumumab or lexatumumab, both approaches enhancing the effect of cisplatin on mesothelioma cells [122, 123]. Inhibition of the met receptor with tyrosine kinase inhibitors and inhibition of activated c-src by desatinib both decreased the growth of mesothelioma cell lines [124, 125]. A humanized antibody to CD26 has been shown to induce antibody-dependent cellular cytotoxicity against mesothelioma cell lines and to inhibit mesothelioma cell growth in a xenograft system [126].

disclosure

The author has not declared any conflict of interest.

References

1.
Kazan-Allen
L
The 2nd ADAO Asbestos Conference
Am J Ind Med
 , 
2007
, vol. 
50
 (pg. 
52
-
62
)
2.
Robinson
BW
Lake
RA
Advances in malignant mesothelioma
N Engl J Med
 , 
2005
, vol. 
353
 (pg. 
1591
-
1603
)
3.
Robinson
BW
Musk
AW
Lake
RA
Malignant mesothelioma
Lancet
 , 
2005
, vol. 
366
 (pg. 
397
-
408
)
4.
Baas
P
Optimising survival in malignant mesothelioma
Lung Cancer
 , 
2007
, vol. 
57
 
Suppl 2
(pg. 
S24
-
S29
)
5.
Fennell
DA
Gaudino
G
O'Byrne
KJ
, et al.  . 
Advances in the systemic therapy of malignant pleural mesothelioma
Nat Clin Pract Oncol
 , 
2008
, vol. 
5
 (pg. 
136
-
147
)
6.
Scherpereel
A
Astoul
P
Baas
P
, et al.  . 
Guidelines of the European Respiratory Society and the European Society of Thoracic Surgeons for the management of malignant pleural mesothelioma
Eur Respir J
 , 
2010
, vol. 
35
 (pg. 
479
-
495
)
7.
Peto
J
Decarli
A
La Vecchia
C
, et al.  . 
The European mesothelioma epidemic
Br J Cancer
 , 
1999
, vol. 
79
 (pg. 
666
-
672
)
8.
Pelucchi
C
Malvezzi
M
La Vecchia
C
, et al.  . 
The mesothelioma epidemic in Western Europe: an update
Br J Cancer
 , 
2004
, vol. 
90
 (pg. 
1022
-
1024
)
9.
Hodgson
JT
McElvenny
DM
Darnton
AJ
, et al.  . 
The expected burden of mesothelioma mortality in Great Britain from 2002 to 2050
Br J Cancer
 , 
2005
, vol. 
92
 (pg. 
587
-
593
)
10.
Marinaccio
A
Binazzi
A
Cauzillo
G
, et al.  . 
Analysis of latency time and its determinants in asbestos related malignant mesothelioma cases of the Italian register
Eur J Cancer
 , 
2007
, vol. 
43
 (pg. 
2722
-
2728
)
11.
Baris
YI
Grandjean
P
Prospective study of mesothelioma mortality in Turkish villages with exposure to fibrous zeolite
J Natl Cancer Inst
 , 
2006
, vol. 
98
 (pg. 
414
-
417
)
12.
Choe
N
Tanaka
S
Xia
W
, et al.  . 
Pleural macrophage recruitment and activation in asbestos-induced pleural injury
Environ Health Perspect
 , 
1997
, vol. 
105
 
Suppl 5
(pg. 
1257
-
1260
)
13.
Sandberg
AA
Bridge
JA
Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors
Mesothelioma. Cancer Genet Cytogenet
 , 
2001
, vol. 
127
 (pg. 
93
-
110
)
14.
Bianchi
AB
Mitsunaga
SI
Cheng
JQ
, et al.  . 
High frequency of inactivating mutations in the neurofibromatosis type 2 gene (NF2) in primary malignant mesotheliomas
Proc Natl Acad Sci USA
 , 
1995
, vol. 
92
 (pg. 
10854
-
10858
)
15.
Sekido
Y
Pass
HI
Bader
S
, et al.  . 
Neurofibromatosis type 2 (NF2) gene is somatically mutated in mesothelioma but not in lung cancer
Cancer Res
 , 
1995
, vol. 
55
 (pg. 
1227
-
1231
)
16.
Deguen
B
Goutebroze
L
Giovannini
M
, et al.  . 
Heterogeneity of mesothelioma cell lines as defined by altered genomic structure and expression of the NF2 gene
Int J Cancer
 , 
1998
, vol. 
77
 (pg. 
554
-
560
)
17.
Poulikakos
PI
Xiao
GH
Gallagher
R
, et al.  . 
Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK
Oncogene
 , 
2006
, vol. 
25
 (pg. 
5960
-
5968
)
18.
Fleury-Feith
J
Lecomte
C
Renier
A
, et al.  . 
Hemizygosity of Nf2 is associated with increased susceptibility to asbestos-induced peritoneal tumours
Oncogene
 , 
2003
, vol. 
22
 (pg. 
3799
-
3805
)
19.
Lecomte
C
Andujar
P
Renier
A
, et al.  . 
Similar tumor suppressor gene alteration profiles in asbestos-induced murine and human mesothelioma
Cell Cycle
 , 
2005
, vol. 
4
 (pg. 
1862
-
1869
)
20.
Kratzke
RA
Otterson
GA
Lincoln
CE
, et al.  . 
Immunohistochemical analysis of the p16INK4 cyclin-dependent kinase inhibitor in malignant mesothelioma
J Natl Cancer Inst
 , 
1995
, vol. 
87
 (pg. 
1870
-
1875
)
21.
Yang
CT
You
L
Yeh
CC
, et al.  . 
Adenovirus-mediated p14(ARF) gene transfer in human mesothelioma cells
J Natl Cancer Inst
 , 
2000
, vol. 
92
 (pg. 
636
-
641
)
22.
Cheng
JQ
Jhanwar
SC
Klein
WM
, et al.  . 
p16 alterations and deletion mapping of 9p21-p22 in malignant mesothelioma
Cancer Res
 , 
1994
, vol. 
54
 (pg. 
5547
-
5551
)
23.
Xio
S
Li
D
Vijg
J
, et al.  . 
Codeletion of p15 and p16 in primary malignant mesothelioma
Oncogene
 , 
1995
, vol. 
11
 (pg. 
511
-
515
)
24.
Prins
JB
Williamson
KA
Kamp
MM
, et al.  . 
The gene for the cyclin-dependent-kinase-4 inhibitor, CDKN2A, is preferentially deleted in malignant mesothelioma
Int J Cancer
 , 
1998
, vol. 
75
 (pg. 
649
-
653
)
25.
Toyooka
S
Pass
HI
Shivapurkar
N
, et al.  . 
Aberrant methylation and simian virus 40 tag sequences in malignant mesothelioma
Cancer Res
 , 
2001
, vol. 
61
 (pg. 
5727
-
5730
)
26.
Wong
IH
Lo
YM
Zhang
J
, et al.  . 
Detection of aberrant p16 methylation in the plasma and serum of liver cancer patients
Cancer Res
 , 
1999
, vol. 
59
 (pg. 
71
-
73
)
27.
Destro
A
Ceresoli
GL
Baryshnikova
E
, et al.  . 
Gene methylation in pleural mesothelioma: Correlations with clinico-pathological features and patient's follow-up
Lung Cancer
 , 
2007
, vol. 
59
 (pg. 
369
-
376
)
28.
Jongsma
J
van Montfort
E
Vooijs
M
, et al.  . 
A conditional mouse model for malignant mesothelioma
Cancer Cell
 , 
2008
, vol. 
13
 (pg. 
261
-
271
)
29.
Chang
LS
Akhmametyeva
EM
Wu
Y
, et al.  . 
Multiple transcription initiation sites, alternative splicing, and differential polyadenylation contribute to the complexity of human neurofibromatosis 2 transcripts
Genomics
 , 
2002
, vol. 
79
 (pg. 
63
-
76
)
30.
Arakawa
H
Hayashi
N
Nagase
H
, et al.  . 
Alternative splicing of the NF2 gene and its mutation analysis of breast and colorectal cancers
Hum Mol Genet
 , 
1994
, vol. 
3
 (pg. 
565
-
568
)
31.
Pykett
MJ
Murphy
M
Harnish
PR
George
DL
The neurofibromatosis 2 (NF2) tumor suppressor gene encodes multiple alternatively spliced transcripts
Hum Mol Genet
 , 
1994
, vol. 
3
 (pg. 
559
-
564
)
32.
Schmucker
B
Tang
Y
Kressel
M
Novel alternatively spliced isoforms of the neurofibromatosis type 2 tumor suppressor are targeted to the nucleus and cytoplasmic granules
Hum Mol Genet
 , 
1999
, vol. 
8
 (pg. 
1561
-
1570
)
33.
Sherman
L
Xu
HM
Geist
RT
, et al.  . 
Interdomain binding mediates tumor growth suppression by the NF2 gene product
Oncogene
 , 
1997
, vol. 
15
 (pg. 
2505
-
2509
)
34.
Gutmann
DH
Geist
RT
Xu
H
, et al.  . 
Defects in neurofibromatosis 2 protein function can arise at multiple levels
Hum Mol Genet
 , 
1998
, vol. 
7
 (pg. 
335
-
345
)
35.
Okada
T
You
L
Giancotti
FG
Shedding light on Merlin's wizardry
Trends Cell Biol
 , 
2007
, vol. 
17
 (pg. 
222
-
229
)
36.
Jin
H
Sperka
T
Herrlich
P
Morrison
H
Tumorigenic transformation by CPI-17 through inhibition of a merlin phosphatase
Nature
 , 
2006
, vol. 
442
 (pg. 
576
-
579
)
37.
Horiguchi
A
Zheng
R
Shen
R
Nanus
DM
Inactivation of the NF2 tumor suppressor protein merlin in DU145 prostate cancer cells
The Prostate
 , 
2008
38.
Tang
X
Jang
SW
Wang
X
, et al.  . 
Akt phosphorylation regulates the tumour-suppressor merlin through ubiquitination and degradation
Nat Cell Biol
 , 
2007
, vol. 
9
 (pg. 
1199
-
1207
)
39.
Altomare
DA
You
H
Xiao
GH
, et al.  . 
Human and mouse mesotheliomas exhibit elevated AKT/PKB activity, which can be targeted pharmacologically to inhibit tumor cell growth
Oncogene
 , 
2005
, vol. 
24
 (pg. 
6080
-
6089
)
40.
Harvey
P
Warn
A
Dobbin
S
, et al.  . 
Expression of HGF/SF in mesothelioma cell lines and its effects on cell motility, proliferation and morphology
Br J Cancer
 , 
1998
, vol. 
77
 (pg. 
1052
-
1059
)
41.
Mohiuddin
I
Cao
X
Ozvaran
MK
, et al.  . 
Phosphatase and tensin analog gene overexpression engenders cellular death in human malignant mesothelioma cells via inhibition of AKT phosphorylation
Ann Surg Oncol
 , 
2002
, vol. 
9
 (pg. 
310
-
316
)
42.
Opitz
I
Soltermann
A
Abaecherli
M
, et al.  . 
PTEN expression is a strong predictor of survival in mesothelioma patients
Eur J Cardiothorac Surg
 , 
2008
, vol. 
33
 (pg. 
502
-
506
)
43.
McLaughlin
ME
Kruger
GM
Slocum
KL
, et al.  . 
The Nf2 tumor suppressor regulates cell-cell adhesion during tissue fusion
Proc Natl Acad Sci USA
 , 
2007
, vol. 
104
 (pg. 
3261
-
3266
)
44.
Ramos-Nino
ME
Testa
JR
Altomare
DA
, et al.  . 
Cellular and molecular parameters of mesothelioma
J Cell Biochem
 , 
2006
, vol. 
98
 (pg. 
723
-
734
)
45.
Beachy
PA
Karhadkar
SS
Berman
DM
Tissue repair and stem cell renewal in carcinogenesis
Nature
 , 
2004
, vol. 
432
 (pg. 
324
-
331
)
46.
Lee
AY
He
B
You
L
, et al.  . 
Expression of the secreted frizzled-related protein gene family is downregulated in human mesothelioma
Oncogene
 , 
2004
, vol. 
23
 (pg. 
6672
-
6676
)
47.
Sartore-Bianchi
A
Gasparri
F
Galvani
A
, et al.  . 
Bortezomib inhibits nuclear factor-kappaB dependent survival and has potent in vivo activity in mesothelioma
Clin Cancer Res
 , 
2007
, vol. 
13
 (pg. 
5942
-
5951
)
48.
Lee
AY
Raz
DJ
He
B
Jablons
DM
Update on the molecular biology of malignant mesothelioma
Cancer
 , 
2007
, vol. 
109
 (pg. 
1454
-
1461
)
49.
Krimpenfort
P
Ijpenberg
A
Song
JY
, et al.  . 
p15Ink4b is a critical tumour suppressor in the absence of p16Ink4a
Nature
 , 
2007
, vol. 
448
 (pg. 
943
-
946
)
50.
Galateau-Salle
F
Vignaud
JM
Burke
L
, et al.  . 
Well-differentiated papillary mesothelioma of the pleura: a series of 24 cases
Am J Surg Pathol
 , 
2004
, vol. 
28
 (pg. 
534
-
540
)
51.
Marchevsky
AM
Application of immunohistochemistry to the diagnosis of malignant mesothelioma
Arch Pathol Lab Med
 , 
2008
, vol. 
132
 (pg. 
397
-
401
)
52.
Mimura
T
Ito
A
Sakuma
T
, et al.  . 
Novel marker D2-40, combined with calretinin, CEA, and TTF-1: an optimal set of immunodiagnostic markers for pleural mesothelioma
Cancer
 , 
2007
, vol. 
109
 (pg. 
933
-
938
)
53.
Kushitani
K
Takeshima
Y
Amatya
VJ
, et al.  . 
Immunohistochemical marker panels for distinguishing between epithelioid mesothelioma and lung adenocarcinoma
Pathol Int
 , 
2007
, vol. 
57
 (pg. 
190
-
199
)
54.
Pu
RT
Pang
Y
Michael
CW
Utility of WT-1, p63, MOC31, mesothelin, and cytokeratin (K903 and CK5/6) immunostains in differentiating adenocarcinoma, squamous cell carcinoma, and malignant mesothelioma in effusions
Diagn Cytopathol
 , 
2008
, vol. 
36
 (pg. 
20
-
25
)
55.
Kushitani
K
Takeshima
Y
Amatya
VJ
, et al.  . 
Differential diagnosis of sarcomatoid mesothelioma from true sarcoma and sarcomatoid carcinoma using immunohistochemistry
Pathol Int
 , 
2008
, vol. 
58
 (pg. 
75
-
83
)
56.
Robinson
BW
Creaney
J
Lake
R
, et al.  . 
Mesothelin-family proteins and diagnosis of mesothelioma
Lancet
 , 
2003
, vol. 
362
 (pg. 
1612
-
1616
)
57.
Hassan
R
Remaley
AT
Sampson
ML
, et al.  . 
Detection and quantitation of serum mesothelin, a tumor marker for patients with mesothelioma and ovarian cancer
Clin Cancer Res
 , 
2006
, vol. 
12
 (pg. 
447
-
453
)
58.
Cristaudo
A
Foddis
R
Vivaldi
A
, et al.  . 
Clinical significance of serum mesothelin in patients with mesothelioma and lung cancer
Clin Cancer Res
 , 
2007
, vol. 
13
 (pg. 
5076
-
5081
)
59.
Pass
HI
Wali
A
Tang
N
, et al.  . 
Soluble mesothelin-related peptide level elevation in mesothelioma serum and pleural effusions
Ann Thorac Surg
 , 
2008
, vol. 
85
 (pg. 
265
-
272
)
60.
van den Heuvel
MM
Korse
CM
Bonfrer
JM
Baas
P
Non-invasive diagnosis of pleural malignancies: the role of tumour markers
Lung Cancer
 , 
2008
, vol. 
59
 (pg. 
350
-
354
)
61.
Maziak
DE
Gagliardi
A
Haynes
AE
, et al.  . 
Surgical management of malignant pleural mesothelioma: a systematic review and evidence summary
Lung Cancer
 , 
2005
, vol. 
48
 (pg. 
157
-
169
)
62.
Nakas
A
Martin Ucar
AE
Edwards
JG
Waller
DA
The role of video assisted thoracoscopic pleurectomy/decortication in the therapeutic management of malignant pleural mesothelioma
Eur J Cardiothorac Surg
 , 
2008
, vol. 
33
 (pg. 
83
-
88
)
63.
Sugarbaker
DJ
Flores
RM
Jaklitsch
MT
, et al.  . 
Resection margins, extrapleural nodal status, and cell type determine postoperative long-term survival in trimodality therapy of malignant pleural mesothelioma: results in 183 patients
J Thorac Cardiovasc Surg
 , 
1999
, vol. 
117
 (pg. 
54
-
65
)
64.
Yan
TD
Yoo
D
Sugarbaker
PH
Significance of lymph node metastasis in patients with diffuse malignant peritoneal mesothelioma
Eur J Surg Oncol
 , 
2006
, vol. 
32
 (pg. 
948
-
953
)
65.
Martin-Ucar
AE
Nakas
A
Edwards
JG
Waller
DA
Case-control study between extrapleural pneumonectomy and radical pleurectomy/decortication for pathological N2 malignant pleural mesothelioma
Eur J Cardiothorac Surg
 , 
2007
, vol. 
31
 (pg. 
765
-
771
)
66.
Flores
RM
Pass
HI
Seshan
VE
, et al.  . 
Extrapleural pneumonectomy versus pleurectomy/decortication in the surgical management of malignant pleural mesothelioma: results in 663 patients
J Thorac Cardiovasc Surg
 , 
2008
, vol. 
135
 (pg. 
620
-
626
)
67.
Weder
W
Kestenholz
P
Taverna
C
, et al.  . 
Neoadjuvant chemotherapy followed by extrapleural pneumonectomy in malignant pleural mesothelioma
J Clin Oncol
 , 
2004
, vol. 
22
 (pg. 
3451
-
3457
)
68.
Weder
W
Stahel
RA
Bernhard
J
, et al.  . 
Multicenter trial of neo-adjuvant chemotherapy followed by extrapleural pneumonectomy in malignant pleural mesothelioma
Ann Oncol
 , 
2007
, vol. 
18
 (pg. 
1196
-
1202
)
69.
Sugarbaker
DJ
Garcia
JP
Richards
WG
, et al.  . 
Extrapleural pneumonectomy in the multimodality therapy of malignant pleural mesothelioma. Results in 120 consecutive patients
Ann Surg
 , 
1996
, vol. 
224
 (pg. 
288
-
294
)
70.
Schipper
PH
Nichols
FC
Thomse
KM
, et al.  . 
Malignant pleural mesothelioma: surgical management in 285 patients
Ann Thorac Surg
 , 
2008
, vol. 
85
 (pg. 
257
-
264
)
71.
Rice
DC
Stevens
CW
Correa
AM
, et al.  . 
Outcomes after extrapleural pneumonectomy and intensity-modulated radiation therapy for malignant pleural mesothelioma
Ann Thorac Surg
 , 
2007
, vol. 
84
 (pg. 
1685
-
1692
)
72.
Vogelzang
NJ
Rusthoven
JJ
Symanowski
J
, et al.  . 
Phase III study of pemetrexed in combination with cisplatin vs cisplatin alone in patients with malignant pleural mesothelioma
J Clin Oncol
 , 
2003
(pg. 
2636
-
2644
)
73.
Ceresoli
GL
Gridelli
C
Santoro
A
Multidisciplinary treatment of malignant pleural mesothelioma
Oncologist
 , 
2007
, vol. 
12
 (pg. 
850
-
863
)
74.
Sugarbaker
DJ
Jaklitsch
MT
Bueno
R
, et al.  . 
Prevention, early detection, and management of complications after 328 consecutive extrapleural pneumonectomies
J Thorac Cardiovasc Surg
 , 
2004
, vol. 
128
 (pg. 
138
-
146
)
75.
Stewart
DJ
Martin-Ucar
AE
Edwards
JG
, et al.  . 
Extra-pleural pneumonectomy for malignant pleural mesothelioma: the risks of induction chemotherapy, right-sided procedures and prolonged operations
Eur J Cardiothorac Surg
 , 
2005
, vol. 
27
 (pg. 
373
-
378
)
76.
Opitz
I
Kestenholz
P
Lardinois
D
, et al.  . 
Incidence and management of complications after neoadjuvant chemotherapy followed by extrapleural pneumonectomy for malignant pleural mesothelioma
Eur J Cardiothorac Surg
 , 
2006
, vol. 
29
 (pg. 
579
-
584
)
77.
Boutin
C
Rey
F
Viallat
JR
Prevention of malignant seeding after invasive diagnostic procedures in patients with pleural mesothelioma. A randomized trial of local radiotherapy
Chest
 , 
1995
, vol. 
108
 (pg. 
754
-
758
)
78.
de Graaf-Strukowska
L
van der Zee
J
van Putten
W
Senan
S
Factors influencing the outcome of radiotherapy in malignant mesothelioma of the pleura–a single-institution experience with 189 patients
Int J Radiat Oncol Biol Phys
 , 
1999
, vol. 
43
 (pg. 
511
-
516
)
79.
Bydder
S
Phillips
M
Joseph
DJ
, et al.  . 
A randomised trial of single-dose radiotherapy to prevent procedure tract metastasis by malignant mesothelioma
Br J Cancer
 , 
2004
, vol. 
91
 (pg. 
9
-
10
)
80.
O'Rourke
N
Garcia
JC
Paul
J
, et al.  . 
A randomised controlled trial of intervention site radiotherapy in malignant pleural mesothelioma
Radiother Oncol
 , 
2007
, vol. 
84
 (pg. 
18
-
22
)
81.
Baldini
EH
Recht
A
Strauss
GM
, et al.  . 
Patterns of failure after trimodality therapy for malignant pleural mesothelioma
Ann Thorac Surg
 , 
1997
, vol. 
63
 (pg. 
334
-
338
)
82.
Rusch
VW
Rosenzweig
K
Venkatraman
E
, et al.  . 
A phase II trial of surgical resection and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma
J Thorac Cardiovasc Surg
 , 
2001
, vol. 
122
 (pg. 
788
-
795
)
83.
Allen
AM
Czerminska
M
Janne
PA
, et al.  . 
Fatal pneumonitis associated with intensity-modulated radiation therapy for mesothelioma
Int J Radiat Oncol Biol Phys
 , 
2006
, vol. 
65
 (pg. 
640
-
645
)
84.
Allen
AM
Schofield
D
Hacker
F
, et al.  . 
Restricted field IMRT dramatically enhances IMRT planning for mesothelioma
Int J Radiat Oncol Biol Phys
 , 
2007
, vol. 
69
 (pg. 
1587
-
1592
)
85.
Rice
DC
Smythe
WR
Liao
Z
, et al.  . 
Dose-dependent pulmonary toxicity after postoperative intensity-modulated radiotherapy for malignant pleural mesothelioma
Int J Radiat Oncol Biol Phys
 , 
2007
, vol. 
69
 (pg. 
350
-
357
)
86.
Ceresoli
GL
Chiti
A
Zucali
PA
, et al.  . 
Assessment of tumor response in malignant pleural mesothelioma
Cancer Treat Rev
 , 
2007
, vol. 
33
 (pg. 
533
-
541
)
87.
Armato
SG
3rd
Entwisle
J
Truong
MT
, et al.  . 
Current state and future directions of pleural mesothelioma imaging
Lung Cancer
 , 
2008
, vol. 
59
 (pg. 
411
-
420
)
88.
Flores
RM
Akhurst
T
Gonen
M
, et al.  . 
Positron emission tomography defines metastatic disease but not locoregional disease in patients with malignant pleural mesothelioma
J Thorac Cardiovasc Surg
 , 
2003
, vol. 
126
 (pg. 
11
-
16
)
89.
Erasmus
JJ
Truong
MT
Smythe
WR
, et al.  . 
Integrated computed tomography-positron emission tomography in patients with potentially resectable malignant pleural mesothelioma: staging implications
J Thorac Cardiovasc Surg
 , 
2005
, vol. 
129
 (pg. 
1364
-
1370
)
90.
Kwek
BH
Aquino
SL
Fischman
AJ
Fluorodeoxyglucose positron emission tomography and CT after talc pleurodesis
Chest
 , 
2004
, vol. 
125
 (pg. 
2356
-
2360
)
91.
Byrne
MJ
Nowak
AK
Modified RECIST criteria for assessment of response in malignant pleural mesothelioma
Ann Oncol
 , 
2004
, vol. 
15
 (pg. 
257
-
260
)
92.
Oxnard
GR
Armato
SG
3rd
Kindler
HL
Modeling of mesothelioma growth demonstrates weaknesses of current response criteria
Lung Cancer
 , 
2006
, vol. 
52
 (pg. 
141
-
148
)
93.
Ceresoli
GL
Chiti
A
Zucali
PA
, et al.  . 
Early response evaluation in malignant pleural mesothelioma by positron emission tomography with [18F]fluorodeoxyglucose
J Clin Oncol
 , 
2006
, vol. 
24
 (pg. 
4587
-
4593
)
94.
Francis
RJ
Byrne
MJ
van der Schaaf
AA
, et al.  . 
Early prediction of response to chemotherapy and survival in malignant pleural mesothelioma using a novel semiautomated 3-dimensional volume-based analysis of serial 18F-FDG PET scans
J Nucl Med
 , 
2007
, vol. 
48
 (pg. 
1449
-
1458
)
95.
Andreopoulou
E
Ross
PJ
O'Brien
ME
, et al.  . 
The palliative benefits of MVP (mitomycin C, vinblastine and cisplatin) chemotherapy in patients with malignant mesothelioma
Ann Oncol
 , 
2004
, vol. 
15
 (pg. 
1406
-
1412
)
96.
Manegold
C
Symanowski
J
Gatzemeier
U
, et al.  . 
Second-line (post-study) chemotherapy received by patients treated in the phase III trial of pemetrexed plus cisplatin versus cisplatin alone in malignant pleural mesothelioma
Ann Oncol
 , 
2005
, vol. 
16
 (pg. 
923
-
927
)
97.
van Meerbeeck
JP
Gaafar
R
Manegold
C
, et al.  . 
Randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma: an intergroup study of the European Organisation for Research and Treatment of Cancer Lung Cancer Group and the National Cancer Institute of Canada
J Clin Oncol
 , 
2005
, vol. 
23
 (pg. 
6881
-
6889
)
98.
Ceresoli
GL
Zucali
PA
Favaretto
AG
, et al.  . 
Phase II study of pemetrexed plus carboplatin in malignant pleural mesothelioma
J Clin Oncol
 , 
2006
, vol. 
24
 (pg. 
1443
-
1448
)
99.
Castagneto
B
Botta
M
Aitini
E
, et al.  . 
Phase II study of pemetrexed in combination with carboplatin in patients with malignant pleural mesothelioma (MPM)
Ann Oncol
 , 
2008
, vol. 
19
 (pg. 
370
-
373
)
100.
Janne
PA
Simon
GR
Langer
CJ
, et al.  . 
Phase II trial of pemetrexed and gemcitabine in chemotherapy-naive malignant pleural mesothelioma
J Clin Oncol
 , 
2008
, vol. 
26
 (pg. 
1465
-
1471
)
101.
O'Brien
ME
Watkins
D
Ryan
C
, et al.  . 
A randomised trial in malignant mesothelioma (M) of early (E) versus delayed (D) chemotherapy in symptomatically stable patients: the MED trial
Ann Oncol
 , 
2005
, vol. 
17
 (pg. 
270
-
275
)
102.
Sorensen
JB
Sundstrom
S
Perell
K
Thielsen
AK
Pemetrexed as second-line treatment in malignant pleural mesothelioma after platinum-based first-line treatment
J Thorac Oncol
 , 
2007
, vol. 
2
 (pg. 
147
-
152
)
103.
Jassem
J
Ramlau
R
Santoro
A
, et al.  . 
Phase III trial of pemetrexed plus best supportive care compared with best supportive care in previously treated patients with advanced malignant pleural mesothelioma
J Clin Oncol
 , 
2008
, vol. 
26
 (pg. 
1698
-
1704
)
104.
Steele
JP
Shamash
J
Evans
MT
, et al.  . 
Phase II study of vinorelbine in patients with malignant pleural mesothelioma
J Clin Oncol
 , 
2000
, vol. 
18
 (pg. 
3912
-
3917
)
105.
Talbot
DC
Margery
J
Dabouis
G
, et al.  . 
Phase II study of vinflunine in malignant pleural mesothelioma
J Clin Oncol
 , 
2007
, vol. 
25
 (pg. 
4751
-
4756
)
106.
Govindan
R
Kratzke
RA
Herndon
JE
2nd
, et al.  . 
Gefitinib in patients with malignant mesothelioma: a phase II study by the Cancer and Leukemia Group B
Clin Cancer Res
 , 
2005
, vol. 
11
 (pg. 
2300
-
2304
)
107.
Garland
LL
Rankin
C
Gandara
DR
, et al.  . 
Phase II study of erlotinib in patients with malignant pleural mesothelioma: a Southwest Oncology Group Study
J Clin Oncol
 , 
2007
, vol. 
25
 (pg. 
2406
-
2413
)
108.
Mathy
A
Baas
P
Dalesio
O
van Zandwijk
N
Limited efficacy of imatinib mesylate in malignant mesothelioma: a phase II trial
Lung Cancer
 , 
2005
, vol. 
50
 (pg. 
83
-
86
)
109.
Porta
C
Mutti
L
Tassi
G
Negative results of an Italian Group for Mesothelioma (G.I.Me.) pilot study of single-agent imatinib mesylate in malignant pleural mesothelioma
Cancer Chemother Pharmacol
 , 
2007
, vol. 
59
 (pg. 
149
-
150
)
110.
Jahan
TM
Gu
L
Wang
X
, et al.  . 
Vatalanib (V) for patients with previously untreated advanced malignant mesothelioma (MM): A phase II study by the Cancer and Leukemia Group B. (CALGB 30107). ASCO Meeting Abstracts
J Clin Oncol
 , 
2006
, vol. 
24
 
Suppl
 
Abstr 7081
111.
 
Jänne, ESMO 06
112.
 
Kindler ASCO 07
113.
Baas
P
Boogerd
W
Dalesio
O
, et al.  . 
Thalidomide in patients with malignant pleural mesothelioma
Lung Cancer
 , 
2005
, vol. 
48
 (pg. 
291
-
296
)
114.
Gordon
GJ
Mani
M
Maulik
G
, et al.  . 
Preclinical studies of the proteasome inhibitor bortezomib in malignant pleural mesothelioma
Cancer Chemother Pharmacol
 , 
2008
, vol. 
61
 (pg. 
549
-
558
)
115.
Krug
LM
Curley
T
Schwartz
L
, et al.  . 
Potential role of histone deacetylase inhibitors in mesothelioma: clinical experience with suberoylanilide hydroxamic acid
Clin Lung Cancer
 , 
2006
, vol. 
7
 (pg. 
257
-
261
)
116.
Steele
NL
Plumb
JA
Vidal
L
, et al.  . 
A phase 1 pharmacokinetic and pharmacodynamic study of the histone deacetylase inhibitor belinostat in patients with advanced solid tumors
Clin Cancer Res
 , 
2008
, vol. 
14
 (pg. 
804
-
810
)
117.
Szlosarek
PW
Klabatsa
A
Pallaska
A
, et al.  . 
In vivo loss of expression of argininosuccinate synthetase in malignant pleural mesothelioma is a biomarker for susceptibility to arginine depletion
Clin Cancer Res
 , 
2006
, vol. 
12
 (pg. 
7126
-
7131
)
118.
Ni
Y
Schwaneberg
U
Sun
ZH
Arginine deiminase, a potential anti-tumor drug
Cancer Lett
 , 
2008
, vol. 
261
 (pg. 
1
-
11
)
119.
Hassan
R
Ho
M
Mesothelin targeted cancer immunotherapy
Eur J Cancer
 , 
2008
, vol. 
44
 (pg. 
46
-
53
)
120.
Hassan
R
Bullock
S
Premkumar
A
, et al.  . 
Phase I study of SS1P, a recombinant anti-mesothelin immunotoxin given as a bolus I.V. infusion to patients with mesothelin-expressing mesothelioma, ovarian, and pancreatic cancers
Clin Cancer Res
 , 
2007
, vol. 
13
 (pg. 
5144
-
5149
)
121.
Hassan
R
Ebel
W
Routhier
EL
, et al.  . 
Preclinical evaluation of MORAb-009, a chimeric antibody targeting tumor-associated mesothelin
Cancer Immunol
 , 
2007
, vol. 
7
 pg. 
20
 
122.
Hopkins-Donaldson
S
Cathomas
R
Simoes-Wust
AP
, et al.  . 
Induction of apoptosis and chemosensitization of mesothelioma cells by Bcl-2 and Bcl-xL antisense treatment
Int J Cancer
 , 
2003
, vol. 
106
 (pg. 
160
-
166
)
123.
Belyanskaya
LL
Marti
TM
Hopkins-Donaldson
S
, et al.  . 
Human agonistic TRAIL receptor antibodies mapatumumab and lexatumumab induce apoptosis in malignant mesothelioma and act synergistically with cisplatin
Mol Cancer
 , 
2007
, vol. 
6
 pg. 
66
 
124.
Jagadeeswaran
R
Ma
PC
Seiwert
TY
, et al.  . 
Functional analysis of c-Met/hepatocyte growth factor pathway in malignant pleural mesothelioma
Cancer Res
 , 
2006
, vol. 
66
 (pg. 
352
-
361
)
125.
Tsao
AS
He
D
Saigal
B
, et al.  . 
Inhibition of c-Src expression and activation in malignant pleural mesothelioma tissues leads to apoptosis, cell cycle arrest, and decreased migration and invasion
Mol Cancer Ther
 , 
2007
, vol. 
6
 (pg. 
1962
-
1972
)
126.
Inamoto
T
Yamada
T
Ohnuma
K
, et al.  . 
Humanized anti-CD26 monoclonal antibody as a treatment for malignant mesothelioma tumors
Clin Cancer Res
 , 
2007
, vol. 
13
 (pg. 
4191
-
4200
)