Breadcrumbs

Bibliographic review


It is important to continue researching this disease to obtain more information about the pathogenesis of MPM so that it can be used to arrive at earlier diagnoses and define effective, more personalized therapies. It is therefore obviously important to stay up-to-date, but researchers and clinicians must also work closely together in order to “translate” what leaves the laboratory bench into something useful at the patient’s bedside.  

The main objectives of this scientific literature review are as follows: 

  1. Provide accurate, scientifically proven information.
  2. Update the experts in the field (among others) on new diagnostic methods and techniques, preclinical and clinical studies, and research currently underway. 
  3. Provide a complete list of analyzed bibliographic references, so that interested parties can find further information on the topic. 
  4. Address a varied audience consisting of specialists and non-specialists alike. 
  5. Provide research results mainly to patients and their families, as well as general practitioners and lastly specialists. This is why the review has been written in a methodical, informative but non-scientific style. Patients and their families can access current, easily comprehensible information supported by scientific studies. 
  6. Provide more information to general practitioners about a rare disease with a growing rate of incidence to increase the prospects of treatment and care of MPM patients. 
  7. Help update Specialists and Researchers in the field, specifically by providing the list of analyzed publications so that they can consult the latest, select and appropriately filtered innovations.  


This section consists of a six-monthly literature review which does not presume to be completely exhaustive (please refer to the scientific articles for further information), but provides the latest MPM research news translated into a non-scientific language.

Review

> Download article as PDF

Introduction

Malignant pleural mesothelioma (MPM) is a highly aggressive, rare form of cancer with a growing rate of incidence and an often unfavorable prognosis. Optimal management of this disease has not yet been defined due to the lack of an indisputedly effective therapy, although various scientific societies have proposed practical guidelines that are being applied in standard clinical practice. These guidelines emphasize the difficulty of diagnosing MPM and note the poor results of current treatments, thus emphasizing the need for innovative therapies and methods to monitor patients suffering from this disease.

Although the prognosis of MPM is often unfavorable and the prospects pessimistic, recent studies investigating the pathogenesis and biology of this disease have revealed some interesting findings, pointing to promising significant progress for the future treatment of these patients. Translational research in this disease is making great progress and different molecular oncogenic pathways leading to the growth and progression of MPM have been characterized and better defined, leading to exciting pharmaceutical developments. However, more in-depth analysis still needs to be done to further define the processes, including increased early mesothelial cell profileration to the progression of invasive mesothelioma. All this information will help define an effective, more personalized treatment for these cancer patients.

The purpose of this bibliographic review of the scientific literature is to provide an overview of the recent advances in our knowledge of the biology of MPM and their potential therapeutic-diagnostic applications.

This article is written in a non-scientific style to make it more available and accessible to a varied audience. We therefore refer interested readers and experts to the chapter containing the references, which could prove useful to anyone who would like to learn more about the studies analyzed in this review.

New therapeutic approaches

The role of surgery and radiotherapy for the treatment of MPM is still controversial and further studies may eventually provide more information in this regard.

However, medical therapy is considered the standard treatment in clinical practice, and the combination of platinum-based chemotherapy with antimetabolites (pemetrexed/raltitrexed) in particular has been considered the best first-line therapy for patients with MPM (1,2). Results obtained thus far have been limited, however, especially in terms of survival.

The main goal is to increase knowledge about the pathogenesis of MPM to define and improve target therapies and new therapeutic agents currently under investigation. The purpose of this review of the scientific literature is to describe the main therapeutic approaches currently being investigated in preclinical and clinical studies.

Epithelial Growth Factor Receptor

The epithelial growth factor receptor (EGFR) performs a role in the proliferation, differentiation, migration, adhesion and survival of cells (3) and is overexpressed in over 50% of MPM patients (4). The expression of the receptor in mesothelioma cells has led to the hypothesis that a therapy targeted against EGFR will inhibit it and prevent its uncontrolled and often harmful activity. This is why a number of studies have investigated the efficacy of EGFR inhibitors such as gefitinib and erlotinib in chemotherapy- naive patients. These studies have demonstrated that these drugs are not very effective as first-line therapy in MPM when they are administered as monotherapy, so not in conjunction with any standard chemotherapy (5, 6, 7). However, although the EGF receptor is overexpressed in mesothelioma, the reason why EGFR inhibitors are not very effective may be because mutations of this receptor are rare (8).

Some studies disagree about the correlation between the overexpression of EGFR in mesothelioma cells and the response to treatment with inhibitors of this receptor. Some research groups have proven that there is no relationship between the overexpression of EGFR and the clinical outcome of MPM patients (9,10), while others have shown that patients who overexpress the receptor may have a better outcome (11-14). These discrepancies confirm the need for further research to better define the results. In any case, it has been shown that overexpression of EGFR in MPM is more common in the epithelial histological subtype, which is associated with better patient survival but is not an independent prognostic marker (13,14).

Recent results indicate the presence of an important communication network between the EGFR pathways and other cellular signaling pathways. For example, some proteins such as PI3K and AKT which play a role in the EGFR signaling pathway, also act in other cellular growth pathways and interact with other factors such as c- MET and IGF-1 (15,17). The histological overexpression of the c-MET protein has been documented in MPM and also in some normal pleura samples. According to this rationale, c-MET inhibitors have been investigated in mesothelioma cell lines; preliminary results have shown a dose-dependent inhibition of tumor growth (18).

This type of dose- dependent inhibition was also observed in MPM cell lines subjected to IGF receptor inhibitors (19). Moreover, the cytotoxic effect of cisplatin also increased when administered together with these inhibitors (20).

An important biological communication also exists between EGFR and cyclooxygenase 2 (COX-2) (21).

COX2 is overexpressed in many solid tumors and so it is considered a potential therapeutic target (22-24). Immunohistochemical studies of this protein in MPM demonstrated that it was overexpressed in 59-100% of the tumor samples analyzed (25-27). They also showed that treating mesothelioma cell lines with COX2 inhibitors induces cytotoxicity and increases the effect of pemetrexed (28-29).

K-ras, BRAF and PI3KCA mutations

In the search for therapeutic targets, researchers have investigated the presence of genetic mutations associated with neoplastic pathogenesis, leading to studies of K-ras, BRAF and PI3KA gene mutations.

Unfortunately, genetic mutations of K-ras were not seen in the initial studies (30-32), thus changing expectations about this protein as a potential therapeutic target.

Studies of BRAF gene mutations have shown that they are absent in various tissues and tumor cell lines (33); other authors (34) have studied different MPM cell lines to analyze the PI3ka gene, but no mutation has been seen.

PTEN

PTEN is a protein that has been investigated in MPM to evaluate a potential therapy that would interact with this pathogenetic pathway.

Recent studies of various mesothelioma samples have shown that there is a loss of expression of the protein and that the mutation of this protein expression can be considered a negative prognostic value. In fact, patients with a decreased or lack of PTEN expression had a worse prognosis, whereas those with no genetic mutation had a greater survival rate (35).

It was also observed that the loss of PTEN expression might result in increased AKT activity, another important factor associated with the pathogenesis of cancer (36, 34). The loss of PTEN expression, which activates AKT, may induce resistance to various biological treatments such as EGFR inhibitors or anti-EGFR monoclonal antibodies. Therefore, these mutations also have consequences on other pathogenetic pathways, demonstrating the complexity of the pathogenesis and the intersecting network between these biological factors.

VEGF / VEGF Receptors

VEGF receptors have also been studied in mesothelioma cells and preclinical studies have shown they are expressed in both tumor tissue and peripheral blood in MPM patients (37).

The rationale for using drugs that inhibit this biological pathway is because they are expressed in greater levels in MPM patients than in healthy subjects. Also, the increased levels of VEGF are associated with increased microvascular density and appear to be associated with an unfavorable prognosis (38) as well as the likelihood of disease progression (39-41).

Anti- VEGF antibodies that actively inhibit this factor have been investigated. Studies have also tested the efficacy of combined VEGF and EGF inhibitors, in which these combinations achieved disease stabilization in 50% of patients, progression-free survival of 2.2 months and a median survival of 5.8 months (42, 43).

Drugs currently being investigated include vatalanib and cediranib, which are VEGF receptor inhibitors with antitumor activity in a variety of solid tumors (44-47).

Semaxanib is another VEGF-1 receptor inhibitor, but it also acts on the PDGF receptor (PDGFR) and c-kit (48). Another drug is thalidomide, which has been investigated in MPM patients with the following results: no partial or complete responses, 27.5% of patients were progression free after 6 months, and median overall survival of 7.6 months (49).

Sorafenib has shown limited activity in non-resectable MPM patients (50). However, it has also been studied in combination with doxorubicin, which confirmed that this combination is well tolerated thus justifying further clinical studies (51).

Sunitinib has been investigated in a Phase II study in MPM as second-line treatment after chemotherapy with platinum and antimetabolites, with the following results: partial response in 12% of patients; disease stabilization in 65% of patients; mean time to progression of 3.5 months and overall survival of 7 months (Nowak et al., IMIG 2011, unpubl. data).

Various Phase II studies have been conducted to determine the efficacy of imatinib mesylate in MPM patients refractory to chemotherapy or chemotherapy-naive patients (52-54). Combination studies between imatinib, cisplatin and pemetrexed are currently underway (55). New research is investigating the utility of these drugs, which appear to be active in MPM due to their ability to induce apoptosis of the tumor cells and by inhibiting various metabolic pathways such as AKT/PI3K, for example; the efficacy of these drugs has also been demonstrated due their ability to increase the sensitivity of the tumor to chemotherapy with gemcitabine or pemetrexed (56).

PDGF / PDGFR

The discovery that the PDGF receptor is highly expressed in mesothelioma cells has further defined the rationale for targeting treatment against this molecule (57).

The increased secretion of PDGF appears to be associated with thrombocythemia, which is considered a prognostic factor of adverse events that is seen in many MPM patients (58-59). In fact, high serum levels of PDGF in MPM patients appear to be a predictive factor of an unfavorable prognosis.

The expression of c-kit in MPM cells has also been shown in 26% of patients, prompting a number of clinical studies investigating imatinib in this disease (60).

Inhibition of PDGFR using imatinib combined with paclitaxel reduced interstitial fluid pressure, thereby enhancing the effect of the drugs and increasing in vitro efficacy (61). A partial response was seen in a Phase I study of imatinib in combination with gemcitabine (62). Dasatinib has shown cytotoxic effects in preclinical studies, leading to decreased migration and invasion in mesothelioma cells (63-64).

PI3K/AKT/mTOR Pathway

The PI3K/AKT/mTOR biological pathway is often aberrant in MPM, and various in vitro studies have shown that inhibiting this intracellular pathway may induce apoptosis in MPM cell lines (36, 65].

Sirolimus is a drug that has been approved as an immunosuppressant and which is currently used mainly in kidney transplantation and has an anti-proliferative effect on the PI3K/AKT/mTOR pathway.

Temsirolimus, a derivative of rapamycin, was investigated in a Phase I study but did not produce meaningful results (66). Studies investigating the combination of cisplatin and sirolimus are also underway, which have shown synergistic anti-tumor effects in MPM cell lines (67).

 Mesothelin

Mesothelin is highly expressed in a number of cancer types, including ovarian, pancreatic, some squamous carcinomas and the epithelial subtype MPM (68, 69).

Overexpression of the membrane protein mesothelin in MPM and its limited distribution in normal tissue has raised interest in this protein as a potential anti-tumor target (70).

Preliminary studies have not yet produced meaningful results (71); however, a number of drugs with anti-mesothelin activity are currently being investigated (72). Synergistic effects from the combination of these new agents with chemotherapy have been observed (73) offering promising results.

Ribonucleases

Ribonucleases are proteins that act on cellular RNA. Ranpirnase belongs to this group of proteins and has been investigated for its potential to induce apoptosis of tumor cells and inhibit cellular growth and proliferation.

However, various treatment-related adverse events have been observed, such as renal insufficiency, allergic reactions, arthralgia and peripheral edema (73).

Asparagine-Glycine- Arginine-human

TNF has known anti-tumor activity which is activated by inducing apoptosis of tumor cells. Studies of systemic treatment with this drug have shown that it is highly toxic and so it must be administered in such low doses to avoid disabling side effects that it is rendered ineffective (75-76).

Researchers have investigated a molecule consisting of a TNF fused to a peptide (tumor-homing peptide asparagine-glycine-arginine (NGR)) which is capable of selectively binding to mesothelial cells and has shown good tolerability as well as promising responses (77).

HDACi

Histone dacetylase inhibitors (HDACi) have been shown to alter the growth of numerous cancerogenic cell types. These molecules, many of which are derived from natural sources, have shown that they can inhibit proliferation, induce differentiation, and induce apoptosis of tumor cells.

Preliminary data from a Phase I study suggest that vorinostat has clinically significant activity in mesothelioma patients (78).

However, other studies have shown that this drug does not increase survival (79).

Vorinostat has also been investigated in combination with carboplatin and paclitaxel (80) and shown disease stabilization in some cases.

Belinostat is another drug that belongs to this group but has not proved to be superior to the other drugs (81). However, in vitro studies have demonstrated increased efficacy of these inhibitors when they are administered in combination with other agents (82, 83).

CBP501 EIMC- A12

Cells constantly undergo control processes to verify whether they are free of mutations and can continue in their cell cycle and multiply, or whether there are anomalies, in which case their life cycle must stop, lead to apoptosis and destruction of the cells to prevent more extensive damage. There are actually check-points that the cells must pass to obtain “permission” to proceed in their cellular cycle. Although they are anomalous, tumor cells can overcome these controls and can escape from being destroyed.

Drugs that act on these checkpoints have been defined to block the cell cycle of tumor cells which otherwise would continue proliferating and multiplying (84). Studies have also documented partial responses to treatment with these drugs when administered in combination with cisplatin (20), by enhancing the chemotherapy induced by these drugs.

Immunotherapy and Gene Therapy

Immunotherapy is another treatment that has contributed to significant advances and is currently being studied. An example of this treatment is the systemic administration of IL-2, which unfortunately had only limited efficacy and some side effects (85-86). Intrapleural administration of IL-2 has also been investigated and found to be well tolerated with objective responses, although further studies are needed to evaluate whether it offers more benefits than conventional treatment (87). Studies are also investigating systemic therapy with IL-2 by gene transfer of endogenous IL-2 as well as artificial regulation (88). Rapamycin is a natural macrolid that has been approved as an immunosuppressant and appears to have anti-proliferative effects by inhibiting some kinases such as mTOR. Synthetic derivatives of rapamycin known as “rapalogs” have been developed to improve the pharmacological properties of this macrolide; several examples are everolimus, temsirolimus and deforolimus.

Bortezomib is a potent proteasome inhibitor that has shown interesting cytotoxic effects in vitro and in vivo (89-90). Several studies are currently underway based on promising preclinical data (91).

Studies are evaluating the combination of interferon and various standard chemotherapy regimens, which have shown variable response rates to the treatment (92-95).

Vaccine therapies have also been studied, aiming to stimulate immune activity against tumor cells in MPM patients.

Some very interesting studies aimed at activating the immunostimulant ability of dendritic cells have also demonstrated variable but promising results (97-99).

Intrapleural therapy

The pleural cavity provides easy access for therapeutic molecules and intrapleural administration of drugs active in this disease could certainly offer excellent therapeutic prospects (100).

Various studies have evaluated the intracavitary administration of chemotherapy even after surgical resection, with the goal of enhancing local control of the disease (101- 103). Results have shown a 50% relapse of the disease after resection together with intrapleural chemotherapy, but further studies are needed to confirm these results that could probably show better responses.

Studies are also evaluating the intrapleural administration of recombinant viruses to try to sensitize tumor cells to drugs administered later (104-106).

Anti-mesothelin agents have also been injected into the pleural cavity (107-112), with the aim of inducing an immune response that could also act against tumor cells (113).

Conclusion

It is clear that clinicians, pathologists (114) and basic researchers must collaborate constantly to improve the treatment of rare but very aggressive diseases which often have an unfavorable prognosis such as MPM.

Numerous studies have been conducted over the last few years to investigate targeted molecular therapy and the biological pathways involved in the pathogenesis of this disease.

We need to gain a better understanding of the basic mechanisms of the development of this cancer in order to sufficiently understand the biomolecular pathways that play a role in cancerogenesis and so more effectively inhibit them. All these new studies, including those currently underway, have contributed to new advances or encouraging findings. However, further studies and more in-depth analyses carefully conducted and controlled will be able to confirm the results obtained thus far, as well as provide new information in order to achieve an effective therapy.

As MPM experts have already emphasized, all MPM patients must be afforded the opportunity to participate in ongoing clinical studies, not just to contribute to translational research but mainly to to gain access to treatments which, even though they are still being defined and investigated, can contribute to as yet undefined treatment lines regimens (115).

References

1. Pinto C, Ardizzoni A, Betta PG, et al: Export opinions of the First Italian Consensus Conference on the Management of Malignant Pleural Mesothelioma. Am J Clin Oncol 2011; 34: 99–109.
2. 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; 35: 479–495.
3. Yarden Y: The EGFR family and its ligands in human cancer. Signalling mechanisms and therapeutic opportunities. Eur J Cancer 2001; 37(suppl 4):S3–S8.
4. Destro A, Ceresoli GL, Falleni M, et al: EGFR overexpression in malignant pleural mesothelioma. An immunohistochemical and molecular study with clinico- pathological correlations. Lung Cancer 2006; 51: 207–215.
5. Herndon JE, Green MR, Chahinian AP, et al: Factors predictive of survival among 337 patients with mesothelioma treated between 1984 and 1994 by the Cancer and Leukemia Group B. Chest 1998; 113: 723– 731.
6. 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; 11: 2300–2304.
7. 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; 25: 2406–2413.
8. Cortese JF, Gowda AL, Wali A, et al: Common EGFR mutations conferring sensitivity to gefitinib in lung adenocarcinoma are not prevalent in human malignant mesothelioma. Int J Cancer 2006; 118: 521–522.
9. Destro A, Ceresoli GL, Falleni M, et al: EGFR overexpression in malignant pleural mesothelioma. An immunohistochemical and molecular study with clinico- pathological correlations. Lung Cancer 2006; 51: 207–215.
10. Gaafar R, Bahnassy A, Abdelsalam I, et al: Tissue and serum EGFR as prognostic factors in malignant pleural mesothelioma. Lung Cancer 2010; 70: 43–50.
11. Okuda K, Sasaki H, Kawano O, et al: Epidermal growth factor receptor gene mutation, amplification and protein expression in malignant pleural mesothelioma. J Cancer Res Clin Oncol 2008; 134: 1105–1111.
12. O’Byrne KJ, Edwards JG, Waller DA: Clinico- pathological and biological prognostic factors in pleural malignant mesothelioma. Lung Cancer 2004; 45(suppl 1):S45–S48.
13. Dazzi H, Hasleton PS, Thatcher N, et al: Malignant pleural mesothelioma and epidermal growth factor receptor (EGF-R). Relationship of EGF-R with histology and survival using fixed paraffin embedded tissue and the F4, monoclonal antibody. Br J Cancer 1990; 61: 924–926.
14. Edwards JG, Swinson DE, Jones JL, et al: EGFR expression: associations with outcome and clinicopathological variables in malignant pleural mesothelioma. Lung Cancer 2006; 54: 399–407.
15. Kono SA, Marshall ME, Ware KE, et al: The fibroblast growth factor receptor signalling pathway as a mediator of intrinsic resistance to EGFR-specific tyrosine kinase inhibitors in non-small cell lung cancer. Drug Resist Updat 2009; 12: 95–102.
16 Eyzaguirre A, Buck E, Iwata K, et al: Mechanisms of resistance to EGFR tyrosine kinase inhibitors: implications for patient selection and drug combination strategies. Target Oncol 2008; 3: 235– 243.
17. Engelman JA, Janne PA: Mechanisms of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in nonsmall cell lung cancer. Clin Cancer Res 2008; 14: 2895–2899.
18. Jagadeeswaran R, Ma PC, Seiwert TY, et al: Functional analysis of c-Met/hepatocyte growth factor pathway in malignant pleural mesothelioma. Cancer Res 2006; 66: 352– 361.
19. Whitson BA, Jacobson BA, Frizelle S, et al: Effects of insulin- like growth factor-1 receptor inhibition in mesothelioma. Thoracic Surgery Directors Association Resident Research Award. Ann Thorac Surg 2006; 82: 996– 1001.
20. Kai K, D’Costa S, Sills RC, et al: Inhibition of the insulin- like growth factor 1 receptor pathway enhances the antitumor effect of cisplatin in human malignant mesothelioma cell lines. Cancer Lett 2009; 278: 49–55.
21. Dannenberg AJ, Lippman SM, Mann JR, et al: Cyclooxygenase-2 and epidermal growth factor receptor: pharmacologic targets for chemoprevention. J Clin Oncol 2005; 23: 254–266.
22. Hull MA: Cyclooxygenase-2: how good is it as a target for cancer chemoprevention? Eur J Cancer 2005; 41: 1854–1863.
23. Amir M, Agarwal HK: Role of COX-2 selective inhibitors for prevention and treatment of cancer. Pharmazie 2005; 60: 563–570.
24. Gasparini G, Longo R, Sarmiento R, Morabito A: Inhibitors of cyclo-oxygenase 2: a new class of anticancer agents? Lancet Oncol 2003; 4: 605–615.
25. Baldi A, Santini D, Vasaturo F, et al: Prognostic significance of cyclooxygenase-2 (COX-2) and expression of cell cycle inhibitors p21 and p27 in human pleural malignant mesothelioma. Thorax 2004; 59: 428–433.
26. Edwards JG, Faux SP, Plummer SM, et al: Cyclooxygenase- 2 expression is a novel prognostic factor in malignant mesothelioma. Clin Cancer Res 2002; 8: 1857–1862.
27 O’Kane SL, Cawkwell L, Campbell A, Lind MJ: Cyclooxygenase-2 expression predicts survival in malignant pleural mesothelioma. Eur J Cancer 2005; 41: 1645–1648.
28. Catalano A, Graciotti L, Rinaldi L, et al: Preclinical evaluation of the nonsteroidal antiinflammatory agent celecoxib on malignant mesothelioma chemoprevention. Int J Cancer 2004; 109: 322–328.
29. O’Kane SL, Eagle GL, Greenman J, et al: COX-2 specific inhibitors enhance the cytotoxic effects of pemetrexed in mesothelioma cell lines. Lung Cancer 2010; 67: 160–165.
30. Kitamura F, Araki S, Tanigawa T, et al: Assessment of mutations of Ha- and Ki-ras oncogenes and the p53 suppressor gene in seven malignant mesothelioma patients exposed to asbestos-PCR-SSCP and sequencing analyses of paraffin-embedded primary tumors. Ind Health 1998; 36: 52–56.
31. Kitamura F, Araki S, Suzuki Y, et al: Assessment of the mutations of p53 suppressor gene and Ha- and Ki-ras oncogenes in malignant mesothelioma in relation to asbestos exposure: a study of 12 American patients. Ind Health 2002; 40: 175–181.
32. Ni Z, Liu Y, Keshava N, et al: Analysis of Kras and p53 mutations in mesotheliomas from humans and rats exposed to asbestos. Mutat Res 2000; 468: 87–92.
33. Dote H, Tsukuda K, Toyooka S, et al: Mutation analysis of the BRAF codon 599 in malignant pleural mesothelioma by enriched PCR-RFLP. Oncol Rep 2004; 11: 361–363.
34. Suzuki Y, Murakami H, Kawaguchi K, et al: Activation of the PI3K-AKT pathway in human malignant mesothelioma cells. Mol Med Rep 2009; 2: 181–188.
35. Opitz I, Soltermann A, Abaecherli M, et al: PTEN expression is a strong predictor of survival in mesothelioma patients. Eur J Cardiothorac Surg 2008; 33: 502–506.
36. 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; 24: 6080–6089.
37. Ohta Y, Shridhar V, Bright RK, et al: VEGF and VEGF type C play an important role in angiogenesis and lymphangiogenesis in human malignant mesothelioma tumours. Br J Cancer 1999; 81: 54–61.
38. Dowell J, Kindler H: Antiangiogenic therapies for mesothelioma. Hematol Oncol Clin North Am 2005; 19: 1137–1145.
39. Yasumitsu A, Tabata C, Tabata R, et al: Clinical significance of serum vascular endothelial growth factor in malignant pleural mesothelioma. J Thorac Oncol 2010; 5: 479–483.
40. König JE, Tolnay E, Wiethege T, Müller KM: Co- expression of vascular endothelial growth factor and its receptor flt-1 in malignant pleural mesothelioma. Respiration 2000;67:36–40.
41. Klabatsa A, Sheaff MT, Steele JP, et al: Expression and prognostic significance of hypoxia- inducible factor 1alpha (HIF-1 alpha) in malignant pleural mesothelioma (MPM). Lung Cancer 2006; 51: 53–59.
42. Jackman DM, Kindler HL, Yeap BY, et al: Erlotinib plus bevacizumab in previously treated patients with malignant pleural mesothelioma. Cancer 2008; 113: 808–814.
43. Jahan T, Gu L, Kratzke R, et al: Vatalanib in malignant mesothelioma: a phase II trial by the Cancer and Leukemia Group B (CALGB 30107). Lung Cancer 2011, E-pub ahead of print.
44. Mitchell CL, O’Connor JP, Roberts C, et al: A two-part phase II study of cediranib in patients with advanced solid tumours: the effect of food on single-dose pharmacokinetics and an evaluation of safety, efficacy and imaging pharmacodynamics. Cancer Chemother Pharmacol 2011; 68: 631–641.
45. Drevs J, Siegert P, Medinger M, et al: Phase I clinical study of AZD2171, an oral vascular endothelial growth factor signaling inhibitor, in patients with advanced solid tumors. J Clin Oncol 2007; 25: 3045–3054.
46. Matulonis UA, Berlin S, Ivy P, Tyburski K, et al: Cediranib, an oral inhibitor of vascular endothelial growth factor receptor kinases, is an active drug in recurrent epithelial ovarian, fallopian tube, and peritoneal cancer. J Clin Oncol 2009; 27: 5601–5606.
47. Garland L, Chansky K, Wosniak A, et al: Phase II study of cediranib in patients with malignant pleural mesothelioma: SWOG S0509. J Thorac Oncol 2011; 6: 1938–1945.
48. Morabito A, De Maio E, Di Maio M, et al: Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials: current status and future directions. Oncologist 2006; 11: 753– 764.
49. Baas P, Boogerd W, Dalesio O, et al: Thalidomide in patients with malignant pleural mesothelioma. Lung Cancer 2005; 48: 291– 296.
50. 97 Dubey S, Jänne PA, Krug L, et al: A phase II study of sorafenib in malignant mesothelioma: results of Cancer and Leukemia Group B 30307. J Thorac Oncol 2010; 5: 1655–1661.
51. Richly H, Henning BF, Kupsch P, et al: Results of a phase I trial of sorafenib (BAY43- 9006) in combination with doxorubicin in patients with refractory solid tumours. Ann Oncol 2006; 17: 866–873.
52. Millward M, Parnis F, Byrne M, et al: Phase II trial of imatinib mesylate in patients with advanced pleural mesothelioma (abstract 912). Proc Am Soc Clin Oncol 2003; 22: 912.
53. Villano J, Husain A, Stadler M, Hanson L, Vogelzang N, Kindler H, et al: A phase II trial of imatinib mesylate in patients (pts) with malignant mesothelioma (MM). J Clin Oncol 2004; 22: 14.
54. Mathy A, Baas P, Dalesio O, et al: Limited efficacy of imatinib mesylate in malignant mesothelioma: a phase II trial. Lung Cancer 2005; 50: 83–86.
55. Bertino P, Porta C, Barbone D, et al: Preliminary data suggestive of a novel translational approach to mesothelioma treatment: imatinib mesylate with gemcitabine or pemetrexed. Thorax 2007; 62: 690–695.
56. 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; 59: 149–150.
57. Vogelzang NJ, Porta C, Mutti L: New agents in the management of advanced mesothelioma. Semin Oncol 2005; 32: 336–350.
58. Filiberti R, Marroni P, Neri M, et al: Serum PDGF-AB in pleural mesothelioma. Tumour Biol 2005; 26: 221–226.
59. Edwards JG, Cox G, Andi A, et al: Angiogenesis is an independent prognostic factor in malignant mesothelioma. Br J Cancer 2001; 85: 863–868.
60. Arber DA, Tamayo R, Weiss LM: Paraffin section detection of the c-kit gene product (CD117) in human tissues: value in the diagnosis of mast cell disorders. Hum Pathol 1998; 29: 498–504.
61. Pietras K, Rubin K, Sjöblom T, et al: Inhibition of PDGF receptor signaling in tumor stroma enhances antitumor effect of chemotherapy. Cancer Res 2002; 62: 5476– 5484.
62. Ali Y, Lin Y, Gharibo MM, et al: Phase I and pharmacokinetic study of imatinib mesylate (Gleevec) and gemcitabine in patients with refractory solid tumors. Clin Cancer Res 2007; 13: 5876–5882.
63. 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; 6: 1962–1972.
64. Dudek A, Pang H, Kratzke A: A phase II study of dasatinib (D) in patients (pts) with previously treated malignant mesothelioma. J Natl Cancer Inst 2010; 28: 15.
65. Ramos-Nino ME, Testa JR, Altomare DA, et al: Cellular and molecular parameters of mesothelioma. J Cell Biochem 2006; 98: 723–734.
66. Raymond E, Alexandre J, Faivre S, et al: Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer. J Clin Oncol 2004; 22: 2336–2347.
67. Hartman ML, Esposito JM, Yeap BY, et al: Combined treatment with cisplatin and sirolimus to enhance cell death in human mesothelioma. J Thorac Cardiovasc Surg 2010; 139: 1233–1240.
68. Chang K, Pai LH, Pass H, et al: Monoclonal antibody K1 reacts with epithelial mesothelioma but not with lung adenocarcinoma. Am J Surg Pathol 1992; 16: 259–268.
69. Chang K, Pastan I: Molecular cloning of mesothelin, a differentiation antigen present on mesothelium, mesotheliomas, and ovarian cancers. Proc Natl Acad Sci USA 1996; 93: 136–140.
70. Hassan R, Bera T, Pastan I: Mesothelin: a new target for immunotherapy. Clin Cancer Res 2004; 10: 3937–3942.
71. Hassan R, Schweizer C, Lu KF, et al: Inhibition of mesothelin-CA-125 interaction in patients with mesothelioma by the anti- mesothelin monoclonal antibody MORAb- 009: implications for cancer therapy. Lung Cancer 2010; 68: 455–459.
72. Greillier L, Baas P, Welch JJ, et al: Biomarkers for malignant pleural mesothelioma: current status. Mol Diagn Ther 2008; 12: 375–390.
73. Hassan R, Broaddus VC, Wilson S, et al: Anti- mesothelin immunotoxin SS1P in combination with gemcitabine results in increased activity against mesothelin- expressing tumor xenografts. Clin Cancer Res 2007; 13: 7166–7171.
74. Mikulski SM, Costanzi JJ, Vogelzang NJ, et al: Phase II trial of a single weekly intravenous dose of ranpirnase in patients with unresectable malignant mesothelioma. J Clin Oncol 2002: 20: 274–281.
75. Mittelman A, Puccio C, Gafney E, et al: A phase I pharmacokinetic study of recombinant human tumor necrosis factor administered by a 5-day continuous infusion. Invest New Drugs 1992; 10: 183–190.
76. Lejeune FJ, Lienard D, Matter M, et al: Efficiency of recombinant human TNF in human cancer therapy. Cancer Immun 2006; 6: 6.
77. Gregorc V, Zucali PA, Santoro A, et al: Phase II study of asparagine-glycine arginine- human tumor necrosis factor alpha, a selective vascular targeting agent, in previously treated patients with malignant pleural mesothelioma. J Clin Oncol 2010; 28: 2604–2611.
78. Kelly WK, O’Connor OA, Krug LM, et al: Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J Clin Oncol 2005; 23: 3923–3931.
79. Paik PK, Krug LM: Histone deacetylase inhibitors in malignant pleural mesothelioma: preclinical rationale and clinical trials. J Thorac Oncol 2010; 5: 275–279.
80. Ramalingam SS, Parise RA, Ramanathan RK, et al: Phase I and pharmacokinetic study of vorinostat, a histone deacetylase inhibitor, in combination with carboplatin and paclitaxel for advanced solid malignancies. Clin Cancer Res 2007; 13: 3605– 3610.
81. Ramalingam SS, Belani CP, Ruel C, et al: Phase II study of belinostat (PXD101), a histone deacetylase inhibitor, for second line therapy of advanced malignant pleural mesothelioma. J Thorac Oncol 2009; 4: 97–101.
82. Marks PA, Richon VM, Miller T, et al: Histone deacetylase inhibitors. Adv Cancer Res 2004; 91: 137–168.
83. Scherpereel A, Berghmans T, Lafitte JJ, etal: Valproate-doxorubicin: promising therapy for progressing mesothelioma. A phase II study. Eur Respir J 2011; 37: 129–135.
84. Shapiro GI, Tibes R, Gordon MS, et al: Phase I studies of CBP501, a G2 checkpoint abrogator, as monotherapy and in combination with cisplatin in patients with advanced solid tumors. Clin Cancer Res 2011; 17: 3431–3442.
85. Mulatero CW, Penson RT, Papamichael D, et al: A phase II study of combined intravenous and subcutaneous interleukin-2 in malignant pleural mesothelioma. Lung Cancer 2001; 31: 67– 72.
86. Nowak AK, Lake RA, Kindler HL, et al: New approaches for mesothelioma: biologics, vaccines, gene therapy, and other novel agents. Semin Oncol 2002; 29: 82–96.
87. Astoul P, Picat-Joossen D, Viallat JR, et al: Intrapleural administration of interleukin- 2 for the treatment of patients with malignant pleural mesothelioma: a phase II study. Cancer 1998; 83: 2099–2104.
88. Caminschi I, Venetsanakos E, Leong CC, et al: Interleukin-12 induces an effective antitumor response in malignant mesothelioma. Am J Respir Cell Mol Biol 1998; 19: 738– 746.
89. Fennell DA, Chacko A, Mutti L: BCL-2 family regulation by the 20S proteasome inhibitor bortezomib. Oncogene 2008; 27: 1189–1197.
90. Sartore-Bianchi A, Gasparri F, Galvani A, et al: Bortezomib inhibits nuclear factorkappa B-dependent survival and has potent in vivo activity in mesothelioma. Clin Cancer Res 2007; 13: 5942–5951.
91. Gordon GJ, Mani M, Maulik G, et al: Preclinical studies of the proteasome inhibitor bortezomib in malignant pleural mesothelioma. Cancer Chemother Pharmacol 2008; 61: 549–558.
92.Trandafir L, Ruffié P, Borel C, et al: Higher doses of alpha- interferon do not increase the activity of the weekly cisplatin-interferon combination in advanced malignant mesothelioma. Eur J Cancer 1997; 33: 1900–1902.
93. Upham JW, Musk AW, van Hazel G, et al: Interferon alpha and doxorubicin in malignant mesothelioma: a phase II study. Aust NZ J Med 1993; 23: 683–687.
94. Parra HS, Tixi L, Latteri F, et al: Combined regimen of cisplatin, doxorubicin, and alpha- 2b interferon in the treatment of advanced malignant pleural mesothelioma: a phase II multicenter trial of the Italian Group on Rare Tumors (GITR) and the Italian Lung Cancer Task Force (FONICAP). Cancer 2001; 92: 650–656.
95. Halme M, Knuuttila A, Vehmas T, et al: High-dose methotrexate in combination with interferons in the treatment of malignant pleural mesothelioma. Br J Cancer 1999; 80: 1781–1785.
96. Bretti S, Berruti A, Dogliotti L, et al: Combined epirubicin and interleukin-2 regimen in the treatment of malignant mesothelioma: a multicenter phase II study of the Italian Group on Rare Tumors. Tumori 1998; 84: 558–561.
97. Hegmans JP, Hemmes A, Aerts JG, et al: Immunotherapy of murine malignant mesothelioma using tumour lysate-pulsed dendritic cells. Am J Respir Crit Care Med 2005; 171: 1168–1177.

98. Hegmans JP, Hemmes A, Hammad H, et al: Mesothelioma environment comprises cytokines and T- regulatory cells that suppress immune responses. Eur Respir J 2006; 27: 1086– 1095.
99. Hegmans JP, Veltman JD, Lambers ME, de Vries IJ, Figdor CG, Hendriks RW, Hoogsteden HC, Lambrecht BN, Aerts JG: Consolidative dendritic cell-based immunotherapy elicits cytotoxicity against malignant mesothelioma. Am J Respir Crit Care Med 2010; 181: 1383–1390.
100. Haas AR, Sterman DH: Novel intrapleural therapies for malignant diseases. Respiration 2012;83:277–292.
101. Tilleman TR, Richards WG, Zellos L, et al: Extrapleural pneumonectomy followed by intracavitary intraoperative hyperthermic cisplatin with pharmacologic cytoprotection for treatment of malignant pleural mesothelioma: a phase II prospective study. J Thorac Cardiovasc Surg 2009; 138: 405–411.
102. Sterman DH, Treat J, Litzky LA, et al: Adenovirus- mediated herpes simplex virus thymidine kinase/ganciclovir gene therapy in patients with localized malignancy: results of a phase I clinical trial in malignant mesothelioma. Hum Gene Ther 1998; 9: 1083–1092.
103. Molnar- Kimber KL, Sterman DH, Chang M, et al: Impact of preexisting and induced humoral and cellular immune responses in an adenovirus-based gene therapy phase I clinical trial for localized mesothelioma. Hum Gene Ther 1998; 9: 2121–2133.
104. Sterman DH, Recio A, Vachani A, et al: Long-term follow-up of patients with malignant pleural mesothelioma receiving high-dose adenovirus herpes simplex thymidine kinase/ganciclovir suicide gene therapy. Clin Cancer Res 2005; 11: 7444–7453.
105. Sterman DH, Recio A, Carroll RG, et al: A phase I clinical trial of single-dose intrapleural IFN-beta gene transfer for malignant pleural mesothelioma and metastatic pleural effusions: high rate of antitumor immune responses. Clin Cancer Res 2007; 13: 4456–4466.
106. Hassan R, Ho M: Mesothelin targeted cancer immunotherapy. Eur J Cancer 2008; 44: 46–53.
107. Hassan R, Zhang J, Pastan I: Antibodybased treatment for mesothelioma: clinical trials and laboratory studies. Lung Cancer 2006; 54:S13.
108. Hassan R, Bullock S, Premkumar A, et al: Phase I study of SS1P, a recombinant antimesothelin immunotoxin given as a bolus I.V. infusion to patients with mesothelinexpressing mesothelioma, ovarian, and pancreatic cancers. Clin Cancer Res 2007; 13: 5144–5149.
109. Li Q, Verschraegen CF, Mendoza J, et al: Cytotoxic activity of the recombinant antimesothelin immunotoxin, SS1(dsFv)PE38, towards tumor cell lines established from ascites of patients with peritoneal mesotheliomas. Anticancer Res 2004; 24: 1327–1335.
110. Armstrong DK, Laheru D, Ma WW, et al: A phase I study of MORAb-009, a monoclonal antibody against mesothelin in pancreatic cancer, mesothelioma, and ovarian adenocarcinoma (abstract). J Clin Oncol 2007; 25: 615s.
111. Brockstedt DG, Giedlin MA, Leong ML, et al: Listeria-based cancer vaccines that segregate immunogenicity from toxicity. Proc Natl Acad Sci USA 2004; 101: 13832– 13837.
112. Thomas AM, Santarsiero LM, Lutz ER, et al: Mesothelin-specific CD8(+) T cell responses provide evidence of in vivo crosspriming by antigen- presenting cells in vaccinated pancreatic cancer patients. J Exp Med 2004; 200: 297–306.
113. Hassan R, Ebel W, Routhier EL, et al: Preclinical evaluation of MORAb-009, a chimeric antibody targeting tumor associated mesothelin. Cancer Immun 2007; 7: 20.
114. Jantz MA, Antony VA: Pathophysiology of the pleura. Respiration 2008;75:121–133.
115. Froudarakis ME: Pleural diseases in the molecular era – time for more answers: introduction. Respiration 2012;83:2–4.

 

> Download article as PDF

Introduction

Second revision of the scientific literature on malignant pleural mesothelioma (MPM).
What new discoveries, studies and research protocols have been developed during the last few months?
How is research progressing on mesothelioma, a subject close to our hearts?

PubMed, the free access database containing articles, references, abstracts, revisions, etc., about science and medicine, serves as the definitive starting point for this new revision.
We therefore consulted all the scientific literature published between January 1 and June 30, 2013.
Under the general topic of “Mesothelioma”, we found the following for this period:

  • 345 total publications
  • By filtering the search to studies conducted in humans only, we narrowed it down to 75 studies during the last 6 months (not bad for a disease considered “rare” by some!)

Our revision does not claim to be a scientific review, but it offers patients, their families and general practitioners a concise idea of the latest scientific research on mesothelioma. This is not a critical analysis of individual articles, rather it is a recent snapshot of the most well-known scientific bibliography in the world. People who would like more detailed information can delve further into the topics by reviewing the references provided at the end of this short revision.

Diagnosis

Various research groups are looking for new biomarkers that can be used to diagnose MPM.
For example, claudin-4 is a protein involved in cellular junctions and is considered a useful immunohistochemical biomarker to distinguish between epithelioid mesothelioma and carcinoma metastases(1).
Another biomarker being studied is BAP1, which is a deubiquitylase involved in the cellular cycle, gluconeogenesis, response to DNA damage, cellular differentiation and cell death. Researchers have discovered that a germline mutation of BAP1 may be associated with a “syndrome” that causes melanoma in young people and may lead to the development of mesothelioma, uveal and cutaneous melanoma, and perhaps other neoplasms in older people(2). Other noteworthy mesothelioma biomarkers currently under investigation include fibulin(4 5 6), PTEN(7), GLUT, MCT-1 and MCT-4(8), IMP3(9).
New technologies and methods are currently being defined for earlier and better identification of this disease(10), others could be developed in addition to those already existing to provide further information(11).
Mesothelioma must be differentiated from other benign diseases such as fibrous pleuritis. Several researchers are focusing on this topic and have evaluated a biomarker that could distinguish between these two diseases(12).
The distinction between mesothelioma and lung cancer is also important, especially because it leads to different treatment approaches; this topic is also being studied(13).
In addition to biomarkers, we must not forget the importance of differential diagnosis(14) and an accurate case history to determine the possibility of environmental exposure(15 16 17 18 19) so we can arrive at the most accurate and early diagnosis possible.

Therapy

Notwithstanding the increased survival rate obtained through multimodal therapy based on a combination of surgery and chemotherapy, we need new treatments to further improve the results.
With this in mind, new therapeutic approaches are appearing on the horizon for the treatment of MPM.
Several researchers have investigated the administration chemotherapy or other agents directly into the thoracic or pleural cavity(20 21 22). Effective results have not yet been obtained, however.
There have been a few case reports of spontaneous remission after intratumoral lymphocytic infiltration, which have increased the median survival rate.
Based on these reports, several researchers are investigating the results further. For example, studies on immunotherapeutic approaches for MPM are underway with the aim of obtaining better results than those offered by standard therapy(23).
Various studies have shown that patients who develop post-operative empyema after pulmonary resection have an improved survival rate.
Based on this data, we can hypothesize about the importance of the immune system against the tumor and the need to find drugs that can increase the immune response against cancer(24 25 26).
Various studies have investigated the intrapleural injection of Calmette-Guerin bacillus as an adjuvant to surgery, but significant clinical benefits have not yet been obtained(27).
Various studies have investigated the systemic administration of immunotherapy such as interleukin and interferon gamma. However, the results thus far have been no more effective than current therapy and it is important to evaluate the side effects to determine the risk versus the benefit of these treatments(28 29).
Several researchers have analyzed the possibility of administering immunostimulant cytokines into the intrapleural cavity to treat MPM. Their research has shown a significant tumoral response using both IL2 and IFN gamma. The treatment seems more effective in patients with early stage MPM and these results could be truly promising(30 31 32 33 34).
The search for an adequate, effective treatment for MPM continues and new methods for novel, more effective and less toxic approaches are under investigation.
Gene therapy and new, emerging technologies in particular are examining the use of “transfer” genes to potentially transport cancer drugs. Gene vectors have been researched in clinical and preclinical studies and are characterized by complex liposomes/DNA or modified viruses, including herpes, vaccinia and adenoviruses(35 36).
The results from these studies have been mixed and need further research, but they are promising and offer much hope for the future.
Several researchers(37) have documented a dose-dependent response to intrapleural administration. The case of two “long surviving” patients whose disease stabilized after 6 months was reported a few years later . Also reported(39) were complete responses to the treatment, partial responses and stable disease evaluations after therapy(40 41 42 43).
There has been much discussion about “suicide gene therapy” and “cytokine gene therapy”.
“Suicide gene therapy” is a treatment characterized by the transduction of tumor cells with a gene codifying for an enzyme that induces sensitivity to the chemotherapy drugs normally used. In other words, a prodrug is transformed into a toxic metabolite by introducing an enzyme into the malignant cells, resulting in the death or suicide of the tumor cells(44 45 46 47 48 49 50).
The rationale behind “cytokine gene therapy” is the fact that activated tumor cells cause the release of many immunostimulatory cytokines, which in turn leads to an immune response against cancer(51 52 53 54).
Local administration of these cytokines could certainly avoid the side effects that have been documented with systemic administration(55 56 57 58 59).
All these new treatments have led to improved patient survival and quality of life than in the past. New studies will certainly help offer patients new hope for the future.

Conclusions

This is the latest news on the scientific research being conducted to find new treatments for MPM. We must emphasize that these clinical studies need further investigation and more data before they can be translated into clinical practice.
Nonetheless, guidelines for the diagnosis and treatment of this disease are being used on a daily basis. Continual congresses and conferences allow physicians to remain up-to-date and exchange information about new scientific achievements. For example, recommendations on total MPM patient care were published following the “Second Italian consensus conference on malignant pleural mesothelioma”(60). We therefore propose that MPM patients consult clinical centers dedicated to this disease in order to receive care that is personalized and focused on the patient rather than just the disease, in the knowledge that there is an answer to the question posed at the beginning of this article: are scholars, scientists and researchers making progress in their work? Are they focusing on a subject that is close to our hearts? Are they studying mesothelioma?

The answer is yes.

References

1. Value of claudin-4 immunostaining in the diagnosis of mesothelioma. Ordóñez NG. Am J Clin Pathol. 2013 May;139(5):611-9. doi: 10.1309/AJCP0B3YJBXWXJII.
2. BAP1 and cancer. Carbone M, Yang H, Pass HI, Krausz T, Testa JR, Gaudino G. Nat Rev Cancer. 2013 Mar;13(3):153-9.
3. Eur Respir J. 2013 Jan;41(1):18-24. doi: 10.1183/09031936.00148211. Epub 2012 Jul 12. A prospective trial evaluating the role of mesothelin in undiagnosed pleural effusions. Hooper CE, Morley AJ, Virgo P, Harvey JE, Kahan B, Maskell NA.
4. Select item 2330174433. Fibulin-3 as a biomarker for pleural mesothelioma. Hollevoet K, Sharon E. N Engl J Med. 2013 Jan 10;368(2):189. doi: 10.1056/NEJMc1213514#SA1. No abstract available.
5. Fibulin-3 as a biomarker for pleural mesothelioma. Lamote K, Baas P, van Meerbeeck JP. N Engl J Med. 2013 Jan 10;368(2):189-90. doi: 10.1056/NEJMc1213514#SA2. No abstract available.
6. Fibulin-3 as a biomarker for pleural mesothelioma. Pass HI, Goparaju C.N Engl J Med. 2013 Jan 10;368(2):190. doi: 10.1056/NEJMc1213514. No abstract available.
7. Tumour Biol. 2013 Apr;34(2):847-51. doi: 10.1007/s13277-012-0615-9. Epub 2012 Dec 15. PTEN protein expression in malignant pleural mesothelioma. Agarwal V, Campbell A, Beaumont KL, Cawkwell L, Lind MJ.
8. Virchows Arch. 2013 Jan;462(1):83-93. doi: 10.1007/s00428-012-1344-6. Epub 2012 Nov 28. Expression and role of GLUT-1, MCT-1, and MCT-4 in malignant pleural mesothelioma. Mogi A, Koga K, Aoki M, Hamasaki M, Uesugi N, Iwasaki A, Shirakusa T, Tamura K, Nabeshima K.
9. IMP3 and GLUT-1 immunohistochemistry for distinguishing benign from malignant mesothelial proliferations. Lee AF, Gown AM, Churg A. Am J Surg Pathol. 2013 Mar;37(3):421-6. doi: 10.1097/PAS.0b013e31826ab1c0.
10. Morphologic and immunocytochemical performances of effusion cell blocks prepared using 3 different methods. Jing X, Li QK, Bedrossian U, Michael CW. Am J Clin Pathol. 2013 Feb;139(2):177-82. doi: 10.1309/AJCP83ADULCXMAIX.
11. Evaluation of soluble mesothelin-related peptide as a diagnostic marker of malignant pleural mesothelioma effusions: its contribution to cytology. Canessa PA, Franceschini MC, Ferro P, Battolla E, Dessanti P, Manta C, Sivori M, Pezzi R, Fontana V, Fedeli F, Pistillo MP, Roncella S. Cancer Invest. 2013 Jan;31(1):43-50. doi: 10.3109/07357907.2012.749265. Epub 2012 Dec 18.
12. Diagnostic usefulness of p16/CDKN2A FISH in distinguishing between sarcomatoid mesothelioma and fibrous pleuritis. Wu D, Hiroshima K, Matsumoto S, Nabeshima K, Yusa T, Ozaki D, Fujino M, Yamakawa H, Nakatani Y, Tada Y, Shimada H, Tagawa M. Am J Clin Pathol. 2013 Jan;139(1):39-46. doi: 10.1309/AJCPT94JVWIHBKRD.
13. J Clin Pathol. 2013 Mar;66(3):256-9. doi: 10.1136/jclinpath-2012-201020. Epub 2012 Oct 19.
14. Extrapulmonary small cell carcinoma mimicking malignant pleural mesothelioma. Noguchi K, Fujimoto N, Asano M, Fuchimoto Y, Ono K, Ozaki S, Hotta K, Kato K, Toda H, Taguchi K, Kishimoto T. J Clin Pathol. 2013 May;66(5):450-1. doi: 10.1136/jclinpath-2012-201401. Epub 2013 Feb 15. No abstract available.
15. Int J Cancer. 2013 Mar 15;132(6):1423-8. doi: 10.1002/ijc.27758. Epub 2012 Aug 16. Familial aggregation of malignant mesothelioma in former workers and residents of Wittenoom, Western Australia. de Klerk N, Alfonso H, Olsen N, Reid A, Sleith J, Palmer L, Berry G, Musk AB.
16. Autopsy findings and pleural plaques in the Malignant Mesothelioma (MM) Regional Register of Friuli-Venezia-Giulia. De Zotti R, Barbati G, Negro C. Med Lav. 2013 Jan-Feb;104(1):55-66. Italian.
17. Analyses of radiation and mesothelioma in the US Transuranium and Uranium Registries. Gibb H, Fulcher K, Nagarajan S, McCord S, Fallahian NA, Hoffman HJ, Haver C, Tolmachev S. Am J Public Health. 2013 Apr;103(4):710-6. doi: 10.2105/AJPH.2012.300928. Epub 2013 Feb 14.
18. Researchers explore possible link between mesothelioma and dust emissions in southern Nevada. O'Hanlon LH. J Natl Cancer Inst. 2013 Mar 6;105(5):312-4. doi: 10.1093/jnci/djt033. Epub 2013 Feb 12. No abstract available.
19. High risk of malignant mesothelioma and pleural plaques in subjects born close to ophiolites. Bayram M, Dongel I, Bakan ND, Yalçin H, Cevit R, Dumortier P, Nemery B. Chest. 2013 Jan;143(1):164-71. Erratum in: Chest. 2013 Mar;143(3):880.
20. Monneuse O, Beaujard AC, Guibert B, et al. Longterm results of intrathoracic chemohyperthermia (ITCH) for the treatment of pleural malignancies. BrJ Cancer 2003;88:1839.
21. IkeO,ShimuzuV,Hitomi S,et al. Treatment ofmalignant pleural effusions with doxorubicin hydrochloridecontaining ply (L-lactic acid) microspheres. Chest 1991;99:911.
22. van Ruth S, Baas P, Haas RL, et al. Cytoreductive surgery combined with intraoperative hyperthermic intrathoracic chemotherapy for stage I malignant pleural mesothelioma. Ann Surg Oncol 2003;10: 176.
23. Antman KH. Natural history and epidemiology of malignant mesothelioma. Chest 1993;103:373S.
24. Lawaetz O, Halkier E. The relationship between postoperative empyema and long-term survival after pneumonectomy. Results of surgical treatment of bronchogenic carcinoma. Scand J Thorac Cardiovasc Surg 1980;14(1):113–7.
25. Minasian H, Lewis CT, Evans SJ. Influence of postoperative empyema on survival after pulmonary resection for bronchogenic carcinoma. Br Med J 1978;2(6148):1329–31.
26. Bone G. Postoperative empyema and survival in lung cancer. Br Med J 1973;2(5859):178.
27. Bakker W, Nijhuis-Heddes JM, van der Velde EA. Post-operative intrapleural BCG in lung cancer: a 5-year follow-up report. Cancer Immunol Immunother 1986;22(2):155–9.
28. Robinson BW, Manning LS, Bowman RV, et al. The scientific basis for the immunotherapy of human malignant mesothelioma. Eur Respir Rev 1993;3:195.
29. Astoul P, Picat-Joossen D, Viallat JR, et al. Intrapleural administration of interleukin-2 for the treatment of patients with malignant pleural mesothelioma: a phase II study. Cancer 1998;83:2099
30. Davidson JA, Musk AW, Wood BR, et al. Intralesional cytokine therapy in cancer: a pilot study of GM-CSF infusion in mesothelioma. J Immunother 1998;21(5): 389–98
31. Boutin C, Nussbaum E, Monnet I, et al. Intrapleural treatment with recombinant gamma-interferon in early stage malignant mesothelioma. Cancer 1994; 74:2460.
32. Boutin C, Viallat JR, Van Zandwijk N, et al. Activity of intrapleural recombinant gamma-interferon in malignant mesothelioma. Cancer 1991;67:2033.
33. Goey SH, Eggermont AM, Punt CJ, et al. Intrapleural administration of interleukin 2 in pleural mesothelioma: a phase I-II study. Br J Cancer 1995;72:1283.
34. Nowak AK, Lake RA, Kindler HL, et al. New approaches for mesothelioma: biologics, vaccines, gene therapy, and other novel agents. Semin Oncol 2002;29:82.
35. Robinson BW, Mukherjee SA, Davidson A, et al. Cytokine gene therapy or infusion as treatment for solid human cancer. J Immunother 1998;21:211
36. Vachani A, Moon E, Wakeam E, et al. Gene therapy for mesothelioma and lung cancer. Am J Respir Cell Mol Biol 2010;42(4):385–93.
37. Sterman D, Treat J, Litzky LA, et al. Adenovirusmediated herpes simplex virus thymidine kinase/ ganciclovir gene therapy in patients with localized malignancy: results of a phase I clinical trial in malignant mesothelioma. Hum Gene Ther 1998;9:1083.
38. Sterman DH, Molnar-Kimber K, Iyengar T, et al. A pilot study of systemic corticosteroid administration in conjunction with intrapleural adenoviral vector administration in patients with malignant pleural mesothelioma. Cancer Gene Ther 2000;7:1511.
39. Sterman DH, Recio A, Carroll RG, et al. A phase I clinical trial of single-dose intrapleural IFN-beta gene transfer for malignant pleural mesothelioma and metastatic pleural effusions: high rate of antitumor immune responses. Clin Cancer Res 2007; 13:4456–66.
40. Sterman DH, Recio A, Haas AR, et al. A phase I trial of repeated intrapleural adenoviral-mediated interferon- beta gene transfer for mesothelioma and metastatic pleural effusions. Mol Ther 2010;18(4): 852–60.
41. Sterman DH, Haas AR, Moon E, et al. A trial of intrapleural adenoviral-mediated interferon-alpha2b gene transfer for malignant pleural mesothelioma. Am J Respir Crit Care Med 2011;184:1395–9.
42. Dong M, Li X, Hong LJ, et al. Advanced malignant pleural or peritoneal effusion in patients treated with recombinant adenovirus p53 injection plus cisplatin. J Int Med Res 2008;36:1273–8.
43. Schwarzenberger P, Byrne P, Gaumer R, et al. Treatment of mesothelioma with gene-modified PA1STK cells and ganciclovir: a phase I study. Cancer Gene Ther 2011;18(12):906–12.
44. Hwang HC, Smythe WR, Elshami AA, et al. Gene therapy using adenovirus carrying the herpes simplex-thymidine kinase gene to treat in vivo models of human malignant mesothelioma and lung cancer. Am J Respir Cell Mol Biol 1995;13:7.
45. Smythe WR, Hwang HC, Amin KM, et al. Successful treatment of experimental human mesothelioma using adenovirus transfer of the herpes simplexthymidine kinase gene. Ann Surg 1995;222:78.
46. Sterman D, Treat J, Litzky LA, et al. Adenovirusmediated herpes simplex virus thymidine kinase/ ganciclovir gene therapy in patients with localized malignancy: results of a phase I clinical trial in malignant mesothelioma. Hum Gene Ther 1998;9:1083.
47. Sterman DH, Molnar-Kimber K, Iyengar T, et al. A pilot study of systemic corticosteroid administration in conjunction with intrapleural adenoviral vector administration in patients with malignant pleural mesothelioma. Cancer Gene Ther 2000;7:1511.
48. Sterman DH, Recio A, Vachani A, et al. Long-term follow-up of patients with malignant pleural mesothelioma receiving high-dose adenovirus herpes simplex thymidine kinase/ganciclovir suicide gene therapy. Clin Cancer Res 2005;11(20):7444–53.
49. Schwarzenberger P, Lei DH, Freeman SM, et al. Antitumor activity with the HSV-tk-gene-modified cell line PA-1-STK in malignant mesothelioma. Am J Respir Cell Mol Biol 1998;19:333.
50. Schwarzenberger P, Byrne P, Gaumer R, et al. Treatment of mesothelioma with gene-modified PA1STK cells and ganciclovir: a phase I study. Cancer Gene Ther 2011;18(12):906–12.
51. Sterman DH, Recio A, Haas AR, et al. A phase I trial of repeated intrapleural adenoviral-mediated interferon- beta gene transfer for mesothelioma and metastatic pleural effusions. Mol Ther 2010;18(4): 852–60.
52. Sterman DH, Recio A, Carroll RG, et al. A phase I clinical trial of single-dose intrapleural IFN-beta gene transfer for malignant pleural mesothelioma and metastatic pleural effusions: high rate of antitumor immune responses. Clin Cancer Res 2007; 13:4456–66.
53. Sterman DH, Haas AR, Moon E, et al. A trial of intrapleural adenoviral-mediated interferon-alpha2b gene transfer for malignant pleural mesothelioma. Am J Respir Crit Care Med 2011;184:1395–9.
54. Zhao Y, Moon E, Carpenito C, et al. Multiple injections of electroporated autologous T cells expressing a chimeric antigen receptor mediated regression of human disseminated tumor. Cancer Res 2010; 70(22):9053–61.
55. Vachani A, Moon E, Wakeam E, et al. Gene therapy for mesothelioma and lung cancer. Am J Respir Cell Mol Biol 2010;42(4):385–93.
56. Robinson BW, Mukherjee SA, Davidson A, et al. Cytokine gene therapy or infusion as treatment for solid human cancer. J Immunother 1998;21:211.
57. Mukherjee S, Haenel T, Himbeck R, et al. Replication- restricted vaccinia as a cytokine gene therapy vector in cancer: persistent transgene expression despite antibody generation. Cancer Gene Ther 2000;7:663.
58. Odaka M, Sterman D, Wiewrodt R, et al. Eradication of intraperitoneal and distant tumor by adenovirusmediated interferon-beta gene therapy due to induction of systemic immunity. Cancer Res 2001; 61:6201–12.
59. Vachani A, Sterman DH, Albelda SM. Cytokine gene therapy for malignant pleural mesothelioma. J Thorac Oncol 2007;2(4):265–7.
60. Second Italian consensus conference on malignant pleural mesothelioma: state of the art and recommendations. Pinto C, Novello S, Torri V, Ardizzoni A, Betta PG, Bertazzi PA, Casalini GA, Fava C, Fubini B, Magnani C, Mirabelli D, Papotti M, Ricardi U, Rocco G, Pastorino U, Tassi G, Trodella L, Zompatori M, Scagliotti G. Cancer Treat Rev. 2013 Jun;39(4):328-39. doi: 10.1016/j.ctrv.2012.11.004. Epub 2012 Dec 12. Review.

> Download article as PDF

A review of the current scientific literature allows us to highlight the latest updates on treating Malignant Pleural Mesothelioma (MPM).
The key points from the world of science were updated in December 2013 and are summarized below to show how MPM is being treated at the dawn of 2014.

Introduction

Mesothelioma, as we know, is a rare neoplasm that usually develops in the mesothelial cells lining the surface of the pleural cavity, less frequently in the peritoneal surface area, and very rarely in the tunica vaginalis or the pericardium.
This neoplasm has a very poor prognosis (1) and the treatments currently used in clinical practice have not yet led to a definitive cure for this disease (2,3).
Many patients with MPM have symptoms that develop gradually and which are often of a respiratory nature (dyspnea, cough, thoracic pain). The presence of symptoms often leads to a diagnosis of extensive intrathoracic disease.
With respect to the diagnosis, we should point out that physicians should always suspect MPM if they see symptoms typically associated with a history of exposure to asbestos. However, a definitive diagnosis can always be made by performing a histological examination of an adequate sample of the neoplastic tissue.
MPM is staged using the same system widely employed by the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC), which is known as TNM: T(Tumor), N (lymph nodes), M (metastasis) (4).
The clinical takes a multidiscplinary approach towards treating MPM, based on evaluating the extent of the disease, the overall condition of the patient (including cardiopulmonary function and other comorbidities) and their agreement to undergo treatment that is more or less aggressive. In fact, we must never forget to evaluate the wishes and hopes of patients to ensure that they have the best quality of life possible in accordance with their own personal parameters.
After evaluating these parameters, the patients can be subdivided into groups depending upon the recommended treatment: surgery or chemotherapy.
Different studies have evaluated various clinical and pathological parameters to identify patients with a good or poor prognosis. These characteristics have a prognostic value and are defined as “prognostic factors” .
The Cancer and Leukemia Group B (CALGB) and the European Organization for Research and Treatment of Cancer (EORTC) have identified some very interesting clinical prognostic factors (5-7). The best known prognostic factor is histology; in fact, patients with sarcomatoid mesothelioma as opposed to biphasic seem to have a worse prognosis than patients with epithelial mesothelioma.
Many biomarkers are currently being studied that could be both prognostic factors and predictive factors, in other words they can identify which patients respond to a certain treatment as opposed to another(8,9).
Defining the clinical benefit is essential for evaluating the effectiveness of the treatment:

  • Treatment response rate
  • Disease control rate
  • Progression free survival
  • Overall survival 10,11.

There are currently two radiographic methods for measuring the response rate used for the Computed Tomography (CT) evaluation: the RECIST system and the modified RECIST system (12,13,14).
Besides CT, other radiographic methods are also used, such as PET/CT (Computed Tomography with Positron Emission Tomography).
PET can define the metabolic activity of the body by evaluating the consumption of radiolabeled glucose that is injected as a contrast just before the scan (15). However, studies have also shown that the PET responses must be evaluated by experts only because this tool cannot be considered a gold standard diagnostic examination due to the various cases of false positives and negatives (16).
The importance of this nuclear exam is aimed at evaluating the response to the disease, tumoral activity or relapse, but the standard method for confirming the diagnosis is to perform a histological analysis.
There are also very promising biomolecular methods such as measuring the serum mesothelin-related peptide (SMRP) levels (16).

Surgery

Patients who are candidates for surgery
These are patients with resectable disease that is limited to one hemithorax and who are able to withstand surgery.
In these cases, multimodal treatment approaches can be used which involve Maximal Complete Resection (MCR) together with chemotherapy and radiation therapy.
Patients who are not candidates for surgery
These are patients whose disease is such that an MCR cannot be performed, or because they are too old and suffer from insufficient cardiopulmonary function or other comorbidities.
In these cases, chemotherapy and symptomatic treatment are the best approaches and which could actually lead to a clinical benefit.

Chemotherapy

Nowadays, MPM is treated with a combination of drugs rather than a single agent. In fact, the chemotherapy regimen of cisplatin combined with pemetrexed administered together with vitamin B12 and folic acid supplements (19), is now the standard of care for patients with non-resectable disease or who cannot undergo surgery. This decision is based on a study that showed an increase in survival using this combination versus cisplatin alone.
Other platinum-based regimens have been shown to be useful but further studies are not required to determine their efficacy (19).
The combination of Raltitrexed on top of cisplatin improves survival versus cisplatin alone in patients with advanced MPM who have not been treated previously (27,28).
Gemcitabine together with platinum has shown response rates with acceptable toxicity levels (29-35).
Cisplatin has also been studied with other older chemotherapy agents such as doxorubicin or epirubicin, the combination of fluoruracil, mitomycin plus etoposide, and the combination of methotrexate and vinblastine (36-41).
The role of maintenance chemotherapy with pemetrexed after completing four or six cycles of therapy with a platinum-based combination is still controversial (19).
It is important to remember that these treatments are not devoid of toxicities, even though treatment with folic acid and vitamin B12 supplements can alleviate these side effects (20-21).
If the side effects need to be reduced, carboplatin can be used instead of cisplatin with pemetrexed (23-25). The treatment response rates appear to be similar and so carboplatin can be a good alternative, especially for patients who are not in good overall condition and cannot tolerate the side effects from cisplatin.
Although treatment with single agents is considered inferior to combinations, they still have a role as second-line therapy (10).
Agents that have been investigated and which can be used for this purpose are cisplatin (42), carboplatin (43-44), pemetrexed /45-50), methotrexate (51), edatrexate (52), raltitrexed (53), gemcitabine (54-56), anthracycline (57-59) and vinca alkaloids (56,60,61).
There are still no predictive biomarkers for response to chemotherapy, although research is moving forward in this area. For example, the serum levels of thymidylate synthase appear to be associated with a better response to chemotherapy and a better prognosis (22).

Experimental approches

There are many new experimental approaches that are being studied to improve the systemic treatment of MPM.
Among new agents are angiogenesis inhibitors, such as bevacizumab (62) or thalidomide (63).
Tyrosine kinase inhibitors could also be very promising, such as sorafenib (64), sunitinib (65), imatinib (65-67), vatalanib (68) and cediranib (69).
Histone deacetylase inhibitors such as vorinostat (70-71) are also new treatments.
Last but not least, immunotherapy could be very useful for treating this disease either alone or in combination with chemotherapy (72-77).

Conclusions

MPM can no longer be considered a rare disease due to the increased incidence and improved diagnostic capabilities.
It should be pointed out that there are guidelines for physicians to follow because they are considered the best treatment approach since they are based on scientific evidence.
As of now, there is no treatment that can completely cure advanced stage MPM, but there is a variety of therapeutic approaches that will allow this disease to become as chronic as possible.
It is essential that we take into account the decisions and personal wishes of the patient so that we can treat their symptoms as effectively as possible and optimize their quality of life.
New experimental approaches are being studied and are very promising, although they are not yet considered as a standard treatment for MPM.
However, future prospects seem to be opening up at the dawn of 2014 and while research is moving forward at the laboratory bench, we hope that the products quickly become effective tools in clinical practice.

References

1. Ong ST, Vogelzang NJ. Chemotherapy in malignant pleural mesothelioma. A review. J Clin Oncol 1996; 14:1007
2. Antman KH. Natural history and epidemiology of malignant mesothelioma. Chest 1993; 103:373S.
3. Aisner J. Current approach to malignant mesothelioma of the pleura. Chest 1995; 107:332S.
4. American Joint Committee on Cancer. Pleural mesothelioma. In: Cancer Staging Manual, Seventh Edition, Springer, 2010. p.271.
5. Herndon JE, Green MR, Chahinian AP, et al. Factors predictive of survival among 337 patients with mesothelioma treated between 1984 and 1994 by the Cancer and Leukemia Group B. Chest 1998; 113:723.
6. Curran D, Sahmoud T, Therasse P, et al. Prognostic factors in patients with pleural mesothelioma: the European Organization for Research and Treatment of Cancer experience. J Clin Oncol 1998; 16:145.
7. Fennell DA, Parmar A, Shamash J, et al. Statistical validation of the EORTC prognostic model for malignant pleural mesothelioma based on three consecutive phase II trials. J Clin Oncol 2005; 23:184.
8. Gordon GJ, Jensen RV, Hsiao LL, et al. Using gene expression ratios to predict outcome among patients with mesothelioma. J Natl Cancer Inst 2003; 95:598.
9. Pass HI, Liu Z, Wali A, et al. Gene expression profiles predict survival and progression of pleural mesothelioma. Clin Cancer Res 2004; 10:849.
10. Vogelzang NJ. Chemotherapy for malignant pleural mesothelioma. Lancet 2008; 371:1640.
11. Francart J, Legrand C, Sylvester R, et al. Progression-free survival rate as primary end point for phase II cancer clinical trials: application to mesothelioma--The EORTC Lung Cancer Group. J Clin Oncol 2006; 24:3007.
12. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92:205.
13. Byrne MJ, Nowak AK. Modified RECIST criteria for assessment of response in malignant pleural mesothelioma. Ann Oncol 2004; 15:257.
14. Nowak AK. CT, RECIST, and malignant pleural mesothelioma. Lung Cancer 2005; 49 Suppl 1:S37.
15. 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; 24:4587.
16. Roca E, Laroumagne S, Vandemoortele T, et al. 18F-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography fused imaging in malignant mesothelioma patients: Looking from outside is not enough. Lung Cancer 2013;79(2):187-90.
17. Wheatley-Price P, Yang B, Patsios D, et al. Soluble mesothelin-related Peptide and osteopontin as markers of response in malignant mesothelioma. J Clin Oncol 2010; 28:3316.
18. Muers MF, Stephens RJ, Fisher P, et al. Active symptom control with or without chemotherapy in the treatment of patients with malignant pleural mesothelioma (MS01): a multicentre randomised trial. Lancet 2008; 371:1685.
19. Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 2003; 21:2636.
20. Vogelzang NJ, Emri S, Boyer MJ, et al. Effect of folic acid and vitamin B12 supplmentation on risk-benefit ratio from phase III study of pemetrexed and cisplatin versus cisplatin in malignan pleural mesothelioma (abstract). Proc Am Soc Clin Oncol 2003; 22:657a.
21. Symanowski JT, Rusthoven J, Nguyen B, et al. Multiple regression analysis of prognostic variables for survival from the phase III study of pemetrexed plus cisplatin vs. cisplatin in malignant pleural mesothelioma (abstract). Proc Am Soc Clin Oncol 2003; 22:647a.
22. Righi L, Papotti MG, Ceppi P, et al. Thymidylate synthase but not excision repair cross-complementation group 1 tumor expression predicts outcome in patients with malignant pleural mesothelioma treated with pemetrexed-based chemotherapy. J Clin Oncol 2010; 28:1534.
23. Ceresoli GL, Zucali PA, Favaretto AG, et al. Phase II study of pemetrexed plus carboplatin in malignant pleural mesothelioma. J Clin Oncol 2006; 24:1443.
24. 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; 19:370.
25. Santoro A, O'Brien ME, Stahel RA, et al. Pemetrexed plus cisplatin or pemetrexed plus carboplatin for chemonaïve patients with malignant pleural mesothelioma: results of the International Expanded Access Program. J Thorac Oncol 2008; 3:756.
26. Ceresoli GL, Castagneto B, Zucali PA, et al. Pemetrexed plus carboplatin in elderly patients with malignant pleural mesothelioma: combined analysis of two phase II trials. Br J Cancer 2008; 99:51.
27. 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; 23:6881.
28. Bottomley A, Gaafar R, Manegold C, et al. Short-term treatment-related symptoms and quality of life: results from an international randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma: an EORTC Lung-Cancer Group and National Cancer Institute, Canada, Intergroup Study. J Clin Oncol 2006; 24:1435.
29. Nowak AK, Byrne MJ, Williamson R, et al. A multicentre phase II study of cisplatin and gemcitabine for malignant mesothelioma. Br J Cancer 2002; 87:491.
30. Castagneto B, Zai S, Dongiovanni D, et al. Cisplatin and gemcitabine in malignant pleural mesothelioma: a phase II study. Am J Clin Oncol 2005; 28:223.
31. Jänne PA, Simon GR, Langer CJ, et al. Phase II trial of pemetrexed and gemcitabine in chemotherapy-naive malignant pleural mesothelioma. J Clin Oncol 2008; 26:1465.
32. Kovac V, Zwitter M, Rajer M, et al. A phase II trial of low-dose gemcitabine in a prolonged infusion and cisplatin for malignant pleural mesothelioma. Anticancer Drugs 2012; 23:230.
33. Kindler HL, Karrison TG, Gandara DR, et al. Multicenter, double-blind, placebo-controlled, randomized phase II trial of gemcitabine/cisplatin plus bevacizumab or placebo in patients with malignant mesothelioma. J Clin Oncol 2012; 30:2509.
34. Favaretto AG, Aversa SM, Paccagnella A, et al. Gemcitabine combined with carboplatin in patients with malignant pleural mesothelioma: a multicentric phase II study. Cancer 2003; 97:2791.
35. Schutte W, Blankenburg T, Lauerwald K, et al. A multicenter phase II study of gemcitabine and oxaliplatin for malignant pleural mesothelioma. Clin Lung Cancer 2003; 4:294.
36. Chahinian AP, Antman K, Goutsou M, et al. Randomized phase II trial of cisplatin with mitomycin or doxorubicin for malignant mesothelioma by the Cancer and Leukemia Group B. J Clin Oncol 1993; 11:1559.
37. Ardizzoni A, Rosso R, Salvati F, et al. Activity of doxorubicin and cisplatin combination chemotherapy in patients with diffuse malignant pleural mesothelioma. An Italian Lung Cancer Task Force (FONICAP) Phase II study. Cancer 1991; 67:2984.
38. Henss H, Fiebig HH, Schildge J, et al. Phase-II study with the combination of cisplatin and doxorubicin in advanced malignant mesothelioma of the pleura. Onkologie 1988; 11:118.
39. Berghmans T, Lafitte JJ, Paesmans M, et al. A phase II study evaluating the cisplatin and epirubicin combination in patients with unresectable malignant pleural mesothelioma. Lung Cancer 2005; 50:75.
40. Hunt KJ, Longton G, Williams MA, Livingston RB. Treatment of malignant mesothelioma with methotrexate and vinblastine, with or without platinum chemotherapy. Chest 1996; 109:1239.
41. Middleton GW, Smith IE, O'Brien ME, et al. Good symptom relief with palliative MVP (mitomycin-C, vinblastine and cisplatin) chemotherapy in malignant mesothelioma. Ann Oncol 1998; 9:269.
42. Berghmans T, Paesmans M, Lalami Y, et al. Activity of chemotherapy and immunotherapy on malignant mesothelioma: a systematic review of the literature with meta-analysis. Lung Cancer 2002; 38:111.
43. Raghavan D, Gianoutsos P, Bishop J, et al. Phase II trial of carboplatin in the management of malignant mesothelioma. J Clin Oncol 1990; 8:151.
44. Vogelzang NJ, Goutsou M, Corson JM, et al. Carboplatin in malignant mesothelioma: a phase II study of the Cancer and Leukemia Group B. Cancer Chemother Pharmacol 1990; 27:239.
45. Scagliotti GV, Shin DM, Kindler HL, et al. Phase II study of pemetrexed with and without folic acid and vitamin B12 as front-line therapy in malignant pleural mesothelioma. J Clin Oncol 2003; 21:1556.
46. Rusthoven JJ, Eisenhauer E, Butts C, et al. Multitargeted antifolate LY231514 as first-line chemotherapy for patients with advanced non-small-cell lung cancer: A phase II study. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 1999; 17:1194.
47. Taylor P, Castagneto B, Dark G, et al. Single-agent pemetrexed for chemonaïve and pretreated patients with malignant pleural mesothelioma: results of an International Expanded Access Program. J Thorac Oncol 2008; 3:764.
48. Jänne PA, Wozniak AJ, Belani CP, et al. Pemetrexed alone or in combination with cisplatin in previously treated malignant pleural mesothelioma: outcomes from a phase IIIB expanded access program. J Thorac Oncol 2006; 1:506.
49. 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; 26:1698.
50. 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; 16:923.
51. Solheim OP, Saeter G, Finnanger AM, Stenwig AE. High-dose methotrexate in the treatment of malignant mesothelioma of the pleura. A phase II study. Br J Cancer 1992; 65:956.
52. Kindler HL, Belani CP, Herndon JE 2nd, et al. Edatrexate (10-ethyl-deaza-aminopterin) (NSC #626715) with or without leucovorin rescue for malignant mesothelioma. Sequential phase II trials by the cancer and leukemia group B. Cancer 1999; 86:1985.
53. Baas P, Ardizzoni A, Grossi F, et al. The activity of raltitrexed (Tomudex) in malignant pleural mesothelioma: an EORTC phase II study (08992). Eur J Cancer 2003; 39:353.
54. van Meerbeeck JP, Baas P, Debruyne C, et al. A Phase II study of gemcitabine in patients with malignant pleural mesothelioma. European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. Cancer 1999; 85:2577.
55. Kindler HL, Millard F, Herndon JE 2nd, et al. Gemcitabine for malignant mesothelioma: A phase II trial by the Cancer and Leukemia Group B. Lung Cancer 2001; 31:311.
56. Toyokawa G, Takenoyama M, Hirai F, et al. Gemcitabine and vinorelbine as second-line or beyond treatment in patients with malignant pleural mesothelioma pretreated with platinum plus pemetrexed chemotherapy. Int J Clin Oncol 2013.
57. Lerner HJ, Schoenfeld DA, Martin A, et al. Malignant mesothelioma. The Eastern Cooperative Oncology Group (ECOG) experience. Cancer 1983; 52:1981.
58. Magri MD, Veronesi A, Foladore S, et al. Epirubicin in the treatment of malignant mesothelioma: a phase II cooperative study. The North-Eastern Italian Oncology Group (GOCCNE)--Mesothelioma Committee. Tumori 1991; 77:49.
59. Skubitz KM. Phase II trial of pegylated-liposomal doxorubicin (Doxil) in mesothelioma. Cancer Invest 2002; 20:693.
60. Steele JP, Shamash J, Evans MT, et al. Phase II study of vinorelbine in patients with malignant pleural mesothelioma. J Clin Oncol 2000; 18:3912.
61. Talbot DC, Margery J, Dabouis G, et al. Phase II study of vinflunine in malignant pleural mesothelioma. J Clin Oncol 2007; 25:4751.
62. Karrison T, Kindler HL, Gandara DR, et al. Final analysis of a multi-center, double-blind, placebo-controlled, randomized phase II trial of gemcitabine/cisplatin (GC) plus bevacizumab (B) or placebo (P) in patients (pts) with malignant mesothelioma (MM)(abstract). J Clin Oncol 2007; 25:391s. (Abstract available online at: www.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnextoid=76f8201eb61a7010VgnVCM100000ed730ad1RCRD, accessed on June 20, 2007).
63. Buikhuisen WA, Burgers JA, Vincent AD, et al. Thalidomide versus active supportive care for maintenance in patients with malignant mesothelioma after first-line chemotherapy (NVALT 5): an open-label, multicentre, randomised phase 3 study. Lancet Oncol 2013; 14:543.
64. Nowak AK, Millward MJ, Francis J, et al. Phase II study of sunitinib as second-line therapy in malignant pleural mesothelioma (MPM). J Clin Oncol 2008; 15s:8063. (Abstract available online at http://meeting.ascopubs.org/cgi/content/abstract/26/15_suppl/8063, accessed April 26, 2010).
65. Mathy A, Baas P, Dalesio O, van Zandwijk N. Limited efficacy of imatinib mesylate in malignant mesothelioma: a phase II trial. Lung Cancer 2005; 50:83.
66. 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; 59:149.
67. Millward M, Parnis F, Byrne M, et al. Phase II trial of imatinib mesylate in patients with advanced pleural mesothelioma (abstract 912). Proc Am Soc Clin Oncol 2003; 22:912.
68. Jahan PA, Wang XF, Krug ML, et al. Sorafenib in malignant mesothelioma (MM): A phase II trial of the Cancer and Leukemia Group B (CALGB 30307) (abstract 7707). J Clin Oncol 2007; 25:18s.
69. Van Schil PE, Baas P, Gaafar R, et al. Phase II feasibility trial of induction chemotherapy followed by extrapleural pneumonectomy and postoperative radiotherapy for cT3N1M0 or less malignant pleural mesothelioma (EORTC 08031) (abstract 7509). J Clin Oncol 2008; 27:384s.
70. Kelly WK, O'Connor OA, Krug LM, et al. Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J Clin Oncol 2005; 23:3923.
71. Krug LM, et al. Vorinostat in patients with advanced malignant pleural mesothelioma who have failed prior pemetrexed and either cisplatin or carboplatin therapy: A phase III, randomized, double-blind, placebo-controlled trial. ECCO-ESMO 2011; Abstract 3BA.
72. Hassan R, Zhang J, Pastan I. Antibody-based treatment for mesothelioma: Clinical trials and laboratory studies. Lung Cancer 2006; 54:S13.
73. 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; 13:5144.
74. Parra HS, Tixi L, Latteri F, et al. Combined regimen of cisplatin, doxorubicin, and alpha-2b interferon in the treatment of advanced malignant pleural mesothelioma: a Phase II multicenter trial of the Italian Group on Rare Tumors (GITR) and the Italian Lung Cancer Task Force (FONICAP). Cancer 2001; 92:650.
75. Halme M, Knuuttila A, Vehmas T, et al. High-dose methotrexate in combination with interferons in the treatment of malignant pleural mesothelioma. Br J Cancer 1999; 80:1781.
76. Bretti S, Berruti A, Dogliotti L, et al. Combined epirubicin and interleukin-2 regimen in the treatment of malignant mesothelioma: a multicenter phase II study of the Italian Group on Rare Tumors. Tumori 1998; 84:558.
77. Calabro L, Morra A, Fonsatti E, et al. Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial. Lancet Oncol 2013.

> Download article as PDF

INTRODUCTION

The literature review in this section focuses on several key concepts regarding the genetics and pathways involved in the tumorigenesis of malignant mesothelioma (MM).

With this in mind, approximately 250 articles were analyzed and summarized below but we do not claim that this is an in-depth, exhaustive review, so please consult the bibliography at the end of this text for further further information.

MOLECULAR BIOLOGY OF MESOTHELIOMA

Malignant mesothelioma (MM) is caused by the abnormal proliferation of tumors in the pleura, pericardium, peritoneum, tunica vaginale testis or ovarian epithelium  (1,2).

Its incidence rate is increasing, and unfortunately the prognosis is often poor (3,4). A number of diverse pathogenetic hypotheses for this disease have been investigated in detail (5-8).

MM is characterized by a long latency period before the appearance of the initial symptoms that can lead to a diagnosis and during this long period, genetic mutations may occur and characterize the neoplastic changes (9-11).  The purpose of this literature review is to focus on the genetics and pathogenetic pathways associated with this neoplasm.

GENES

The main chromosomes affected by this neoplasm are: 1, 3, 4, 6, 9, 13 and 14 (12).

The genetic abnormalities most commonly associated with malignant pleural mesothelioma (MPM), and which will be analyzed individually, are the following: p16INK4a /p14ARF (13,14), NF2 (15,16), p53 (17-20), PTEN (21-23), BAP-1 (24), LATS2 (25), PI3K/AKT/mTOR (22,26), EGFR (27,28), VEGF (29-31), pRb (32,33), BCL-2 (34-36), hippo (37-39) and Wnt (40,41).

p16 INK4a/p14ARF

The p16INK4a/p14ARF gene is also known as CDKN2A/ARF and is located on chromosome 9p21.

This is a very important tumor suppressor gene that codifies for two proteins: p16INK4a and p14ARF.  (42-43)

Protein p16INK4a inhibits CDK, which inactivates pRb.

Protein p14ARF, on the other hand, regulates the function of p53 and inhibits its degradation by interacting with MDM2 (27,44,45).

These modifications play a fundamental role in regulating the control of the cell cycle; these genetic mutations also appear to be associated with more aggressive tumors and a poorer prognosis (13,14).

These genes in particular are implicated in the development of different types of neoplasia (46-48). Similarly, the same type of genetic mutations may also occur in MPM (13, 50-54).

Scientific studies have shown that if this gene is “switched off”, cancerogenesis may be “accelerated” due to exposure to asbestos  (55-59).

Gene therapy studies are aimed at reactivating the p16INK4a/p14ARF gene to restore the functions that have been lost if the gene is mutated. The studies have shown that reactivating this gene halts the cell cycle of mesothelioma cells, inhibits the phosphorylation of pRb, and decreases cell growth. All these modifcations may therefore increase survival, increase the levels of protein p53, and boost cell apoptosis (60-63,12).  Gene therapy aimed at restoring the functions altered by the mutation of this gene has shown promising preliminary results.

NF2

NF2, the abbreviation for the type 2 neurofibromatosis gene, is a genetic trait that follows an autosomal dominant inheritance pattern leading to tumor predisposition syndrome, and is characterized by the development of bilateral vestibular schwannomas on the eighth cranial nerve and other brain tumors, including meningiomas and ependymomas.  

This syndrome results from the lack of expression of the NF2 gene, which is a tumor suppressor.

Although known for the above syndrome, this gene is also associated with malignant mesothelioma (64-69).

The lack of protein activity associated with the codification of the mutated gene appears to be associated with a greater possibility of carcinogenesis, as opposed to patients who do not have this genetic mutation, and which is certainly greater for patients who have been exposed to asbestos (22,70).  However, the precise functionality of this gene has not yet been fully defined.

Gene therapy associated with this gene involves trying to “over-express” it through the use of viral vectors. These studies have shown interesting results, such as controlling the cell cycle and proliferation (71-75).

Re-expression of the NF2 gene in patients with MM could certainly be of considerable help in inhibiting cell proliferation and tumor invasion (76).

BAP-1

Several clinical studies have sought to understand how there appears to be a genetic predisposition to MPM in certain localities.  BAP-1 was found among the genes that were mutated and thus deemed to be involved in this disease (77-79).

Recent studies have also shown that BAP-1 is a tumor suppressor located on chromosome 3p21, which appears to play a role in regulating the cell cycle and responding to DNA damage (80-81).

This genetic mutation was found in patients with MM, especially the squamous histotype rather than the epithelial histotype  (82-84).

This pathologic genetic modification seems to be particularly associated with a poorer prognosis (85-86), as well as the development of neoplasia (87).

Gene therapy is being investigated not only to find an effective treatment for patients with a genetic alteration of this gene, but also to eventually prevent MM in subjects with a mutated BAP-1 gene.

LATS2

The Large Tumor Suppressor (LATS) was the first tumor marker identified in Drosophila (88).

In humans, this gene is located in a region of chromosome 13 (13q11-12) and is often mutated in tumors (89-90).

Two forms of LATS have been identified: LATS1 and LATS2. LATS2 in particular is a centrosomal protein which appears to be involved in mitotic subdivision (91), regulating the inhibition of the growth of Hippo (37) and activating p53 (92-93).

This gene has been studied in MM, particularly in cell lines characterized by a deletion of chromosome 13q11-12. Comparative genomic hybridization techniques were used for these analyses, subsequently confirmed by PCR.

These studies have shown the presence of genetic mutations of LATS2 in MM cells (25).

According to these studies, LATS2 appears to play a role in cell proliferation and survival. However, further studies are needed to confirm whether this gene actually plays a causal role in the development of MM.

DNA methylation

Studies investigating DNA methylation in MM have shown promising results.

They have shown that the methylation profile can be a differentiating factor between the physiological pleura and their pathological mutations, especially those that are characteristic of mesothelioma (94).

Some studies maintain that the methylation profile could even be considered a diagnostic marker that can be used to identify primitive and secondary pleural tumors (95).

Other studies investigated the relationship between patient outcomes and their methylation status and have observed interesting differences in survival associated this genetic mutation (96).

Other studies have also analyzed diagnosis and an eventual epigenetic therapeutic approach (15,97).

MicroRNA

miRNA expression is another important mechanism in the development of tumors, which supports their ability to control different biological processes.

For this reason, many researchers have focused their attention on the profile of miRNA to verify if there are any discrepancies/associations between these various genetic expressions and the pleura (98-103).

Other genes

A component of the Hippo cascade, the salvador gene (SAV) was dicovered in the Drosophila 81349 and is considered one of the gene suppresors altered in different neoplastic forms (16, 104-105).  Deletion of the chromosome 14q22 was recently demonstrated in approximately 5% of mesothelioma cell lines; however, the actual role of this gene in the pathogenesis of this disease is still being studied (25).

Deletion of the β-catenin (CTNNB1) gene in MM cell lines was discovered in approximately 10% of cases (106). CTNNB1 appears to be a cell growth stimulation factor in different tumor forms (107), although further studies are needed in this case too to clarify their pathogenetic role.

Recent studies have suggested that the Hedgehog signal pathway is activated in MM cell lines (108). This pathway in fact appears to be regulated by 13 genes in cancer pathogenesis.  However, only three of these genes were mutated in MM cell lines: PTCH1, SMO and SUFU (108-110).

The circadian rhythm is regulated by different genes and proteins that involve different processes: sleep, body temperature, hormones, the immune response and many others (111). Various studies have demonstrated a possible correlation between changes in the circadian rhythm and the development of cancer (112-113). Studies are investigating different genes with respect to MM, including the following: the clock genes PER (period), CRY (cryptochrome) BMAL1 (aryl hydrocarbonreceptor nuclear translocator-like) (114-116).

CONCLUSIONS

Genetic mutations associated with MM are being studied, with many already identified and many others being defined.

All these studies are aimed at increasing our knowledge about the genetics of MM, to understand how genetic mutations are associated with this disease.

Defining their pathogenetic role and cause would open up new avenues of research and certainly to potential experimental therapeutic strategies aimed at restoring the correct genetics whenever possible, which appear to be distorted in this disease.

BIBLIOGRAPHY

[1] C. Tan, T. Treasure, Mesothelioma: time to take stock, J. R. Soc. Med. 98 (2005) 455–458.

[2] M.R. Becklake, E. Bagatin, J.A. Neder, Asbestos-related diseases of the lungs and pleura: uses, trends and management over the last century, Int. J. Tuberc. Lung Dis. 11 (2007) 356–369.

[3] H. Yang, J. Testa, M. Carbone, Mesothelioma epidemiology, carcinogenesis, and pathogenesis, Curr. Treat. Options in Oncol. 9 (2008) 147–157.

[4] J.P. van Meerbeeck, R. Gaafar, C. Manegold, R.J. Van Klaveren, E.A. Van Marck, M. Vincent, C. Legrand, A. Bottomley, C. Debruyne, G. Giaccone, 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. 23 (2005) 6881–6889.

[5] J.C. Wagner, C.A. Sleggs, P. Marchand, Diffuse pleural mesothelioma and asbestos exposure in the North Western Cape Province, Br. J. Ind. Med. 17 (1960) 260–271.

[6] ATSDR, Public Health Statement for Asbestos, 2001.

[7] J.J. Manfredi, J. Dong, W.J. Liu, L. Resnick-Silverman, R. Qiao, P. Chahinian, M. Saric, A.R. Gibbs, J.I. Phillips, J. Murray, C.W. Axten, R.P. Nolan, S.A. Aaronson, Evidence against a role for SV40 in humanmesothelioma, Cancer Res. 65 (2005) 2602–2609.

[8] P. Carthew, R. Hill, R. Edwards, P. Lee, Intrapleural administration of fibres induces mesothelioma in rats in the same relative order of hazard as occurs in man after exposure, Hum. Exp. Toxicol. 11 (1992) 530–534.

[9] F.E. Mott, Mesothelioma: a review, Ochsner J. 12 (2012) 70–79.

[10] D.A. Fennell, Genetics and molecular biology of mesothelioma, Malignant Mesothelioma, vol. 189, Springer, Berlin Heidelberg, 2012, pp. 149–167.

 [11] M. Cheung, J. Talarchek, K. Schindeler, E. Saraiva, L.S. Penney,M. Ludman, J.R. Testa, Further evidence for germline BAP1 mutations predisposing to melanoma and malignant mesothelioma, Cancer Genet. 206 (2013) 206–210.

[12] C.T. Yang, L. You, C.C. Yeh, J.W.C. Chang, F. Zhang, F. McCormick, D.M. Jablons, Adenovirus-mediated p14ARF gene transfer in human mesothelioma cells, J. Natl. Cancer Inst. 92 (2000) 636–641.

[13] S. Xio, D. Li, J. Vijg, D.J. Sugarbaker, J.M. Corson, J.A. Fletcher, Codeletion of p15 and p16 in primary malignant mesothelioma, Oncogene 11 (1995) 511–515.

[14] M. Ladanyi, Implications of P16/CDKN2A deletion in pleural mesotheliomas, Lung Cancer 49 (2005) S95–S98(Amsterdam, Netherlands).

[15] D. Jean, J. Daubriac, F.o. Le Pimpec-Barthes, F.o. Galateau-Salle, M.C. Jaurand, Molecular changes in mesothelioma with an impact on prognosis and treatment, Arch. Pathol. Lab. Med. 136 (2012) 277–293.

[16] K.P. Lee, J.H. Lee, T.S. Kim, T.H. Kim, H.D. Park, J.S. Byun, M.C. Kim, W.I. Jeong, D.F. Calvisi, J.M. Kim, D.S. Lim, The Hippo–Salvador pathway restrains hepatic oval cell proliferation, liver size, and liver tumorigenesis, Proc. Natl. Acad. Sci. 107 (2010) 8248–8253.

[17] C. Frezza, C.P. Martins, From tumor prevention to therapy: empowering p53 to fight back, Drug Resist. Updat. 15 (2012) 258–267.

[18] Y. Sekido, Genomic abnormalities and signal transduction dysregulation in malignant mesothelioma cells, Cancer Sci. 101 (2009) 1–6.

[19] A.A. Bahnassy, A.-R.N. Zekri, A.A. Abou-Bakr, M.M. El-Deftar, A. El-Bastawisy, M.A. Sakr, G.M. El-sherif, R.M. Gaafar, Aberrant expression of cell cycle regulatory genes predicts overall and disease free survival in malignant pleuralmesothelioma patients, Exp. Mol. Pathol. 93 (2012) 154–161.

[20] S.L. O'Kane, R.J. Pound, A. Campbell, N. Chaudhuri, M.J. Lind, L. Cawkwell, Expression of bcl-2 family members in malignant pleural mesothelioma, Acta Oncol. 45 (2006) 449–453.

[21] T. Maehama, J.E. Dixon, The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate, J. Biol. Chem. 273 (1998) 13375–13378.

[22] D.A. Altomare, H. You, G.H. Xiao, M.E. Ramos-Nino, K.L. Skele, A. De Rienzo, S.C. Jhanwar, B.T. Mossman, A.B. Kane, J.R. Testa, Human and mouse mesotheliomas exhibit elevated AKT/PKB activity, which can be targeted pharmacologically to inhibit tumor cell growth, Oncogene 24 (2005) 6080–6089.

[23] S.M. Wilson, D. Barbone, T.-M. Yang, D.M. Jablons, R. Bueno, D.J. Sugarbaker, S.L. Nishimura, G.J. Gordon, V.C. Broaddus, mTOR mediates survival signals in malignant mesothelioma grown as tumor fragment spheroids, Am. J. Respir. Cell Mol. Biol. 39 (2008) 576–583.

[24] M. Carbone, L. Ferris, F. Baumann, A. Napolitano, C. Lum, E. Flores, G. Gaudino, A. Powers, P. Bryant-Greenwood, T. Krausz, E. Hyjek, R. Tate, J. Friedberg, T. Weigel, H. Pass, H. Yang, BAP1 cancer syndrome: malignant mesothelioma, uveal and cutaneous melanoma, and MBAITs, J. Transl. Med. 10 (2012) 179.

[25] H. Murakami, T. Mizuno, T. Taniguchi, M. Fujii, F. Ishiguro, T. Fukui, S. Akatsuka, Y. Horio, T. Hida, Y. Kondo, S. Toyokuni,H. Osada, Y. Sekido, LATS2 is a tumor suppressor gene of malignant mesothelioma, Cancer Res. 71 (2011) 873–883.

[26] Y. Suzuki, H.Murakami, K. Kawaguchi, T. Tanigushi, M. Fujii, K. Shinjo, Y. Kondo, H. Osada, K. Shimokata, Y. Horio, Y. Hasegawa, T. Hida, Y. Sekido, Activation of the PI3K-AKT pathway in human malignant mesothelioma cells, Mol. Med. Rep. 2 (2009) 181–188.

[27] A.Y. Lee, D.J. Raz, B. He, D.M. Jablons, Update on the molecular biology of malignant mesothelioma, Cancer 109 (2007) 1454–1461.

[28] J.G. Edwards, D.E.B. Swinson, J.L. Jones, D.A. Waller, K.J. O'Byrne, EGFR expression: associations with outcome and clinicopathological variables in malignant pleural mesothelioma, Lung Cancer 54 (2006) 399–407(Amsterdam, Netherlands).

[29] D. Hanahan, J. Folkman, Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis, Cell 86 (1996) 353–364.

[30] L. Strizzi, A. Catalano, G. Vianale, S. Orecchia, A. Casalini, G. Tassi, R. Puntoni, L. Mutti, A. Procopio, Vascular endothelial growth factor is an autocrine growth factor in human malignant mesothelioma, J. Pathol. 193 (2001) 468–475.

[31] H.L. Kindler, Moving beyond chemotherapy: novel cytostatic agents for malignant mesothelioma, Lung Cancer 45 (2004) S125–S127(Amsterdam, Netherlands).

[32] R.A. Kratzke, G.A. Otterson, C.E. Lincoln, S. Ewing, H. Oie, J. Geradts, F.J. Kaye, Immunohistochemical analysis of the p16INK4 cyclin-dependent kinase inhibitor in malignant mesothelioma, J. Natl. Cancer Inst. 87 (1995) 1870–1875.

[33] S.W. Lowe, C.J. Sherr, Tumor suppression by Ink4a-Arf: progress and puzzles, Curr. Opin. Genet. Dev. 13 (2003) 77–83.

[34] K. Segers, M. Ramael, S.K. Singh, E. Marck, J. Weyler, J. Meerbeeck, P. Vermeire, Immunoreactivity for bcl-2 protein in malignant mesothelioma and nonneoplastic mesothelium, Virchows Arch. 424 (1994) 631 634.

[35] Y. Soini, V. Kinnula, R. Kaarteenaho-Wiik, E. Kurttila, K. Linnainmaa, P. Pääkkö, Apoptosis and expression of apoptosis regulating proteins bcl-2, mcl-1, bcl-X, and bax in malignant mesothelioma, Clin. Cancer Res. 5 (1999) 3508–3515.

[36] S. Hopkins-Donaldson, R. Cathomas, A.P. Simões-Wüst, S. Kurtz, L. Belyanskya, R.A. Stahel, U. Zangemeister-Wittke, Induction of apoptosis and chemosensitization of mesothelioma cells by Bcl-2 and Bcl-xL antisense treatment, Int. J. Cancer 106 (2003) 160–166.

[37] F.-X. Yu, K.-L. Guan, The Hippo pathway: regulators and regulations, Genes Dev. 27 (2013) 355–371.

[38] T. Mizuno, H. Murakami, M. Fujii, F. Ishiguro, I. Tanaka, Y. Kondo, S. Akatsuka, S. Toyokuni, K. Yokoi, H. Osada, Y. Sekido, YAP induces malignant mesothelioma cell proliferation by upregulating transcription of cell cycle-promoting genes, Oncogene 31 (2012) 5117–5122.

[39] M. Fujii, T. Toyoda, H. Nakanishi, Y. Yatabe, A. Sato, Y. Matsudaira, H. Ito, H. Murakami, Y. Kondo, E. Kondo, T. Hida, T. Tsujimura, H. Osada, Y. Sekido, TGF-β synergizes with defects in the Hippo pathway to stimulate human malignant mesothelioma growth, J. Exp. Med. 209 (2012) 479–494.

[40] K. Saito-Diaz, T. Chen, X. Wang, C. Thorne, H. Wallace, A. Page-McCaw, E. Lee, The way Wnt works: components and mechanism, Growth Factors 31 (2013) 1–31.

[41] K. Uematsu, S. Kanazawa, L. You, B. He, Z. Xu, K. Li, B.M. Peterlin, F. McCormick, D.M. Jablons, Wnt pathway activation in mesothelioma: evidence of disheveled overexpression and transcriptional activity of Î2-catenin, Cancer Res. 63 (2003) 4547–4551.

[42] M. Ruas, G. Peters, The p16INK4a/CDKN2A tumor suppressor and its relatives, Biochim. Biophys. Acta 1378 (1998) F115–F177.

[43] G. Thillainadesan, J.M. Chitilian, M. Isovic, J.N. Ablack, J.S. Mymryk, M. Tini, J. Torchia, TGF-beta-dependent active demethylation and expression of the p15ink4b tumor suppressor are impaired by the ZNF217/CoREST complex, Mol. Cell 46 (2012) 636–649.

[44] P. Krimpenfort, A. Ijpenberg, J.Y. Song, M. van der Valk, M. Nawijn, J. Zevenhoven, A. Berns, p15Ink4b is a critical tumour suppressor in the absence of p16Ink4a, Nature 448 (2007) 943–946.

[45] P. Berggren, R. Kumar, S. Sakano, L. Hemminki, T.Wada, G. Steineck, J. Adolfsson, P. Larsson, U. Norming, H. Wijkström, K. Hemminki, Detecting homozygous deletions in the CDKN2A(p16INK4a)/ARF(p14ARF) gene in urinary bladder cancer using real-time quantitative PCR, Clin. Cancer Res. 9 (2003) 235–242.

[46] L.L. Chang, W.T. Yeh, S.Y. Yang, W.J. Wu, C.H. Huang, Genetic alterations of p16INK4a and p14ARF genes in human bladder cancer, J.Urol. 170 (2003) 595–600.

[47] V.L. Brown, C.A. Harwood, T. Crook, J.G. Cronin, D.P. Kelsell, C.M. Proby, p16INK4a and p14ARF tumor suppressor genes are commonly inactivated in cutaneous squamous cell carcinoma, J. Invest. Dermatol. 122 (2004) 1284–1292.

[48] J.L. Wang, B.Y. Zheng, X.D. Li, K. Nokelainen, T. Angstrom, M.S. Lindstrom, K.L. Wallin, p16INK4A and p14ARF expression pattern by immunohistochemistry in human papillomavirus-related cervical neoplasia, Mod. Pathol. 18 (2005) 629–637.

[49] J.Q. Cheng, S.C. Jhanwar, W.M. Klein, D.W. Bell,W.-C. Lee, D.A. Altomare, T. Nobori, O.I. Olopade, A.J. Buckler, J.R. Testa, p16 Alterations and deletion mapping of 9p21– p22 in malignant mesothelioma, Cancer Res. 54 (1994) 5547–5551.

[50] P.B. Illei, V.W. Rusch, M.F. Zakowski, M. Ladanyi, Homozygous deletion of CDKN2A and codeletion of the methylthioadenosine phosphorylase gene in the majority of pleural mesotheliomas, Clin. Cancer Res. 9 (2003) 2108–2113.

[51] F.B. Onofre, A.S. Onofre, N. Pomjanski, B. Buckstegge, H.J. Grote, A. Bocking, 9p21 Deletion in the diagnosis of malignantmesothelioma in serous effusions additional to immunocytochemistry, DNA–ICM, and AgNOR analysis, Cancer 114 (2008) 204–215.

[52] M. Takeda, T. Kasai, Y. Enomoto, M. Takano, K. Morita, E. Kadota, N. Iizuka, H.Maruyama, A. Nonomura, Genomic gains and losses in malignant mesothelioma demonstrated by FISH analysis of paraffin-embedded tissues, J. Clin. Pathol. 65 (2012) 77–82.

[53] S. Chiosea, A. Krasinskas, P.T. Cagle, K.A. Mitchell, D.S. Zander, S. Dacic, Diagnostic importance of 9p21 homozygous deletion in malignant mesotheliomas, Mod. Pathol. 21 (2008) 742–747.

[54] J.R. Fischer, U. Ohnmacht, N. Rieger, M. Zemaitis, C. Stoffregen, M. Kostrzewa, E. Buchholz, C. Manegold, H. Lahm, Promoter methylation of RASSF1A, RARÎ2 and DAPK predict poor prognosis of patients with malignant mesothelioma, Lung Cancer 54 (2006) 109–116.

[55] T. Kamijo, F. Zindy, M.F. Roussel, D.E. Quelle, J.R. Downing, R.A. Ashmun, G. Grosveld, C.J. Sherr, Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF, Cell 91 (1997) 649–659.

[56] N.E. Sharpless, N. Bardeesy, K.H. Lee, D. Carrasco, D.H. Castrillon, A.J. Aguirre, E.A. Wu, J.W. Horner, R.A. DePinho, Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis, Nature 413 (2001) 86–91.

[57] M. Serrano, H. Lee, L. Chin, C. Cordon-Cardo, D. Beach, R.A. DePinho, Role of the INK4a locus in tumor suppression and cell mortality, Cell 85 (1996) 27–37.

[58] D.A. Altomare, C.W. Menges, J. Pei, L. Zhang, K.L. Skele-Stump, M. Carbone, A.B. Kane, J.R. Testa, Activated TNF-alpha/NF-kappaB signaling via down-regulation of Fas-associated factor 1 in asbestos-induced mesotheliomas from Arf knockout mice, Proc. Natl. Acad. Sci. U.S.A. 106 (2009) 3420–3425.

[59] D.A. Altomare, C.W. Menges, J. Xu, J. Pei, L. Zhang, A. Tadevosyan, E. Neumann- Domer, Z. Liu, M. Carbone, I. Chudoba, A.J. Klein-Szanto, J.R. Testa, Losses of both products of the Cdkn2a/Arf locus contribute to asbestos-induced mesothelioma development and cooperate to accelerate tumorigenesis, PLoS One 6 (2011) e18828.

[60] S. Frizelle, J. Rubins, J. Zhou, D. Curiel, R. Kratzke, Gene therapy of established mesothelioma xenografts with recombinant p16INK4a adenovirus, Cancer Gene Ther. 7 (2000) 1421–1425.

[61] S. Frizelle, J. Rubins, J. Zhou, D. Curiel, R. Kratzke, Gene therapy of established mesothelioma xenografts with recombinant p16INK4a adenovirus, Cancer Gene Ther. 7 (2000) 1421–1425.

[62] C. Yang, L. You, Y. Lin, C. Lin, F. McCormick, D. Jablons, A comparison analysis of anti-tumor efficacy of adenoviral gene replacement therapy (p14ARF and p16INK4A) in human mesothelioma cells, Anticancer Res. 23 (2003) 33–38.

[63] Y. Tada, H. Shimada, K. Hiroshima, M. Tagawa, A potential therapeutic strategy for malignant mesothelioma with gene medicine, Biomed. Res. Int. 2013 (2013) 8.

[64] D.G.R. Evans, Neurofibromatosis 2 [bilateral acoustic neurofibromatosis, central neurofibromatosis, NF2, neurofibromatosis type II], Genet. Med. 11 (2009) 599.

[65] Y. Sekido, H.I. Pass, S. Bader, D.J.Y. Mew, M.F. Christman, A.F. Gazdar, J.D. Minna, Neurofibromatosis type 2 (NF2) gene is somatically mutated in mesothelioma but not in lung cancer, Cancer Res. 55 (1995) 1227–1231.

[66] A.B. Bianchi, S.I. Mitsunaga, J.Q. Cheng, W.M. Klein, S.C. Jhanwar, B. Seizinger, N. Kley, A.J. Klein-Szanto, J.R. Testa, High frequency of inactivating mutations in the neurofibromatosis type 2 gene (NF2) in primary malignant mesotheliomas, Proc. Natl. Acad. Sci. U.S.A. 92 (1995) 10854–10858.

[67] P. Andujar, J.C. Pairon, A. Renier, A. Descatha, I. Hysi, I. Abd-Alsamad, M.A. Billon- Galland, H.l.n. Blons, B.n.d. Clin, C. Danel, D. Debrosse, F.o. Galateau-Sallé, B. Housset, P. Laurent-Puig, F.o. Le Pimpec-Barthes, M. Letourneux, I. Monnet, J.F.o. Régnard, P. Validire, J. Zucman-Rossi, M.C. Jaurand, D. Jean, Differential mutation profiles and similar intronic TP53 polymorphisms in asbestos-related lung cancer and pleural mesothelioma, Mutagenesis 28 (2013) 323–331.

[68] H. Nemoto, G. Tate, K. Kishimoto,M. Saito, A. Shirahata, T. Umemoto, T. Matsubara, T. Goto, H.Mizukami, G. Kigawa, T.Mitsuya, K. Hibi, Heterozygous loss of NF2 is an early molecular alteration in well-differentiated papillary mesothelioma of the peritoneum, Cancer Genet. 205 (2012) 594–598.

[69] M. Guled, L. Lahti, P.M. Lindholm, K. Salmenkivi, I. Bagwan, A.G. Nicholson, S. Knuutila, CDKN2A, NF2, and JUN are dysregulated among other genes by miRNAs in malignant mesothelioma—a miRNA microarray analysis, Genes Chromosom. Cancer 48 (2009) 615–623.

[70] J. Jongsma, E. van Montfort, M. Vooijs, J. Zevenhoven, P. Krimpenfort, M. van derValk, M. van de Vijver, A. Berns, A conditional mouse model for malignant mesothelioma, Cancer Cell 13 (2008) 261–271.

[71] K. Ikeda, Y. Saeki, C. Gonzalez-Agosti, V. Ramesh, E.A. Chiocca, Inhibition of NF2-negative and NF2-positive primary human meningioma cell proliferation by overexpression of merlin due to vector-mediated gene transfer, J. Neurosurg. 91 (1999) 85–92.

[72] K.M.M. Schulze, C.O. Hanemann, H.W. Müller, H. Hanenberg, Transduction of wild-type merlin into human schwannoma cells decreases schwannoma cell growth and induces apoptosis, Hum. Mol. Genet. 11 (2002) 69–76.

[73] J. Fraenzer, H. Pan, L.J. Minimo, G. Smith, D. Knauer, G. Hung, Overexpression of the NF2 gene inhibits schwannoma cell proliferation through promoting PDGFR degradation, Int. J. Oncol. 2003 (2003) 1493–1500.

[74] F.C. Morales, J.R. Molina, Y. Hayashi, M.-M. Georgescu, Overexpression of ezrin inactivates NF2 tumor suppressor in glioblastoma, Neuro-Oncology 12 (2010) 528–539.

[75] P. Poulikakos, G. Xiao, R. Gallagher, S. Jablonski, S. Jhanwar, J. Testa, Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK, Oncogene 25 (2006) 5960–5980.

[76] G.H. Xiao, R. Gallagher, J. Shetler, K. Skele, D.A. Altomare, R.G. Pestell, S. Jhanwar, J.R. Testa, The NF2 tumor suppressor gene product, merlin, inhibits cell proliferation and cell cycle progression by repressing cyclin D1 expression, Mol. Cell. Biol. 25 (2005) 2384–2394.

[77] I. Roushdy-Hammady, J. Siegel, S. Emri, J.R. Testa, M. Carbone, Geneticsusceptibility factor and malignant mesothelioma in the Cappadocian region of Turkey, Lancet 357 (2001) 444–445.

[78] A.U. Dogan, Y.I. Baris, M. Dogan, S. Emri, I. Steele, A.G. Elmishad,M. Carbone,Genetic predisposition to fiber carcinogenesis causes a mesothelioma epidemic in Turkey, Cancer Res. 66 (2006) 5063–5068.

[79] M. Metintas,G.Hillerdal, S.Metintas, P.Dumortier, Endemicmalignantmesothelioma: exposure to erionite is more important than genetic factors, Arch. Environ. Occup. Health 65 (2010) 86–93.

[80] J.R. Testa,M. Cheung, J. Pei, J.E. Below, Y. Tan, E. Sementino, N.J. Cox, A.U. Dogan, H.I. Pass, S. Trusa, M. Hesdorffer, M. Nasu, A. Powers, Z. Rivera, S. Comertpay, M. Tanji, G. Gaudino, H. Yang, M. Carbone, Germline BAP1 mutations predispose to malignant mesothelioma, Nat. Genet. 43 (2011) 1022–1025.

[81] T. Popova, L. Hebert, V. Jacquemin, S. Gad, V. Caux-Moncoutier, C. Dubois-d Enghien, B. Richaudeau, X. Renaudin, J. Sellers, A. Nicolas, X. Sastre-Garau, L. Desjardins, G. Gyapay, V. Raynal, Olga M. Sinilnikova, N. Andrieu, E. Manié, A. de Pauw, P. Gesta, V. Bonadona, Christine M. Maugard, C. Penet, M.F. Avril, E. Barillot, O. Cabaret, O. Delattre, S. Richard, O. Caron, M. Benfodda, H.-H. Hu, N. Soufir, B. Bressac-de Paillerets, D. Stoppa-Lyonnet, M.-H. Stern, Germline BAP1 mutations predispose to renal cell carcinomas, Am. J. Hum. Genet. 92 (2013) 974–980.

[82] M. Bott, M. Brevet, B.S. Taylor, S. Shimizu, T. Ito, L.Wang, J. Creaney, R.A. Lake, M.F. Zakowski, B. Reva, C. Sander, R. Delsite, S. Powell, Q. Zhou, R. Shen, A. Olshen, V. Rusch, M. Ladanyi, The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma, Nat. Genet. 43 (2011) 668–672.

[83] Y. Yoshikawa, A. Sato, T. Tsujimura, M. Emi, T. Morinaga, K. Fukuoka, S. Yamada, A. Murakami, N. Kondo, S. Matsumoto, Y. Okumura, F. Tanaka, S. Hasegawa, T. Nakano, T. Hashimoto-Tamaoki, Frequent inactivation of the BAP1 gene in epithelioid-type malignant mesothelioma, Cancer Sci. 103 (2012) 868–874.

[84] M. Zauderer, M. Bott, R. McMillan, C. Sima, V. Rusch, L. Krug, M. Ladanyi, Clinical characteristics of patients withmalignant pleuralmesothelioma harboring somatic BAP1 mutations, J. Thorac. Oncol. 8 (2013) 1430–1433.

[85] L. Arzt, F. Quehenberger, I. Halbwedl, T. Mairinger, H. Popper, BAP1 protein is a progression factor in malignant pleural mesothelioma, Pathol. Oncol. Res. (2013) 1–7.

[86] R.Murali, T.Wiesner,R. Scolyer, Tumours associated with BAP1mutations, Pathology 45 (2013) 116–126.

[87] R. Pilarski, C.M. Cebulla, J.B.Massengill, K. Rai, T. Rich, L. Strong, B. McGillivray,M.-J. Asrat, F.H. Davidorf, M.H. Abdel-Rahman, Expanding the clinical phenotype of hereditary BAP1 cancer predisposition syndrome, reporting three new cases, Genes Chromosom. Cancer 53 (2) (2013) 177–182.

[88] R.W. Justice, O. Zilian, D.F. Woods, M. Noll, P.J. Bryant, The Drosophila tumor suppressor gene warts encodes a homolog of human myotonic dystrophy kinase and is required for the control of cell shape and proliferation, Genes Dev. 9 (1995) 534–546.

[89] N. Yabuta, T. Fujii, N.G. Copeland, D.J. Gilbert, N.A. Jenkins, H. Nishiguchi, Y. Endo, S. Toji, H. Tanaka, Y. Nishimune, H. Nojima, Structure, expression, and chromosome mapping of LATS2, a mammalian homologue of the Drosophila tumor suppressor gene lats/warts, Genomics 63 (2000) 263–270.

[90] C.F. Chen, S.H. Yeh, D.S. Chen, P.J. Chen, Y.S. Jou, Molecular genetic evidence supporting a novel human hepatocellular carcinoma tumor suppressor locus at 13q12.11, Genes Chromosom. Cancer 44 (2005) 320–328.

[91] Y. Aylon, D. Michael, A. Shmueli, N. Yabuta, H. Nojima,M. Oren, A positive feedback loop between the p53 and Lats2 tumor suppressors prevents tetraploidization, Genes Dev. 20 (2006) 2687–2700.

[92] Y. Aylon, Y. Ofir-Rosenfeld, N. Yabuta, E. Lapi, H. Nojima, X. Lu, M. Oren, The Lats2 tumor suppressor augments p53-mediated apoptosis by promoting the nuclear proapoptotic function of ASPP1, Genes Dev. 24 (2010) 2420–2429.

[93] S. Visser, X. Yang, LATS tumor suppressor: a new governor of cellular homeostasis, Cell Cycle 9 (2010) 3922–3933.

[94] B.C. Christensen, E.A. Houseman, J.J. Godleski, C.J.Marsit, J.L. Longacker, C.R. Roelofs, M.R. Karagas, M.R. Wrensch, R.-F. Yeh, H.H. Nelson, J.L. Wiemels, S. Zheng, J.K. Wiencke, R. Bueno, D.J. Sugarbaker, K.T. Kelsey, Epigenetic profiles distinguish pleural mesothelioma from normal pleura and predict lung asbestos burden and clinical outcome, Cancer Res. 69 (2009) 227–234.

[95] Y. Goto, K. Shinjo, Y. Kondo, L. Shen,M. Toyota, H. Suzuki,W. Gao, B. An, M. Fujii, H. Murakami, H. Osada, T. Taniguchi, N. Usami,M. Kondo, Y. Hasegawa, K. Shimokata, K. Matsuo, T. Hida, N. Fujimoto, T. Kishimoto, J.-P.J. Issa, Y. Sekido, Epigenetic profiles distinguish malignant pleural mesothelioma from lung adenocarcinoma, Cancer Res. 69 (2009) 9073–9082.

[96] J.R. Fischer, U. Ohnmacht, N. Rieger, M. Zemaitis, C. Stoffregen, M. Kostrzewa, E. Buchholz, C. Manegold, H. Lahm, Promoter methylation of RASSF1A, RARβ and DAPK predict poor prognosis of patients with malignant mesothelioma, Lung Cancer 54 (2006) 109–116.

[97] F. Vandermeers, S. Neelature Sriramareddy, C. Costa, R. Hubaux, J.-P. Cosse, L. Willems, The role of epigenetics in malignant pleural mesothelioma, Lung Cancer 81 (2013) 311–318(Amsterdam, Netherlands).

[98] S.V. Ivanov, C.M.V. Goparaju, P. Lopez, J. Zavadil, G. Toren-Haritan, S. Rosenwald,M. Hoshen, A. Chajut, D. Cohen, H.I. Pass, Pro-tumorigenic effects of miR-31 loss in mesothelioma, J. Biol. Chem. 285 (2010) 22809–22817.

[99] G. Reid, M.E. Pel, M.B. Kirschner, Y.Y. Cheng, N. Mugridge, J.Weiss, M.Williams, C. Wright, J.J.B. Edelman, M.P. Vallely, B.C. McCaughan, S. Klebe, H. Brahmbhatt, J.A. MacDiarmid, N. van Zandwijk, Restoring expression of miR-16: a novel approach to therapy for malignant pleural mesothelioma, Ann. Oncol. 24 (12) (2013) 3128–3135.

[100] G.V. Gee, D.C. Koestler, B.C. Christensen, D.J. Sugarbaker, D. Ugolini, G.P. Ivaldi, M.B. Resnick, E.A. Houseman, K.T. Kelsey, C.J. Marsit, Downregulated microRNAs in the differential diagnosis of malignant pleural mesothelioma, Int. J. Cancer 127 (2010) 2859–2869.

[101] M.B. Kirschner, Y.Y. Cheng, B. Badrian, S.C. Kao, J. Creaney, J.J. Edelman, N.J. Armstrong, M.P. Vallely, A.W. Musk, B.W. Robinson, B.C. McCaughan, S. Klebe, S.E. Mutsaers, N. van Zandwijk, G. Reid, Increased circulating miR-625–3p: a potential biomarker for patients with malignant pleural mesothelioma, J Thorac Oncol 7 (2012) 1184–1191.

[102] T.Muraoka, J. Soh, S. Toyooka, K. Aoe, N. Fujimoto, S. Hashida, Y.Maki, N. Tanaka, K. Shien, M. Furukawa, H. Yamamoto, H. Asano, K. Tsukuda, T. Kishimoto, T. Otsuki, S. Miyoshi, The degree of microRNA-34b/c methylation in serum-circulating DNA is associated with malignant pleural mesothelioma, Lung Cancer 82 (3) (2013) 485–490.

[103] M. Cioce, F. Ganci, V. Canu, A. Sacconi, F. Mori, C. Canino, E. Korita, B. Casini, G. Alessandrini, A. Cambria, M.A. Carosi, R. Blandino, V. Panebianco, F. Facciolo, P. Visca, S. Volinia, P. Muti, S. Strano, C.M. Croce, H.I. Pass, G. Blandino, Protumorigenic effects of mir-145 loss in malignant pleural mesothelioma, Oncogene (2013), in press, (Epub ahead of print).

[104] N. Tapon, K.F. Harvey, D.W. Bell, D.C.R. Wahrer, T.A. Schiripo, D.A. Haber, I.K. Hariharan, Salvador Promotes both cell cycle exit and apoptosis in Drosophila and is mutated in human cancer cell lines, Cell 110 (2002) 467–478.

[105] L. Lu, Y. Li, S.M. Kim, W. Bossuyt, P. Liu, Q. Qiu, Y. Wang, G. Halder, M.J. Finegold, J.-S. Lee, R.L. Johnson, Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver, Proc. Natl. Acad. Sci. 107 (2010) 1437–1442.

[106] K. Shigemitsu, Y. Sekido, N. Usami, S.Mori,M. Sato, Y. Horio, Y. Hasegawa, S. Bader, A. Gazdar, J. Minna, T. Hida, H. Yoshioka, M. Imaizumi, Y. Ueda, M. Takahashi, K. Shimokata, Genetic alteration of the beta-catenin gene (CTNNB1) in human lung cancer and malignant mesothelioma and identification of a new 3p21.3 homozygous deletion, Oncogene 20 (2001) 4249–4257.

[107] N. Usami, Y. Sekido, O. Maeda, K. Yamamoto, J. Minna, Y. Hasegawa, H. Yoshioka, M. Imaizumi, Y. Ueda, M. Takahashi, K. S., Beta-catenin inhibits cell growth of a malignant mesothelioma cell line, NCI-H28, with a 3p21.3 homozygous deletion, Oncogene 22 (2003) 7923–7930.

[108] M. You, J. Varona-Santos, S. Singh, D.J. Robbins, N. Savaraj, D.M. Nguyen, Targeting of the Hedgehog signal transduction pathway suppresses survival ofmalignant pleural mesothelioma cells in vitro, J. Thorac. Cardiovasc. Surg. 147 (1) (2013) 508–516.

[109] C.B. Lim, C.M. Prêle, H.M. Cheah, Y.Y. Cheng, S. Klebe, G. Reid, D.N.Watkins, S. Baltic, P.J. Thompson, S.E. Mutsaers, Mutational analysis of hedgehog signaling pathway genes in human malignant mesothelioma, PLoS One 8 (2013) e66685.

[110] G. Klorin, E. Rozenblum, O. Glebov, R.L. Walker, Y. Park, P.S. Meltzer, I.R. Kirsch, F.J. Kaye, A.V. Roschke, Integrated high-resolution array CGH and SKY analysis of homozygous deletions and other genomic alterations present in malignant mesothelioma cell lines, Cancer Genet. 206 (2013) 191–205.

[111] C. Savvidis, M. Koutsilieris, Circadian rhythm disruption in cancer biology, Mol. Med. 18 (2012) 1249–1260.

[112] R.G. Stevens, Circadian disruption and breast cancer: from melatonin to clock genes, Epidemiology 16 (2005) 254–258.

[113] S. Giacchetti, G. Bjarnason, C. Garufi, D. Genet, S. Iacobelli, M. Tampellini, R. Smaaland, C. Focan, B. Coudert, Y. Humblet, J.L. Canon, A. Adenis, G.L. Re, C. Carvalho, J. Schueller, N. Anciaux, M.A. Lentz, B.t. Baron, T. Gorlia, F. Lévi, Phase III trial comparing 4-day chronomodulated therapy versus 2-day conventional

delivery of fluorouracil, leucovorin, and oxaliplatin as first-line chemotherapy of metastatic colorectal cancer: the European Organisation for Research and Treatment of Cancer Chronotherapy Group, J. Clin. Oncol. 24 (2006) 3562–3569.

[114] O.D. Røe, E. Anderssen, E. Helge, C.H. Pettersen, K.S. Olsen, H. Sandeck, R. Haaverstad, S. Lundgren, E. Larsson, Genome-wide profile of pleuralmesothelioma versus parietal and visceral pleura: the emerging gene portrait of themesothelioma phenotype, PLoS One 4 (2009) e6554.

[115] M. Elshazley, M. Sato, T. Hase, R. Yamashita, K. Yoshida, S. Toyokuni, F. Ishiguro, H. Osada, Y. Sekido, K. Yokoi, N. Usami, D.S. Shames, M. Kondo, A.F. Gazdar, J.D.Minna, Y. Hasegawa, The circadian clock gene BMAL1 is a novel therapeutic target for malignant pleural mesothelioma, Int. J. Cancer 131 (2012) 2820–2831.

[116] M. Brevet, S. Shimizu, M.J. Bott, N. Shukla, Q. Zhou, A.B. Olshen, V. Rusch, M. Ladanyi, Coactivation of receptor tyrosine kinases in malignant mesothelioma as a rationale for combination targeted therapy, J. Thorac. Oncol. 6 (2011) 864–874.

> Download article as PDF

INTRODUCTION

Malignant pleural mesothelioma (MPM) is a tumor associated with exposure to asbestos (1, 2). It is an aggressive disease with a poor prognosis whose standard treatment does not greatly improve survival (3-9), and it is the reason why many studies are currently investigating MPM to discover new findings that may help increase our knowledge about the disease and thus optimize treatment goals (10-26).

Emerging scientific evidence has shown that tumor aggressiveness may be associated with the genome and the aberrant expression of some genes. Several studies have therefore focused on the role of microRNAs (miRNAs) in the tumor genesis of MPM.

MiRNAs are small (17–22 nucleotides), single-stranded, non-coding RNAs involved in many cellular processes that regulate gene expression (7).

MiRNA are often aberrantly expressed in tumors. Specifically, multiple miRNA expression profiles have been documented in MPM cells as opposed to healthy mesothelial cells, suggesting a potential role for miRNAs as both oncogenes and tumor suppressors in tumor genesis.

We hope that new diagnostic methods will be found to improve the diagnosis and treatment of MPM (8,10), which is why research has focused on defining new clinical prognostic factors. New biomarkers are also being investigated because they can help predict the evolution of the disease. Specific biomarkers that can diagnose MPM have not yet been validated, although studies are currently being conducted (27-31). Identifying new MPMP tumor markers could certainly help in the early diagnosis and treatment of this disease.

The purpose of this bibliography revision is to communicate the recent findings about the new class of microRNA markers.

DEFINITION OF miRNAs

Biogenesis of miRNAs
MicroRNA (miRNA) are short, single-stranded, non-coding RNAs acting as a new class of regulatory genes (32) that bind to the 3’ untranslated region of their target mRNAs, thus regulating post-transcriptional gene expression.

The translation of miRNA in proteins is inhibited due to the partial complementary binding between the miRNA and its target. Conversely, full complementary binding leads to the degradation of the miRNA.

Function of miRNAs
A single miRNA can regulate hundreds of targets downstream, so these molecules play an important role in various cell processes, including proliferation, development, differentiation, apoptosis, and response to stress. They are also aberrantly expressed in various cancers and so could play a key role in tumor genesis.

Recent studies have shown that miRNAs are non-invasive biomarkers that may offer new pathways for early diagnosis and treatment of various cancers (33-35) due to their tumor-specific expression profiles and presence in peripheral blood (36-37). MiRNAs could be useful for defining profiles that identify different tumor subtypes (50-51).

MiRNAs are tissue-specific and can be investigated to identify cancer tissue origin (36-37).

The presence of miRNAs in bodily fluids such as serum, plasma, saliva and urine might be useful to predict the clinical outcome and response to cancer treatment (38-41).

They could also be used as prognostic markers, which has been documented in various cancer types (43-49).

Analysis of miRNAs
Microarray analysis and quantitative real-time polymerase chain reaction (qRT-PCR) are the most commonly used methods of investigating miRNAs.

Microarray profiling is a technique in which microscopic probes are attached to a solid surface such as glass, plastic or silicon chips to form an array (matrix) (52), permitting the simultaneous analysis of many genes within a sample.

Microarrays use a technique known as inverse hybridization, which consists of attaching all the DNA segments (known as probes) onto a medium and marking the nucleic acid that we want to identify (known as the target). This method was developed in the 1990s and allows us to analyze gene expression by monitoring the RNA produced by thousands of genes in a single procedure.

MiRNAs are studied by first extracting them from the cells, converting them into cDNA using an enzyme known as reverse transcriptase and marking them with a fluorescent probe. When the probe in the matrix and the cDNA hybridize, the cDNA target binds to the probe and can be identified simply by looking at the position where it is bound.

The second method is qRT-PCR, which is a more sensitive, quantitative profiling instrument that analyzes the expression of a single cell, which could be applied in real time using primers together with specific samples (or tests?) [53].

These two methods should be used together to confirm the data and make them more credible, even though many studies have obtained results using a single techniqe.

Role of miRNAs

Few studies have actually evaluated the different expression of mRNAs with the aim of improving the diagnosis and treatment of MPM.

Early studies investigated the microarrays used to analyze how miRNAs are expressed differently in cancerous tissue versus normal tissue (54).

Biomarkers for the early identification of MPM
There is a growing desire to discover new biomarkers to identify MPM and a number of studies have been involved in defining the accuracy, feasibility and specificity of miRNAs as clinical biomarkers.

Abnormal increases in miRNA levels in different tumor types have been observed, and researchers suggest that these data could also be used to define the development and progression of MPM (55). Vascular endothelial growth factor (VEGF) has also been described as one of the targets of a specific miRNA, miR-126, and MPM patients have very high VEGF levels in their blood (55).

Several studies have shown that miR-126 expression is reduced in cancerous cells, which are characterized instead by increased VEGF expression, suggesting that this miRNA may play a role in tumor suppression (56).

A correlation between the levels of miR-126 found in serum and SMRP, a specific marker in patients at high risk of developing MPM, has been observed so it could presumably be used as a marker for the early diagnosis of MPM.

Recent research has shown that miR-126 can distinguish patients with MPM from patients with NSCLC (non-small cell lung cancer), and low levels of circulating miR-126 have in fact been found in MPM versus NSCLC samples (57).

This marker is not tumor-specific, however, and is often expressed in low levels in other tumor types so it should be used in combination with other markers such as mesothelin rather than alone (57).

Diagnosis
Up to now, it has been difficult to differentiate between MPM and adenocarcinomas or epithelial metastases of other cancers, and since there are no accurate markers miRNA expression could be an interesting option for obtaining a more differential diagnosis.

Several studies have shown that different patterns of miRNA expression can distinguish between MPM, lung adenocarcinoma or other cancers of the pleura (58-59).

Recent research has shown that some miRNA (miR-17-92) may be up-regulated in MPM cells, while other miRNA are down-regulated as typically occurs in other tumor types (miR-31, miR-221, miR-222) (60-61).

However, some statistical studies have shown that although specific miRNA (miR-17-5p, miR-30, miR-221, miR-222) are more characteristic of some histological tumor types, they cannot be considered as diagnostic markers to differentiate MPM from malignant mesothelial proliferations (58,59,61,63).

MiR-625-3p could be a promising marker, and some studies have shown that it is up-regulated in patients with MPM compared to the controls (65).

The miR-103 marker may be able to differentiate between the diagnosis of MPM and the controls who were exposed to asbestos (66).

Prognostic factors
MiRNAs have also been studied as prognostic factors.

Specifically, some researchers have observed that the patient population can be divided into two groups, namely those with a good prognosis and those with a bad prognosis based on the expression profile of the specific miRNAs (67-69).

MiR-29 is considered a prognostic factor in terms of relapse and survival after cytoinductive surgery, and it does seem to be more highly expressed in patients with epithelial MPM as opposed to those with non-epithelial MPM.

High levels of miR-29 expression may be able to predict a more favorable prognosis compared to patients with lower levels of this miRNA. MiR-29 probably plays a role in inhibiting proliferation, migration, cell invasion and the formation of colonies.

On the other hand, other miRNAs such as miR-31 are associated with a worse prognosis.

Several miRNAs also appear to be specific to some histological subgroups of MPM, such as miR-17-5p, miR-29a, miR-30e-5p, miR-106a and miR-143 (64).

Other miRNAs such as mi-17-5p and miR-30c also have prognostic value, and might be able to identify sarcomatoid MPM with better outcomes.

It is important to remember that besides serving as prognostic markers, miRNAs have also been investigated for their potential role as predictive markers with promising results (54, 55, 58, 59, 61, 63).

Potential targets for anti-tumoral therapies
Several researchers have studied the role of miRNA biomarkers.

Various studies have shown that there is an actual pattern of miRNA that distinguishes between malignant mesothelioma and healthy mesothelial cell cultures (63). The genes involved in regulating the cell cycle could be targets of various mRNA, such as the members of the onco-miR miR-17-92 (miR 17-5p, 18a, 19b, 20a, 25, 92, 106a, 106b) cluster.

There are also specific miRNAs such as miR-31 that could be useful for defining new approaches to treating MPM.

Functional studies have shown that the forced re-expression of this miRNA may lead to the overexpression of the cell cycle and inhibit important factors involved in DNA replication and progression of the cell cycle.

It has been shown that miR-31 has tumor-suppression properties, suggesting the possibility of developing new therapeutic agents for MPM and other tumor types expressing the loss of chromosome 9p21.3 (71).

Another miRNA that has been studied at length is miR-34b/c, which appears to play a role in gene-silencing and suppression of some oncologic characteristics. Here too, the forced expression of this miRNA resulted in a significant anti-cancer effect, secondary to cell cycle arrest, suppression of migration, invasion and cell mobility. MiRNA may also have important therapeutic implications in the near future (72-73).

Cells transfected with miR-34 inhibitors are characterized by increased proliferation, migration and cell invasion (74).

It has been observed that methylation of miR-34b/c circulating in the blood is associated with MPM (75).

Treatment with ranpirnase (Onconase) induces an increase in miR-17 expression, which leads to a down-regulation of miR-30 and NF-kB expression, translating in turn to an increase in apoptosis and a decrease in the aggressiveness of the tumor (77).

MiR-1 appears to have a tumor-suppressive function in MPM treatment (80), and is in fact down-regulated in MPM cell lines versus normal mesothelium (78-79).

A decrease in miR-15 and miR-16 expression has been observed in mesothelioma cell lines. Strong expression of these miRNA is associated with an inhibition of the growth of MPM cells (81-85).

CONCLUSIONS AND FUTURE PROSPECTS

All the studies described in this bibliography revision show the importance of miRNAs in MPM due to their potential role as both diagnostic and prognostic markers and as antineoplastic agents for the treatment of this disease.

The Buzzi Foundation has also funded research in the miRNA field, and a report on the current project is available for consultation: “New targets in mesothelioma cells: hitting translational control and mirnas”. The project researchers have been able to describe a miRNA signature present in mesothelioma tissues. They have analyzed the level of expression of these and other miRNAs in 10 mesothelioma cell lines. The researchers have also demonstrated an extremely heterogeneous situation. In summary, it is very difficult at this stage to define if and which miRNAs have any diagnostic, prognostic or therapeutic significance. The results are in line with the heterogeneity seen in the literature about miRNAs in mesothelioma. However, a review of the data available points to not only heterogeneity in the tumor but also in the analytical methods. In this context, the researchers decided to develop an innovative method to unambiguously define which miRNA are expressed in human mesothelioma tissue, a necessary step in order to understand whether miRNAs are effective markers. This technology could be transferred to diagnostic laboratories in the near future.

Very few studies have actually focused on miRNA expression in MPM, so it is not surprising that there are discordant results among the different histotypes, the various sampling sources used in the in vitro and in vivo research, the control groups, the approaches, the standardization techniques and the qRT-PCR and microarray analyses.

Further standardized, multicenter studies are needed using proven and standardized methods. In conclusion, all the results shown confirm the significance of miRNAs in the diagnosis, prognosis and treatment of MPM. All these data should be validated in a uniform manner to identify miRNAs as potential predictive and prognostic markers.

The recent progress in this field will certainly help define future prospects based on new treatment approaches and new opportunities for experimental treatment protocols.

BIBLIOGRAPHY

1. Wagner JC, Sleggs CA, Marchand P (1960) Diffuse pleural mesothelioma and asbestos exposure in the North Western Cape Province. Br J Ind Med 17:260–271
2. Albin M, Magnani C, Krstev S, Rapiti E, Sheferl I (1999) Asbestos and cancer: an overview of current trends in Europe. Environ Health Perspect 107(Suppl 2):289–298
3. Ismail-Khan R, Robinson LA, Williams CC Jr, Garrett CR, Bepler G, Simon GR (2006) Malignant pleural mesothelioma: a comprehensive review. Cancer Control 13:255–263
4. Carbone M, Kratzke RA, Testa JR (2002) The pathogenesis of mesothelioma. Semin Oncol 29:2–17
5. Kaufman AJ, Pass HI (2008) Current concepts in malignant pleural mesothelioma. Expert Rev Anticancer Ther 8:293–303
6. Bridda A, Padoan I, Mencarelli R, Frego M (2007) Peritoneal mesothelioma: a review. MedGenMed 9:32
7. Mathonnet G, Fabian MR, Svitkin YV, Parsyan A, Huck L, Murata T, Biffo S, Merrick WC, Darzynkiewicz E, Pillai RS, Filipowicz W, Duchaine TF, Sonenberg N. MicroRNA inhibition of translation initiation in vitro by targeting the cap-binding complex eIF4F. Science. 2007 Sep 21;317(5845):1764-7. Epub 2007 Jul 26.<(li>
8. Husain AN, Colby T, Ordonez N, Krausz T, Attanoos R, Beasley MB, Borczuk AC, Butnor K, Cagle PT, Chirieac LR, Churg A, Dacic S, Fraire A, Galateau-Salle F, Gibbs A, Gown A, Hammar S, Litzky L, Marchevsky AM, Nicholson AG, Roggli V, Travis WD, Wick M, International Mesothelioma Interest Group (2013) Guidelines for pathologic diagnosis of malignant mesothelioma: 2012 update of the consensus statement from the International Mesothelioma Interest Group. Arch Pathol Lab Med 137:647–667
9. Grondin SC, Sugarbaker DJ (1999) Malignant mesothelioma of the pleural space. Oncology (Williston Park) 13:919–926 (discussion 926, 931–932)
10. Neumann V, Löseke S, Nowak D, Herth FJ, Tannapfel A (2013) Malignant pleural mesothelioma: incidence, etiology, diagnosis, treatment, and occupational health. Dtsch Arztebl Int 110:319–326
11. Bölükbas S, Schirren J (2013) Malignant pleural mesothelioma : Comparison of radical pleurectomy und extrapleural pneumonectomy. Chirurg 84:487–491
12. Rice D (2011) Surgical therapy of mesothelioma. Recent Results Cancer Res 189:97–125
13. Cao C, Tian D, Manganas C, Matthews P, Yan TD (2012) Systematic review of trimodality therapy for patients with malignant pleural mesothelioma. Ann Cardiothorac Surg 1:428–437
14. Kaufman AJ, Flores RM (2011) Surgical treatment of malignant pleural mesothelioma. Curr Treat Options Oncol 12:201–216
15. Butchart EG, Ashcroft T, Barnsley WC, Holden MP (1976) Pleuropneumonectomy in the management of diffuse malignant mesothelioma of the pleura. Experience with 29 patients. Thorax 31:15–24
16. Stewart DJ, Martin-Ucar A, Pilling JE, Edwards JG, O’Byrne KJ, Waller DA (2004) The effect of extent of local resection on patterns of disease progression in malignant mesothelioma. Ann Thorac Surg 78:245–252
17. Treasure T, Lang-Lazdunski L, Waller D, Bliss JM, Tan C, Entwisle J, Snee M, O’Brien M, Thomas G, Senan S, O’Byrne K, Kilburn LS, Spicer J, Landau D, Edwards J, Coombes G, Darlison L, Peto J, MARS trialists (2011) Extra-pleural pneumonectomy versus no extra-pleural pneumonectomy for patients with malignant pleural mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomised feasibility study. Lancet Oncol 12:763–772
18. Soysal O, Karaog?lanog?lu N, Demiracan S, Topçu S, Tas¸tepe I, Kaya S, Unlü M, Celtin G (1997) Pleurectomy/decortication for palliation in malignant pleural mesothelioma: results of surgery. Eur J Cardiothorac Surg 11:210–213
19. V ogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, Gatzemeier U, Boyer M, Emri S, Manegold C, Niyikiza C, Paoletti P (2003) Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 21:2636–2644
20. van Meerbeeck JP, Gaafar R, Manegold C, Klaveren RJ, Van Marck EA, Vincent M, Legrand C, Bottomley A, Debruyne C, Giaccone G, European Organisation for Research and Treatment of Cancer Lung Cancer Group; National Cancer Institute of Canada (2005) 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 23:6881–6889 2876 A. Truini et al. 1 3
21. van Meerbeeck JP, Baas P, Debruyne C, Groen HJ, Manegold C, Ardizzoni A, Gridelli C, van Marck EA, Lentz M, Giaccone G (1999) A phase II study of gemcitabine in patients with malignant pleural mesothelioma. European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. Cancer 85:2577–2582
22. Stebbing J, Powles T, McPherson K, Shamash J, Wells P, SheaffMT, Slater S, Rudd RM, Fennell D, Steele JP (2009) The efficacy and safety of weekly vinorelbine in relapsed malignant pleural mesothelioma. Lung Cancer 63:94–97
23. Scherpereel A, Astoul P, Baas P, Berghmans T, Clayson H, de Vuyst P, Galateau-Salle F, Hennequin C, Hillerdal G, Le Péchoux C, Mutti L, Pairon JC, Stahel R, van Houtte P, van Meerbeeck J, Waller D, Weder W, European Respiratory Society/European Society of Thoracic Surgeons Task Force (2010) Guidelines of the European Respiratory Society and the European Society of Thoracic Surgeons for the management of malignant pleura mesothelioma. Eur Respir J 35:479–495
24. Dhalluin X, Scherpereel A (2011) Chemotherapy and radiotherapy for mesothelioma. Recent Results Cancer Res 189:127–147
25. Sienel W, Kirschbaum A, Passlick B (2008) Multimodal therapy for malignant pleural mesothelioma including extrapleural pneumonectomy. Zentralbl Chir 133:231–237
26. Sugarbaker DJ, Garcia JP, Richards WG, Harpole DH Jr, Healy- Baldini E, DeCamp MM Jr, Mentzer SJ, Liptay MJ, Strauss GM, Swanson SJ (1996) Extrapleural pneumonectomy in the multimodality therapy of malignant pleural mesothelioma. Results in 120 consecutive patients. Ann Surg 224:288–294 (discussion 294–296)
27. Klebe S, Henderson DW (2011) Early stages of mesothelioma, screening and biomarkers. Recent Results Cancer Res 189:169–193
28. Paganuzzi Onetto M, Marroni P, Filiberti R, Tassara E, Parodi S, Felletti R (2011) Diagnostic value of CYFRA 21-1 tumor marker and CEA in pleural effusion due to mesothelioma. Chest 119:1138–1142
29. Onda M, Nagata S, Ho M, Bera TK, Hassan R, Alexander RH, Pastan I (2006) Megakaryocyte potentiation factor cleaved from mesothelin precursor is a useful tumor marker in the serum of patients with mesothelioma. Clin Cancer Res 12:4225–4423
30. Pass HI, Lott D, Lonardo F, Harbut M, Liu Z, Tang N, Carbone M, Webb C, Wali A (2005) Asbestos exposure, pleural mesothelioma, and serum osteopontin levels. N Engl J Med 353:1564–1573
31. Robinson BW, Creaney J, Lake R, Nowak A, Musk AW, de Klerk N, Winzell P, Hellstrom KE, Hellstrom I (2003) Mesothelin- family proteins and diagnosis of mesothelioma. Lancet 362:1612–1616
32. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297
33. E squela-Kerscher A, Slack FJ (2006) Oncomirs-microRNAs with a role in cancer. Nat Rev Cancer 6:259–269
34. Bentwich I (2005) Prediction and validation of microRNAs and their targets. FEBS Lett 579:5904–5910
35. Jean D, Daubriac J, Le Pimpec-Barthes F, Galateau-Salle F, Jaurand MC (2012) Molecular changes in mesothelioma with an impact on prognosis and treatment. Arch Pathol Lab Med 136:277–293
36. Rosenfeld N, Aharonov R, Meiri E, Rosenwald S, Spector Y, Zepeniuk M, Benjamin H, Shabes N, Tabak S, Levy A, Lebanony D, Goren Y, Silberschein E, Targan N, Ben-Ari A, Gilad S, Sion- Vardy N, Tobar A, Feinmesser M, Kharenko O, Nativ O, Nass D, Perelman M, Yosepovich A, Shalmon B, Polak-Charcon S, Fridman E, Avniel A, Bentwich I, Bentwich Z, Cohen D, Chajut A, Barshack I (2008) MicroRNAs accurately identify cancer tissue origin. Nat Biotechnol 26:462–469
37. Gilad S, Meiri E, Yogev Y, Benjamin S, Lebanony D, Yerushalmi N, Benjamin H, Kushnir M, Cholakh H, Melamed N, Bentwich Z, Hod M, Goren Y, Chajut A (2008) Serum microRNAs are promising novel biomarkers. PLoS One 3:e3148
38. W eber JA, Baxter DH, Zhang S, Huang DY, Huang KH, Lee MJ, Galas DJ, Wang K (2010) The microRNA spectrum in 12 body fluids. Clin Chem 56:1733–1741
39. Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova- Agadjanyan EL, Peterson A, Noteboom J, O’Briant KC, Allen A, Lin DW, Urban N, Drescher CW, Knudsen BS, Stirewalt DL, Gentleman R, Vessella RL, Nelson PS, Martin DB, Tewari M (2008) Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci USA 105:10513–10518
40. Chen X, Ba Y, Ma L, Cai X, Yin Y, Wang K, Guo J, Zhang Y, Chen J, Guo X, Li Q, Li X, Wang W, Zhang Y, Wang J, Jiang X, Xiang Y, Xu C, Zheng P, Zhang J, Li R, Zhang H, Shang X, Gong T, Ning G, Wang J, Zen K, Zhang J, Zhang CY (2008) Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res 18:997–1006
41. McDonald JS, Milosevic D, Reddi HV, Grebe SK, Algeciras- Schimnich A (2011) Analysis of circulating microRNA: preanalytical and analytical challenges. Clin Chem 57:833–840
42. Fabbri M (2013) MicroRNAs and cancer: towards a personalized medicine. Curr Mol Med 13:751–756
43. Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, Aldler H, Rattan S, Keating M, Rai K, Rassenti L, Kipps T, Negrini M, Bullrich F, Croce CM (2002) Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 99:15524–15529
44. Heneghan HM, Miller N, Lowery AJ, Sweeney KJ, Kerin MJ (2009) MicroRNAs as novel biomarkers for breast cancer. J Oncol 2009:950201
45. Roldo C, Missiaglia E, Hagan JP, Falconi M, Capelli P, Bersani S, Calin GA, Volinia S, Liu CG, Scarpa A, Croce CM (2006) MicroRNA expression abnormalities in pancreatic endocrine and acinar tumors are associated with distinctive pathologic features and clinical behavior. J Clin Oncol 24:4677–4684
46. Xu YZ, Xi QH, Ge WL, Zhang XQ (2013) Identification of serum microRNA-21 as a biomarker for early detection and prognosis in human epithelial ovarian cancer. Asian Pac J Cancer Prev 14:1057–1060
47. Raponi M, Dossey L, Jatkoe T, Wu X, Chen G, Fan H, Beer DG (2009) MicroRNA classifiers for predicting prognosis of squamous cell lung cancer. Cancer Res 69:5776–5783
48. Pass HI, Beer DG, Joseph S, Massion P (2013) Biomarkers and molecular testing for early detection, diagnosis, and therapeutic prediction of lung cancer. Thorac Surg Clin 23:211–224
49. Nadal E, Chen G, Gallegos M, Lin L, Ferrer-Torres D, Truini A, Wang Z, Lin J, Reddy RM, Llatjos R, Escobar I, Moya J, Chang AC, Cardenal F, Capella G, Beer DG (2013) Epigenetic inactivation of microRNA-34b/c predicts poor disease-free survival in early stage lung adenocarcinoma. Clin Cancer Res 19:6842–6852
50. Minoia C, Sturchio E, Porro B, Ficociello B, Zambelli A, Imbriani M (2011) MicroRNAs as biological indicators of environmental and occupational exposure to asbestos. G Ital Med Lav Ergon 33:420–434

51. Calin GA, Croce CM (2006) MicroRNA signatures in human cancers. Nat Rev Cancer 6:857–866
52. Yin JQ, Zhao RC, Morris KV (2008) Profiling microRNA expression with microarrays. Trends Biotechnol 26:70–76
53. Chen C, Ridzon DA, Broomer AJ, Zhou Z, Lee DH, Nguyen JT, Barbisin M, Xu NL, Mahuvakar VR, Andersen MR, Lao KQ, Livak KJ, Guegler KJ (2005) Real-time quantification of microRNAs by stem-loop RT-PCR. Nucleic Acids Res 33:e179
54. Guled M, Lahti L, Lindholm PM, Salmenkivi K, Bagwan I, Nicholson AG, Knuutila S (2009) CDKN2A, NF2, and JUN are dysregulated among other genes by miRNAs in malignant Role of microRNAs 2877 1 3 mesothelioma—a miRNA microarray analysis. Genes Chromosomes Cancer 48:615–623
55. Santarelli L, Strafella E, Staffolani S, Amati M, Emanuelli M, Sartini D, Pozzi V, Carbonari D, Bracci M, Pignotti E, Mazzanti P, Sabbatini A, Ranaldi R, Gasparini S, Neuzil J, Tomasetti M (2011) Association of MiR-126 with soluble mesothelin-related peptides, a marker for malignant mesothelioma. PLoS One 6:e18232
56. Liu B, Peng XC, Zheng XL, Wang J, Qin YW (2009) MiR-126 restoration down-regulate VEGF and inhibit the growth of lung cancer cell lines in vitro and in vivo. Lung Cancer 66:169–175
57. Tomasetti M, Staffolani S, Nocchi L, Neuzil J, Strafella E, Manzella N, Mariotti L, Bracci M, Valentino M, Amati M, Santarelli L (2012) Clinical significance of circulating miR-126 quantification in malignant mesothelioma patients. Clin Biochem 45:575–581
58. Benjamin H, Lebanony D, Rosenwald S, Cohen L, Gibori H, Barabash N, Ashkenazi K, Goren E, Meiri E, Morgenstern S, Perelman M, Barshack I, Goren Y, Edmonston TB, Chajut A, Aharonov R, Bentwich Z, Rosenfeld N, Cohen D (2010) A diagnostic assay based on microRNA expression accurately identifies malignant pleural mesothelioma. J Mol Diagn 12:771–779
59. Gee GV, Koestler DC, Christensen BC, Sugarbaker DJ, Ugolini D, Ivaldi GP, Resnick MB, Houseman EA, Kelsey KT, Marsit CJ (2010) Downregulated microRNAs in the differential diagnosis of malignant pleural mesothelioma. Int J Cancer 127:2859–2869
60. V olinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, Visone R, Iorio M, Roldo C, Ferracin M, Prueitt RL, Yanaihara N, Lanza G, Scarpa A, Vecchione A, Negrini M, Harris CC, Croce CM (2006) A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA 103:2257–2261
61. Busacca S, Germano S, De Cecco L, Rinaldi M, Comoglio F, Favero F, Murer B, Mutti L, Pierotti M, Gaudino G (2010) MicroRNA signature of malignant mesothelioma with potential diagnostic and prognostic implications. Am J Respir Cell Mol Biol 42:312–319
62. Andersen M, Grauslund M, Muhammad-Ali M, Ravn J, Sørensen JB, Andersen CB, Santoni Rugiu E (2012) Are differentially expressed microRNAs useful in the diagnostics of malignant pleural mesothelioma? APMIS 120:767–769
63. Balatti V, Maniero S, Ferracin M, Veronese A, Negrini M, Ferrocci G, Martini F, Tognon MG (2011) MicroRNAs dysregulation in human malignant pleural mesothelioma. J Thorac Oncol 6:844–851
64. Pass HI, Goparaju C, Ivanov S, Donington J, Carbone M, Hoshen M, Cohen D, Chajut A, Rosenwald S, Dan H, Benjamin S, Aharonov R (2010) hsa-miR-29c* is linked to the prognosis of malignant pleural mesothelioma. Cancer Res 70:1916–1924
65. Kirschner MB, Cheng YY, Badrian B, Kao SC, Creaney J, Edelman JJ, Armstrong NJ, Vallely MP, Musk AW, Robinson BW, McCaughan BC, Klebe S, Mutsaers SE, van Zandwijk N, Reid G (2012) Increased circulating miR-625-3p: a potential biomarker for patients with malignant pleural mesothelioma. J Thorac Oncol 7:1184–1191
66. W eber DG, Johnen G, Bryk O, Jöckel KH, Brüning T (2012) Identification of miRNA-103 in the cellular fraction of human peripheral blood as a potential biomarker for malignant mesothelioma—a pilot study. PLoS ONE 7:e30221
67. Fabbri M, Garzon R, Cimmino A, Liu Z, Zanesi N, Callegari E, Liu S, Alder H, Costinean S, Fernandez-Cymering C, Volinia S, Guler G, Morrison CD, Chan KK, Marcucci G, Calin GA, Huebner K, Croce CM (2007) MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proc Natl Acad Sci USA 104:15805–15810
68. Pekarsky Y, Santanam U, Cimmino A, Palamarchuk A, Efanov A, Maximov V, Volinia S, Alder H, Liu CG, Rassenti L, Calin GA, Hagan JP, Kipps T, Croce CM (2006) Tcl1 expression in chronic lymphocytic leukemia is regulated by miR-29 and miR-181. Cancer Res 66:11590–11593
69. Gebeshuber CA, Zatloukal K, Martinez J (2009) miR-29a suppresses tristetraprolin, which is a regulator of epithelial polarity and metastasis. EMBO Rep 10:400–405
70. Ivanov SV, Miller J, Lucito R, Tang C, Ivanova AV, Pei J, Carbone M, Cruz C, Beck A, Webb C, Nonaka D, Testa JR, Pass HI (2009) Genomic events associated with progression of pleural malignant mesothelioma. Int J Cancer 124:589–599
71. Ivanov SV, Goparaju CM, Lopez P, Zavadil J, Toren-Haritan G, Rosenwald S, Hoshen M, Chajut A, Cohen D, Pass HI (2010) Pro-tumorigenic effects of miR-31 loss in mesothelioma. J Biol Chem 285:22809–22817
72. Kubo T, Toyooka S, Tsukuda K, Sakaguchi M, Fukazawa T, Soh J, Asano H, Ueno T, Muraoka T, Yamamoto H, Nasu Y, Kishimoto T, Pass HI, Matsui H, Huh NH, Miyoshi S (2011) Epigenetic silencing of microRNA-34b/c plays an important role in the pathogenesis of malignant pleural mesothelioma. Clin Cancer Res 17:4965–4974
73. Maki Y, Asano H, Toyooka S, Soh J, Kubo T, Katsui K, Ueno T, Shien K, Muraoka T, Tanaka N, Yamamoto H, Tsukuda K, Kishimoto T, Kanazawa S, Miyoshi S (2012) MicroRNA miR-34b/c enhances cellular radiosensitivity of malignant pleural mesothelioma cells. Anticancer Res 32:4871–4875
74. Tanaka N, Toyooka S, Soh J, Tsukuda K, Shien K, Furukawa M, Muraoka T, Maki Y, Ueno T, Yamamoto H, Asano H, Otsuki T, Miyoshi S (2013) Downregulation of microRNA-34 induces cell proliferation and invasion of human mesothelial cells. Oncol Rep 29:2169–2174
75. Muraoka T, Soh J, Toyooka S, Aoe K, Fujimoto N, Hashida S, Maki Y, Tanaka N, Shien K, Furukawa M, Yamamoto H, Asano H, Tsukuda K, Kishimoto T, Otsuki T, Miyoshi S (2013) The degree of microRNA-34b/c methylation in serum-circulating DNA is associated with malignant pleural mesothelioma. Lung Cancer [Epub ahead of print]
76. Khodayari N, Mohammed KA, Goldberg EP, Nasreen N (2011) EphrinA1 inhibits malignant mesothelioma tumor growth via let-7 microRNA-mediated repression of the RAS oncogene. Cancer Gene Ther 18:806–816
77. Goparaju CM, Blasberg JD, Volinia S, Palatini J, Ivanov S, Donington JS, Croce C, Carbone M, Yang H, Pass HI (2011) ONCONASE- mediated NFKß downregulation in malignant pleural mesothelioma. Oncogene 30:2767–2777
78. Datta J, Kutay H, Nasser MW, Nuovo GJ, Wang B, Majumder S, Liu CG, Volinia S, Croce CM, Schmittgen TD, Ghoshal K, Jacob ST (2008) Methylation mediated silencing of MicroRNA-1 gene and its role in hepatocellular carcinogenesis. Cancer Res 68:5049–5058
79. Yoshino H, Chiyomaru T, Enokida H, Kawakami K, Tatarano S, Nishiyama K, Nohata N, Seki N, Nakagawa M (2011) The tumour-suppressive function of miR-1 and miR-133a targeting TAGLN2 in bladder cancer. Br J Cancer 104:808–818
80. Xu Y, Zheng M, Merritt RE, Shrager JB, Wakelee H, Kratzke RA, Hoang CD (2013) miR-1 induces growth arrest and apoptosis in malignant mesothelioma. Chest 144:1632–1643
81. Bonci D, Coppola V, Musumeci M, Addario A, Giuffrida R, Memeo L, D’Urso L, Pagliuca A, Biffoni M, Labbaye C, Bartucci M, Muto G, Peschle C, De Maria R (2008) The miR-15amiR- 16-1 cluster controls prostate cancer by targeting multiple oncogenic activities. Nat Med 14:1271–1277
82. Bandi N, Zbinden S, Gugger M, Arnold M, Kocher V, Hasan L, Kappeler A, Brunner T, Vassella E (2009) miR-15a and miR-16 are implicated in cell cycle regulation in a Rb-dependent manner and are frequently deleted or down-regulated in non-small cell lung cancer. Cancer Res 69:5553–5559 2878 A. Truini et al. 1 3
83. W ang X, Wang J, Ma H, Zhang J, Zhou X (2012) Downregulation of miR-195 correlates with lymph node metastasis and poor prognosis in colorectal cancer. Med Oncol 29:919–927
84. Bhattacharya R, Nicoloso M, Arvizo R, Wang E, Cortez A, Rossi S, Calin GA, Mukherjee P (2009) MiR-15a and MiR-16 control Bmi-1 expression in ovarian cancer. Cancer Res 69:9090–9095
85. Reid G, Pel ME, Kirschner MB, Cheng YY, Mugridge N, Weiss J, Williams M, Wright C, Edelman JJ, Vallely MP, McCaughan BC, Klebe S, Brahmbhatt H, Macdiarmid JA, van Zandwijk N (2013) Restoring expression of miR-16: a novel approach to therapy for malignant pleural mesothelioma. Ann Oncol 24:3128–3135

 

> Download article as PDF

Introduction

Tumours are characterised by a series of genetic anomalies with a proliferative potential that leads to cellular transformation.

Nevertheless, it is believed that the micro-environment that surrounds the tumour (tumour micro-environment or TME) may also have an important role in the fate of tumour cells, acting on the cellular progression or regression.

The correlations which exist between cancer and inflammation have been documented since 1863, when Virchow observed that tumour tissue is often surrounded by inflammatory cells which are discovered in the analysis of bioptic samples(i).

In immunodeficient mouse models, it has been demonstrated that inflammation may precede the development of malignant mesothelioma(ii). Moreover, epidemiological studies have revealed that chronic inflammation caused by chemical or physical agents and the inflammatory and autoimmune reactions of uncertain origin predispose people to certain types of tumours(iii iv).

Growing evidence shows that the «inflammation-cancer» connection is not only limited to initial processes of tumour development; in fact, all types of cancers would seem to have an active inflammatory component in their micro-environment. These experimental and clinical observations lead to a greater confirmation that inflation related to cancer may be one of the main typical characteristics of neoplasias itself(v).

Inflammation

One of the main factors that characterise the tumour micro-environment is persistent chronic inflammation(vi).

Tumour-related inflammation is mainly triggered by innate immunity cells (especially macrophages), which are present in large quantities in the tumour micro-environment, but it is also maintained by stromal cells, such as fibroblasts, by blood vessel cells or by the same tumour cellsvii.

Two pathogenic ways correlate cancer and inflammation.

The intrinsic way is guided by genetic alterations that cause neoplasias. For example, these genetic modifications may lead to the triggering of various types of oncogenes, to mutation, to rearrangement or to chromosomal amplification, or they may make oncosuppressor genes inactive, which initiate an inflammatory process inside the neoplastic cell.

The extrinsic way, on the other hand, is mediated by inflammatory cells of the innate immunity; we are talking mainly of macrophages.

These two inflammatory paths join the activation of transcription factors, such as the NF-.B, of signal transducers, of transcriptional activators 3 (STAT3) and of the hypoxia-inducible factor 1 (HIF1).

In the past ten years, the mechanisms through which chronic inflammation supports tumour growth have been further delved into. Different soluble inflammatory mediators, either produced by macrophages or by tumour cells, act as growth factors that directly stimulate the proliferation of tumour cells and increase their resistance to apoptotic stimuli. These include, for example, the primary inflammatory cytokines IL-1 and TNF, which activate NF-kB, the key regulator of the inflammatory response.

In tumour cells, NF-kB activates the expression of anti-apoptotic genes (for example, c-IAP, BCL2, c-FLIP) and of genes that regulate cellular proliferation (for example, Cyclin, c-Myc).

In the macrophages, NF-kB activates different genes that encode for cytokines (Egil-1, TNF, IL-6), chemokines (i.e., CCL2, CCL5, CXCL8) and reactive enzymes (for example, COX-2), which further stimulate the inflammatory response, thus amplifying the recruitment of new inflammatory cells in the tumour.

Cytokine IL-6 activates transcription factor STAT3, another important inflammation and tumour development regulator. In tumour cells, STAT3 stimulates cellular survival and proliferation, whilst in the macrophages its persistent activation leads to immune suppression.

Besides, little is known about the mechanisms that lead to tumour initiation within the context of chronic inflammation. There is evidence that inflammatory mediators such as cytokines, reactive oxygen species (ROS) and reactive nitrogen species (RNS) lead to epigenetic alterations in pre-cancerous cells, cause the silencing of onco-suppressor genes and the inhibition of DNA repairing mechanismsviii. Certain inflammatory cytokines and other mediators increase the survival of tumour cells, the motility and invasiveness, also encouraging the angiogenic capacity, which is crucial for allowing oxygen, nutrients and growth factors to reach tumour cells(ix x).

In this way, chronic inflammation favours the accumulation of DNA mutations and increases the proliferation potential of the cells. It is believed that this cancerogenesis process induced by inflammation may require several years, as a consequence of a lack of balance between continuous casual mutations and DNA repair, cellular death and cellular proliferation, recognition or escape from control of the immune system.

While in the past 15 years incredible progress has been made in terms of understanding the mechanisms through which cancer-related inflammation might have a negative impact on tumour progression, little is known to this day with regards to the effects of chronic inflammation on cancerogenesis. It is believed that long-term exposure to inflammatory mediators (cytokines, reactive oxygen and nitrogen species) causes genotoxic damage to the DNA, constantly putting pressure on the DNA repair system. Cells where the DNA repair response is inhibited or is less efficient are at high risk of genomic instability and are more predisposed to malignant transformation. At present, little is known about the mechanisms underlying these processes.

Macrophages associated with tumours

Macrophages associated with tumours (TAM) are innate immunity cells that are abundantly present in tumours. They are key initiators of the persistent inflammation present in the tumour micro-environment (TME), since they are the main producers of reactive mediators that perpetuate and amplify the inflammatory cascade(xi xii).

A typical characteristic of macrophages is their functional plasticity. In fact, the acquisition of their various functions is precisely dictated by specific local stimuli that activate separate functional processes: actually, they are not only able to fight the onset and progression of the tumour but also lead to the start of the tumour as well(xiii).

Macrophages can be classified, in a simplistic way, as M1 or classic macrophages, having the tumour-suppressor phenotype and capable of product large quantities of inflammatory cytokines and M2, or alternative macrophages that have the immune-suppressor phenotype and control the trophic activity of tissues as well as the angiogenesis(xiv xv xvi).

Macrophages perform many actions aimed at encouraging tumour progression: they produce growth and survival factors for tumour cells and the vascularisation (neoangiogenesis), they contribute to the deterioration of the extracellular matrix and to the remodelling, they facilitate the invasion of tumour cells and the metastasis, and they produce immunity mediators that suppress anti-tumour activity(xvii xviii).

Consequently, the quantity of TAM in most solid and haematological tumours has been associated with an unlucky prognosis and resistance to therapies (xix).

The TAMs have a limited cytotoxic action against neoplastic cells and, according to certain studies, it appears that they are in fact capable of encouraging tumour proliferation, the deterioration of the extra-cellular matrix and the ability to elude the control of the immune system(xx xxi xxii xxiii xxiv).

Moreover, the presence of TAMs in tumour tissue is associated with the quick rate of progression (xxv xxvi). Hence, macrophages constitute a source of inflammatory mediators at the tumour level. This also occurs for MPM, although it has been reported in literature that the mesothelial cells of the pleura are also capable of producing reactive mediators in response to asbestos fibres.

On the basis of functional activities and gene expression profiles, some researchers have demonstrated that TAMS are polarised macrophages M2xxvii. Moreover, TAMs have been characterised in various mouse tumour models, and the inflammatory paths that are involved the most in the pro-tumour activity have been defined(xxvii xxix).

In recent years, great emphasis has been placed in identifying macrophages at the tumour site for therapeutic purposes. Moreover, it has been demonstrated that inhibiting these cells in experimental contexts would limit tumour growth and metastatic spreading(xxx). Inhibiting the recruitment of monocytes at the tumour sites, in combination with chemotherapy, appears to significantly increase the efficacy of the therapeutic treatment in mice with tumours. This is probably due to the fact that the presence of TAMs and myeloid cells is also strongly implicated in the ineffectiveness of anti-tumour therapies(xxxi xxxii xxxiii). Recent clinical studies have also provided interesting results, through the use of inhibitors that limit the action of the chemokines(xxxiv).

pleural mesothelioma

Pleural mesothelioma is a pathological condition characterised by chronic persistent inflammation. It is a very aggressive tumour caused by the neoplastic transformation of the mesothelial cells that line the body’s serous cavities and internal organs; in 80% of the cases it is of pleural origin and it is defined as malignant pleural mesothelioma (MPM)(xxxv). MPM is usually discovered in the advanced stage, since there are no markers that allow early diagnosis(xxxvi). Malignant mesothelioma is almost insensitive to current chemotherapy, and still has a very limited global survival rate.

It is a highly malignant disease associated with long-term exposure to asbestos or other particulate fibres(xxxvii). In fact, its incidence is strongly linked to exposure to airborne asbestos fibres(xxxviii). Once the asbestos enters the lungs, the macrophages are locally recruited and activated in an attempt to eliminate the fibres, but they are unable to carry out this «clean up» due to the non-degradable nature of asbestos. This failed deterioration of asbestos fibres by the macrophages leads to a state of chronic inflammation and to a fibrogenic response by the fibroblasts, which in the long term facilitates the transformation of healthy pleural cells into tumour cells(xxxix xl xli xlii).

Hence, the inhaled fibres are not degradable, and they cause a persistent local state of inflammation. Due to the volatile nature of particulate fibres, the people who work directly with asbestos are not the only ones at risk, as entire populations who live in areas where asbestos was present may also be affected. Therefore, it is possible to state that malignant mesothelioma is a tumour that is certainly related to chronic inflammations(xliii).

Genetic anomalies tied to MPM have been widely studied. In fact, a wide range of genetic mutations has been identified, including, for example: BAP1, CDKN2A, Ras, Wnt, p16, TP53, SMACB1, NF2, PIK3CA(xliv xlv xlvi).

This wide spectrum of genetic mutation indicates that the anomalous proliferation of the neoplastic cells is not caused by the oncogenic activity of one or of some oncogenes, as it happens in many types of tumours (for example, KRAS and pancreatic or lung cancer, BRCA1 and breast cancer)xlvii xlviii. In this case, we are dealing instead with the result of casual damage to the DNA, due to an upstream condition (for example, long-term inflammation), confirming that inflammation is indeed one of the main causes of carcinogenesis(xlix 1).

It is known that certain polymorphisms of genes related to inflammations cause a predisposition to the disease. For example, SNPs in Toll-like receptors have been found to be related to infections and chronic inflammatory diseasesli. For example, the SNPs of gene NLRP3 appear to be related to susceptibility to the HIV virus, to Crohn’s Disease, to rheumatoid arthritis and to diabeteslii liii liv. Girardelli et all have demonstrated that in patients suffering from MPM, the SNPs in gene NLRP1 are more frequent(lv).

Several studies have reported the expression of inflammatory mediators in MPM(lvi lvii lviii). Hegmans JP et all have demonstrated that the inflammatory cellular infiltrate of MPM is full of macrophages, thus implying that these cells play a crucial role in the biology of the mesotheliomalix.

It is well known that asbestos fibres cause the inflammatory sublayerlx lxi. The recruitment of the macrophages is also induced by the adipocytes involved in the inflammation caused by the presence of asbestos. In fact, some researchers have demonstrated that adipocytes exposed to asbestos fibres are capable of producing inflammatory cytokines (IL6 and CCL2), which in turn draw and recruit macrophages in the inflammatory micro-environment.

However, at present a complete characterisation of the inflammatory paths involved in MPL is still not available.

Conclusions

Inflammation is present in the micro-environment that surrounds the tumour tissue and, probably, it is not simply a cellular characteristic surrounding the neoplasias, but instead appears to be and active component involved in the carcinogenesis.

Several studies aim to study the mechanisms that lead to the neoplastic transformation of various neoplasias and, among these, of mesothelioma, focusing on the inflammatory response.

Researchers are currently attempting to understand which inflammatory paths are most involved in the onset and progression of mesothelioma, and if there are specific characteristics that can explain why the selected individuals develop the disease.

It would be crucial to identify subjects at a high risk of developing mesothelioma, and to find out more about chronic inflammation and its capacity to create a predisposition to carcinogenesis.

This research may lead to the discovery of new molecular targets useful for therapy or for prevention drugslxii.

Reference

i Balkwill F, Mantovani A, Inflammation and cancer: back to Vircow? Lancet. 2001; 357(9255):539-545.
ii Hillegass JM, Shukla A, Lathrop SA, et al; Inflammation precedes the development to human maignant mesotheliomas in a SCID mous xenograft model. Annals of the New York Academy of Sciences. 2010; 1203(1):7-14
iii Coussens M, Werb Z, Inflammation and cancer, Nature. 2002; 420(6917):860-867
iv Sethi G, Shanmugam MK, Ramachandran L, Kumar AP, Tergaonkar V. Multifaceted link between cancer and inflammation. Biosci Rep. 2012;32(1):1-15
v Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis. 2009;30(7):1073-1081
vi Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: the next generation. Cell 2011, 144, 646-674.
vii Belgiovine, C.; Chiodi, I.; Mondello, C. Relocalization of cell adhesion molecules during neoplastic transformation of human fibroblasts. Int J Oncol 2011, 39, 1199-1204.
viii Grivennikov, S.I.; Karin, M. Inflammation and oncogenesis: a vicious connection. Curr Opin Genet Dev 2010, 20, 65-71.
ix DeNardo, D.G.; Johansson, M.; Coussens, L.M. Immune cells as mediators of solid tumor metastasis. Cancer Metastasis Rev 2008, 27, 11-18.
x Zumsteg, A.; Christofori, G. Corrupt policemen: inflammatory cells promote tumor angiogenesis. Curr Opin Oncol 2009, 21, 60-70.
xi Solinas, G.; Schiarea, S.; Liguori, M.; Fabbri, M.; Pesce, S.; Zammataro, L.; Pasqualini, F.; Nebuloni, M.; Chiabrando, C.; Mantovani, A.; Allavena, P. Tumor-conditioned macrophages secrete migration-stimulating factor: a new marker for M2polarization, influencing tumor cell motility. J Immunol 2010, 185, 642-652.
xii Liguori, M.; Solinas, G.; Germano, G.; Mantovani, A.; Allavena, P. Tumor-associated macrophages as incessant builders and destroyers of the cancer stroma. Cancers (Basel) 2011, 3, 3740-3761.
xiii Solinas, G.; Germano, G.; Mantovani, A.; Allavena, P. Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J Leukoc Biol 2009, 86, 1065-1073.
xiv Martinez, F.O.; Helming, L.; Gordon, S. Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol 2009, 27, 451-483.
xv Martinez, F.O.; Sica, A.; Mantovani, A.; Locati, M. Macrophage activation and polarization. Front Biosci 2008, 13, 453-461.
xvi Ferrara, N. Role of myeloid cells in vascular endothelial growth factor-independent tumor angiogenesis. Curr Opin Hematol 2010, 17, 219-224.
xvii Allavena, P.; Mantovani, A. Immunology in the clinic review series; focus on cancer: tumour-associated macrophages: undisputed stars of the inflammatory tumour microenvironment. Clin Exp Immunol 2012, 167, 195-205.
xviii Castelli, C.; Rivoltini, L.; Rodolfo, M.; Tazzari, M.; Belgiovine, C.; Allavena, P. Modulation of the myeloid compartment of the immune system by angiogenic-and kinase inhibitor-targeted anti-cancer therapies. Cancer Immunol Immunother 2015, 64, 83-89.
xix Pollard, J.W. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 2004, 4, 71-78.
xx Condeelis, J.; Pollard, J.W. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 2006, 124, 263-266.
xxi Bingle, L.; Brown, N.J.; Lewis, C.E. The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol 2002, 196, 254265.
xxii Allavena, P.; Mantovani, A. Immunology in the clinic review series; focus on cancer: tumour-associated macrophages: undisputed stars of the inflammatory tumour microenvironment. Clin Exp Immunol 2012, 167, 195-205.
xxiii Joyce, J.A.; Pollard, J.W. Microenvironmental regulation of metastasis. Nat Rev Cancer 2009, 9, 239-252.
xxiv Mantovani, A.; Allavena, P. The interaction of anticancer therapies with tumor associated macrophages. J Exp Med 2015, 212, 435-445.
xxv Bingle, L.; Brown, N.J.; Lewis, C.E. The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol 2002, 196, 254265.
xxvi Allavena, P.; Mantovani, A. Immunology in the clinic review series; focus on cancer: tumour-associated macrophages: undisputed stars of the inflammatory tumour microenvironment. Clin Exp Immunol 2012, 167, 195-205.
xxvii Mantovani, A.; Sozzani, S.; Locati, M.; Allavena, P.; Sica, A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 2002, 23, 549-555.
xxviii Germano, G.; Frapolli, R.; Belgiovine, C.; Anselmo, A.; Pesce, S.; Liguori, M.; Erba, E.; Uboldi, S.; Zucchetti, M.; Pasqualini, F.; Nebuloni, M.; van Rooijen, N.; Mortarini, R.; Beltrame, L.; Marchini, S.; Fuso Nerini, I.; Sanfilippo, R.; Casali, P.G.; Pilotti, S.; Galmarini, C.M.; Anichini, A.; Mantovani, A.; D'Incalci, M.; Allavena, P. Role of macrophage targeting in the antitumor activity of trabectedin. Cancer Cell 2013, 23, 249-262.
xxix Germano, G.; Frapolli, R.; Simone, M.; Tavecchio, M.; Erba, E.; Pesce, S.; Pasqualini, F.; Grosso, F.; Sanfilippo, R.; Casali, P.G.; Gronchi, A.; Virdis, E.; Tarantino, E.; Pilotti, S.; Greco, A.; Nebuloni, M.; Galmarini, C.M.; Tercero, J.C.; Mantovani, A.; D'Incalci, M.; Allavena, P. Antitumor and anti-inflammatory effects of trabectedin on human myxoid liposarcoma cells. Cancer Res 2010, 70, 2235-2244.
xxx Qian, B.Z.; Pollard, J.W. Macrophage diversity enhances tumor progression and metastasis. Cell 2010, 141, 39-51.
xxxi Welford, A.F.; Biziato, D.; Coffelt, S.B.; Nucera, S.; Fisher, M.; Pucci, F.; Di Serio, C.; Naldini, L.; De Palma, M.; Tozer, G.M.; Lewis, C.E. TIE2-expressing macrophages limit the therapeutic efficacy of the vascular-disrupting agent combretastatin A4 phosphate in mice. J Clin Invest 2011, 121, 1969-1973.
xxxii DeNardo, D.G.; Brennan, D.J.; Rexhepaj, E.; Ruffell, B.; Shiao, S.L.; Madden, S.F.; Gallagher, W.M.; Wadhwani, N.; Keil, S.D.; Junaid, S.A.; Rugo, H.S.; Hwang, E.S.; Jirstrom, K.; West, B.L.; Coussens, L.M. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov 2011, 1, 54-67.
xxxiii Sluijter, M.; van der Sluis, T.C.; van der Velden, P.A.; Versluis, M.; West, B.L.; van der Burg, S.H.; van Hall, T. Inhibition of CSF-1R supports T-cell mediated melanoma therapy. PLoS One 2014, 9, e104230.
xxxiv Zhu, Y.; Knolhoff, B.L.; Meyer, M.A.; Nywening, T.M.; West, B.L.; Luo, J.; Wang-Gillam, A.; Goedegebuure, S.P.; Linehan, D.C.; DeNardo, D.G. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res 2014, 74, 5057-5069.
xxxv Robinson, B.W.; Lake, R.A. Advances in malignant mesothelioma. N Engl J Med 2005, 353, 1591-1603.
xxxvi Sekido, Y. Molecular pathogenesis of malignant mesothelioma. Carcinogenesis 2013, 34, 1413-1419.
xxxvii Below, J.E.; Cox, N.J.; Fukagawa, N.K.; Hirvonen, A.; Testa, J.R. Factors that impact susceptibility to fiber-induced health effects. J Toxicol Environ Health B Crit Rev 2011, 14, 246-266.
xxxviii Liu, G.; Cheresh, P.; Kamp, D.W. Molecular basis of asbestos-induced lung disease. Annu Rev Pathol 2013, 8, 161-187.
xxxix Liu, G.; Cheresh, P.; Kamp, D.W. Molecular basis of asbestos-induced lung disease. Annu Rev Pathol 2013, 8, 161-187.
xl Mossman, B.T.; Churg, A. Mechanisms in the pathogenesis of asbestosis and silicosis. Am J Respir Crit Care Med 1998, 157, 1666-1680.
xli Mossman, B.T.; Lippmann, M.; Hesterberg, T.W.; Kelsey, K.T.; Barchowsky, A.; Bonner, J.C. Pulmonary endpoints (lung carcinomas and asbestosis) following inhalation exposure to asbestos. J Toxicol Environ Health B Crit Rev 2011, 14, 76-12.
xlii Bograd, A.J.; Suzuki, K.; Vertes, E.; Colovos, C.; Morales, E.A.; Sadelain, M.; Adusumilli, P.S. Immune responses and immunotherapeutic interventions in malignant pleural mesothelioma. Cancer Immunol Immunother 2011, 60, 1509-1527.
xliii Davis, M.R.; Manning, L.S.; Whitaker, D.; Garlepp, M.J.; Robinson, B.W. Establishment of a murine model of malignant mesothelioma. Int J Cancer 1992, 52, 881886.
xliv Guo, G.; Chmielecki, J.; Goparaju, C.; Heguy, A.; Dolgalev, I.; Carbone, M.; Seepo, S.; Meyerson, M.; Pass, H.I. Whole-exome sequencing reveals frequent genetic alterations in BAP1, NF2, CDKN2A, and CUL1 in malignant pleural mesothelioma. Cancer Res 2015, 75, 264-269.
xlv de Assis, L.V.; Locatelli, J.; Isoldi, M.C. The role of key genes and pathways involved in the tumorigenesis of Malignant Mesothelioma. Biochim Biophys Acta 2014, 1845, 232-247.
xlvi Belgiovine, C.; Frapolli, R.; Bonezzi, K.; Chiodi, I.; Favero, F.; Mello-Grand, M.; Dei Tos, A.P.; Giulotto, E.; Taraboletti, G.; D'Incalci, M.; Mondello, C. Reduced expression of the ROCK inhibitor Rnd3 is associated with increased invasiveness and metastatic potential in mesenchymal tumor cells. PLoS One 2010, 5, e14154.
xlvii Testa, J.R.; Cheung, M.; Pei, J.; Below, J.E.; Tan, Y.; Sementino, E.; Cox, N.J.; Dogan, A.U.; Pass, H.I.; Trusa, S.; Hesdorffer, M.; Nasu, M.; Powers, A.; Rivera, Z.; Comertpay, S.; Tanji, M.; Gaudino, G.; Yang, H.; Carbone, M. Germline BAP1 mutations predispose to malignant mesothelioma. Nat Genet 2011, 43, 1022-1025.
xlviii de Bakker, P.I.; Yelensky, R.; Pe'er, I.; Gabriel, S.B.; Daly, M.J.; Altshuler, D. Efficiency and power in genetic association studies. Nat Genet 2005, 37, 1217-1223.
xlix Matullo, G.; Guarrera, S.; Betti, M.; Fiorito, G.; Ferrante, D.; Voglino, F.; Cadby, G.; Di Gaetano, C.; Rosa, F.; Russo, A.; Hirvonen, A.; Casalone, E.; Tunesi, S.; Padoan, M.;Giordano, M.; Aspesi, A.; Casadio, C.; Ardissone, F.; Ruffini, E.; Betta, P.G.; Libener, R.; Guaschino, R.; Piccolini, E.; Neri, M.; Musk, A.W.; de Klerk, N.H.; Hui, J.; Beilby, J.; James, A.L.; Creaney, J.; Robinson, B.W.; Mukherjee, S.; Palmer, L.J.; Mirabelli, D.; Ugolini, D.; Bonassi, S.; Magnani, C.; Dianzani, I. Genetic variants associated with increased risk of malignant pleural mesothelioma: a genome-wide association study. PLoS One 2013.
l Melaiu, O.; Melissari, E.; Mutti, L.; Bracci, E.; De Santi, C.; Iofrida, C.; Di Russo, M.; Cristaudo, A.; Bonotti, A.; Cipollini, M.; Garritano, S.I.; Foddis, R.; Lucchi, M.; Pellegrini, S.; Gemignani, F.; Landi, S. Expression status of candidate genes in mesothelioma tissues and cell lines. Mutat Res 2015, 771, 6-12.
li Noreen, M.; Arshad, M. Association of TLR1, TLR2, TLR4, TLR6, and TIRAP polymorphisms with disease susceptibility. Immunol Res 2015.
lii Pontillo, A.; Brandao, L.; Guimaraes, R.; Segat, L.; Araujo, J.; Crovella, S. Two SNPs in NLRP3 gene are involved in the predisposition to type-1 diabetes and celiac disease in a pediatric population from northeast Brazil. Autoimmunity 2010, 43, 583-589.
liii Pontillo, A.; Brandao, L.A.; Guimaraes, R.L.; Segat, L.; Athanasakis, E.; Crovella, S. A 3'UTR SNP in NLRP3 gene is associated with susceptibility to HIV-1 infection. J Acquir Immune Defic Syndr 2010, 54, 236-240.
liv Girardelli, M.; Maestri, I.; Rinaldi, R.R.; Tognon, M.; Boldorini, R.; Bovenzi, M.; Crovella, S.; Comar, M. NLRP1 polymorphisms in patients with asbestos-associated mesothelioma. Infect Agent Cancer 2012, 7, 25.
lv Girardelli, M.; Maestri, I.; Rinaldi, R.R.; Tognon, M.; Boldorini, R.; Bovenzi, M.; Crovella, S.; Comar, M. NLRP1 polymorphisms in patients with asbestos-associated mesothelioma. Infect Agent Cancer 2012, 7, 25.
lvi Thompson, J.K.; Westbom, C.M.; MacPherson, M.B.; Mossman, B.T.; Heintz, N.H.; Spiess, P.; Shukla, A. Asbestos modulates thioredoxin-thioredoxin interacting protein interaction to regulate inflammasome activation. Part Fibre Toxicol 2014, 11, 24.
lvii Izzi, V.; Masuelli, L.; Tresoldi, I.; Foti, C.; Modesti, A.; Bei, R. Immunity and malignant mesothelioma: from mesothelial cell damage to tumor development and immune response-based therapies. Cancer Lett 2012, 322, 18-34.
lviii Hegmans, J.P.; Hemmes, A.; Hammad, H.; Boon, L.; Hoogsteden, H.C.; Lambrecht, B.N. Mesothelioma environment comprises cytokines and T-regulatory cells that suppress immune responses. Eur Respir J 2006, 27, 1086-1095.
lix Hegmans, J.P.; Hemmes, A.; Hammad, H.; Boon, L.; Hoogsteden, H.C.; Lambrecht, B.N. Mesothelioma environment comprises cytokines and T-regulatory cells that suppress immune responses. Eur Respir J 2006, 27, 1086-1095.
lx Chow, M.T.; Tschopp, J.; Moller, A.; Smyth, M.J. NLRP3 promotes inflammation induced skin cancer but is dispensable for asbestos-induced mesothelioma. Immunol Cell Biol 2012, 90, 983-986.
lxi Pavan, C.; Rabolli, V.; Tomatis, M.; Fubini, B.; Lison, D. Why does the hemolytic activity of silica predict its pro-inflammatory activity? Part Fibre Toxicol 2014, 11, 76.
lxii D'Incalci, M.; Badri, N.; Galmarini, C.M.; Allavena, P. Trabectedin, a drug acting on both cancer cells and the tumour microenvironment. Br J Cancer 2014, 111, 646-650.

> Download article as PDF

Introduction

Tumors have developed multiple mechanisms to avoid destruction by the immune system(1).
There are, in fact, various inhibitory pathways in the immune system that allow this complex system to tolerate cells and antigens physiologically present in the body, and not to mount an excessive immune response. These inhibitory pathways are essential because they allow the immune T-cells to block the growth of cancer cells; however, tumors use mechanisms to escape the control of the immune system, preventing the T-cells from using their cytotoxic activity against the tumor. Both the innate and adaptive immune responses can act against tumors.
A deficiency in cytotoxic T lymphocytes and natural killer cells can, in fact, increase tumor incidence.
One of the mechanisms by which tumors can escape the immune system is the expression of ligands that inhibit T-cell expression, such as CTLA-4 (cytotoxic T-lymphocyte antigen 4), PD-L1 (programmed death-ligand 1) and PD-1 (programmed death-1)(2). Malignant Pleural Mesothelioma (MPM) is considered an “inflammatory” tumor because it is often characterized by a prominent infiltration of lymphocytes, macrophages and T-cells(3 4).
The continuous, chronic inflammation of the mesothelial cells helps at first to promote, progress and transform these healthy cells into cancer cells. Similarly, the escape mechanisms from the immune system allow the tumor to evade the immune response from the host.
The role of the immune system in the biogenesis of MPM is also complex and multifaceted and appears to involve both the innate and adaptive immune responses.(5 6) This is why research is being conducted in immune mechanisms that allow tumors to grow by escaping the body’s control, with the goal of identifying suitable targets for an effective immunotherapy for MPM.
PD-L1 expression in MPM appears to be associated with a greater extent of disease at the time of presentation and with a greater incidence of sarcomatoid histology.(7) This could be a plausible explanation for the poor prognosis seen in these cases.
Immunotherapy represents a new frontier in the treatment of cancer. The significant progress made in our understanding of the immune system has led to the development of new molecules that can increase the immune response of patients. Regardless of their genetic or metabolic disorders, many cancer patients may benefit from treatment because it is the immune response itself of the patient that is targeted and not the cancer cell.

Immune Check-Points

The term immune-checkpoints refers to a series of inhibitory pathways in the immune system that are crucial for maintaining self-tolerance and preventing the excessive, prolonged and potentially harmful activity of T-cells in peripheral tissues.(8)
It is now clear that tumors can use these immune-checkpoints to evade the antitumor immune response, such as through the loss of expression of tumor-associated antigens (TAA) and/or major histocompatibility complex (MHC) antigens, or through the production of cytokines and the expression of new, inhibitory membrane molecules.
This continuous molecular remodeling phenomenon is known as “cancer immunoediting”, and consists of three main, consecutive phases:
- Elimination (complete destruction of the tumor cells by the host’s immune system)
- Equilibrium (tumor cells selected by the T-cells become resistant to the immune system)
- Escape (the tumor cells give rise to clinically detectable lesions)(9)
The immune-checkpoints currently known to be involved in the development of lung cancer are the cytotoxic T-lymphocyte antigen-4 receptor (CTLA-4) and the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1).

Cytotoxic T lymphocyte antigen-4

Because immune-checkpoints are activated in most cases by a ligand-receptor interaction, they can be inhibited by antagonist antibodies or recombinant forms of ligands/receptors.
The CTLA-4 receptor, known also as CD152, is a member of the immunoglobulin (Ig) superfamily that is expressed on cytotoxic T lymphocytes.(10 11 12) After binding with one of its ligands, B7-1 or B7-2 expressed on the antigen-presenting cells (APC), it transmits an inhibitory signal to the lymphocyte, thus helping to homeostatically regulate the immune response.(13)
CTLA-4 plays a vital role in the maintenance of immune tolerance to the tumor.(14) Specifically, the CTLA-4 receptor acts on the CD80 and CD86 costimulatory immune signals activated by the antigen-presenting cells, so they increase the activation threshold of the T lymphocytes. The systemic administration of anti-CTLA-4 inhibitors as monotherapy or in combination with other therapeutic cancer vaccines has been shown to induce a regression of melanoma and colon cancer in murine models.(15 16)
In a Phase II study evaluating the activity of an anti-CTLA-4 antibody (tremelimumab) that enrolled 29 patients with chemotherapy-resistant MPM (28 pleural and 1 peritoneal)(17 18 19), objective clinical responses were observed only in 29 patients, however, stable disease was seen in 9 patients, or approximately 31% of patients with epithelial histology. The median overall survival rate at one year was 48% and 37% at two years.

Programmed death-1 receptor

PD-1 is a cell surface receptor belonging to the Ig superfamily that is expressed on T-cells and pro-B cells and binds two ligands, PD-L1 and PD-L2. PD-L1 is a transmembrane protein that binds to its PD-1 and B7.1 receptors on the surface of T-cells, deactivating them.(20)
The PD-1 receptor stimulates the cells into inactivation by allowing the tumor cell to escape the surveillance of the immune system. (21)
This receptor is activated by binding with its ligand: programmed death-ligand 1 (PD-L1), which is usually found in the tumor microenvironment on the surface of cancer cells. (22)
Researchers have shown that PD-L1 is present on rat murine cells in vivo.(23) PD-L1 expression increases in response to an increase in the concentration of interferon y (IFN)-? and the draining of T-cells into the tumor-draining lymph nodes, supporting the hypothesis that this is an important local immunosuppressive pathway.
The inhibitory action of PD-L1 on the different subpopulations of T-cells produces opposite effects on tumor progression and suggests that the immune suppression of the tumor is mediated by a specific subclass of T-cells.
Researchers have demonstrated that PD-L1 was expressed in approximately 40% of 106 samples of mesothelioma analyzed, all of which were tumors with sarcomatoid histology with a poor prognosis (5.0 months versus 14.5).

Treatments

Targeted immunotherapies

The first immunopotentiation study dates back to 1975, investigating the intrapleural administration of a vaccine consisting of irradiated and sterilized BCG, which led to a reduction in tumor growth, secondary to the activation of the immune system.(25 26) Other studies followed the same line of research using Mycobacterium vaccae in combination with chemotherapy, for example.(27 28 29) Another attempt at potentiating the immune response is the use of cytokines, such as interferon.(30 31 32 33( Viral vectors have also been used to increase the efficacy of therapy.34 35 36 Interleukin-2 has also been tested in this disease to activate the immune system against the tumor. (37 38 39 40) Another cytokine used in immunopotentiation studies is GM-CSF (granulocyte/macrophage colony-stimulating factor)(41 42 43 44) Several studies have evaluated the possibility of increasing the expression of major histocompatibility molecules (MHCs) to increase T-cell clones with antitumor effect. Other studies have evaluated coadjuvant therapies such as CpGm oligodeoxynucleotide, CpG ODNs, Toll-like receptor 3 agonist, Toll-like receptor-7 agonist. (47 48 49) Immunomodulation involves modifying the lack of cell immunity within tumor sites. (50 51)
The first immunomodulation studies were conducted in the 1990s, evaluating therapies such as autologous and allogeneic LAK cells to reduce pleural effusions.(52) Other studies demonstrated the cytotoxic action of CTLs against MPM cells.53 More recently, research has been conducted on the activity of dendritic cells and their ability to protect antitumor immunity. (54) Other studies have investigated CD40-activated follicular B-cells and autologous T-cells expressing a chimeric antigen receptor (CAR).(55 56)
Immunodepletion, often known as lymphodepletion, is another area of immunotherapy that involves eliminating the cells that have infiltrated the tumor foci.57 Promising studies have investigated the depletion of tumor-associated macrophages (TAMs) from the tumor mass and the possibility of reversing these cells from TAMs to M1 status.(58 59) Similarly, other studies have demonstrated the utility of activating the TAMs infiltrating MPM tissue, promoting the release of cytokines and chemokines such as TNF-a, IFN-inducible protein 10 and IL6.(60 61)

Vaccines

The discovery of mesothelin in the 1990s was very important because researchers hoped it could be used as a specific marker for MPM.(62) Indeed, since this protein is also expressed in other tumor types, promising vaccines against these cancers were developed. (63 64)
Notwithstanding the controversy surrounding the possible role of the SV40 virus in the biogenesis of MPM, SV40 antigens have been tested as potential immunological targets for the disease.(65 66 67 68)
Wilms’ tumor 1 protein (WT1) has also been investigated as a potential diagnostic marker specifically for MPM.(69 70 71 72)
One of the treatment strategies for this disease is developing cellular vaccines and a number of studies have evaluated the effects of cancer cells transfected with IL-4, IL-2, GM-CSF, B7-1, as vaccine cells.(73 74 75 76) Dendritic-cell based vaccines have also been investigated to activate both Th1 cells and CTLs by activating phagocytosis and apoptosis.(77 78) Researchers have also reported that MPM cells in apoptosis could be used as potent inducers of anticancer CTLS.79

Monoclonal Antibodies

Monoclonal antibodies have long been used in immunohistochemical techniques to obtain a differential diagnosis between MPM and other tumors.(80)
The first approach in this area was to test a monoclonal antibody and in combination with a toxin as a potential immunotherapy. (81) Other studies evaluated monoclonal antibody reagents in combination with the 7D3 transferrin receptor, ricin A or doxorubicin. (82 83)
The monoclonal antibody K1 targeting mesothelin has been investigated as a potential immunotherapy for MPM.(84)
Various biomedical engineering methods have been used to design monoclonal antibodies combined with toxins to construct chimeric agents. (85 86 87 88)
Fusion proteins that can target cancer cells when subjected to radiotherapy have also been developed, and whose results suggest greater cytotoxic effects with fewer side effects. (89)
Researchers have developed an anti-MPM immunotoxin by combining Pseudomonas exotoxin with a fragment of the anti-mesothelin antibody. (90) Human mesothelin has also been combined with an antibody targeting a dendritic cell receptor, increasing the potential for vaccination with mesothelin.(91)
Wingless-type (Wnt) protein, which is involved in various cancers, is another important antigen against which monoclonal antibodies have been developed.(92 93 94)
Antibodies against the surface antigen CD26, which is involved in tumor growth, have also been developed.(95)
Other examples of monoclonal antibodies described above include CTLA-4 inhibitors (ipilimumab and tremelimumab), and PD-L1 (pembrolizumab) and PD-1 receptor (nivolumab) inhibitors. (96 97 98 99)
Tremelimumab was investigated in a single-arm Phase II study of pretreated patients but the primary endpoint of objective response rate was not achieved. (100) The disease control rate of patients treated with tremelimumab was around 31%, progression-free survival (PFS) was 6.2 months (95% CI 1.3–11.1), and the mean survival time (mST) was 10.7 months (0.0–21.9).(101) Studies of anti-PD-L1 and PD-1 monoclonal antibodies are also currently underway.(102)

Recent clinical trials

Below is a short list of recent clinical studies that have been completed or currently ongoing. Please see www.clinicaltrials.gov for further details about these studies.

Completed studies:

- Dendritic Cell-based Immunotherapy in Mesothelioma (tumor lysate-loaded autologous dendritic cells).
- Dendritic Cell-based Immunotherapy Combined With Low-dose Cyclophosphamide in Patients With Malignant Mesothelioma (DC+CTX)(103)
(Allogeneic Tumor Cell Vaccine (K562); Drug: Celecoxib; Drug: cyclophosphamide)(104 105 106).
- Pilot Study of Allogeneic Tumor Cell Vaccine With Metronomic Oral Cyclophosphamide and Celecoxib in Patients Undergoing Resection of Lung and Esophageal Cancers, Thymic Neoplasms, and Malignant Pleural Mesotheliomas (Allogeneic Tumor Cell Vaccine (K562); Drug: Celecoxib; Drug: cyclophosphamide).(104 105 106).
- Cyclophosphamide Plus Vaccine Therapy in Treating Patients With Advanced Cancer (allogeneic tumor cell vaccine; Biological:autologous tumor cell vaccine; Biological: recombinant interferon alfa; Biological: recombinant interferon gamma; Biological:sargramostim; Drug:cyclophosphamide).
- Study of Safety and Tolerability of Intravenous CRS-207 in Adults With Selected Advanced Solid Tumors Who Have Failed or Who Are Not Candidates for Standard Treatment (Biological: CRS-207, Live-attenuated Listeria monocytogenes expressing human Mesothelin).
- Safety and Immune Response to a Multi-component Immune Based Therapy (MKC1106-PP) for Patients With Advanced Cancer (PSMA/PRAME).

Ongoing studies:

- Safety and Efficacy of Listeria in Combination With Chemotherapy as Front-line Treatment for Malignant Pleural Mesothelioma (Immunotherapy plus chemotherapy; Biological: Immunotherapy with cyclophosphamide plus chemotherapy).
- Dendritic Cells Loaded With Allogeneous Cell Lysate in Mesothelioma Patients (MesoCancerVac).
- CAR T Cell Receptor Immunotherapy Targeting Mesothelin for Patients With Metastatic Cancer (Fludarabine; Biological:Anti-mesothelin CAR; Drug:Cycolphosphamide; Drug:Aldesleukin).
- Genetically Modified T Cells in Treating Patients With Stage III-IV Non-small Cell Lung Cancer or Mesothelioma (Aldesleukin; Biological: Autologous WT1-TCRc4 Gene-transduced CD8-positive Tcm/TnLymphocytes; Drug:Cyclophosphamide; Other: Laboratory Biomarker Analysis; Procedure: Therapeutic Conventional Surgery).
- The Anti-CTLA-4 Monoclonal Antibody Tremelimumab in Malignant Mesothelioma (Tremelimumab).
- Adjuvant Tumor Lysate Vaccine and Iscomatrix With or Without Metronomic Oral Cyclophosphamide and Celecoxib in Patients With Malignancies Involving Lungs, Esophagus, Pleura, or Mediastinum (H1299 Lysate Vaccine; Drug:Cyclophosphamide; Drug:Celecoxib).
- A Study of Tremelimumab Combined With the Anti-PD-L1 MEDI4736 Antibody in Malignant Mesothelioma (NIBIT-MESO-1) (tremelimumab plus MEDI4736).
- A Clinical Study With Tremelimumab as Monotherapy in Malignant Mesothelioma (Tremelimumab).
- Phase II Study of Adjuvant WT-1 Analog Peptide Vaccine in MPM Patients After MSK10-134 (WT-1-vaccine Montanide+GM-CSF; Biological:Montanide adjuvant + GM-CSF).
- Randomized Study of Adjuvant WT-1 Analog Peptide Vaccine in Patients With Malignant Pleural Mesothelioma (MPM) After Completion of Combined Modality Therapy (WT-1-vaccine Montanide +GM-CSF; Biological: Montanide adjuvant + GM-CSF (This arm is closed))
- Nivolumab in Patients With Recurrent Malignant Mesothelioma.
- Gene Therapy for Pleural Malignancies (Adenoviral-mediated Interferon-beta; Biological:SCH721015).
- Four Versus Six Cycles of Pemetrexed/Platinum for MPM (Pemetrexed/platinum chemotherapy).
- Intrapleural AdV-tk Therapy in Patients With Malignant Pleural Effusion (AdV-tk+ valacyclovir).

Response to Immunotherapy

Immunotherapy has changed the way in which we measure objective responses in both clinical studies as well as clinical practice. Melanoma immunotherapy studies have shown that the antitumor response is not seen until weeks or months after the start of treatment, with a survival gain seen after several months. This is because immunotherapy drugs activate the immune system, which in turn elicits a cell-mediated response.
The response to treatment is measured by using RECIST or WHO criteria. During immunotherapy, these conventional criteria are not capable of adequately measuring the presence of peritumoral inflammatory infiltrate which may mimic a pseudoprogression, a phenomenon typically encountered during this type of treatment. To avoid this problem, immune-related response criteria (irRC) have been developed, in which an initial radiographic progression, in other words the appearance of new lesions and/or an increase in the size of existing lesions, in the absence of clinical progression, must be confirmed by another evaluation.(107) The correct use of irRC can identify long-term survivors, including patients who would be considered by coventional criteria to be progressing and so may not continue to benefit from targeted treatment.(108) Another aspect evidenced by immunotherapy is the need to understand whether this treatment is suitable for everyone or only certain patients who are most likely to benefit from immunotherapy.

Conclusions

The association between the immune system and MPM is complex and multifaceted. Immunity certainly plays a key role in inducing damage to the DNA of mesothelial cells, which is strongly and pathogenically linked to exposure to asbestos.
Dividing the immune system into innate response and adaptive response also helps balance the inhibition and activation of the cells involved in this complex mechanism.
Although the results from immunotherapy studies have not yet been earth-shattering, they are nevertheless extremely promising and provide a new view of this disease in anticipation that it will lead to new therapeutic approaches.

Reference

1. Hanahan D., Weinberg R.A., Hallmarkis of cancer: the next generation. Cell 2011;144:646-74 2. Currie AJ, Prosser A, McDonnell A, Cleaver AL, Robinson BW, Freeman GJ, et al. Dual control of antitumor CD8 T cells through the programmed death-1/programmed death-ligand 1 pathway and immunosuppressive CD4 T cells: regulation and counterregulation. J Immunol 2009;183:7898–908.
3. Gr.goire M. What’s the place of immunotherapy in malignant mesothelioma treatments? Cell Adh Migr 2010; 4: 153–61.
4. Cornelissen R, Heuvers ME, Maat AP, et al. New roads open up for implementing immunotherapy in mesothelioma. Clin Dev Immunol 2012; 2012: 927240.
5. H. Bielefeldt-Ohmann, A.G. Jarnicki, D.R. Fitzpatrick, Molecular pathobiology and immunology of malignant mesothelioma, J. Pathol. 178 (1996) 369–378.
6. M.J. Garlepp, C.C. Leong, Biological and immunological aspects of malignant mesothelioma, Eur. Respir. J. 8 (1995) 643–650.
7. Mansfield AS, Roden A, Peikert T, Sheinin YM, Harrington SM, Krco CJ, et al. B7–H1 expression in malignant pleural mesothelioma is associated with sarcomatoid histology and poor prognosis. J Thorac Oncol 2014;9:1036–40.
8. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12:252-264.
9. Dun GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol 2004; 22:329-360.
10. Calabr. L, Danielli R, Sigalotti L, Maio M. Clinical studies with anti-CTLA-4 antibodies in non-melanoma indications. Semin Oncol 2010; 37: 460–67.
11. Hoos A, Ibrahim R, Korman A, et al. Development of ipilimumab: contribution to a new paradigm for cancer immunotherapy. Semin Oncol 2010; 37: 53–46.
12. Lynch TJ, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as fi rst-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol 2012; 30: 2046–54.
13. Reck M, Paz-Ares L. Immunologic checkpoint blockade in lung cancer. Semin Oncol 2015; 42:402-417.
14. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immu¬nity by CTLA-4 blockade. Science. 1996;271(5256):1734–1736.
15. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immu¬nity by CTLA-4 blockade. Science. 1996;271(5256):1734–1736.
16. van Elsas A, Hurwitz AA, Allison JP. Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation. J Exp Med. 1999;190(3):355–366.
17. Ribas A, Keff ord R, Marshall MA, et al. Phase III randomized, clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol 2013; 31: 616–22.
18. Tarhini AA, Cherian J, Moschos SJ, et al. Safety and effi cacy of combination immunotherapy with interferon alfa-2b and tremelimumab in patients with stage IV melanoma. J Clin Oncol 2012; 30: 322–28.
19. Reck M, Paz-Ares L. Immunologic checkpoint blockade in lung cancer. Semin Oncol 2015; 42:402-417.
20. Reck M, Paz-Ares L. Immunologic checkpoint blockade in lung cancer. Semin Oncol 2015; 42:402-417.
21. Currie AJ, Prosser A, McDonnell A, et al. Dual control of antitumor CD8 T cells through the programmed death-1/programmed death-ligand 1 pathway and immunosuppressive CD4 T cells: regulation and counterregulation. J Immunol. 2009;183(12):7898–7908.
22. Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol. 2008;8(6):467–477.
23. Currie AJ, Prosser A, McDonnell A, et al. Dual control of antitumor CD8 T cells through the programmed death-1/programmed death-ligand 1 pathway and immunosuppressive CD4 T cells: regulation and counterregulation. J Immunol. 2009;183(12):7898–7908.
24. Mansfield AS, Peikert T, Roden A, et al. Programmed cell death 1 ligand 1 expression and association with survival in mesothelioma. European Lung Cancer Conference 2014; 2014 Mar 26–29; Geneva, Switzerland. J Thorac Oncol. 2014;9(Supplement 9):S7–S52. Abstract #1270.
25. M.V. Pimm, R.W. Baldwin, BCG therapy of pleural and peritoneal growth of transplanted rat tumours, Int. J. Cancer 15 (1975) 260–269.
26. I. Webster, J.W. Cochrane, K.R. Burkhardt, Immunotherapy with BCG vaccine in 30 cases of mesothelioma, S. Afr. Med. J. 61 (1982) 277–278.
27. M.E. O’Brien, A. Saini, I.E. Smith, A. Webb, K. Gregory, R. Mendes, C. Ryan, K. Priest, K.V. Bromelow, R.D. Palmer, N. Tuckwell, D.A. Kennard, B.E. Souberbielle, A randomized phase II study of SRL172 (Mycobacterium vaccae) combined with chemotherapy in patients with advanced inoperable nonsmall- cell lung cancer and mesothelioma, Br. J. Cancer 83 (2000) 853–857
28. M.E. O’Brien, A. Saini, I.E. Smith, A. Webb, K. Gregory, R. Mendes, C. Ryan, K. Priest, K.V. Bromelow, R.D. Palmer, N. Tuckwell, D.A. Kennard, B.E. Souberbielle, A randomized phase II study of SRL172 (Mycobacterium vaccae) combined with chemotherapy in patients with advanced inoperable nonsmall- cell lung cancer and mesothelioma, Br. J. Cancer 83 (2000) 853–857
29. H.S. Pandha, P. Mortimer, B. Souberbeille, P. McCoubrie, M.E. O’Brien, Cutaneous toxicity after intradermal vaccination with Mycobacterium vaccae against lung cancer and malignant mesothelioma, Br. J. Dermatol. 144 (2001) 648–649
30. R. Mendes, M.E. O’Brien, A. Mitra, A. Norton, R.K. Gregory, A.R. Padhani, K.V. Bromelow, A.R. Winkley, S. Ashley, I.E. Smith, B.E. Souberbielle, Clinical and immunological assessment of Mycobacterium vaccae (SRL172) with chemotherapy in patients with malignant mesothelioma, Br. J. Cancer 86 (2002) 336–341.
31. R. Rosso, R. Rimoldi, F. Salvati, M. De Palma, A. Cinquegrana, G. Nicoló, A. Ardizzoni, U. Fusco, A. Capaccio, R. Centofanti, M. Neri, A.R. Cruciani, L. Maisto, Intrapleural natural beta interferon in the treatment of malignant pleural effusions, Oncology 45 (1988) 253–256..
32. A. Hand, K. Pelin, K. Mattson, K. Linnainmaa, Interferon (IFN)-alpha and IFNgamma in combination with methotrexate: in vitro sensitivity studies in four human mesothelioma cell lines, Anticancer Drugs 6 (1995) 77–82
33. F. Gattacceca, Y. Pilatte, C. Billard, I. Monnet, S. Moritz, J. Le Carrou, M. Eloit, M.C. Jaurand, Ad-IFN gamma induces antiproliferative and antitumoral responses in malignant mesothelioma, Clin. Cancer Res. 8 (2002) 3298–3304
34. D.H. Sterman, A. Recio, A.R. Haas, A. Vachani, S.I. Katz, C.T. Gillespie, G. Cheng, J. Sun, E. Moon, L. Pereira, X. Wang, D.F. Heitjan, L. Litzky, C.H. June, R.H. Vonderheide, R.G. Carroll, S.M. Albelda, A phase I trial of repeated intrapleural adenoviral-mediated interferon-beta gene transfer for mesothelioma and metastatic pleural effusions, Mol. Ther. 18 (2010) 852–860.
35. C.L. Willmon, V. Saloura, Z.G. Fridlender, P. Wongthida, R.M. Diaz, J. Thompson, T. Kottke, M. Federspiel, G. Barber, S.M. Albelda, R.G. Vile, Expression of IFN-beta enhances both efficacy and safety of oncolytic vesicular stomatitis virus for therapy of mesothelioma, Cancer Res. 69 (2009) 7713–7720.
36. H. Li, K.W. Peng, D. Dingli, R.A. Kratzke, S.J. Russell, Oncolytic measles viruses encoding interferon beta and the thyroidal sodium iodide symporter gene for mesothelioma virotherapy, Cancer Gene. Ther. 17 (2010) 550–558.
37. P. Lissoni, S. Barni, A. Ardizzoia, F. Paolorossi, E. Tisi, S. Crispino, G. Tancini, Intracavitary administration of Interleukin-2 as palliative therapy for neoplastic effusions, Tumori 30 (1992) 118–120.
38. R. Nano, E. Capelli, M. Civallero, G. Terzuolo, E. Volpini, C. Nascimbene, P. Cremaschi, Effects of Interleukin-2 for the treatment of malignant mesothelioma, Oncol. Rep. 5 (1998) 489–492.
39. S.H. Goey, A.M. Eggermont, C.J. Punt, R. Slingerland, J.W. Gratama, R. Oosterom, R. Oskam, R.L. Bolhuis, G. Stoter, Intrapleural administration of Interleukin 2 in pleural mesothelioma: a phase I-II study, Br. J. Cancer 72 (1995) 1283–1288.
40. C. Jackaman, C.S. Bundell, B.F. Kinnear, A.M. Smith, P. Filion, D. van Hagen, B.W. Robinson, D.J. Nelson, IL-2 intratumoral immunotherapy enhances CD8+ T cells that mediate destruction of tumor cells and tumor-associated vasculature: a novel mechanism for IL-2, J. Immunol. 171 (2003) 5051–5063.
41. G. Alì, L. Boldrini, M. Lucchi, A. Picchi, M. Dell’Omodarme, M.C. Prati, A. Mussi, V. Corsi, G. Fontanini, Treatment with Interleukin-2 in malignant pleural mesothelioma: immunological and angiogenetic assessment and prognostic impact, Br. J. Cancer 101 (2009) 1869–1875.
42. J.A. Davidson, A.W. Musk, B.R. Wood, S. Morey, M. Ilton, L.L. Yu, P. Drury, K. Shilkin, B.W. Robinson, Intralesional cytokine therapy in cancer: a pilot study of GM-CSF infusion in mesothelioma, J. Immunother. 21 (1998) 389–398.
43. P.L. Triozzi, W. Aldrich, K.O. Allen, J. Lima, D.R. Shaw, T.V. Strong, Antitumor activity of the intratumoral injection of fowlpox vectors expressing a triad of costimulatory molecules and granulocyte/macrophage colony stimulating factor in mesothelioma, Int. J. Cancer 113 (2005) 406–414.
44. A. Yoshimoto, K. Kasahara, K. Saito, M. Fujimura, S. Nakao, Granulocyte colony-stimulating factor-producing malignant pleural mesothelioma with the expression of other cytokines, Int. J. Clin. Oncol. 10 (2005) 58–62.
45. A. Powell, J. Creaney, S. Broomfield, I. Van Bruggen, B. Robinson, Recombinant GM-CSF plus autologous tumor cells as a vaccine for patients with mesothelioma, Lung. Cancer 52 (2006) 189–197
46. C. Leong, J. Marley, S. Loh, B. Robinson, M. Garlepp, Induction and maintenance of T-cell response to a nonimmunogenic murine mesothelioma cell line requires expression of B7-1 and the capacity to upregulate class II major histocompatibility complex expression, Cancer Gene. Ther. 3 (1996) 321–330.
47. C.C. Leong, J.V. Marley, S. Loh, N. Milech, B.W. Robinson, M.J. Garlepp, Transfection of the gene for B7-1 but not B7-2 can induce immunity to murine malignant mesothelioma, Int. J. Cancer 71 (1997) 476–482.
48. R.G. van der Most, H. Himbeck, S. Aarons, S.J. Carter, I. Larma, C. Robinson, A. Currie, R.A. Lake, Antitumor efficacy of the novel chemotherapeutic agent coramsine is potentiated by cotreatment with CpG-containing oligodeoxynucleotides, J. Immunother. 29 (2006) 134–142.
49. G.W. Stone, S. Barzee, V. Snarsky, C. Santucci, B. Tran, R.S. Kornbluth, Regression of established AB1 murine mesothelioma induced by peritumorale injections of CpG oligodeoxynucleotide either alone or in combination with poly(I:C) and CD40 ligand plasmid DNA, J. Thorac. Oncol. 4 (2009) 802–808.
50. M. Mamede, T. Saga, T. Ishimori, Y. Nakamoto, N. Sato, T. Higashi, T. Mukai, H. Kobayashi, J. Konishi, Differential uptake of (18)F-fluorodeoxyglucose by experimental tumors xenografted into immunocompetent and immunode ficient mice and the effect of immunomodification, Neoplasia 5 (2003) 179–183.

51. C.J. Bradish, K. Allner, R. Fitzgeorge, Immunomodification and the expression nof virulence in mice by defined strains of semliki forest virus: the effects of cyclophosphamide, J. Gen. Virol. 28 (1975) 225–237.
52. H. Yanagawa, S. Sone, K. Fukuta, Y. Nishioka, T. Ogura, Local adoptive immunotherapy using lymphokine-activated killer cells and Interleukin-2 against malignant pleural mesothelioma: report of two cases, Jpn. J. Clin. Oncol. 21 (1991) 377–383
53. M. Tani, H. Tanimura, H. Yamaue, S. Mizobata, M. Yamamoto, M. Iwahashi, K. Ura, Y. Nagai, T. Tsunoda, H. Wakasaki, K. Nanjo, K. Fujino, S. Yukawa, Successful immunochemotherapy for patients with malignant mesothelioma: report of two cases, Surg. Today 28 (1998) 647–651.
54. J.P. Hegmans, A. Hemmes, J.G. Aerts, H.C. Hoogsteden, B.N. Lambrecht, Immunotherapy of murine malignant mesothelioma using tumor lysate
55. Y. Zhao, E. Moon, C. Carpenito, C.M. Paulos, X. Liu, A.L. Brennan, A. Chew, R.G. Carroll, J. Scholler, B.L. Levine, S.M. Albelda, C.H. June, Multiple injections of electroporated autologous T cells expressing a chimeric antigen receptor mediate regression of human disseminated tumor, Cancer Res. 70 (2010) 9053–9061.
56. G.E. Plautz, P.A. Cohen, S. Shu, Considerations on clinical use of T cell immunotherapy for cancer, Arch. Immunol. Ther. Exp. 51 (2003) 245–257.
57. N.R. Miselis, Z.J. Wu, N. Van Rooijen, A.B. Kane, Targeting tumor-associated macrophages in an orthotopic murine model of diffuse malignant mesothelioma, Mol. Cancer Ther. 7 (2008) 788–799.
58. J.D. Veltman, M.E. Lambers, M. van Nimwegen, R.W. Hendriks, H.C. Hoogsteden, J.P. Hegmans, J.G. Aerts, Zoledronic acid impairs myeloid differentiation to tumour-associated macrophages in mesothelioma, Br. J. Cancer 103 (2010) 629–641.
59. A.S. Jassar, E. Suzuki, V. Kapoor, J. Sun, M.B. Silverberg, L. Cheung, M.D. Burdick, R.M. Strieter, L.M. Ching, L.R. Kaiser, S.M. Albelda, Activation of tumor-associated macrophages by the vascular disrupting agent 5,6- dimethylxanthenone-4-acetic acid induces an effective CD8+ T-cellmediated antitumor immune response in murine models of lung cancer and mesothelioma, Cancer Res. 65 (2005) 11752–11761.
60. K. Chang, I. Pastan, Molecular cloning of mesothelin, a differentiation antigen present on mesothelium, mesotheliomas, and ovarian cancers, Proc. Natl. Acad. Sci. USA 93 (1996) 136–140.
61. K. Chang, I. Pastan, Molecular cloning and expression of a cDNA encoding a protein detected by the K1 antibody from an ovarian carcinoma (OVCAR-3)cell line, Int. J. Cancer 57 (1994) 90–97.
62. P. Argani, C. Iacobuzio-Donahue, B. Ryu, C. Rosty, M. Goggins, R.E. Wilentz, S.R. Murugesan, S.D. Leach, E. Jaffee, C.J. Yeo, J.L. Cameron, S.E. Kern, R.H. Hruban, Mesothelin is overexpressed in the vast majority of ductal adenocarcinomas of the pancreas: identification of a new pancreatic cancer marker by serial analysis of gene expression (SAGE), Clin. Cancer Res. 7 (2001) 3862–3868.
63. J. Yokokawa, C. Palena, P. Arlen, R. Hassan, M. Ho, I. Pastan, J. Schlom, K.Y. Tsang, Identification of novel human CTL epitopes and their agonist epitopes of mesothelin, Clin. Cancer Res. 11 (2005) 6342–6351.
64. Adams, A. Gibbs, Simian virus 40 detection in human mesothelioma: reliability and significance of the available molecular evidence, Front. Biosci. 6 (2001) E12–E22.
65. A.G. Elmishad, M. Bocchetta, H.I. Pass, M. Carbone, Polio vaccines, SV40 and human tumours, an update on false positive and false negative results, Dev. Biol. 123 (2006) 109–117.
66. Y.C. Xie, C. Hwang, W. Overwijk, Z. Zeng, M.H. Eng, J.J. Mulé, M.J. Imperiale, N.P. Restifo, M.G. Sanda, Induction of tumor antigen-specific immunity in vivo by a novel vaccinia vector encoding safety-modified simian virus 40 T antigen, J. Natl. Cancer Inst. 91 (1999) 169–175.
67. R.K. Bright, E.T. Kimchi, M.H. Shearer, R.C. Kennedy, H.I. Pass, SV40 Tagspecific cytotoxic T lymphocytes generated from the peripheral blood of malignant pleural mesothelioma patients, Cancer Immunol. Immunother. 50 (2002) 682–690.
68. N.G. Ordóñez, Immunohistochemical diagnosis of epithelioid mesothelioma: an update, Arch. Pathol. Lab. Med. 129 (2005) 1407–1414.
69. R. Bei, A. Scardino, TAA polyepitope DNA-based vaccines: a potential tool for cancer therapy, J. Biomed. Biotechnol. 2010 (2010) 102758.
70. R.J. May, T. Dao, J. Pinilla-Ibarz, T. Korontsvit, V. Zakhaleva, R.H. Zhang, P. Maslak, D.A. Scheinberg, Peptide epitopes from the Wilms’ tumor 1 oncoprotein stimulate CD4+ and CD8+ T cells that recognize and kill human malignant mesothelioma tumor cells, Clin. Cancer Res. 13 (2007) 4547–4555.
71. L.M. Krug, T. Dao, A.B. Brown, P. Maslak, W. Travis, S. Bekele, T. Korontsvit, V. Zakhaleva, J. Wolchok, J. Yuan, H. Li, L. Tyson, D.A. Scheinberg, WT1 peptide vaccinations induce CD4 and CD8 T cell immune responses in patients with mesothelioma and non-small cell lung cancer, Cancer Immunol. Immunother. 59 (2010) 1467–1479.
72. C. Palumbo, R. Bei, A. Procopio, A. Modesti, Molecular targets and targeted therapies for malignant mesothelioma, Curr. Med. Chem. 15 (2008) 855–867.
73. A.K. Nowak, R.A. Lake, H.L. Kindler, B.W. Robinson, New approaches for mesothelioma: biologics, vaccines, gene therapy, and other novel agents, Semin. Oncol. 29 (2002) 82–96.
74. C.L. Chang, T.C. Wu, C.F. Hung, Control of human mesothelin-expressing tumors by DNA vaccines, Gene. Ther. 14 (2007) 1189–1198.
75. S. Mukherjee, D. Nelson, S. Loh, I. van Bruggen, L.J. Palmer, C. Leong, M.J. Garlepp, B.W. Robinson, The immune anti-tumor effects of GM-CSF and B7–1 gene transfection are enhanced by surgical debulking of tumor, Cancer Gene. Ther. 8 (2001) 580–588.
76. M. Grégoire, C. Ligeza-Poisson, N. Juge-Morineau, R. Spisek, Anti-cancer therapy using dendritic cells and apoptotic tumour cells: pre-clinical data in human mesothelioma and acute myeloid leukaemia, Vaccine 21 (2003) 791–794.
77. F. Ebstein, C. Sapede, P.J. Royer, M. Marcq, C. Ligeza-Poisson, I. Barbieux, L. Cellerin, G. Dabouis, M. Grégoire, Cytotoxic T cell responses against mesothelioma by apoptotic cell-pulsed dendritic cells, Am. J. Respir. Crit. Care Med. 169 (2004) 1322–1330.
78. F. Ebstein, C. Sapede, P.J. Royer, M. Marcq, C. Ligeza-Poisson, I. Barbieux, L. Cellerin, G. Dabouis, M. Grégoire, Cytotoxic T cell responses against mesothelioma by apoptotic cell-pulsed dendritic cells, Am. J. Respir. Crit. Care Med. 169 (2004) 1322–1330.
79. J.E. King, N. Thatcher, C.A. Pickering, P.S. Hasleton, Sensitivity and specificity of immunohistochemical markers used in the diagnosis of epithelioid mesothelioma: a detailed systematic analysis using published data, Histopathology 48 (2006) 223–232.
80. S.M. Hsu, P.L. Hsu, X. Zhao, C.S. Kao-Shan, J. Whang-Peng, Establishment of human mesothelioma cell lines (MS-1, -2) and production of a monoclonal antibody (anti-MS) with diagnostic and therapeutic potential, Cancer Res. 48 (1988) 5228–5236.
81. T.W. Griffin, J. Collins, F. Bokhari, M. Stochl, A.B. Brill, T. Ito, G. Emond, H. Sands, Intraperitoneal immunoconjugates, Cancer Res. 50 (1990) 1031–1038.
82. T.W. Griffin, M. Stocl, J. Collins, J. Fernandes, V.E. Maher, Combined antitumor therapy with the chemotherapeutic drug doxorubicin and an anti-transferrin receptor immunotoxin: in vitro and in vivo studies, J. Immunother. 11 (1992) 12–18.
83. U. Brinkmann, K. Webber, A. Di Carlo, R. Beers, P. Chowdhury, K. Chang, V. Chaudhary, M. Gallo, I. Pastan, Cloning and expression of the recombinant FAb fragment of monoclonal antibody K1 that reacts with mesothelin present on mesotheliomas and ovarian cancers, Int. J. Cancer 71 (1997) 638–644.
84. P.S. Chowdhury, J.L. Viner, R. Beers, I. Pastan, Isolation of a high-affinity stable single-chain Fv specific for mesothelin from DNA-immunized mice by phage display and construction of a recombinant immunotoxin with anti-tumor activity, Proc. Natl. Acad. Sci. USA 95 (1998) 669–674.
85. P.S. Chowdhury, G. Vasmatzis, R. Beers, B. Lee, I. Pastan, Improved stability and yield of a Fv-toxin fusion protein by computer design and protein engineering of the Fv, J. Mol. Biol. 281 (1998) 917–928.
86. R. Hassan, W. Ebel, E.L. Routhier, R. Patel, J.B. Kline, J. Zhang, Q. Chao, S. Jacob, H. Turchin, L. Gibbs, M.D. Phillips, S. Mudali, C. Iacobuzio-Donahue, E.M. Jaffee, M. Moreno, I. Pastan, P.M. Sass, N.C. Nicolaides, L. Grasso, Preclinical evaluation of MORAb-009, a chimeric antibody targeting tumor-associated mesothelin, Cancer Immun. 7 (2007) 20–30.
87. R. Hassan, S.J. Cohen, M. Phillips, I. Pastan, E. Sharon, R.J. Kelly, C. Schweizer, S. Weil, D. Laheru, Phase I clinical trial of the chimeric anti-mesothelin monoclonal antibody MORAb-009 in patients with mesothelin-expressing cancers, Clin. Cancer Res. 16 (2010) 6132–6138.
88. N. Sato, R. Hassan, D.B. Axworthy, K.J. Wong, S. Yu, L.J. Theodore, Y. Lin, L. Park, M.W. Brechbiel, I. Pastan, C.H. Paik, J.A. Carrasquillo, Pretargeted radioimmunotherapy of mesothelin-expressing cancer using a tetravalent single-chain Fv-streptavidin fusion protein, J. Nucl. Med. 46 (2005) 1201– 1209.
89. T.K. Bera, J. Williams-Gould, R. Beers, P. Chowdhury, I. Pastan, Bivalent disulfide-stabilized fragment variable immunotoxin directed against mesotheliomas and ovarian cancer, Mol. Cancer Ther. 1 (2001) 79–84
90. B. Wang, J.M. Kuroiwa, L.Z. He, A. Charalambous, T. Keler, R.M. Steinman, The human cancer antigen mesothelin is more efficiently presented to the mouse immune system when targeted to the DEC-205/CD205 receptor on dendritic cells, Ann. N.Y. Acad. Sci. 1174 (2009) 6–17.
91. P. Polakis, Wnt signaling and cancer, Genes Dev. 14 (2000) 1837–1851.
92. B. He, L. You, K. Uematsu, Z. Xu, A.Y. Lee, M. Matsangou, F. McCormick, D.M. Jablons, A monoclonal antibody against Wnt-1 induces apoptosis in human cancer cells, Neoplasia 6 (2004) 7–14.
93. J. Mazieres, L. You, B. He, Z. Xu, S. Twogood, A.Y. Lee, N. Reguart, S. Batra, I. Mikami, D.M. Jablons, Wnt2 as a new therapeutic target in malignant pleural mesothelioma, Int. J. Cancer 117 (2005) 326–332.
94. T. Inamoto, T. Yamada, K. Ohnuma, S. Kina, N. Takahashi, T. Yamochi, S. Inamoto, Y. Katsuoka, O. Hosono, H. Tanaka, N.H. Dang, C. Morimoto, Humanized anti-CD26 monoclonal antibody as a treatment for malignant mesothelioma tumors, Clin. Cancer Res. 13 (2007) 4191–4200.
95. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011; 364: 2517–26.
96. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363: 711–23.
97. Lebbe C, Weber JS, Maio M, et al. Five-year survival rates for patients (pts) with metastatic melanoma (MM) treated with ipilimumab (ipi) in phase II trials. Ann Oncol 2012; 23: abstr 1116PD.
98. Maio M, Bondarenko I, Robert C, et al. Four-year survival update for metastatic melanoma (MM) patients (pts) treated with ipilimumab (ipi) plus dacarbazine (DTIC) on phase 3 study CA184-024.Ann Oncol 2012; 23: abstr 1127P.
99. Calabro` L, Morra A, Fonsatti E, Cutaia O, Amato G, Giannarelli D, et al. Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial. Lancet Oncol 2013;14: 1104–11.
100. Maio M, Scherpereel A, Di Pietro A, Vasey P, Tsao AS, Calabro` L, et al. Randomized, double-blind, placebo-controlled study of tremelimumab for second- and third-line treatment of unresectable pleural or peritoneal mesothelioma. J Clin Oncol 2014;32:5s (suppl; abstr TPS7609^).
101. Kindler HL, Zuo Z, Khattri A, Keck MK, Vigneswaran W, Husain AN, et al. T-cell inflamed phenotype and PDL1 expression in malignant mesothelioma. J Clin Oncol 2014;32 (suppl; abstr 7589).
102. Hegmans JP, Veltman JD, Lambers ME, de Vries IJ, Figdor CG, Hendriks RW, Hoogsteden HC, Lambrecht BN, Aerts JG. Consolidative dendritic cell-based immunotherapy elicits cytotoxicity against malignant mesothelioma. Am J Respir Crit Care Med. 2010 Jun 15;181(12):1383-90. doi: 10.1164/rccm.200909-1465OC. Epub 2010 Feb 18.
103. Hegmans JP, Hemmes A, Aerts JG, Hoogsteden HC, Lambrecht BN. Immunotherapy of murine malignant mesothelioma using tumor lysate-pulsed dendritic cells. Am J Respir Crit Care Med. 2005 May 15;171(10):1168-77. Epub 2005 Mar 11.
104. Flores RM, Zakowski M, Venkatraman E, Krug L, Rosenzweig K, Dycoco J, Lee C, Yeoh C, Bains M, Rusch V. Prognostic factors in the treatment of malignant pleural mesothelioma at a large tertiary referral center. J Thorac Oncol. 2007 Oct;2(10):957-65.
105. Kelsen DP, Winter KA, Gunderson LL, Mortimer J, Estes NC, Haller DG, Ajani JA, Kocha W, Minsky BD, Roth JA, Willett CG; Radiation Therapy Oncology Group; USA Intergroup. Long-term results of RTOG trial 8911 (USA Intergroup 113): a random assignment trial comparison of chemotherapy followed by surgery compared with surgery alone for esophageal cancer. J Clin Oncol. 2007 Aug 20;25(24):3719-25.
106. Manegold C, Thatcher N. Survival improvement in thoracic cancer: progress from the last decade and beyond. Lung Cancer. 2007 Aug;57 Suppl 2:S3-5.
107. Wolchok JD, Hoos A, O’Day S et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 2009; 15:7412-7415.
108. McCormick KA, Fleming B. Clinical practice guidelines. The Agency for Health Care Policy and Research fosters the development of evidence-based guidelines. Health Progress 1992; 73:30-40.

> Download article as PDF

Introduction

Here we are once again to discuss scientific information and to disclose news about Malignant Pleural Mesothelioma (MPM).
At this time, we deem it useful to involve the readers in a new consensus conference, in other words in a meeting of experts which resulted in the drafting an update of the state-of-the-art of this topic and in the collection of recommendations on how to deal with this disease.
We are talking about the Third Italian Consensus Conference that took place in Bari back in January 2015, with the support of AIOM (Italian Association of Medical Oncology).
The resulting publication, the tangible output of the work carried out by experts on MPM, is available online at the following link: http://www.ncbi.nlm.nih.gov/pubmed/?term=Mezzapelle+et+al%2C+Sci+Rep+6%3A+22850.
This article is organised into nine different chapters: Introduction, Methods, Epidemiology, Diagnosis, Radiological Check-ups, Surgery, Radiotherapy, Chemotherapy, Psycho-social and legal aspects and future prospects.
This review contains a collection of the main references and an outline summary of the main concepts of this Consensus Conference. For more in-depth information and more specific details, please refer to the full text.

State-of-the-art and recommendations for Malignant Pleural Mesothelioma, according to Italian experts

Epidemiological data

In 2011, the incidence of MPM in Italy was 3.49 and 1.25 cases every 100,000 people/year, respectively, for men and women. A total of 1428 cases were reported: 1035 men and 393 women (Anon, 2015). The national incidence and mortality are currently stable, and there seems to be a one-plateau trend. However, it is believed that a peak will take place in 2020-2025, especially in industrialised countries.
As everyone knows, exposure to asbestos is strictly related to the incidence of MPM, and there is a veritable dose-response relationship (Prince, 2005; Mastrangelo, 2014).
Cumulative exposure to asbestos is an indicator that takes into account the sum of the exposure and is used in various research fields. However, it fails to consider important data such as the duration or intensity of the exposure itself (Thomas, 2013; Lubin, 2006; Vlandereen, 2013; Richardson, 2012).
Nevertheless, we can safely say that, with regards to cumulative exposure to asbestos, there does not seem to be a large difference compared to the previously published Consensus Conferences (Pinto, 2011; Pinto, 2013).
Exposure to asbestos can be of the occupational type, in other words tied to the work which the patient carries out or has carried out in the past, or non-occupational, tied above all to atmospheric and domestic pollution. In Italy, it is estimated that non-occupational exposure takes place in about 10.2% of the cases (National Mesothelioma Register 2012).
Asbestos can also spread through the air under the form of fibres. The WHO (World Health Organisation) has estimated that continuous exposure to 0.4-1 fibre/l can lead to the risk of becoming ill with MPM in 0.4-0.5 cases out of 100,000 people (World Health Organisation Regional Office for Europe, 2000).
Moreover, asbestos can also be found in water; however, there is no evidence of cases of mesothelioma caused by the ingestion of fibres.
There are documented cases of asbestos-containing talc, although this has never happened on Italian soil (Finkelstein, 2012).
Other carcinogenic substances tied to asbestos that have been the cause of MPM in Italy are fluoro-edenite, as in the area of Biancavilla (CT). These cases are similar to those described in Japan, in volcanic areas.
Although there is data of cancerogenesis only in test animals and no cases of MPM were ever described in man, silica carbide is also a carcinogenic agent that can potential cause this disease (Grosse, 2014).
There are also hereditary cases of MPM, associated with genetic alterations such as, for example, the mutations of BAP1 (Klerk, 2013; Betti, 2015. Some of these have also been described in Italy (Ascoli, 2007; Ascoli, 2014).

Diagnosis

Oftentimes, MPM manifests itself with a pleural effusion; however, this collection of fluid in the pleural cavity can also be a secondary effect of different medical conditions. Therefore, it is important to first of all proceed with a differential diagnosis between primitive tumour of the pleura, MPM, and other neoplasias that may metastasize at the pleural level, the most common ones being lung, breast and kidney neoplasias (Smith, 2014). Moreover, it is important to remember that many non-neoplastic pathologies are included within the differential diagnosis which may however cause pleural effusion: for example, infectious or inflammatory pleurisies, cardiac failure, parapneumonic effusion.
The diagnosis of MPM is carried out above all through the analysis of a pleural biopsy, which is often obtained by means of a thoracoscopy or, more rarely, by means of an eco or TC guided percutaneous biopsy (Pinto, 2013; Scherpereel, 2010; van Zandwijk, 2013).
In addition to the histological analysis carried out on the tissue obtained through a biopsy, it is also possibly to conduct a cytological analysis, evaluating the cells found in the pleural fluid. In some cases, this may allow the diagnosis to be made; however, this is exam is not as sensitive as histology (Kawai, 2014; Paintal, 2013; Hjerpe, 2015, Henderson, 2013).
In accordance with WHO, a histological classification of MPM has been defined, according to which tMPM can be subdivided into the epithelioid, sarcomatoid and biphasic histotype (Larsen, 2013).
Different markers are used to better define these tumour characteristics and, in particular to differentiate pleural metastasis from adenocarcinoma and primitive lesions caused by MPM (Ordonez, 2013; Betta, 2012).
The following markers are more commonly used to differentiate epithelioid MPM from adenocarcinomas: calretinin, D2-40 (anti-podoplanin antibody), the protein of Wilms-1 tumour, cytokeratin 5 and 6, mesothelin and thrombomodulin. Markers which are considered negative are; CEA, BerEP4, MOC-31, claudin-4 and CD155 (Henderson, 2013b; Lonardi, 2011, Jo, 2014). Napsin A, TTF1, CDX2, PAX-8, apocrine markers and hormonal receptors are instead useful for differentiating MPM from other localised metastasis at the pleural level. The marker BAP1 has been recently tested to differentiate benign mesothelial lesions from malignant ones (Cigognetti, 2015).
Sarcomatoid MPM expresses above all markers such as pan-cytokeratin, vimentin, smooth muscle differentiation markers, D2-40, calretinin (Pinto, 2013; Ordonez, 2013; Scherpereel, 2010; Churg, 2015; Henderson, 2013b).
Other useful markers for the diagnosis of MPM are mesothelin-related peptides (SMRP), osteopontin, and fibulin-3 (Lao, 2014; Creaney, 2011; Hollevoet 2011; Hollevoet, 2010; Luo, 2010; Wheatley-Price, 2010; Creaney 2014a; Franceschini, 2014).

Radiological tests

There are different radiological methods mainly used to diagnose MPM (Hallifax, 2015). The first approach usually takes place through a chest X-ray, which normally allows to identify the presence of a pleural or pericardial effusion or even very extended pleural lesions.
The chest TC, on the other hand, is considered a second-choice exam that allows one to obtain much more detailed morphological information compared to the chest X-ray.
The ultrasound scan can be useful to visualise some specific pleural anomalies, in addition to being used as a guide for conducting a thoracentecis procedure and, if necessary, as a guide for pleural biopsies.
The PET scan can be applied above all to evaluate the metabolism of some lesions; no changes have occurred since the previous Consensus Conference (Pinto, 2013).
As regards invasive diagnostic procedures, there are no changes in indications and recommendations compared to the ones described in the previous experts’ review (Pinto, 2013).
Thoracentesis is still the first minimally invasive diagnostic approach, and cytological analysis can be useful to diagnose the presence of malignant cells in about 60% of the cases. The thoracentesis procedure applied under ultrasound guidance can be useful to minimise any complications that may arise (Hooper, 2010).
Ultrasound and CT-guided biopsy have permanently replaced biopsies done blindly, and they are useful for performing accurate biopsies of lesions, irregularities or pleural thickening (Maskell, 2003; Qureshi, 2006; Adamset, 2001; Metintas, 2010a).
Thoracoscopy is the “gold standard” invasive diagnostic technique, and allows to obtain a diagnosis in 90% of the cases (Churg, 2014; Boutin, 1993; Hansen, 1998; Galbis, 2011; Brimset, 2012).
The Endo-Bronchial UltraSound (EBUS) technique, used to analyses lymph nodes that drain neoplastic cells deriving from MPM, can offer certain advantages with respect to the mediastinoscopy (Rice, 2009; Tournoy, 2008; Zielinski, 2010; Richards, 2010).
All of the radiological techniques used for diagnostic purposes also play a crucial role in establishing the stage the disease is in, thus allowing, in addition to the determination of the prognosis, a definition of the therapeutic approaches, which obviously change depending on the stage of the disease.
The methods mostly used for this purpose are still the CT scan and the PET scan (Truong, 2013a; Nickellet, 2014; Basu, 2011; Erasmus, 2005; Rice, 2009; Flores, 2003; Sørensen, 2008; Truong, 2013b; Armato, 2013; Frauenfelder, 2011; Labby, 2013a; Labby, 2013b; Byrne, 2004).

Therapeutic approaches

Surgery
Surgery plays a role in the diagnostic approach since, through invasive methods, including the ones described above, it can be extremely useful for obtaining histological material (Greillier, 2007; Buenoet, 2004; Attanoos, 2008 ).
Surgery is also employed in the treatment of malignant pleural effusion. In fact, in addition to being used for diagnostic purposes, thoracoscopy can also be for medical purposes since it allows the intrapleural administration of talc for the purpose of obtaining a pleurodesis. In the same way, specific surgical drainage methods can be applied for each clinical case (Waller, 1995; Halstead 2005; Martin-Ucar, 2001; Nakas, 2008).
Of course, the role of surgery in the treatment of MPM aims at the complete resection of the disease. It is important to remember that this is possible only in those cases where the MPM is resectable and, consequently, it can only be used in the earlier stages (Rice, 2011 Aug; Gomez, 2014; Treasure, 2014; Flores Pass, 2008; Lang-Lazdunski, 2012; Taioli, 2015; (Cao, 2014; Sugarbaker, 2014; Nakas, 2012 ).
(For specific recommendations and detailed indications of surgery in MPM, please refer to the full text of the Consensus Conference.)

Radiotherapy
In the past, radiotherapy was used to treat the progress of the section used for access of thoracoscopy or pleural drainages. In fact, it was believed that irradiating this tract would decrease the possibility of developing metastasis along the anatomical course of the optic instrument or of the drainage used during invasive procedures. However, studies are contradictory and, as of today, there is no evidence such as to suggest stopping the use of radiotherapy (Boutin, 1995; Bydder, 2004; O’Rourke, 2007).
There is no random data in support of the usefulness of adjuvant therapy for MPM. Nevertheless, it is believed that a total dosage of 54 Gy may be associated to a reduced failure of the local treatment (Rusch, 2001). Different studies have compared radiotherapy technique with modulated intensity with standard radiotherapy. However, effective radiotherapy would seem to be the one applied to the entire hemi-thorax concerned by the disease (Forster, 2003; Rice, 2007; Stahel, 2014). At present, there is some preliminary data available on the potential use of radiotherapy with modulated intensity, used to spare the lung contained in the hemi-thorax affected by MPM (Rosenzweig, 2012; Minatel, 2014; Chance, 2015).
Palliative radiotherapy is certainly crucial for controlling the symptoms and, in particular, for pain management (Bissett, 1991; Lindén, 1996; MacLeod, 2015).
(For specific recommendations and detailed indications of radiotherapy in MPM, please refer to the full text of the Consensus Conference.)

Chemotherapy
Standard chemotherapy indications were widely described in the previous Consensus Conference (Pinto, 2013).
Nevertheless, please remember that the first therapeutic line of this disease is based on the administration of a combination of platinum salts and third-generation antifolates (Fennell, 2008; Muers, 2008; Vogelzang, 2003; Van Meerbeeck, 2005; Santoro, 2008; van den Bogaert, 2006; Buikhuisen, 2013, Anon, 2016; Ceresoli, 2008; Ceresoli 2014).
New knowledge aimed at understanding the pathogenic ways of this disease have allowed the identification of new therapeutic targets, including of the biological type (Kindler, 2012; Zalcman, 2010, Zalcman, 2015; Hassan, 2014).
The second-line therapy has not allowed a clear improvement in terms of survival compared to the support therapy only, although certain standard drugs, such as Pemetrexed, have contributed favourable data in terms of better objective response and control of the disease rate (Jassem, 2008; Ceresoli, 2014). There are no pharmaceutical agents approved for second-line therapy, consequently the possibility to enrol patients in clinical studies may be considered a good treatment opportunity.
There is still no confirmed scientific evidence concerning the use of second-line biological drugs (Ceresoli, 2014; Krug, 2015; Calabrò, 2013; Anon, 2016; Alley, 2015; Ceresoli, 2011; Bearz, 2012; Zucali, 2012).

Conclusions

Unfortunately, the efficacy of current therapies for MPM is still quite limited, and the prognosis of this disease remains regrettably negative.
New therapeutic approaches are needed, and the research conducted in this area is offering interesting results that require confirming, randomised, multicentric and reproducible studies.
In the meantime, it is useful to continue with a strict surveillance of the subjects at risks and, consequently, there is some advice that can be easily applied.
In fact, the surveillance programmes being implemented are aimed at different objectives, such as:

  • informing subjects exposed to asbestos of the possible risks associated with it, both in terms of present exposure and past exposure;
  • informing the relatives of subjects exposed to asbestos and the possible risk for these individuals, even though they may have not been directly exposed;
  • carefully reconstructing the patient’s work history, especially entering into details of exposure to carcinogenic substances, its duration and intensity;
  • arranging for spreading information concerning diagnostic and therapeutic instruments and the medical prospects available abroad as well;
  • providing support for claims in order to obtain payments and compensations;
  • conduct proper counselling aimed at getting people to stop smoking cigarettes and follow a proper and healthy lifestyle.

Future therapeutic prospects are just around the corner, and a series of research projects underway offer new hope for the treatment of this pathology.

References

1. Adams, R.F., Gray, W., Davies, R.J., Gleeson, F.V. Percutaneous image-guided cutting needle biopsy of the pleura in the diagnosis of malignant mesothelioma. Chest. 2001;120:1798–1802.
2. Alley, E.W., Molife, L.R., Santoro, A. et al, Clinical safety and efficacy of pembrolizumab (MK-3475) in patients with malignant pleural mesothelioma: preliminary results from KEYNOTE-028. Proc AACR Annual Meeting. 2015; (abstract CT103).
3. American Joint Committee on Cancer. Pleural Mesothelioma. AJCC Cancer Staging Manual. 7th ed. Springer, New York (NY); 2010:271–274.
4. V ReNaM Report, 2015 (in press)
5. Anon, 2016. www.clinicaltrials.gov. Pemetrexed disodium or observation in treating patients with malignant pleural mesothelioma without progressive disease after first-line ClinicalTrials.gov Identifier NCT01085630.
6. Anon, 2016. www.clinicaltrials.gov. Placebo controlled study of VS-6063 in subjects with malignant pleural mesothelioma (COMMAND) ClinicalTrials.gov Identifier NCT01870609.
7. Anon, 2016 www.clinicaltrials.gov. Randomized, double-blind study comparing tremelimumab to placebo in subjects with unresectable malignant mesothelioma ClinicalTrials.gov Identifier Brozek.
8. Anon, 2016. IOM documento di consenso sulle cure simultanee at www.aiom.it.
9. Armato, S.G. 3rd, Labby, Z.E., Coolen, J., Klabatsa, A., Feigen, M., Persigehl, T., Gill, R.R. Imaging in pleural mesothelioma: a review of the 11th International Conference of the International Mesothelioma Interest Group. Lung Cancer. 2013;82:190–196.
10. Ascoli, V., Cavone, D., Merler, E. et al, Mesothelioma in blood related subjects: report of 11 clusters among 1954 Italy cases and review of the literature. Am. J. Ind. Med. 2007;50:357–369.
11. Ascoli, V., Romeo, E., Carnovale Scalzo, C. et al, Familial malignant mesothelioma: a population-based study in Central Italy (1980–2012). Cancer Epidemiol. 2014;38:273–278.
12. Attanoos, R.L., Gibbs, A.R. The comparative accuracy of different pleural biopsy techniques in the diagnosis of malignant mesothelioma. Histopathology. 2008;53:340–344.
13. Barnes, G., Baxter, J., Litva, A., Staples, B. The social and psychological impact of the chemical contamination incident in Weston Village, UK: a qualitative analysis. Soc. Sci. Med. 2002;55:2227–2241.
14. Basu, S., Saboury, B., Torigian, D.A., Alavi, A. Current evidence base of FDG-PET/CT imaging in the clinical management of malignant pleural mesothelioma: emerging significance of image segmentation and global disease assessment. Mol. Imaging Biol. 2011;13:801–811.
15. Baum, A. Implications of psychological research on stress and technological accidents. Am. Psychol. 1993;48:665.
16. Bearz, A., Talamini, R., Rossoni, G. et al, Re-challenge with pemetrexed in advanced mesothelioma: a multi-institutional experience. BMC Res. Notes. 2012;5:482.
17. Berry, G. Relative risk and acceleration in lung cancer. Stat. Med. 2007;26:3511–3517.
18. Betta, P.G., Magnani, C., Bensi, T., Trincheri, N.F., Orecchia, S. Immunohistochemistry and molecular diagnostics of pleural malignant mesothelioma. Arch. Pathol. Lab. Med. 2012;136:253–261.
19. Betti, M., Casalone, E., Ferrante, D. et al, Inference in germline BAP1 mutations and asbestos exposure from the analysis of familial and sporadic mesothelioma in a high-risk area. Genes. Chromosomes Cancer. 2015;54:51–62.
20. Bissett, D., Macbeth, F.R., Cram, I. The role of palliative radiotherapy in malignant mesothelioma. Clin. Oncol. (R. Coll. Radiol.). 1991;3:315–317.
21. Boardman, J.D., Downey, L., Jackson, J.S., Merrill, J.B., Saint Onge, J.M., Williams, D.R. Proximate industrial activity and psychological distress. Popul. Environ. 2008;2008:3–25.
22. Boutin, C., Rey, F. Thoracoscopy in pleural malignant mesothelioma: a prospective study of 188 consecutive patients. Part 1: diagnosis. Cancer. 1993;72:389–393.
23. Boutin, C., Rey, F., Viallat, J.R. Prevention of malignant seeding after invasive diagnostic procedures in patients with pleural mesothelioma. A randomized trial of local radiotherapy. Chest. 1995;108:754–758.
24. Brims, F.J.H., Arif, M., Chauhan, A.J. et al, Outcomes and complications following medical thoracoscopy. Clin. Respir. J. 2012;6:144–149.
25. British Lung Foundation. An unnatural death. A report into investigations of mesothelioma death and their impact on bereaved families. ; 2007 (Retrieved online at)http://www.blf.org.uk/Files/fa7128ca-3269-438d-9661-a06200e1303c/An-unnatural-death-final-report.pdf-..
26. British Lung Foundation. Survey of people affected by mesothelioma 2013. ; 2013 (Retrieved online at)http://www.blf.org.uk/Files/87d9e3ee-3056-4e4d-af16-a21f011cb06b/BLF-mesothelioma-survey-report.pdf..
27. Bueno, R., Reblando, J., Glickman, J. et al, Pleural biopsy: a reliable method for determining the diagnosis but not subtype in mesothelioma. Ann. Thorac. Surg. 2004;78:1774–1776.
28. Buikhuisen, W.A., Burgers, J.A., Vincent, A.D. et al, Thalidomide versus active supportive care for maintenance in patients with malignant mesothelioma after first-line chemotherapy (NVALT 5): an open-label, multicentre, randomised phase 3 study. Lancet Oncol. 2013;14:543–551.
29. Bydder, S., Phillips, M., Joseph, D.J., Cameron, F., Spry, N.A., DeMelker, Y., Musk, A.W. A randomised trial of single-dose radiotherapy to prevent procedure tract metastasis by malignant mesothelioma. Br. J. Cancer. 2004;91:9–10.
30. Byrne, M.J., Nowak, A.K. Modified RECIST criteria for assessment of response in malignant pleural mesothelioma. Ann. Oncol. 2004;15:257–260.
31. Calabrò, L., Morra, A., Fonsatti, E. et al, Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial. Lancet Oncol. 2013;14:1104–1111.
32. Cao, C., Tian, D., Park, J., Allan, J., Pataky, K.A., Yan, T.D. A systematic review and meta-analysis of surgical treatments for malignant pleural mesothelioma. Lung Cancer. 2014;83:240–245.
33. Ceresoli, G.L., Castagneto, B., Zucali, P.A. et al, Pemetrexed plus carboplatin in elderly patients with malignant pleural mesothelioma: combined analysis of two phase II trials. Br. J. Cancer. 2008;99:51–56.
34. Ceresoli, G.L., Zucali, P.A., De Vincenzo, F. et al, Retreatment with pemetrexed-based chemotherapy in patients with malignant pleural mesothelioma. Lung Cancer. 2011;72:73–77.
35. Ceresoli, G.L., Grosso, F., Zucali, P.A. et al, Prognostic factors in elderly patients with malignant pleural mesothelioma: results of a multicenter survey. Br. J. Cancer. 2014;111:220–226.
36. Ceresoli, G.L. Second line treatment in malignant pleural mesothelioma: translating the evidence into clinical practice. Lung Cancer Manage. 2014;3:263–271.
37. Chance, W.W., Rice, D.R., Allen, P.K., Tsao, A.S., Fontanilla, H.P., Liao, X.Z., Chang, J.Y., Tang, C., Pan, H.Y., Welsh, J.W., Mehran, R.J., Gomez, D.R. Hemithoracic intensity modulated radiation therapy after pleurectomy/decortication for malignant pleural mesothelioma: toxicity, patterns of failure, and a matched survival analysis. Int. J. Radiat. Oncol. Biol. Phys. 2015;91:149–156.
38. Checkoway, H., Pearce, N., Kriebel, D. Research Methods in Occupational Epidemiology. second ed. University Press, Oxford; 2004:163–167.
39. Cherny, N., Catane, R., Schrijvers, D. et al, European society of medical oncology (ESMO) program for the integration of oncology and palliative care: a 5-year review of the designated centers’ incentive program. Ann. Oncol. 2010;21:362–369.
40. Cheung, M., Talarchek, J., Schindeler, K. et al, Further evidence for germline BAP1 mutations predisposing to melanoma and malignant mesothelioma. Cancer Genet. 2013;206:206–210.
41. Churg, A., Roggli, V., Galateau-Salle, F. Mesothelioma. in: W.D. Travis, E. Brambilla, H.K. Muller-Hermelink et al, (Eds.) Pathology & Genetics: Tumours of the Lung Pleura, Thymus and Heart. IARC Press, Lyon; 2004:128–136.
42. Churg, A., Allen, T., Borczuk, A.C. et al, Well-differentiated papillary mesothelioma with invasive foci. Am. J. Surg. Pathol. 2014;38:990–998.
43. Churg, A., Roggli, V.L., Galateau-Salle, F. Tumours of the pleura: mesothelial tumours. in: W.D. Travis, E. Brambilla, A.P. Burke, A. Marx, A.G. Nicholson (Eds.) WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. IARC Press, Lyon; 2015.
44. Cigognetti, M., Lonardi, S., Fisogni, S., Balzarini, P., Pellegrini, V., Tironi, A., Bercich, L., Bugatti, M., Rossi, G., Murer, B., Barbareschi, M., Giuliani, S., Cavazza, A., Marchetti, G., Vermi, W., Facchetti, F. BAP1 (BRCA1-associated protein 1) is a highly specific marker for differentiating mesothelioma from reactive mesothelial proliferations. Mod. Pathol. 2015; (Epub ahead of print).
45. Couch, S.R., Coles, C.J. Community stress, psychosocial hazards, and EPA decision-Making in communities impacted by chronic technological disasters. Am. J. Public Health. 2011;101:S140–S148.
46. Creaney, J., Francis, R.J., Dick, I.M. et al, Serum soluble mesothelin concentrations in malignant pleural mesothelioma: relationship to tumor volume, clinical stage and changes in tumor burden. Clin. Cancer Res. 2011;17:1181–1189.
47. Creaney, J., Segal, A., Olsen, N. et al, Pleural fluid mesothelin as an adjunct to the diagnosis of pleural malignant mesothelioma. Dis. Markers. 2014;2014:413946.
48. Creaney, J., Dick, I.M., Meniawy, T.M. et al, Comparison of fibulin-3 and mesothelin as markers in malignant mesothelioma. Thorax. 2014;69:895–902.
49. Crighton, E.J., Elliott, S.J., van der Meer, J., Small, I., Upshur, R. Impacts of an environmental disaster on psychosocial health and well-being in Karakalpakstan. Soc. Sci. Med. 2003;2003:551–567.
50. Downey, L., Willigen, M.V. Environmental stressors the mental health impacts of living near industrial activity. J. Health Soc. Behav. 2005;46:289–305.
51. Drescher, C.F., Schulenberg, S.E., Smith, C.V. The deepwater horizon oil spill and the Mississippi Gulf coast: mental health in the context of a technological disaster. Am. J. Orthopsychiatry. 2014;84:142–151.
52. de Assis, L.V., Locatelli, J., Isoldi, M.C. The role of key genes and pathways involved in the tumorigenesis of malignant mesothelioma. Biochim. Biophys. Acta. 2014;1845:232–247.
53. de Klerk, N., Alfonso, H., Olsen, N. et al, Familial aggregation of malignant mesothelioma in former workers and residents of Wittenoom, Western Australia. Int. J. Cancer. 2013;132:1423–1428.
54. Erasmus, J.J., Truong, M.T., Smythe, W.R., Munden, R.F., Marom, E.M., Rice, D.C., Vaporciyan, A.A., Walsh, G.L., Sabloff, B.S., Broemeling, L.D., Stevens, C.W., Pisters, K.M., Podoloff, D.A., Macapinlac, H.A. Integrated computed tomography-positron emission tomography in patients with potentially resectable malignant pleural mesothelioma: staging implications. J. Thorac. Cardiovasc. Surg. 2005;129:1364–1370.
55. Fennell, D.A., Gaudino, G., O'Byrne, K.J. et al, Advances in the systemic therapy of malignant pleural mesothelioma. Nat. Clin. Pract. Oncol. 2008;5:136–147.
56. Finkelstein, M.M. Malignant mesothelioma incidence among talc miners and millers in New York State. Am. J. Ind. Med. 2012;55:863–868.
57. Flores Pass, H.I., Seshan, V.E. et al, Extrapleural pneumonectomy versus pleurectomy/decortication in the surgical management of malignant pleural mesothelioma: results in 663 patients. J. Thorac. Cardiovasc. Surg. 2008;135:620–626.
58. Flores, R.M., Akhurst, T., Gonen, M., Larson, S.M., Rusch, V.W. Positron emission tomography defines metastatic disease but not locoregional disease in patients with malignant pleural mesothelioma. J. Thorac. Cardiovasc. Surg. 2003;126:11–16.
59. Forster, K.M., Smythe, W.R., Starkshall, G. Intensity modulated radiotherapy following extrapleural pneumonectomy for the treatment of malignant mesothelioma: clinical implementation. Int. J. Radiat. Oncol. Biol. Phys. 2003;55:606–616.
60. Foster, R.P., Goldstein, M.F. Chernobyl disaster sequelae in recent immigrants to the United States from the former Soviet Union (FSU). J. Immigr. Minor. Health. 2007;9:115–124.
61. Franceschini, M.C., Ferro, P., Canessa, P.A. et al, Mesothelin in serum and pleural effusion in the diagnosis of malignant pleural mesothelioma with non-positive cytology. Anticancer Res. 2014;34:7425–7429.
62. Frauenfelder, T., Tutic, M., Weder, W., Götti, R.P., Stahel, R.A., Seifert, B., Opitz, I. Volumetry: an alternative to assess therapy response for malignant pleural mesothelioma. Eur. Respir. J. 2011;38:162–168.
63. Galbis, J.M., Mata, M., Guijarro, R. et al, Clinical-therapeutic management of thoracoscopy in pleural effusion: a groundbreaking technique in the twentyfirst century. Clin. Transl. Oncol. 2011;13:57–60.
64. Glik, D.C. Risk communication for public health emergencies. Annu. Rev. Public Health. 2007;28:33–54.
65. Gomez, D., Tsao, A.S. Local and systemic therapies for malignant pleural mesothelioma. Curr. Treat. Options Oncol. 2014;4:683–699.
66. Granieri, A., Tamburello, S., Tamburello, A., Casale, S., Cont, C., Guglielmucci, F., Innamorati, M. Quality of life and personality traits in patients with malignant pleural mesothelioma and their first-degree caregivers. Neuropsychiatr. Dis. Treat. J. 2013;9:1193–1202.
67. Grattan, L.M., Roberts, S., Mahan, W.T., McLaughlin, P.K., Otwell, W.S., Morris, J.G. The early psychological impacts of the Deepwater Horizon oil spill on Florida and Alabama communities. Environ. Health Perspect. 2011;119:838–843.
68. Greillier, L., Cavailles, A., Fraticelli, A. et al, Accuracy of pleural biopsy using thoracoscopy for the diagnosis of histologic subtype in patients with malignant pleural mesothelioma. Cancer. 2007;110:2248–2252.
69. Grosse, Y., Loomis, D., Guyton, K.Z. et al, Carcinogenicity of fluoro-edenite, silicon carbide fibres and whiskers, and carbon nanotubes. Lancet Oncol. 2014;15:1427–1428.
70. Guglielmucci, F., Franzoi, I.G., Barbasio, C.P., Borgogno, F.V., Granieri, A. Helping traumatized people survive: a psychoanalytic intervention in a contaminated site. Front. Psychol. 2014;5:1419.
71. Hallifax, R.J., Haris, M., Corcoran, J.P., Leyakathalikhan, S., Brown, E., Srikantharaja, D., Manuel, A., Gleeson, F.V., Munavvar, M., Rahman, N.M. Role of CT in assessing pleural malignancy prior to thoracoscopy. Thorax. 2015;70:192–193.
72. Halstead, J.C., Lim, E., Venkateswaran, R.M. et al, Improved survival with VATS pleurectomy—decortication in advanced malignant mesothelioma. Eur. J. Surg. Oncol. 2005;31:314–320.
73. Hansen, M., Faurschou, P., Clementsen, P. Medical thoracoscopy, results and complications in 146 patients: a retrospective study. Respir. Med. 1998;92:228–232.
74. Hassan, R., Kindler, H.L., Jahan, T. et al, Phase II clinical trial of amatuximab, a chimeric antimesothelin antibody with pemetrexed and cisplatin in advanced unresectable pleural mesothelioma. Clin. Cancer Res. 2014;20:5927–5936.
75. Henderson, D.W., Reid, G., Kao, S.C., van Zandwijk, N., Klebe, S. Challenges and controversies in the diagnosis of mesothelioma: part 1. Cytology-only diagnosis, biopsies, immunohistochemistry, discrimination between mesothelioma and reactive mesothelial hyperplasia, and biomarkers. J. Clin. Pathol. 2013;66:847–853.

76. Henderson, D.W., Reid, G., Kao, S.C., van Zandwijk, N., Klebe, S. Challenges and controversies in the diagnosis of malignant mesothelioma: part 2. Malignant mesothelioma subtypes, pleural synovial sarcoma, molecular and prognostic aspects of mesothelioma, BAP1, aquaporin-1 and microRNA. J. Clin. Pathol. 2013;66:854–861.
77. Hjerpe, A., Ascoli, V., Bedrossian, C.W.M., Boon, M.E., Creaney, J., Davidson, B., Dejmek, A., Dobra, K., Fassina, A., Field, A., Firat, P., Kamei, T., Kobayashi, T., Michael, C.W., Önder, S., Segal, A., Vielh, P. Guidelines for the cytopathologic diagnosis of epithelioid and mixed-type malignant mesothelioma. Complementary statement from the International Mesothelioma Interest Group, also endorsed by the International Academy of Cytology and the Papanicolaou Society of Cytopathology. Acta Cytol. 2015;59:2–16.
78. Hollevoet, K., Nackaerts, K., Thimpont, J. et al, Diagnostic performance of soluble mesothelin and megakaryocyte potentiating factor in mesothelioma. Am. J. Respir. Crit. Care Med. 2010;181:620–625.
79. Hollevoet, K., Nackaerts, K., Gosselin, R. et al, Soluble mesothelin, megakaryocyte potentiating factor, and osteopontin as markers of patient response and outcome in mesothelioma. J. Thorac. Oncol. 2011;6:1930–1937.
80. Hooper, C., Lee, Y.C., BTS Pleural Guideline Group. Investigation of a unilateral pleural effusion in adults: british thoracic society pleural disease guideline 2010. Thorax. 2010;65:ii4–ii17.
81. Hui, D., Kim, Y.J., Park, J.C. et al, Integration of Oncology and palliative care: a systematic review. Oncologist. 2015;20:1–7.
82. IARC International Agency for Research on Cancer (IARC). Arsenic, metals, fibres, and dusts. IARC working group on the evaluation of carcinogenic risks to humans. IARC Monogr. Eval. Carcinog. Risks Hum. 2012;100:11–465.
83. Iavicoli, S., Buresti, G., Colonna, F. et al, Economic burden of Mesothelioma in Italy. in: Communication at International Conference on Monitoring and Surveillance of Asbestos-related Diseases Proceedings Book 2014. ; 2014.
84. 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;26:1698–1704.
85. Jo, V.Y., Cibas, E.S., Pinkus, G.S. Claudin-4 immunohistochemistry is highly effective in distinguishing adenocarcinoma from malignant mesothelioma in effusion cytology. Cancer Cytopathol. 2014;122:299–306.
86. Kao, S.C., Yan, T.D., Lee, K., Burn, J. et al, Accuracy of diagnostic biopsy for the histological subtype of malignant pleural mesothelioma. J. Thorac. Oncol. 2011;6:602–605.
87. Kawai, T., Hiroshima, K., Kamei, T. Pulmonary pathology: SY22-2 diagnosis of mesothelioma using japanese criteria. Pathology (Phila.). 2014;46:S39.
88. Kindler, H.L., Karrison, T., Gandara, D.R. et al, Multi-center, double-blind, placebo- controlled, randomized phase II trial of gemcitabine/cisplatin plus bevacizumab or placebo in patients with malignant mesothelioma. J. Clin. Oncol. 2012;30:2509–2515.
89. Krug, L.M., Kindler, H.L., Calvert, H. et al, Vorinostat in patients with advanced malignant pleural mesothelioma who have progressed on previous chemotherapy (VANTAGE-014): a phase 3, double-blind, randomised, placebo-controlled trial. Lancet Oncol. 2015;16:447–456.
90. Labby, Z.E., Nowak, A.K., Dignam, J.J., Straus, C., Kindler, H.L. Armato SG 3rd: disease volumes as a marker for patient response in malignant pleural mesothelioma. Ann. Oncol. 2013;24:999–1005.
91. Labby, Z.E., Armato, S.G. 3rd, Dignam, J.J., Straus, C., Kindler, H.L., Nowak, A.K. Lung volume measurements as a surrogate marker for patient response in malignant pleural mesothelioma. J. Thorac. Oncol. 2013;8:478–486.
92. Ladanyi, M., Zauderer, M.G., Krug, L.M. et al: new strategies in pleural mesothelioma: BAP1 and NF2 as novel targets for therapeutic development and risk assessment. Clin. Cancer Res. 2012;18:4485–4490.
93. Lang-Lazdunski, L., Bille, A., Lal, R. et al, Pleurectomy/decortication is superior to extrapleural pneumonectomy in the multimodality management of patients with malignant pleural mesothelioma. J. Thorac. Oncol. 2012;7:737–743.
94. Langholz, B., Thomas, D., Xiang, A., Stram, D. Latency analysis in epidemiologic studies of occupational exposures: application to the Colorado Plateau uranium miners cohort. Am. J. Ind. Med. 1999;35:246–256.
95. Lao, I., Chen, Q., Yu, L., Wang, J. Sarcomatoid malignant mesothelioma: a clinicopathologic and immunohistochemical analysis of 22 cases. Zhonghua Bing Li Xue Za Zhi. 2014;43:364–369.
96. Larsen, B.T., Klein, J.R., Hornychová, H. et al, Diffuse intrapulmonary malignant mesothelioma masquerading as interstitial lung disease: a distinctive variant of mesothelioma. Am. J. Surg. Pathol. 2013;37:1555–1564.
97. Lindén, C.J., Mercke, C., Albrechtsson, U., Johansson, L., Ewers, S.B. Effect of hemithorax irradiation alone or combined with doxorubicin and cyclophosphamide in 47 pleural mesotheliomas: a nonrandomized phase II study. Eur. Respir. J. 1996;9:2565–2572.
98. Lonardi, S., Manera, C., Marucci, R., Santoro, A., Lorenzi, L., Facchetti, F. Usefulness of claudin 4 in the cytologic al diagnosis of serosal effusions. Diagn. Cytopathol. 2011;39:313–317.
99. Lubin, J.H., Caporaso, N.E. Cigarette smoking and lung cancer: modeling total exposure and intensity. Cancer Epidemiol. Biomarkers Prev. 2006;15:517–523.
100. Luo, L., Shi, H.Z., Liang, Q.L. et al, Diagnostic value of soluble mesothelin-related peptides for malignant mesothelioma: a meta-analysis. Respir. Med. 2010;104:149–156.
101. MacLeod, N., Chalmers, A., O'Rourke, N., Moore, K., Sheridan, J., McMahon, L., Bray, C., Stobo, J., Price, A., Fallon, M., Laird, B.J. Is radiotherapy useful for treating pain in mesothelioma?: a phase II trial. J. Thorac. Oncol. 2015;10:944–950.
102. Martin-Ucar, A.E., Edwards, J.G., Rengajaran, A. et al, Palliative surgical debulking in malignant mesothelioma: predictors of survival and symptom control. Eur. J. Cardiothorac. Surg. 2001;20:1117–1121.
103. Maskell, N.A., Gleeson, F.V., Davies, R.J. Standard pleural biopsy versus CT guided cutting-needle biopsy for diagnosis of malignant disease in pleural effusions: a randomised controlled trial. Lancet. 2003;361:1326–1330.
104. Mastrangelo, G., Fadda, E., Comiati, V. et al, A rare occupation causing mesothelioma: mechanisms and differential etiology. Med. Lav. 2014;105:337–347.
105. Metintas, M., Ak, G., Dundar, E. et al, Medical thoracoscopy vs CT scan-guided Abrams pleural needle biopsy for diagnosis of patients with pleural effusions: a randomized, controlled trial. Chest. 2010;137:1362–1368.
106. Metintas, M., Ak, G., Dundar, E. et al, Medical thoracoscopy vs CT scan-guided Abrams pleural needle biopsy for diagnosis of patients with pleural effusions: a randomized, controlled trial. Chest. 2010;137:1362–1368.
107. Minatel, E., Trovo, M., Polesel, J., Baresic, T., Bearz, A., Franchin, G., Gobitti, C., Rumeileh, I.A., Drigo, A., Fontana, P., Pagan, V., Trovo, M.G. Radical pleurectomy/decortication followed by high dose of radiation therapy for malignant pleural mesothelioma. Final results with long-term follow-up. Lung Cancer. 2014;83:78–82.
108. Muers, M.F., Stephens, R.J., Fisher, P. et al, Active symptom control with or without chemotherapy in the treatment of patients with malignant pleural mesothelioma (MS01): a multicentre randomised trial. Lancet. 2008;17:1685–1694.
109. Nakas, A., Martin-Ucar, A.E., Edwards, J.G. et al, The role of video-assisted thoracoscopic pleurectomy/decortication in the therapeutic management of malignant pleural mesothelioma. Eur. J. Cardiothorac. Surg. 2008;33:83–88.
110. Nakas, A., Waller, D., Lau, K., Richards, C., Muller, S. The new case for cervical mediastinoscopy in selection for radical surgery for malignant pleural mesothelioma. Eur. J. Cardiothorac. Surg. 2012;42:72–76.
111. Nickell, L.T. Jr., Lichtenberger, J.P. 3rd, Khorashadi, L., Abbott, G.F., Carter, B.W. Multimodality imaging for characterization, classification, and staging of malignant pleural mesothelioma. Radiographics. 2014;34:1692–1706.
112. O’Leary, J., Covell, K. The Tar Ponds kids: toxic environments and adolescent well-being. Can. J. Behav. Sci. 2002;34:34–43.
113. O'Rourke, N., Garcia, J.C., Paul, J., Lawless, C., McMenemin, R., Hill, J. A randomised controlled trial of intervention site radiotherapy in malignant pleural mesothelioma. Radiother. Oncol. 2007;84:18–22.
114. Ordóñez, N.G. Deciduoid mesothelioma: report of 21 cases with review of the literature. Mod. Pathol. 2012;25:1481–1495.
115. Ordóñez, N.G. Mesotheliomas with small cell features: report of eight cases. Mod. Pathol. 2012;25:689–698.
116. Ordóñez, N.G. Pleomorphic mesothelioma: report of 10 cases. Mod. Pathol. 2012;25:1011–1022.
117. Ordóñez, N.G. Mesothelioma with signet-ring cell features: report of 23 cases. Mod. Pathol. 2013;26:370–384.
118. Ordóñez, N.G. Application of immunohistochemistry in the diagnosis of epithelioid mesothelioma: a review and update. Hum. Pathol. 2013;44:1–19.
119. Paintal, A., Raparia, K., Zakowski, M.F., Nayar, R. The diagnosis of malignant mesothelioma in effusion cytology: a reappraisal and results of a multi-institution survey. Cancer Cytopathol. 2013;121:703–707.
120. Palinkas, L.A. A conceptual framework for understanding the mental health impacts of oil spills: lessons from the Exxon Valdez oil spill. Psychiatry. 2012;75:203–222.
121. Partridge, A.H., Seah, D.S., King, T. Developing a service model that integrates palliative care throughout cancer care: the time is now. J. Clin. Oncol. 2014;32:3330–3367.
122. Pike, M.C., Doll, R. Age at onset of lung cancer: significance in relation to effect of smoking. Lancet. 1965;1:665–668.
123. Pinto, C., Ardizzoni, A., Betta, P.G. et al, Expert opinions of the first Italian consensus conference on the management of malignant pleural mesothelioma. Am. J. Clin. Oncol. 2011;34:99–109.
124. Pinto, C., Novello, S., Torri, V. et al, Second Italian consensus conference on malignant pleural mesothelioma: state of the art and recommendations. Cancer Treat. Rev. 2013;39:328–339.
125. Price, B., Ware, A. Mesothelioma: risk apportionment among asbestos exposure sources. Risk Anal. 2005;25:937–943.
126. Qureshi, N.R., Gleeson, F.V. Imaging of pleural disease. Clin. Chest Med. 2006;27:193–213.
127. Registro Nazionale Mesoteliomi (ReNaM), 2012 Quarto Rapporto Edizioni INAIL Roma.
128. Reid, A., de Klerk, N.H., Magnani, C. et al, Mesothelioma risk after 40 years since first exposure to asbestos: a pooled analysis. Thorax. 2014;69:843–850.
129. Rice, D.C., Smythe, W.R., Liao, Z. et al, Dose-dependent pulmonary toxicity after postoperative intensity-modulated radiotherapy for malignant pleural mesothelioma. Int. J. Radiat. Oncol. Biol. Phys. 2007;69:350–357.
130. Rice, D.C., Steliga, M.A., Stewart, J. et al, Endoscopic ultrasound-guided fine needle aspiration for staging of malignant pleural mesothelioma. Ann. Thorac. Surg. 2009;88:862–868.
131. Rice, D., Rusch, V., Pass, H. et al, Recommendations for uniform definitions of surgical techniques for malignant pleural mesothelioma: a consensus report of the international association for the study of lung cancer international staging committee and the international mesothelioma interest group. J. Thorac. Oncol. 2011 Aug;6:1304–1312.
132. Richards, W.G., Godleski, J.J., Yeap, B.Y. et al, Proposed adjustments to pathologic staging of epithelial malignant pleural mesothelioma based on analysis of 354 cases. Cancer. 2010;116:1510–1517.
133. Richardson, D.B., Cole, S.R., Langholz, B. Regression models for the effects of exposure rate and cumulative exposure. Epidemiology. 2012;23:892–898.
134. Rosenzweig, K.E., Zauderer, M.G., Laser, B. et al, Pleural intensity modulated radiotherapy for malignant pleural mesothelioma. Int. J. Radiat. Oncol. Biol. Phys. 2012;83:1278–1283.
135. Rusch, V.W., Rosenzweig, K., Venkatraman, E. et al, A phase II trial of surgical resection and adjuvant high-dose hemothoracic radiation for malignant pleural mesothelioma. J. Thorac. Cardiovasc. Surg. 2001;122:788–795.
136. Sørensen, J.B., Ravn, J., Loft, A., Brenøe, J., Berthelsen AK for the Nordic Mesothelioma Group. Preoperative staging of mesothelioma by 18F-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography fused imaging and mediastinoscopy compared to pathological findings after extrapleural pneumonectomy. Eur. J. Cardiothorac. Surg. 2008;34:1090–1096.
137. Santoro, A., O’Brien, M.E., Stahel, R.A. et al, Pemetrexed plus cisplatin or pemetrexed plus carboplatin for chemonaive patients with malignant pleural mesothelioma: results of the international expanded access program. J. Thorac. Oncol. 2008;3:756–763.

138. Sartori, S., Postorivo, S., Vece, F.D., Ermili, F., Tassinari, D., Tombesi, P. Contrast-enhanced ultrasonography in peripheral lung consolidations: what's its actual role. World J. Radiol. 2013;5:372–380.
139. 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;35:479–495.
140. Schu¨nemann, H.J., Oxman, A.D., Brozek, J. et al, GRADE: grading quality of evidence and strength of recommendations for diagnostic tests and strategies. Br. Med. J. 2008;336:1106–1110.
141. Smith, M., Colby, T. The Diagnosis of thoracic malignant mesothelioma: practical considerations and recent developments. Turk. Patoloji Derg. 2014;30:1–10.
142. Smith, T.J., Temin, S., Alesi, E.R. American Society of Clinical Oncology provisional clinical opinion: the integration of palliative care into standard oncology care. J. Clin. Oncol. 2012;30:880–887.
143. Stahel, R.A., Riesterer, O., Alexandros, X., Opitz, I., Beyeler, M., Ochsenbein, A. et al, Neoadjuvant chemotherapy and extrapleural pneumonectomy (EPP) of malignant pleural mesothelioma (MPM) with or without hemithoracic radiotherapy: final results of the randomized multicenter phase II trial SAKK17/04. Ann. Oncol. 2014;25:v1–v41.
144. Stahel, R.A., Weder, W., Felley-Bosco, E. et al, Searching for targets for the systemic therapy of mesothelioma. Ann. Oncol. 2015; (Epub ahead of print).
145. Sugarbaker, D.J., Richards, W.G., Bueno, R. Extrapleural pneumonectomy in the treatment of epithelioid malignant pleural mesothelioma: novel prognostic implications of combined N1 and N2 nodal involvement based on experience in 529 patients. Ann. Surg. 2014;260:577–580.
146. Sureka, B., Thukral, B.B., Mittal, M.K., Mittal, A., Sinha, M. Radiological review of pleural tumors. Indian J. Radiol. Imaging. 2013;23:313–320.
147. Taioli, E., Wolf, A.S., Flores, R.M. Meta-analysis of survival after pleurectomy decortication versus extrapleural pneumonectomy in mesothelioma. Ann. Thorac. Surg. 2015;99:472–480.
148. Testa, J.R., Cheung, M., Pei, J. et al, Germline BAP1 mutations predispose to malignant mesothelioma. Nat. Genet. 2011;43:1022–1025.
149. Thomas, D.C. Invited commentary is it time to retire the pack-years variable? Maybe Not!. Am. J. Epidemiol. 2013;179:299–302.
150. Tournoy, K.G., Burgers, S.A., Annema, J.T. et al, Transesophageal endoscopic ultrasound with fine needle aspiration in the preoperative staging of malignant pleural mesothelioma. Clin. Cancer Res. 2008;14:6259–6263.
151. Treasure, T., Dusmet, M., Fiorentino, F. et al, Surgery for malignant pleural mesothelioma: why we need controlled trials. Eur. J. Cardiothorac. Surg. 2014;45:591–592.
152. Truong, M.T., Viswanathan, C., Godoy, M.B., Carter, B.W., Marom, E.M. Malignant pleural mesothelioma: role of CT, MRI, and PET/CT in staging evaluation and treatment considerations. Semin. Roentgenol. 2013;48:323–334.
153. Truong, M.T., Viswanathan, C., Godoy, M.B., Carter, B.W., Marom, E.M. Malignant pleural mesothelioma: role of CT, MRI, and PET/CT in staging evaluation and treatment considerations. Semin. Roentgenol. 2013;48:323–334.
154. Van Meerbeeck, J.P., 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;23:6881–6889.
155. Vlandereen, J., Portengen, L., Shuz, J. et al, Effect modification of the association of cumulative exposure and cancer risk by intensity of exposure and time since exposure cessation: a flexible method applied to cigarette smoking and lung cancer in the SYNERGY study. Am J. Epidemiol. 2013;179:290–298.
156. Vogelzang, N.J., Rusthoven, J.J., Symanowski, J. et al, Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J. Clin. Oncol. 2003;21:2636–2644.
157. van den Bogaert, D.P., Pouw, E.M., van Wijhe, G. et al, Pemetrexed maintenance therapy in patients with malignant pleural mesothelioma. J. Thorac. Oncol. 2006;1:25–30.
158. Waller, D.A., Morritt, G.N., Forty, J. Video-assisted thoracoscopic pleurectomy in the management of malignant pleural effusion. Chest. 1995;107:1454–1456.
159. Weber, D.G., Casjens, S., Johnen, G. et al, Combination of MiR-103a-3p and mesothelin improves the biomarker performance of malignant mesothelioma diagnosis. PLoS One. 2014;9:e114483.
160. Wheatley-Price, P., Yang, B., Patsios, D. et al, Soluble mesothelin-related peptide and osteopontin as markers of response in malignant mesothelioma. J. Clin. Oncol. 2010;28:3316–3322.
161. World Health Organization Regional Office for Europe. Air Quality Guidelines for Europe Copenhagen 2000. WHO Regional Publications, ; 2000 (European Series, No. 9).
162. Yoshikawa, Y., Sato, A., Tsujimura, T. et al, Frequent inactivation of the BAP1 gene in epithelioid-type malignant mesothelioma. Cancer Sci. 2012;103:868–874.
163. Zahid, I., Sharif, S., Routledge, T., Scarci, M. What is the best way to diagnose and stage malignant pleural mesothelioma. Interact Cardiovasc. Thorac. Surg. 2011;12:254–259.
164. Zalcman, G., Margery, J., Scherpereel, A. et al, IFCT-GFPC-0701 MAPS trial, a multicenter randomized phase II/III trial of pemetrexed-cisplatin with or without bevacizumab in patients with malignant pleural mesothelioma. J. Clin. Oncol. 2010;28 (abstract 7020).
165. Zalcman, G., Mazieres, J., Margery, J. et al, Bevacizumab 15 mg/kg plus cisplatin-pemetrexed (CP) triplet versus CP doublet in malignant pleural mesothelioma (MPM): results of the IFCT-GFPC-0701 MAPS randomized phase 3 trial. J. Clin. Oncol. 2015;33 (abstract 7500).
166. Zielinski, M., Hauer, J., Hauer, L. et al, Staging algorithm for diffuse malignant pleural mesotelioma. Interact Cardiovasc. Thorac. Surg. 2010;10:185–189.
167. Zucali, P.A., Simonelli, M., Michetti, G. et al, Second-line chemotherapy in malignant pleural mesothelioma: results of a retrospective multicenter survey. Lung Cancer. 2012;75:360–367.
168. van Zandwijk, N., Clarke, C., Henderson, D. et al, Guidelines for the diagnosis and treatment of malignant pleural mesothelioma. J. Thorac. Dis. 2013;5:E254–E307.

> Download article as PDF

Foreword

New findings about the interaction between the immune system and the immune microenvironment have led to the development of important checkpoint inhibitors drugs for cancer. More specifically, these drugs target the PD-1/PD-L1 pathway.

One of these drugs, pembrolizumab, has been the subject of many articles and press releases.
It has even been hailed by some as the “syrup that dissolves tumors”, but this assertion needs to be clarified!
The press often goes beyond its own expertise by describing some treatments as miraculous but without having any knowledge of the drugs in question and without any actual rigorous documentation about the scientific studies published.
By doing this, the concerns of patients and their loved ones are not taken into account and we become caught in a vortex of words that do not contain any actual knowledge.

In view of this, we thought it would be useful to describe the main studies involving this therapy in our bi-annual review of the literature.
We will attempt to evaluate how this drug could be useful for the treatment of malignant pleural mesothelioma (MPM), and will describe as simply and graphically as possible some of the other immunotherapies that have been investigated or are being studied for MPM.
For the "insiders" who are involved in the study of MPM and for further information, please see the Reference section at the end of this revision for a list of publications.

Introduction

Immune checkpoint inhibitors

To prevent autoimmune phenomena, the activation and functions of T lymphocytes are finely regulated to different levels through “control points”, known as immune checkpoints.
Cytotoxic T lymphocytes associated with the antigen 4 (CTLA-4) and "programmed death 1" (PD-1) play an essential role in this process. Specifically, CTLA-4 (CD152) is an immunosuppressive receptor and a member of the superfamily of immunoglobulin CD28/B7, which is expressed mainly in the CD4 T lymphocytes and to a lesser extent in the antigen-presenting cells (APC) and granulocytes(1) . The recruitment of CTLA-4 decreases the amplitude of the T cell response: it competes with its costimulatory CD28 receptor by inhibiting B7-1 (CD80) and B7-2 (CD86). These interactions are critically important for the initial activation of naïve T cells, by inhibiting the function of the T cells and preventing an inappropriate immune response against the “self” (or the body’s own) antigens in the secondary lymph organs and by limiting the extent and duration of the immune response(2) .

On the other hand, the PD-1 pathway regulates the effector T cells in the later stages of the immune response in peripheral tissues(3) .
PD-1 is expressed primarily in activated T and B cells, but also in monocytes, natural killer cells and tumor-infiltrating lymphocytes (TILS) (4) .
PD-1 binds two molecules, PD-L1 and PD-L2, which are members of the B7 family. PD-1 is expressed in leukocytes, while PD-2 only in dendritic cells and monocytes. PD-1 directly inhibits the functions of the TRC-mediated effector, acting as a negative regulator of the immune response. Additionally, PD-L1 is highly expressed in many malignancies, including MPM (5). PD-L1 expression in tumor cells appears to attenuate the immune response against tumors by inhibiting the activation of T cells and increasing the apoptosis of antigen-specific cell clones (6 7) .
CTLA-4 plays an important role in regulating the suppressive function of regulatory T lymphocytes (Treg), which are usually found in tumor tissue and are thought to locally inhibit antitumor immunity by inhibiting the response of effector T cells (8 9) .
In this context, by using a model of human suppressor T cell lines (MT-2), it has recently been shown that exposure to asbestos increases the function of Tregs with an increase in the production of suppressive cytokines such as IL-10 and TGFb (10).
In some tumors, the CTLA-4 and PD-1 inhibitory pathways are activated much more than in physiological conditions, so they are therefore believed to be involved in the suppression of the immune response by the tumor and in the ability to escape recognition by the immune system.
Various therapeutic approaches targeting CTLA-4 and PD-1/PD-L1 have therefore been designed over the last few years.

Anti CTLA-4

The efficacy of inhibiting CTLA-4 in combination with chemotherapy or radiotherapy in MPM has been shown in several in vivo and animal model studies (11 12 13).
In fact, several mouse models of mesothelioma treated with an anti-CTLA-4 monoclonal antibody have demonstrated a significant inhibition of tumor growth, inhibition of repopulation by cancer cells, and an increase in T infiltrating lymphocytes (14).

Anti PD-1

PD-L1 expression has been reported in 40% of patients with mesothelioma and appears to be associated with a poor prognosis (15 16 17) . However, it is important to remember that guidelines and standard methods for investigating these targets and determining the cut-off, i.e, the thresholds indicating the positivity or negativity of this alteration, have not yet been defined 18. Another aspect still being investigated is clarifying which cell types should be evaluated for PD-L1 expression (19 20) .

Pembrolizumab

Pembrolizumab (MK-3475, lambrolizumab, Keytruda®) is a highly selective humanized IgG4 monoclonal antibody against PD-1. The amplified regulation of PD-1 occurs in some tumors and the pathway that is activated through this molecule helps to inhibit the active T cells as immune surveillance against tumors.
Pembrolizumab is able to destroy the bond that occurs between PD-1 and its PD-L1 and PD-L2 ligands, thus blocking the inhibitory signal to the T cells. By so doing, the cancer cells can be recognized by the cytotoxic T cells(21) .
This drug was recently approved for solid tumors such as non-small cell lung cancer (NSCLC) expressing PD-L1, and advanced unresectable melanoma (22 23).
The diagram below shows the immune system activation against tumor cells and regulation of the signal occurring between PD-1 and its PD-L1-PD-L2 ligands.

(From: S. Karim, et al. Future Oncol. 2016)

Efficacy of pembrolizumab

The efficacy of this drug has been recently documented in various clinical studies in patients with solid tumors of different histologies.
The Phase I KEYNOTE-001 study is evaluating the efficacy and safety of pembrolizumab in patients with NSCLC. The results of this study showed an objective response rate (ORR) of 19.4% with a median duration of response of 12.5 months, progression-free survival (PFS) of about 3.7 months, and a median overall survival (OS) of 12 months . An analysis of the results showed an association between the efficacy of pembrolizumab and the presence of PD-L1 expression. Specifically, in patients with expression of PD-L1>/= 50%, the ORR was 45.2%, together with greater PFS and OS rates versus those patients with lower PD -L1 expression(25) .
Other studies have been initiated to assess the efficacy of the pembrolizumab, which for the sake of simplicity are listed in the following table:

(From: S. Karim, et al. Future Oncol. 2016)

(From: S. Karim, et al. Future Oncol. 2016)

(From: S. Karim, et al. Future Oncol. 2016)

Safety of pembrolizumab

The safety and side effects of pembrolizumab were also evaluated in the above-mentioned KEYNOTE-001 study. We can say that pembrolizumab is generally well tolerated, without any clear evidence of adverse effects associated with it.
However, the most frequently reported side effects were asthenia, pruritus and decreased appetite.
The most serious grade 3 adverse events reported in a small percentage of patients (9.5%) were mainly dyspnea (3.8%), pneumonia (1.8%), decreased appetite (1%) and asthenia (1%) (26).
Some side effects involving the immune-mediated response were also reported. More specifically, there were cases of hypothyroidism (6.9%), pneumonia (3.6%) and drug infusion reactions (3%) (27).

Pembrolizumab and mesothelioma

The first data from the KEYNOTE-028 study of pembrolizumab in MPM were presented at the American Association for Cancer Research (AACR) conference.
Data from the study entitled "Single-agent pembrolizumab for patients with malignant pleural mesothelioma” were presented at the International Association for the Study of Lung Cancer (IASLC), World Conference on Lung Cancer (WCLC), in September 2015.
For completeness, the original abstract is included below:

“Single-agent pembrolizumab for patients with malignant pleural mesothelioma”
EW Alley, JH Schellens, A Santoro, K Beckey, SS Yuan, J Cheng, B Piperdi, LR Molife

Summary: Researchers presented updated safety and efficacy data for pembrolizumab (MK-3475), currently approved for the the treatment of advanced melanoma that progressed after ipilimumab, and BRAF inhibitor therapy if BRFV600 mutant in patients with PD-L1-positive advanced solid tumors with malignant pleural mesothelioma (MPM) enrolled in the KEYNOTE-028 study. In patients with PD-L1—positive MPM, pembrolizumab had significant clinical activity, they concluded. Further study of the durability of responses and the 49.4% 6-month progression-free survival rate is warranted.

Methods:

  • For this nonrandomized, multicohort phase 1b study, researchers included patients with measurable disease who had failed standard therapy, had ECOG PS 0-1, adequate organ function, and no autoimmune or interstitial lung disease.
  • They defined PD-L1 positivity as expression in ≥1% of tumor cells by IHC at a central laboratory.
  • Patients were treated with pembrolizumab (10 mg/kg) every 2 weeks for up to 2 years, or until confirmed progression or unacceptable toxicity.
  • Every 8 weeks for the first 6 months and every 12 weeks thereafter, researchers assessed response using RECIST v1.1.
  • The primary endpoint was overall response rate (ORR) and secondary endpoints included safety, tolerability, and progression free survival (PFS).

Results:

  • In all, 84 patients with MPM were screened for PD-L1 expression; of these, 38 (45%) had PD-L1—positive tumors; and of these, 25 were included in the study.
  • As of March 20, 2015, the ORR was 28% (n=7), and 12 patients (48%) had stable disease, for a disease control rate of 76%.
  • In 15 patients with only one previous line of therapy, ORR was 20% and DCR was 73%.
  • Researchers observed durable responses, with 10 (40%) of patients remaining on treatment.
  • After a median follow-up of 8.6 months, median PFS is 5.5 months (95% CI, 3.4-NR) and the 6-month PFS was 49.4%.
  • Researchers observed no new safety signals.
  • Drug-related adverse events (DRAE) occurred in 15 patients (60%), including 3 (12%) who had grade 3-4 DRAEs.
  • Only two patients required dose interruption due to immune-related adverse events, which included transaminitis and uveitis (1 each).
  • No treatment-related mortality occurred, and no patients discontinued treatment due to DRAEs.

The study design displayed below shows that pembrolizumab was administered to patients with advanced MPM who had progressed after prior treatment or who could not be treated with standard chemotherapy.
These patients had to be in overall good condition (ECOG PS 0-1) and PD-L1 positive. Patients with autoimmune diseases or interstitial lung disease were excluded.
Other baseline characteristics of the patients are summarized in the figure below:

(From WCLC, September 7, 2015, Denver, Colorado, USA)

Patients received pembrolizumab intravenously at a dose of 10 mg/kg bi-weekly.
Response to treatment was assessed every eight weeks for the first six months and then every 12 weeks thereafter. If patients achieved a partial or complete response, they were treated for 24 months or until disease progression or the emergence of toxicity. Treatment with pembrolizumab was discontinued if patients experienced disease progression or unacceptable toxicity

(From WCLC, September 7, 2015, Denver, Colorado, USA)

Below is an example of microscope images showing the negative or positive PD-L1 expression of this molecule.

(From WCLC, September 7, 2015, Denver, Colorado, USA)

Evaluated by immunohistochemistry, the PD-L1 levels do not appear to be correlated with the ability to respond better to treatment with pembrolizumab, as shown in this graph:

(From WCLC, September 7, 2015, Denver, Colorado, USA)

The drug was generally well tolerated, as evidenced by the low rate of serious side effects.
The most common adverse events were asthenia (24%) and nausea (24%); however, these side effects were reported in less than 20% of patients. Grade 3 side effects included an increase in transaminases (ALT) and thrombocytopenia. There were no patient discontinuations in the study due to pembrolizumab-related side effects, nor were there any drug-related deaths.
Below is a summary of the drug-related side effects:

(From WCLC, September 7, 2015, Denver, Colorado, USA)

The anti-tumor activity of this treatment was as follows:

(From WCLC, September 7, 2015, Denver, Colorado, USA)

The PFS was approximately 5.8 months. Additionally, the PFS after six months of treatment was approximately 50%.

(From WCLC, September 7, 2015, Denver, Colorado, USA)

The results of this study are encouraging, but more studies are needed to confirm whether this treatment can actually increase the survival of these patients.

Other immunotherapy drugs

The Phase II study MEST-TREM-2008 (NCT01649024) is investigating tremelimumab, an anti-CTLA4 human monoclonal antibody, as monotherapy in patients with advanced MPM that has progressed after standard first-line chemotherapy. The results of this study can be summarized as follows: no patients achieved a complete response, while 31% had stable disease; the median overall survival was 10.7 months(28) .
The Phase II study MEST-TREM-2012 (NCT01655888) evaluated a higher dose of tremelimumab, which led to the following results: a disease control rate of 52% was achieved, with a median overall survival of 10.9 months (29 30) .
An international, randomized, double-blind, placebo-controlled Phase IIb study is currently underway, DETERMINE (NCT01843374), in patients with advanced pleural or peritoneal mesothelioma who have progressed after a standard first-line therapy (31) .
Emerging immunotherapy findings have led to other study protocols, such as the Phase II study NIBIT-mESO-1 (NCT02588131), which is evaluating the efficacy of tremelimumab in combination with anti-PD-L1 durvalumab (32) .
The KEYNOTE-028 study (NCT02054806) investigated the efficacy of PD-1 antibody pembrolizumab in PD-L1-positive patients (33 34) .
The NCT02399371 study is also evaluating pembrolizumab in patients with MPM and the role of PD-L1 positivity (35) .
Additionally, pembrolizumab was recently investigated in combination with gemcitabine and defactinib (NCT02546531).
Another drug, nivolumab, was recently tested in MPM in the NivoMes study (NCT02497508), which enrolled patients with recurrent mesothelioma, and in a study investigating the combination of ipilimumab and nivolumab (NCT02716272), in patients with unresectable MPM (36) .
Avelumab is another PD-L1 inhibitor that was investigated for this disease, which resulted in a partial response of 15%, disease control rate of 60% and PFS of approximately 16.3 months (37) .

Future prospects

There are still many unresolved issues, and many aspects need to be clarified in order to better understand the results of these clinical trials. Of particular importance is the definition of a specific, sensitive biomarker to serve as a predictor of response because the association between PD-L1 expression and the response to immunotherapy remains controversial (39 40) .
It is important to remember, however, that there is no standardized method to test for this biomarker and a cut-off threshold to precisely determine positivity has not yet been defined (41).
In some MPM cases, the mutation burden was associated with an increase in the neo-antigen burden and inhibition of PD-1 (42 43) .
Consequently, mutation burden and gene instability are aspects of the pathogenesis of MPM that need to be studied further in order to fully understand this disease and define the most effective drugs.
Although these immunotherapies appear to be very well tolerated, it should also be remembered that the toxicity of these drugs, particularly in the long-term, is not yet well known. Although rare, there may also be autoimmune side effects that could even be lethal (44).

Conclusions

In conclusion, the immune checkpoint blockade appears to be an attractive and certainly promising therapeutic strategy for the treatment of malignant pleural mesothelioma.
However, the results obtained to date are preliminary and many studies are still underway; as such, we are looking forward to the final results.
Additionally, drug combinations acting on different pathogenetic pathways related to immunotherapy must still be investigated.
The discovery of new, more sensitive markers that are predictive of response to these treatments will certainly be useful to identify patients who will truly benefit from these therapies.

References

1 E. Marcq, P. Pauwels, J.P. van Meerbeeck, E.L. Smits, Targeting immune checkpoints: new opportunity for mesothelioma treatment? Cancer Treat. Rev. 41 (10) (2015) 914–924.
2 S.L. Topalian, C.G. Drake, D.M. Pardoll, Immune checkpoint blockade: a common denominator approach to cancer therapy, Cancer Cell 27 (4) (2015)450–461.
3 E.I. Buchbinder, A. Desai, CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition, Am. J. Clin. Oncol. 39 (1) (2016) 98–106.
4 M.E. Keir, M.J. Butte, G.J. Freeman, A.H. Sharpe, PD-1 and its ligands in tolerance and immunity, Annu. Rev. Immunol. 26 (2008) 677–704.
5 A.S. Mansfield, A.C. Roden, T. Peikert, Y.M. Sheinin, S.M. Harrington, C.J. Krco, H. Dong, E.D. Kwon, B7-H1 expression in malignant pleural mesothelioma is associated with sarcomatoid histology and poor prognosis, J. Thorac. Oncol. 9 (7) (2014) 1036–1040.
6 J.A. Brown, D.M. Dorfman, F.R. Ma, E.L. Sullivan, O. Munoz, C.R. Wood, E.A. Greenfield, G.J. Freeman, Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production, J. Immunol. 170 (3) (2003) 1257–1266.
7 H. Dong, S.E. Strome, D.R. Salomao, H. Tamura, F. Hirano, D.B. Flies, P.C. Roche, J. Lu, G. Zhu, K. Tamada, V.A. Lennon, E. Celis, L. Chen, Tumor-associated B7- H1 promotes T-cell apoptosis: a potential mechanism of immune evasion, Nat. Med. 8 (8) (2002) 793–800.
8 K. Wing, Y. Onishi, P. Prieto-Martin, T. Yamaguchi, M. Miyara, Z. Fehervari, T. Nomura, S. Sakaguchi, CTLA-4 control over Foxp3+ regulatory T cell function, Science 322 (5899) (2008) 271–275.
9 K.S. Peggs, S.A. Quezada, C.A. Chambers, A.J. Korman, J.P. Allison, Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti CTLA-4 antibodies, J. Exp. Med. 206 (8) (2009) 1717–1725.
10 C. Ying, M. Maeda, Y. Nishimura, N. Kumagai-Takei, H. Hayashi, H. Matsuzaki, S. Lee, K. Yoshitome, S. Yamamoto, T. Hatayama, T. Otsuki, Enhancement of regulatory T cell-like suppressive function in MT-2 by long-term and lowdose exposure to asbestos, Toxicology 338 (2015) 86–94.
11 W.J. Lesterhuis, J. Salmons, A.K. Nowak, E.N. Rozali, A. Khong, I.M. Dick, J.A. Harken, B.W. Robinson, R.A. Lake, Synergistic effect of CTLA-4 blockade and cancer chemotherapy in the induction of anti-tumor immunity, PLoS ONE 8 (4) (2013) e61895.
12 S. Demaria, S.C. Formenti, Radiation as an immunological adjuvant: current evidence on dose and fractionation, Front. Oncol. 2 (2012) 153.
13 L. Wu, M.O. Wu, L. De la Maza, Z. Yun, J. Yu, Y. Zhao, J. Cho, M. de Perrot, Targeting the inhibitory receptor CTLA-4 on T cells increased abscopal effects in murine mesothelioma model, Oncotarget 6 (14) (2015) 12468–12480.
14 L. Wu, Z. Yun, T. Tagawa, K. Rey-McIntyre, M. de Perrot, CTLA-4 blockade expands infiltrating T cells and inhibits cancer cell repopulation during the intervals of chemotherapy in murine mesothelioma, Mol. Cancer Ther. 11 (8) (2012) 1809–1819.
15 A.S. Mansfield, A.C. Roden, T. Peikert, Y.M. Sheinin, S.M. Harrington, C.J. Krco, H. Dong, E.D. Kwon, B7-H1 expression in malignant pleural mesothelioma is associated with sarcomatoid histology and poor prognosis, J. Thorac. Oncol. 9 (7) (2014) 1036–1040.
16 C. Combaz-Lair, F. Galateau-Salle, A. McLeer-Florin, N. Le Stang, L. David- Boudet, M. Duruisseaux, G.R. Ferretti, E. Brambilla, S. Lebecque, S. Lantuejoul, Immune biomarkers PD-1/PD-L1 and TLR3 in malignant pleural mesotheliomas, Hum. Pathol. (2016).
17 Marcq E, Pauwels P, van Meerbeeck JP, et al. Targeting immune checkpoints: new opportunity for mesothelioma treatment? Cancer Treat Rev. 2015;41:914–924.
18 S.P. Patel, R. Kurzrock, PD-L1 expression as a predictive biomarker in cancer immunotherapy, Mol. Cancer Ther. 14 (4) (2015) 847–856.
19 A.M. Schultheis, A.H. Scheel, L. Ozretic, J. George, R.K. Thomas, T. Hagemann, T. Zander, J. Wolf, R. Buettner, PD-L1 expression in small cell neuroendocrine carcinomas, Eur. J. Cancer 51 (3) (2015) 421–426
. 20 R.S. Herbst, J.C. Soria, M. Kowanetz, G.D. Fine, O. Hamid, M.S. Gordon, J.A. Sosman, D.F. McDermott, J.D. Powderly, S.N. Gettinger, H.E. Kohrt, L. Horn, D. P. Lawrence, S. Rost, M. Leabman, Y. Xiao, A. Mokatrin, H. Koeppen, P.S. Hegde, I. Mellman, D.S. Chen, F.S. Hodi, Predictive correlates of response to the anti- PD-L1 antibody MPDL3280A in cancer patients, Nature 515 (7528) (2014) 563–567.
22 US Food and Drug Administration Press Release. www.fda.gov
23 US Food and Drug Administration website. www.accessdata.fda.gov
24 Garon EB, Rizvi NA, Hui R et al. Pembrolizumab for the treatment of non-small cell lung cancer. N. Engl. J. Med. 372, 2018–2028 (2015).
25 Garon EB, Rizvi NA, Hui R et al. Pembrolizumab for the treatment of non-small cell lung cancer. N. Engl. J. Med. 372, 2018–2028 (2015).
26 Garon EB, Rizvi NA, Hui R et al. Pembrolizumab for the treatment of non-small cell lung cancer. N. Engl. J. Med. 372, 2018–2028 (2015).
27 Garon EB, Rizvi NA, Hui R et al. Pembrolizumab for the treatment of non-small cell lung cancer. N. Engl. J. Med. 372, 2018–2028 (2015).
28 A. Hoos, R. Ibrahim, A. Korman, K. Abdallah, D. Berman, V. Shahabi, K. Chin, R. Canetta, R. Humphrey, Development of ipilimumab: contribution to a new paradigm for cancer immunotherapy, Semin. Oncol. 37 (5) (2010) 533–546.
29 L. Calabro, A. Morra, E. Fonsatti, O. Cutaia, C. Fazio, D. Annesi, M. Lenoci, G. Amato, R. Danielli, M. Altomonte, D. Giannarelli, A.M. Di Giacomo, M. Maio, Efficacy and safety of an intensified schedule of tremelimumab for chemotherapy-resistant malignant mesothelioma: an open-label, singlearm, phase 2 study, Lancet Respir. Med. 3 (4) (2015) 301–309.
30 L. Calabrò L, Morra A, Fonsatti E, et al. Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial. Lancet Oncol. 2013;14:1104–1111.
31 Antonia S, Goldberg SB, Balmanoukian A, et al. Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. Lancet Oncol. 2016;17:299–308.
32 L. Calabro’, A. Morra, D. Giannarelli, D. Annesi, E. Bertocci, R. Danielli, M. Altomonte, A.M. Di Giacomo, M. Maio, Tremelimumab and Durvalumab combination for first and second-line treatment of mesothelioma patients: the NIBIT-MESO-1 study, in: 13th International Conference of the iMig Abstract Book, 2016, [abstract MS10.03]
33E.W. Alley, L.R. Molife, A. Santoro, K. Beckey, S. Yuan, J.D. Cheng, B. Piperdi, J. H.M. Shellens, Clinical safety and efficacy of pembrolizumab (MK-3475) in patients with malignant pleural mesothelioma: preliminary results from KEYNOTE-028, in: AACR Annual Meeting, 2015, [abstract CT103].
34 Alley EW, Schellens JHM, Santoro A, et al. Single-agent pembrolizumab for patients with malignant pleural mesothelioma. Presented at: 2015 World Conference on Lung Cancer; Sep 6–9; Denver, Colorado (US); 2015. Abs 3011.
35 J. Quispel-Janssen, M. Zimmerman, W. Buikhuisen, S. Burgers, G. Zago, P. Baas, Nivolumab in malignant pleural mesothelioma (NIVOMES): an interim analysis, in: 13th International Conference of the iMig Abstract Book, 2016, [abstract MS04.07]
36 J. Quispel-Janssen, M. Zimmerman, W. Buikhuisen, S. Burgers, G. Zago, P. Baas, Nivolumab in malignant pleural mesothelioma (NIVOMES): an interim analysis, in: 13th International Conference of the iMig Abstract Book, 2016, [abstract MS04.07]
37 Marcq E, Pauwels P, van Meerbeeck JP, et al. Targeting immune checkpoints: new opportunity for mesothelioma treatment? Cancer Treat Rev. 2015;41:914–924.
38 Marcq E, Pauwels P, van Meerbeeck JP, et al. Targeting immune checkpoints: new opportunity for mesothelioma treatment? Cancer Treat Rev. 2015;41:914–924.
39 Zou W, Wolchok JD, Chen L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations. Sci Transl Med. 2016;8:328rv4.
40 Alley EW, Schellens JHM, Santoro A, et al. Single-agent pembrolizumab for patients with malignant pleural mesothelioma. Presented at: 2015 World Conference on Lung Cancer; Sep 6–9; Denver, Colorado (US); 2015. Abs 3011.
41 Hassan R, Thomas A, Patel M, et al. Safety and clinical activity of avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with advanced, unresectable mesothelioma: a phase IB trial. Presented at: 2015 European Cancer Congress; Sep 25–29; Vienna, Austria; 2015. Abs 3110.
42 McGranahan N, Furness AJ, Rosenthal R, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science. 2016;351:1463–1469.
43 Bueno R, Stawiski EW, Goldstein LD, et al. Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations. Nat Genet. 2016;48:407–416.
44 Champiat S, Lambotte O, Barreau E, et al. Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper. Ann Oncol. 2016;27:559–574.

> Download article as PDF

INTRODUCTION

A major change has been brought to thoracic oncology by the advent of biological therapies, and by “targeted” treatments in particular. These new approaches have changed the natural course of disease in patients with lung cancer, particularly those whose lung cancer is characterized by specific genetic mutations and rearrangements who may benefit from therapies that target these biomolecular alterations.
Among these drugs, molecules acting against multiple molecular targets have also been investigated, particularly Vargatef, which is a mult-target TKI that inhibits the VEGFR, FGFR and PDGFR receptors. It is currently approved in combination with docetaxel for advanced/metastatic lung adenocarcinoma after front-line chemotherapy. The scientific data for this treatment in lung cancer has shown benefit compared to standard chemotherapy alone in terms of progression-free survival (PFS) (4,0 vs 2,8) and overall survival (OS) (12,6 vs 10,3), with a reduction of 17% in the risk of death and a disease control rate of 60,2% (vs 44,0%). An analysis of the European population of the Lume-Lung 1 study showed a further increase in survival (13,4 vs 8,7).
This treatment was therefore considered as potentially useful also for MPM, an aggressive disease with a poor prognosis.
The purpose of this bibliographic review is to provide preliminary data on the use of nintedanib in mesothelioma.

Malignant pleural mesothelioma (MPM) is a cancerous disease that is no longer rare and unfortunately is very aggressive: if it is not treated, the average survival is 6-9 months.(1-4)
The standard first-line treatment for unresectable MPM is cisplatin and pemetrexed chemotherapy.(5-9) Although this therapy helps increase median survival, it is still only reaches approximately one year so it is essential that new first-line treatments are developed.(10-13)
One approach to fulfil this goal is the investigation of antiangiogenics.(14-22)

Specifically, the effectiveness of bevacizumab in combination with standard treatment as demonstrated in the MAPS study (Mesothelioma Avastin Cisplatin Pemetrexed Study), has led to renewed interest in inhibiting VEGF (vascular endothelial growth factor) as a therapeutic approach. In fact, many signaling molecules, which are involved in the angiogenesis regulation processes, are involved in both the pathogenesis and the prognosis of MPM.(23,24) The VEGF pathway therefore plays a key role in regulating angiogenesis and consequently tumor growth, and is an important factor that can induce the proliferation of MPM cells.(25) MPM patients also have high blood levels of VEGF, which is considered a negative prognostic factor.25
In the MAPS study, survival was shown to be significantly greater in MPM patients treated with cisplatin and pemetrexed plus bevacizumab, compared to those who received chemotherapy alone (18.8 months [confidence interval 95% (CI), 15.9-22.6] vs 16.1 months [95% CI 14.0-17.9]; hazard ratio [HR], 0.77 [95% CI 0.62-0.95]; P =.0167).(26) Up until then, no therapy had ever been shown to increase survival in MPM since the approval of pemetrexed by the US Food and Drug Administration in 2004. These results show that VEGF could be an effective approach as a therapeutic target.
One such drug is nintedanib, which acts on different signal transduction pathways that are involved in the pathogenesis of MPM. Specifically, the VEGF receptor is one of the targets of nintedanib and so this molecule is also considered an angiogenesis inhibitor.
The Phase III portion of the global Phase II/III LUME-Meso is evaluating the safety and efficacy of nintedanib in combination with pemetrexed and cisplatin in patients with unresectable epithelioid MPM.
Initially, this was a randomized, double-blind exploratory Phase II study, which was amended to include a confirmatory Phase III study, following an evaluation by an Internal Data Monitoring Committee after they had reviewed the Phase II results.
The Phase III study will enroll 450 patients not previously treated with chemotherapy, who will be randomized to receive pemetrexed/cisplatin on Day 1 and nintedanib or placebo from Day 2 to 21 for up to 6 cycles. Patients without progressive disease who are eligible to continue treatment in the study may receive maintenance treatment with nintedanib or placebo until disease progression or excessive toxicity. The primary endpoint of the study is progression-free survival (PFS); the key secondary endpoint is overall survival (OS). The study will also include interim analyses to ensure it is adequately powered for the statistical survival analyses. The study is currently enrolling patients.

THE DRUG

Nintedanib is a tyrosine kinase inhibitor (TKI) that targets three growth factor receptors: the vascular endothelial growth factor receptor (VEGFR), the fibroblast growth factor receptor (FGFR), and the platelet-derived growth factor receptor (PDGFR), as well as other targets such as FLT3, RET, Abl and Src tyrosine-protein kinase signaling.(27,28)

This drug is also indicated for idiopathic pulmonary fibrosis (IPF), which is a non-cancerous disease characterized by slow progression and fatal.(29-31)
It is associated with dyspnea, cough and reduced quality of life. Currently, the objectives of patient care include improving outcomes, obtained by slowing disease progression, increasing life expectancy and improving the quality of life.(32-34) Timely and accurate diagnosis is important so that patients can be treated in the early stages of the disease and also so they can be considered for a lung transplant.(35)
The conditional recommendation of nintedanib for IPF is based on the results of the TOMORROW and INPULSIS studies, which showed that nintedanib 150 mg administered twice daily lowered the annual rate of change in FVC compared to patients who received placebo.(36-41) The INPULSIS study results showed that nintedanib was consistently effective across the various subgroups defined by different characteristics such as age (<65 vs ≥65 years), race (Caucasian vs Asian), predicted FVC % (≤70% vs >70%; ≤80% vs >80%, <90% vs >90%), predicted DLCO % (>40% vs ≤40%), and several other diagnostic criteria (such as the presence of honeycombing on high-resolution CT and or confirmation of the presence of UIP by biopsy vs the potential presence of UIP with traction bronchiectasis detected by high-resolution CT, without biopsy evaluation).(42-46)
The TOMORROW and INPULSIS studies also showed that nintedanib reduced exacerbations and mortality due to IPF vs. placebo.(47)
Regarding the tolerability profile, adverse events occurred in more than 10% of patients treated with nintedanib. These adverse events included diarrhea, nausea, abdominal pain, vomiting, and raised liver enzymes, which occurred more frequently in patients receiving nintedanib than placebo.(48,49) For the most part, the adverse events were managed by reducing the dose of the drug or discontinuing treatment.(50) Results from INPULSIS_ON, the ongoing extension of the INPULSIS study, confirm the good tolerability profile of nintedanib and its effectiveness in lowering FVC for over three years.(51)
In oncology, nintedanib (BIBF 1120) in combination with docetaxel was approved by the European Medicines Agency (EMA) for use in the European Union and several other countries for the treatment of locally advanced, metastatic or locally recurrent NSCLC after first-line chemotherapy.(52)
It can also be given in combination with various anti-neoplastic treatments due to the efficacy and good safety profile it has shown when used for the treatment of different types of tumors.(27)
The ability of nintedanib to act on the three major pro-antiangiogenic signaling pathways (VEGF, PDGF and FGF) may offer greater clinical benefit to patients with unresectable MPM than that obtained with agents that target other known anti-angiogenic targets. Nintedanib also inhibits Src,(27) a molecule that plays an important role in several neoplastic pathways and is involved in the pathogenesis of mesothelioma. Inhibition of Src has also been proposed as a therapeutic target for MPM.(53) In preclinical studies, nintedanib reduced the growth and ability of MPM cell lines to metastasize and increased survival in an orthotopic xenograft model of MPM. It is therefore considered a valid candidate for the treatment of unresectable MPM.(54)

THE STUDY

LUME-Meso is a randomized, double-blind, placebo-controlled Phase II/III study.
The study compares the efficacy of nintedanib in combination with backbone pemetrexed+cisplatin chemotherapy followed by maintenance treatment with nintedanib, vs. placebo in combination with pemetrexed+cisplatin followed by placebo monotherapy in patients with unresectable MPM.
The study was initially an exploratory randomized, double-blind Phase II study only, but it was enlarged to include a confirmatory Phase III following the recommendation of an Internal Data Monitoring Committee after a review of the Phase II results.
After completing enrollment in the Phase II study, the results for the primary endpoint of PFS were presented.(55) This led to nintedanib being granted Orphan Drug Designation by the US FDA on 12 December 2016. The Phase III study is currently enrolling and the data will be reviewed by an independent committee.

Study Purpose and Design and Treatment Regimen

The purpose of the study is to evaluate the tolerability and efficacy of backbone chemotherapy in combination with nintedanib followed by maintenance therapy with nintedanib, vs. backbone chemotherapy of cisplatin+pemetrexed in combination with placebo, followed by placebo monotherapy, as first-line treatment of unresectable MPM.

Patients are randomized 1:1 to receive pemetrexed (500 mg/m2)/cisplatin (75 mg/m2) on Day 1 for up to 6 cycles, in combination with nintedanib (200 mg twice per day) or placebo (twice per day) from Day 2 to Day 21. Patients will subsequently receive maintenance therapy with nintedanib or placebo until evidence of progressive disease (PD), the development of severe toxicity, withdrawal of consent or death. Patients who, in the opinion of the investigator, may derive a clinical benefit from continuing treatment after disease progression may continue treatment with nintedanib/placebo.
Based on the results of the Phase II study, which included patients with epithelioid and biphasic MPM histologies, the Phase III will enroll 450 patients with epithelioid MPM only.
Figure 1. Design of the Phase III LUME-Meso trial∗Nintedanib is administered from Day 2 to 21; ¶Cisplatin 75 mg/m2 intravenously for 2 hours on Day 1 of each cycle, for a duration of 21 days, for up to 6 cycles; §Pemetrexed 500 mg/m2 intravenously for 10 minutes on Day 1 of each cycle, for a duration of 21 days, for up to 6 cycles; &lowest;∗Treatment after progression is permitted if clinical benefit is anticipated.
Abbreviations: b.i.d. = twice daily; I.V. = intravenous; MPM = malignant pleural mesothelioma; OS = overall survival; PD = Progressive disease; PFS = progression-free survival.

Inclusion criteria

The study is conducted in accordance with the Helsinki Declaration and following approval by the Ethics Committee.
All patients must provide their informed consent in writing. The Phase III study is currently enrolling patients with histologically confirmed unresectable epithelioid MPM. Although patients eligible for radical resection or elective surgery (e.g., pleurectomy) are not eligible for enrollment, prior surgery, if performed at least 4 weeks before randomization, is permitted if the patient is fully healed and still has measurable disease.

Study Endpoint

The primary endpoint is PFS, while OS is the main secondary endpoint. Other secondary endpoints include overall response rate (ORR) and the percentage of patients with a complete or partial response, or stable disease control rate (DCR), as measured by modified RECIST Criteria.(56) Another objective of the Phase III study includes evaluating the quality of life associated with health status as measured by the EuroQoL-5 self-evaluation questionnaire and the Lung Cancer Symptom Scale (LCSS-Meso) for mesothelioma.(57,58)
Biological samples will be tested by immunohistochemical or molecular genetic analysis to determine the value of markers such as mesothelin, merlin protein (produced by the NF2 gene) and protein 1 associated with BRCA1, as predictive or prognostic factors.
During the study, tolerability of the treatment will be monitored by evaluating variations in the laboratory parameters and the frequency and severity of adverse events in accordance with the CTCAE criteria (Common Terminology Criteria for Adverse Events version 4.03), established by National Cancer Institute (NCI). .(59)

CONCLUSION

As always, the main objective of the study is to increase survival and improve the quality of life.
The study of the new therapy aims to achieve these objectives, although the research requires time in order to validate the data before the results can be applied in clinical practice.
The Phase II/III LUME-Meso study will determine whether nintedanib in combination with the backbone of cisplatin+pemetrexed can provide clinical benefit to patients.
The Phase III study is currently underway, and eligible patients with unresectable MPM are being enrolled at sites in North and South America, Europe, Africa, Australia and Asia.

REFERENCES

1. Baas, P. et al. Malignant pleural mesothelioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 26 Suppl 5, v31-39 (2015).
2. Scherpereel, A. 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 35, 479-495 (2010).
3. Wagner, J. C., Sleggs, C. A. & Marchand, P. Diffuse pleural mesothelioma and asbestos exposure in the North Western Cape Province. Br J Ind Med 17, 260-271 (1960).
4. Steele, J. P. C. Prognostic factors for mesothelioma. Hematol Oncol Clin North Am 19, 1041-1052, vi (2005).
5. NCCN Guidelines. Malignant Pleural Mesothelioma Version 3.2016. (Available at:) https://www.ncbi.nlm.nih.gov/labs/articl.
6. van Meerbeeck, J. P., Scherpereel, A., Surmont, V. F. & Baas, P. Malignant pleural mesothelioma: the standard of care and challenges for future management. Crit Rev Oncol Hematol 78, 92-111 (2011).
7. Vogelzang, N. J. et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 21, 2636-2644 (2003).
8. Gelvez-Zapata, S. M., Gaffney, D., Scarci, M. & Coonar, A. S. What is the survival after surgery for localized malignant pleural mesothelioma? Interact Cardiovasc Thorac Surg 16, 533-537 (2013).
9. Ceresoli, G. L. et al. Phase II study of pemetrexed plus carboplatin in malignant pleural mesothelioma. J Clin Oncol 24, 1443-1448 (2006).
10. Dubey, S. et al. A phase II study of sorafenib in malignant mesothelioma: results of Cancer and Leukemia Group B 30307. J Thorac Oncol 5, 1655-1661 (2010).
11. Nowak, A. K. et al. A phase II study of intermittent sunitinib malate as second-line therapy in progressive malignant pleural mesothelioma. J Thorac Oncol 7, 1449-1456 (2012).
12. Buikhuisen, W. A. et al. Thalidomide versus active supportive care for maintenance in patients with malignant mesothelioma after first-line chemotherapy (NVALT 5): an open-label, multicentre, randomised phase 3 study. Lancet Oncol 14, 543-551 (2013).
13. Kindler, H. L. et al. Multicenter, double-blind, placebo-controlled, randomized phase II trial of gemcitabine/cisplatin plus bevacizumab or placebo in patients with malignant mesothelioma. J Clin Oncol 30, 2509-2515 (2012).
14. Ohta, Y. et al. VEGF and VEGF type C play an important role in angiogenesis and lymphangiogenesis in human malignant mesothelioma tumours. Br J Cancer 81, 54¿61 (1999).
15. Jackman, D. M. et al. Erlotinib plus bevacizumab in previously treated patients with malignant pleural mesothelioma. Cancer 113, 808-814 (2008).
16. Dowell, J. E. et al. A multicenter phase II study of cisplatin, pemetrexed, and bevacizumab in patients with advanced malignant mesothelioma. Lung Cancer 77, 567-571 (2012).
17. Ceresoli, G. L. et al. Phase II study of pemetrexed and carboplatin plus bevacizumab as first-line therapy in malignant pleural mesothelioma. Br J Cancer 109, 552-558 (2013).
18. Reck, M. et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol 27, 1227-1234 (2009).
19. Hurwitz, H. et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350, 2335-2342 (2004).
20. Giantonio, B. J. et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 25, 1539-1544 (2007).
21. Zhu, X., Wu, S., Dahut, W. L. & Parikh, C. R. Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis. Am J Kidney Dis 49, 186-193 (2007).
22. Gray, R., Bhattacharya, S., Bowden, C., Miller, K. & Comis, R. L. Independent review of E2100: a phase III trial of bevacizumab plus paclitaxel versus paclitaxel in women with metastatic breast cancer. J Clin Oncol 27, 4966-4972 (2009).
23. Strizzi, L. et al. Vascular endothelial growth factor is an autocrine growth factor in human malignant mesothelioma. J Pathol 193, 468-475 (2001).
24. Garland, L. L. et al. Phase II study of cediranib in patients with malignant pleural mesothelioma: SWOG S0509. J Thorac Oncol 6, 1938-1945 (2011).
25. Tsao, A. S. 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 6, 1962-1972 (2007).
26. Zalcman, G. et al. Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial. Lancet 387, 1405-1414 (2016).
27. Roth, G. J. et al. Nintedanib: from discovery to the clinic. J Med Chem 58, 1053-1063 (2015).
28. Stinchcombe, T. E. Novel agents in development for advanced non-small cell lung cancer. Ther Adv Med Oncol 6, 240-253 (2014).
29. Buendia-Roldan, I., Mejia, M., Navarro, C. & Selman, M. Idiopathic pulmonary fibrosis: Clinical behavior and aging associated comorbidities. Respir Med 129, 46-52 (2017).
30. Raghu, G. & Richeldi, L. Current approaches to the management of idiopathic pulmonary fibrosis. Respir Med 129, 24-30 (2017).
31. Hewitt, R. J. & Molyneaux, P. L. The respiratory microbiome in idiopathic pulmonary fibrosis. Ann Transl Med 5, 250 (2017).
32. Koo, S.-M. & Uh, S.-T. Treatment of connective tissue disease-associated interstitial lung disease: the pulmonologist¿s point of view. Korean J Intern Med 32, 600¿610 (2017).
33. Johannson, K. A. et al. Antacid therapy in idiopathic pulmonary fibrosis: more questions than answers? Lancet Respir Med 5, 591-598 (2017).
34. Chioma, O. S. & Drake, W. P. Role of Microbial Agents in Pulmonary Fibrosis. Yale J Biol Med 90, 219-227 (2017).
35. Aiello, M. et al. The earlier, the better: Impact of early diagnosis on clinical outcome in idiopathic pulmonary fibrosis. Pulm Pharmacol Ther 44, 7-15 (2017).
36. Fukihara, J. & Kondoh, Y. Nintedanib (OFEV) in the treatment of idiopathic pulmonary fibrosis. Expert Rev Respir Med 10, 1247-1254 (2016).
37. Inomata, M., Nishioka, Y. & Azuma, A. Nintedanib: evidence for its therapeutic potential in idiopathic pulmonary fibrosis. Core Evid 10, 89-98 (2015).
38. Mazzei, M. E., Richeldi, L. & Collard, H. R. Nintedanib in the treatment of idiopathic pulmonary fibrosis. Ther Adv Respir Dis 9, 121-129 (2015).
39. Richeldi, L. et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med 365, 1079-1087 (2011).
40. Richeldi, L. et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 370, 2071-2082 (2014).
41. Woodcock, H. V., Molyneaux, P. L. & Maher, T. M. Reducing lung function decline in patients with idiopathic pulmonary fibrosis: potential of nintedanib. Drug Des Devel Ther 7, 503-510 (2013).
42. Costabel, U. et al. Efficacy of Nintedanib in Idiopathic Pulmonary Fibrosis across Prespecified Subgroups in INPULSIS. Am J Respir Crit Care Med 193, 178-185 (2016).
43. Kolb, M. et al. Nintedanib in patients with idiopathic pulmonary fibrosis and preserved lung volume. Thorax 72, 340-346 (2017).
44. Raghu, G. et al. Effect of Nintedanib in Subgroups of Idiopathic Pulmonary Fibrosis by Diagnostic Criteria. Am J Respir Crit Care Med 195, 78-85 (2017).
45. T.M. Maher, Effect of baseline FVC on lung function decline with nintedanib in patients with IPF Eur. Respir. J., Suppl.
46. T.M. Maher, No effect of baseline diffusing capacity of lung for carbon monoxide on benefit of nintedanib Eur. Respir. J.
47. Richeldi, L. et al. Nintedanib in patients with idiopathic pulmonary fibrosis: Combined evidence from the TOMORROW and INPULSIS((R)) trials. Respir Med 113, 74-79 (2016).
48. Boehringer Ingelheim Pharmaceuticals, Inc http://bidocs.boehringeringelheim.com/BIWebAccess/ViewServlet.ser?docBase=ren.
49. Boehringer Ingelheim International GmbH http://products.boehringer-ingelheim.com/OFEV/sites/default/files/OFEV_SmPC_2016.
50. Corte, T. et al. Safety, tolerability and appropriate use of nintedanib in idiopathic pulmonary fibrosis. Respir Res 16, 116 (2015).
51. Crestani, Long-term treatment with nintedanib in patients with IPF: an update from INPULSIS®-ON Eur. Respir. J., 48 (Su.
52. Reck, M. et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol 15, 143-155 (2014).
53. Menges, C. W. et al. A Phosphotyrosine Proteomic Screen Identifies Multiple Tyrosine Kinase Signaling Pathways Aberrantly Activated in Malignant Mesothelioma. Genes Cancer 1, 493-505 (2010).
54. Laszlo V, Ozsar J, Klikovits T, et al. Preclinical investigation of the therapeutic potential of nintedanib in malignant.
55. Grosso, N. Steele, S. Novello, et al. OA22.02 Nintedanib plus pemetrexed/cisplatin in patients with MPM: phase II findi.
56. Byrne, M. J. & Nowak, A. K. Modified RECIST criteria for assessment of response in malignant pleural mesothelioma. Ann Oncol 15, 257-260 (2004).
57. Trippoli, S., Vaiani, M., Lucioni, C. & Messori, A. Quality of life and utility in patients with non-small cell lung cancer. Quality-of-life Study Group of the Master 2 Project in Pharmacoeconomics. Pharmacoeconomics 19, 855-863 (2001).
58. Hollen, P. J., Gralla, R. J., Liepa, A. M., Symanowski, J. T. & Rusthoven, J. J. Measuring quality of life in patients with pleural mesothelioma using a modified version of the Lung Cancer Symptom Scale (LCSS): psychometric properties of the. Support Care Cancer 14, 11-21 (2006).
59. Elman, S. A., Ware, J. H., Gottlieb, A. B. & Merola, J. F. Adaptive Clinical Trial Design: An Overview and Potential Applications in Dermatology. J Invest Dermatol 136, 1325-1329 (2016).

> Download article as PDF

Heading

Neoplastic pathologies are treated using different approaches depending on the stage of the disease; hence, there are early-stage tumours attacked by radical therapies, such as, for example, surgery and radiotherapy, and there are advanced-stage or metastatic tumours which are usually treated with palliative therapies, such as chemotherapy, immunotherapy or radiotherapy.
Malignant Pleural Mesothelioma (MPM) generally has an unlucky prognosis, and it is usually diagnosed at a late phase, when the disease is already in an advanced stage and cannot be subjected to radical treatment through a surgical approach. Therefore, most patients affected by MPM are treated with systemic chemotherapy or experimental protocols, which have nevertheless a merely palliative purpose, in addition to aiming at making the disease a chronic one for as long as possible.
However, radiotherapy also plays a role in the treatment of MPM, and can be used in different settings and even for opposite purposes.
This bibliographic review aims to evaluate the last studies published in scientific reviews which investigate the role of radiotherapy in the treatment of MPM.

Introduction

  

MPM is considered to be a radiotherapy-resistant neoplasia. Indeed, several studies have shown minimum benefits of this approach combined with the other standard treatments usually implemented in this area(1) . Moreover, very often the use of radiotherapy is postponed due to the significant toxicity which this treatment can have on the lung itself.
In fact, a common collateral effect is represented by post-actinic pneumonias(2). Already back in 1991, studies were published highlighting the pulmonary toxicity caused by radiotherapy applied at the level of the entire hemi-thorax: this data underscores how this treatment entails a moderate-severe and irreversible pulmonary damage in most patients subjected to radiotherapy(3).
Therefore, radiotherapy has been mainly considered within the setting of palliative treatments, such as, for example, pain management(4).
However, recent publications have determined that this recommendation should be changed as it has been observed that patients subjected to radiotherapy for palliative purposes also showed a good response depending on the administration of specific dosages(5).
In vitro studies were also conducted assessing the usefulness of radiotherapy on the cell lines of malignant mesothelioma(6). This data described the cellular sensitivity of mesothelioma to radiotherapy treatments, and it was shown that after two dosages of 2 Gy of radiation were administered, about 60-80% of the mesothelioma cells suffered a damage resulting in the inability to generate new colonies(7).
With regards to this, experiments were also carried out on cell lines of murine models, which have demonstrated cellular survival in only 10% of the cases after 5 Gy of radiotherapy were administered(8).
It is interesting to observe that some authors also proved the existence of a systemic activation and an increase in the proliferation of immune system cells (T-cells), in murine models in which cells previously irradiated in vitro with 5-15 Gy were injected under the skin9 .
If this research conducted on murine cells is applied to human cells, we can observe that sensitivity to radiotherapy is closely dependent upon the histological sub-type of the MPM. For instance, administering 25 Gy in vitro determines an increase in the release of damage signals, such as, for example, HMGB1 (High Mobility Group box 1), especially in the case of epithelioid MPA cells and not of sarcomatoid MPA cells. Since the release of HMGB1 is considered a pro-inflammatory factor able to activate dendritic cells and induce an immunotherapy response against the tumour, the absence of HMGB1 in sarcomatoid MPM might explain the different sensitivity of the two histological subtypes to radiotherapy(10).
Medicines that act on the cell cycle could increase sensibility to radiotherapy, and this was tested on MPM cell lines MPM(11 12 13). Indeed, the radiotherapy treatment causes damage at the DNA level through the generation of oxygen free radicals, consequently causing the cells to die(14 15). Treatments that inhibit DNA repair or increase death of the cells therefore work in synergy with the radiotherapy.
In this case as well, however, the data is inconsistent since this was observed above all in the epithelioid MPM cell lines and not in sarcomatoid MPM cell lines. This difference may be tied to the fact that sarcomatoid tumours have such a resilience that allows them to better defend themselves against the DNA damage due to the sarcomatoid histotypes. Another explanation for the resistance of the sarcomatoid phenotype seems to be tied to the influence of the expression and of the release of fibroblasts growth factor(16).

Prophylactic radiotherapy

In the case of surgery or surgical diagnostic procedures, there may be a dissemination of tumour cells at the level of the site where said approach was implemented.
The risk of local dissemination during a biopsy increases with the size of the procedure and ranges from 10% in case of transparietal biopsy, 13% in case of pleuroscopy, up to 26% in case a thoracotomy is performed(17).
The metastasised tract may cause serious problems not only related to the worsening of the stage and of the prognosis, but also in terms of quality of life, since it can be the cause of several symptoms, the most frequent of which is pain.
For this reason, prophylactic therapy plays a role in these patients, since it reduces the risk of metastasis resulting from these diagnostic or therapeutic procedures.
The initial data pertaining to these findings was published in 1995; the authors proved that a reduction in this dissemination could be tied to the reduced angiogenesis and to the diminished release in tumour growth factors which occur thanks to the use of radiotherapy treatment(18).
Nevertheless, this data is inconsistent, since other studies have not confirmed this research and, on the contrary, have shown a difference in terms of reduction of the risk of metastasis after an invasive procedure, between the group of patients treated with radiotherapy and the control group(19 20 21 22 23 34 25 26).

Palliative radiotherapy

We speak of palliative radiotherapy for patients suffering from MPM when the treatment is aimed, for example, at the management of pain, of dysphagia, of obstruction of the upper respiratory tract and at relief of vena cava compression(27). In fact, the radiotherapy treatment is able to bring about an improvement in severe symptoms for the patient and, although this setting does not entail an increase in survival, it is nevertheless an effective method for improving the quality of life.
Actually, radiotherapy can be used for palliative purposes also for the remote treatment of metastasis, such as, for example, bone or encephalic lesions. In this case, radiotherapy aims at blocking the secondary lesion, improving any symptoms that may be present, as wells as at reducing any symptoms and signs that may develop in the future due to these metastases, and that may lead to a further worsening of the patient’s quality of life(28 29 30 31).
In fact, it has been demonstrated that, especially for non-sarcomatoid histology, palliative radiotherapy was useful and that sensitivity to radiotherapy was correlated to an improvement of the patient’s overall conditions and, consequently, a clear clinical benefit(32 33 34).

Adjuvant radiotherapy

Adjuvant radiotherapy is the treatment administered after surgery as an “adjuvant” to the surgical approach in order to obtain the best outcome.
The Memorial Sloan Kettering Cancer Center (MSKCC, New York City, NY, USA) was a pioneer in the study of this technique(35 36 37 38 39 40).
The radiotherapy approach may also be used intra-surgery. However, it was demonstrated that this option is not an effective treatment and, moreover may cause severe complications such as pleural empyema(41 42 43).
The use of hemithoracic adjuvant radiotherapy at high dosages seems to entail a reduction in the risk of relapse; in fact, some authors claim that with this treatment, the risk of locoregional relapse is approximately 15%(44 45 46).
Intensity-modulated radiotherapy (IMRT) has also been used as hemithoracic therapy at high dosages, and it has shown to provide a benefit in terms of relapse reduction, especially when applied at the level of the base of the ribcage, in areas with a higher risk of a relapse of the locoregional disease(47 48 49).
It is important to remember that these treatments are not risk-free. For example, the literature includes cases of lethal contralateral pneumonia, especially after use of radiotherapy after an extrapleural pneumonectomy(50 51 52). For this reason, a crucial factor is the proper dosage of the radiotherapy in addition to a careful evaluation of the patient’s respiratory functionality(53 54 55).
Other authors, on the other hand, have demonstrated how radiotherapy, and in particular the modulated-intensity type, may be an approach that is easily tolerated by patient and featuring a not-so-high risk of post-actinic pneumonias(56 57 58 59 60 61 62).
Moreover, a more innovative technique would allow a further reduction in the risk of complications: this innovative technique is called VMAT (Volumetric-Modulated Arc Therapy)(63 64 65).
Increased control over the disease has been described in patients subjected to adjuvant radiotherapy(66 67).
With these purposes, new randomised and prospective studies on the association between chemotherapy and adjuvant radiotherapy may possibly provide data demonstrating greater efficacy(68 69 70 71 72 73 74). Indeed, chemotherapy may reduce the risk of a relapse while radiotherapy may increase local control(75 76 77 78 79 80 81 82 83 84 85 86).

Induction radiotherapy

Trimodal therapy consists of the application of chemotherapy, followed by extrapleural pneumonectomy and by hemithoracic adjuvant radiotherapy at high dosages.
Use of the therapy in this setting resulted in better survival and local control of the disease(87). On the basis of this research, we can hypothesise that radiotherapy can also be applied at the early stages of MPM, rather than using chemotherapy: this therapy setting is known as "induction" radiotherapy(88 89).
In studies on the application of radiotherapy in this setting, the surgical complications which occurred after the induction radiotherapy treatment were similar to those recorded after the adjuvant chemotherapy treatment(90).
In this case too, the patients with epithelioid MPM had a better outcome compared to those affected by the other histological type(91).
Several studies have underscored how the tumour volume is correlated with the outcome and how it could also be a guiding factor in the choice of whether or not to subject a patient to induction therapy(92 93 94 95). On the contrary, the same data cannot be applied to the response to chemotherapy, which instead does not depend on the volume of the neoplasias, as it happens with radiotherapy and surgery(96). This data indicates that patients with localised disease may be good candidates for treatment with induction radiotherapy, whilst those with a large-sized tumour would benefit instead from chemotherapy(97).

Conclusions

Future prospects include the possibility to combine standard treatments for MPM, such as radiotherapy, and immune-system treatments(98 99 100). In the past fifteen years, the role of radiotherapy in the treatment of MPM has grown, also supported by scientific evidence demonstrated in various treatment settings.
However, the real benefit of this method has yet to be completely defined for this type of neoplasia, but new and innovative approaches, such as IMRT at the pleural level and induction-accelerated hemithoracic radiotherapy performed after surgery may very well be feasible and well-tolerated.
New studies will make it possible to provide an answer these still unanswered questions.

Bibliography

1. Wanebo HJ, Martini N, Melamed MR, Hilaris B, Beattie EJ Jr. Pleural mesothelioma. Cancer 1976; 38: 2481–88.
2. Ball DL, Cruickshank DG. The treatment of malignant mesothelioma of the pleura: review of a 5-year experience, with special reference to radiotherapy. Am J Clin Oncol 1990;13: 4–9.
3. Maasilta P1, Kivisaari L, Holsti LR, Tammilehto L, Mattson K. Radiographic chest assessment of lung injury following hemithorax irradiation for pleural mesothelioma. Eur Respir J 1991; 4: 76–83.
4. Gordon W Jr, Antman KH, Greenberger JS, Weichselbaum RR, Chaffey JT. Radiation therapy in the management of patients with mesothelioma. Int J Radiat Oncol Biol Phys 1982; 8: 19–25.
5. 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; 43: 511–16.
6. Carmichael J, Degraff WG, Gamson J, et al. Radiation sensitivity of human lung cancer cell lines. Eur J Cancer Clin Oncol 1989; 25: 527–34.
7. Shearin JC Jr, Jackson D. Malignant pleural mesothelioma. Report of 19 cases. J Thorac Cardiovasc Surg 1976; 71: 621–27.
8. Wu L, Wu MO, De la Maza L, et al. Targeting the inhibitory receptor CTLA-4 on T cells increased abscopal effects in murine mesothelioma model. Oncotarget 2015; 6: 12468–80.
9. Mattson K, Holsti LR, Tammilehto L, et al. Multimodality treatment programs for malignant pleural mesothelioma using high-dose hemithorax irradiation. Int J Radiat Oncol Biol Phys 1992; 24: 643–50.
10. Sharabi AB, Lim M, DeWeese TL, Drake CG. Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy. Lancet Oncol 2015; 16: e498–509.
11. Indovina P, Marcelli E, Di Marzo D, et al. Abrogating G₂/M checkpoint through WEE1 inhibition in combination with chemotherapy as a promising therapeutic approach for mesothelioma. Cancer Biol Ther 2014; 15: 380–88.
12. Sudo H, Tsuji AB, Sugyo A, Ogawa Y, Sagara M, Saga T. ZDHHC8 knockdown enhances radiosensitivity and suppresses tumor growth in a mesothelioma mouse model. Cancer Sci 2012; 103: 203–09.
13. Verbrugge I, Wissink EH, Rooswinkel RW, et al. Combining radiotherapy with APO010 in cancer treatment. Clin Cancer Res 2009; 15: 2031–38.
14. Indovina P, Marcelli E, Di Marzo D, et al. Abrogating G₂/M checkpoint through WEE1 inhibition in combination with chemotherapy as a promising therapeutic approach for mesothelioma. Cancer Biol Ther 2014; 15: 380–88.
15. Verbrugge I, Wissink EH, Rooswinkel RW, et al. Combining radiotherapy with APO010 in cancer treatment. Clin Cancer Res 2009; 15: 2031–38.
16. Schelch K, Hoda MA, Klikovits T, et al. Fibroblast growth factor receptor inhibition is active against mesothelioma and synergizes with radio- and chemotherapy. Am J Respir Crit Care Med 2014; 190: 763–72.
17. Metintas M, Ak G, Parspour S, et al. Local recurrence of tumor at sites of intervention in malignant pleural mesothelioma. Lung Cancer 2008; 61: 255–61.
18. 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; 108: 754–58
19. 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; 91: 9–10.
20. O’Rourke N, Garcia JC, Paul J, Lawless C, McMenemin R, Hill J. A randomised controlled trial of intervention site radiotherapy in malignant pleural mesothelioma. Radiother Oncol 2007; 84: 18–22.
21. Clive AO, Taylor H, Dobson L, et al. Prophylactic radiotherapy for the prevention of procedure-tract metastases after surgical and large-bore pleural procedures in malignant pleural mesothelioma (SMART): a multicentre, open-label, phase 3, randomised controlled trial. Lancet Oncol 2016; 17: 1094–104.
22. Bayman N, Ardron D, Ashcroft L, et al. Protocol for PIT: a phase III trial of prophylactic irradiation of tracts in patients with malignant pleural mesothelioma following invasive chest wall intervention. BMJ Open 2016; 6: e010589.
23. Bayman N, Ardron D, Ashcroft L, et al. Protocol for PIT: a phase III trial of prophylactic irradiation of tracts in patients with malignant pleural mesothelioma following invasive chest wall intervention. BMJ Open 2016; 6: e010589.
24. Clive AO, Taylor H, Maskell NA. Prophylactic radiotherapy to prevent procedure-tract metastases—Author’s reply. Lancet Oncol 2016; 17: e419.
25. Bölükbas S, Manegold C, Eberlein M, Bergmann T, Fisseler-Eckhoff A, Schirren J. Survival after trimodality therapy for malignant pleural mesothelioma: radical pleurectomy, chemotherapy with cisplatin/pemetrexed and radiotherapy. Lung Cancer 2011; 71: 75–81.
26. Lang-Lazdunski L, Bille A, Papa S, et al. Pleurectomy/decortication, hyperthermic pleural lavage with povidone-iodine, prophylactic radiotherapy, and systemic chemotherapy in patients with malignant pleural mesothelioma: a 10-year experience. J Thorac Cardiovasc Surg 2015; 149: 558–65.
27. Gordon W Jr, Antman KH, Greenberger JS, Weichselbaum RR, Chaffey JT. Radiation therapy in the management of patients with mesothelioma. Int J Radiat Oncol Biol Phys 1982; 8: 19–25.
28. Ball DL, Cruickshank DG. The treatment of malignant mesothelioma of the pleura: review of a 5-year experience, with special reference to radiotherapy. Am J Clin Oncol 1990; 13: 4–9.
29. 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; 43: 511–16.
30. Davis SR, Tan L, Ball DL. Radiotherapy in the treatment of malignant mesothelioma of the pleura, with special reference to its use in palliation. Australas Radiol 1994; 38: 212–14.
31. Bissett D, Macbeth FR, Cram I. The role of palliative radiotherapy in malignant mesothelioma. Clin Oncol (R Coll Radiol) 1991; 3: 315–17.
32. Jenkins P, Milliner R, Salmon C. Re-evaluating the role of palliative radiotherapy in malignant pleural mesothelioma. Eur J Cancer 2011; 47: 2143–49.
33. MacLeod N, Chalmers A, O’Rourke N, et al. Is radiotherapy useful for treating pain in mesothelioma?: a phase II trial. J Thorac Oncol 2015; 10: 944–50.
34. Aston M, O’Rourke N, Macleod N, Chalmers A. SYSTEMS-2: a randomised phase II trial of standard versus dose escalated radiotherapy in the treatment of pain in malignant pleural mesothelioma. Lung Cancer 2016; 91 (suppl 1): s71 (abstr 194).
35. Kutcher GJ, Kestler C, Greenblatt D, Brenner H, Hilaris BS, Nori D. Technique for external beam treatment for mesothelioma. Int J Radiat Oncol Biol Phys 1987; 13: 1747–52.
36. Hilaris BS, Nori D, Kwong E, Kutcher GJ, Martini N. Pleurectomy and intraoperative brachytherapy and postoperative radiation in the treatment of malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys 1984; 10: 325–31.
37. Cao C, Tian D, Park J, Allan J, Pataky KA, Yan TD. A systematic review and meta-analysis of surgical treatments for malignant pleural mesothelioma. Lung Cancer 2014; 83: 240–45.
38. Rimner A, Spratt DE, Zauderer MG, et al. Failure patterns after hemithoracic pleural intensity modulated radiation therapy for malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys 2014; 90: 394–401.
39. Shaikh F, Zauderer MG, von Reibnitz D, et al. Improved outcomes with modern lung-sparing trimodality therapy in patients with malignant pleural mesothelioma. J Thorac Oncol 2017; 12: 993–1000.
40. Pan HY, Jiang S, Sutton J, et al. Early experience with intensity modulated proton therapy for lung-intact mesothelioma: a case series. Pract Radiat Oncol 2015; 5: e345–e353.
41. Cupta V, Mychalczak B, Krug L, et al. Hemithoracic radiation therapy after pleurectomy/decortication for malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys 2005; 63: 1045–52.
42. Cupta V, Mychalczak B, Krug L, et al. Hemithoracic radiation therapy after pleurectomy/decortication for malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys 2005; 63: 1045–52.
43. 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;122: 788–95.
44. Gomez DR, Hong DS, Allen PK, et al. Patterns of failure, toxicity, and survival after extrapleural pneumonectomy and hemithoracic intensity-modulated radiation therapy for malignant pleural mesothelioma. J Thorac Oncol 2013; 8: 238–45.
45. Thieke C, Nicolay NH, Sterzing F, et al. Long-term results in malignant pleural mesothelioma treated with neoadjuvant chemotherapy, extrapleural pneumonectomy and intensity-modulated radiotherapy. Radiat Oncol 2015; 10: 267.
46. 32
47. Allen AM, Czerminska M, Jänne PA, et al. Fatal pneumonitis associated with intensity-modulated radiation therapy for mesothelioma. Int J Radiat Oncol Biol Phys 2006; 65: 640–45.
48. Vedere nota 47
49. Forster KM, Smythe WR, Starkschall G, et al. Intensity-modulated radiotherapy following extrapleural pneumonectomy for the treatment of malignant mesothelioma: clinical implementation. Int J Radiat Oncol Biol Phys 2003; 55: 606–16
50. Vedere nota 47
51. Kristensen CA, N.ttrup TJ, Berthelsen AK, et al. Pulmonary toxicity following IMRT after extrapleural pneumonectomy for malignant pleural mesothelioma. Radiother Oncol 2009; 92: 96–99.
52. Chi A, Liao Z, Nguyen NP, et al. Intensity-modulated radiotherapy after extrapleural pneumonectomy in the combined-modality treatment of malignant pleural mesothelioma. J Thorac Oncol 2011; 6: 1132–41.
53. 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; 69: 350–57.
54. Vedere nota 52

55. Patel PR, Yoo S, Broadwater G, et al. Effect of increasing experience on dosimetric and clinical outcomes in the management of malignant pleural mesothelioma with intensity-modulated radiation therapy. Int J Radiat Oncol Biol Phys 2012; 83: 362–68.
56. Thieke C, Nicolay NH, Sterzing F, et al. Long-term results in malignant pleural mesothelioma treated with neoadjuvant chemotherapy, extrapleural pneumonectomy and intensity-modulated radiotherapy. Radiat Oncol 2015; 10: 267.
57. 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; 69: 350–57.
58. Patel PR, Yoo S, Broadwater G, et al. Effect of increasing experience on dosimetric and clinical outcomes in the management of malignant pleural mesothelioma with intensity-modulated radiation therapy. Int J Radiat Oncol Biol Phys 2012; 83: 362–68.
59. Ahamad A, Stevens CW, Smythe WR, et al. Intensity-modulated radiation therapy: a novel approach to the management of malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys 2003; 55: 768–75.
60. Tonoli S, Vitali P, Scotti V, et al. Adjuvant radiotherapy after extrapleural pneumonectomy for mesothelioma. Prospective analysis of a multi-institutional series. Radiother Oncol 2011; 101: 311–15
61. Buduhan G, Menon S, Aye R, Louie B, Mehta V, Vallières E. Trimodality therapy for malignant pleural mesothelioma. Ann Thorac Surg 2009; 88: 870–75.
62. Du KL, Both S, Friedberg JS, Rengan R, Hahn SM, Cengel KA. Extrapleural pneumonectomy, photodynamic therapy and intensity modulated radiation therapy for the treatment of malignant pleural mesothelioma. Cancer Biol Ther 2010; 10: 425–29
63. Scorsetti M, Bignardi M, Clivio A, et al. Volumetric modulation arc radiotherapy compared with static gantry intensity-modulated radiotherapy for malignant pleural mesothelioma tumor: a feasibility study. Int J Radiat Oncol Biol Phys 2010; 77: 942–49.
64. Botticella A, Defraene G, Nackaerts K, et al. Does selective pleural irradiation of malignant pleural mesothelioma allow radiation dose escalation?: A planning study. Strahlenther Onkol 2017; 193: 285–94.
65. Runxiao L, Yankun C, Lan W. A pilot study of volumetric-modulated arc therapy for malignant pleural mesothelioma. J Appl Clin Med Phys 2016; 17: 139–44.
66. Buduhan G, Menon S, Aye R, Louie B, Mehta V, Vallières E. Trimodality therapy for malignant pleural mesothelioma. Ann Thorac Surg 2009; 88: 870–75.
67. Krayenbuehl J, Dimmerling P, Ciernik IF, Riesterer O. Clinical outcome of postoperative highly conformal versus 3D conformal radiotherapy in patients with malignant pleural mesothelioma. Radiat Oncol 2014; 9: 32.
68. Rea F, Marulli G, Bortolotti L, et al. Induction chemotherapy, extrapleural pneumonectomy (EPP) and adjuvant hemi-thoracic radiation in malignant pleural mesothelioma (MPM): feasibility and results. Lung Cancer 2007; 57: 89–95.
69. Flores RM, Krug LM, Rosenzweig KE, et al. Induction chemotherapy, extrapleural pneumonectomy, and postoperative high-dose radiotherapy for locally advanced malignant pleural mesothelioma: a phase II trial. J Thorac Oncol 2006; 1: 289–95.
70. Batirel HF, Metintas M, Caglar HB, et al. Trimodality treatment of malignant pleural mesothelioma. J Thorac Oncol 2008; 3: 499–504.
71. Van Schil PE, Baas P, Gaafar R, et al. Trimodality therapy for malignant pleural mesothelioma: results from an EORTC phase II multicentre trial. Eur Respir J 2010; 36: 1362–69.
72. Hasegawa S, Okada M, Tanaka F, et al. Trimodality strategy for treating malignant pleural mesothelioma: results of a feasibility study of induction pemetrexed plus cisplatin followed by extrapleural pneumonectomy and postoperative hemithoracic radiation (Japan mesothelioma interest group 0601 trial. Int J Clin Oncol 2016; 21: 523–30.
73. 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; 18: 1196–202.
74. Krug LM, Pass HI, Rusch VW, et al. Multicenter phase II trial of neoadjuvant pemetrexed plus cisplatin followed by extrapleural pneumonectomy and radiation for malignant pleural mesothelioma. J Clin Oncol 2009; 27: 3007–13.
75. Federico R, Adolfo F, Giuseppe M, et al. Phase II trial of neoadjuvant pemetrexed plus cisplatin followed by surgery and radiation in the treatment of pleural mesothelioma. BMC Cancer 2013; 13: 22.
76. Minatel E, Trovo M, Polesel J, et al. Radical pleurectomy/ decortication followed by high dose of radiation therapy for malignant pleural mesothelioma. Final results with long-term follow-up. Lung Cancer 2014; 83: 78–82.
77. Cho BC, Feld R, Leighl N, et al. A feasibility study evaluating surgery for mesothelioma after radiation therapy: the “SMART” approach for resectable malignant pleural mesothelioma. J Thorac Oncol 2014; 9: 397–402.
78. 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; 135: 620–26.
79. Yan TD, Boyer M, Tin MM, et al. Extrapleural pneumonectomy for malignant pleural mesothelioma: outcomes of treatment and prognostic factors. J Thorac Cardiovasc Surg 2009; 138: 619–24.
80. Pass HI, Giroux D, Kennedy C, et al. Supplementary prognostic variables for pleural mesothelioma: a report from the IASLC staging committee. J Thorac Oncol 2014; 9: 856–64.
81. Rusch VW, Piantadosi S, Holmes EC. The role of extrapleural pneumonectomy in malignant pleural mesothelioma. A lung cancer study group trial. J Thorac Cardiovasc Surg 1991; 102: 1–9.
82. Treasure T, Lang-Lazdunski L, Waller D, et al. Extra-pleural pneumonectomy versus no extra-pleural pneumonectomy for patients with malignant pleural mesothelioma: clinical outcomes of the mesothelioma and radical surgery (MARS) randomised feasibility study. Lancet Oncol 2011; 12: 763–72.
83. Vedere nota 83
84. Weder W, Stahel RA, Baas P, et al. The MARS feasibility trial: conclusions not supported by data. Lancet Oncol 2011; 12: 1093–94.
85. Rimner A, Simone CB 2nd, Zauderer MG, Cengel KA, Rusch VW. Hemithoracic radiotherapy for mesothelioma: lack of benefit or lack of statistical power? Lancet Oncol 2016; 17: e43–44.
86. Kostron A, Friess M, Crameri O, et al. Relapse pattern and second-line treatment following multimodality treatment for malignant pleural mesothelioma. Eur J Cardiothorac Surg 2016; 49: 1516–23.
87. de Perrot M, Feld R, Cho BC, et al. Trimodality therapy with induction chemotherapy followed by extrapleural pneumonectomy and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma. J Clin Oncol 2009; 27: 1413–18.
88. Cho BC, Feld R, Leighl N, et al. A feasibility study evaluating surgery for mesothelioma after radiation therapy: the “SMART” approach for resectable malignant pleural mesothelioma. J Thorac Oncol 2014; 9: 397–402
89. de Perrot M, Feld R, Leighl NB, et al. Accelerated hemithoracic radiation followed by extrapleural pneumonectomy for malignant pleural mesothelioma. J Thorac Cardiovasc Surg 2016; 151: 468–73.
90. Mordant P, McRae K, Cho J, et al. Impact of induction therapy on postoperative outcome after extrapleural pneumonectomy for malignant pleural mesothelioma: does induction-accelerated hemithoracic radiation increase the surgical risk? Eur J Cardiothorac Surg 2016; 50: 433–38.
91. de Perrot M, Dong Z, Bradbury P, et al. Impact of tumour thickness on survival after radical radiation and surgery in malignant pleural mesothelioma. Eur Respir J 2017; 49: 1601428
92. Opitz I, Friess M, Kestenholz P, et al. A new prognostic score supporting treatment allocation for multimodality therapy for malignant pleural mesothelioma: a review of 12 years’ experience. J Thorac Oncol 2015; 10: 1634–41.
93. Gill RR, Richards WG, Yeap BY, et al. Epithelial malignant pleural mesothelioma after extrapleural pneumonectomy: stratification of survival with CT-derived tumor volume. AJR Am J Roentgenol 2012; 198: 359–63.
94. Rusch VW, Gill R, Mitchell A, et al. A multicenter study of volumetric computed tomography for staging malignant pleural mesothelioma. Ann Thorac Surg 2016; 102: 1059–66.
95. Pass HI, Temeck BK, Kranda K, Steinberg SM, Feuerstein IR. Preoperative tumor volume is associated with outcome in malignant pleural mesothelioma. J Thorac Cardiovasc Surg 1998; 115: 310–17.
96. Liu F, Zhao B, Krug LM, et al. Assessment of therapy responses and prediction of survival in malignant pleural mesothelioma through computer-aided volumetric measurement on computed tomography scans. J Thorac Oncol 2010; 5: 879–84.
97. Vedere nota 96
98. Wu L, Yun Z, Tagawa T, Rey-McIntyre K, de Perrot M. CTLA-4 blockade expands infiltrating T cells and inhibits cancer cell repopulation during the intervals of chemotherapy in murine mesothelioma. Mol Cancer Ther 2012; 11: 1809–19.
99. Alley EW, Katz SI, Cengal KA, Simone CB 2nd. Immunotherapy and radiation therapy for malignant pleural mesothelioma. Transl Lung Cancer Res 2017; 6: 212–19.
100. Wu L, Wu MO, De la Maza L, et al. Targeting the inhibitory receptor CTLA-4 on T cells increased abscopal effects in murine mesothelioma model. Oncotarget 2015; 6: 12468–80.

> Download article as PDF

INTRODUCTION

Like most neoplastic diseases, malignant pleural mesothelioma (MPM) requires a great deal of radiological evaluation both at the time of diagnosis and for monitoring patient response during therapy.
For this reason, the FBU also wished to be involved in this area of diagnosis and treatment of MPM and has initiated a project to fund a radiologist specializing in this field, currently under way at the UFIM of Alessandria / Casale Monferrato.
This month's bibliography review provides an informative and simplified overview of the use of radiology in this disease.
(Please see the bibliography for further information or for the "experts in the field".)

USE OF RADIOLOGY

  

Chest X-rays
Radiological techniques allow us to determine pleural alterations and their characteristics, such as the presence of thickening and pleural plaques, their pattern of distribution, and the eventual presence of pleural effusion. Radiological analysis can be used to arrive at the diagnosis as well as for staging the disease (1).
The initial examination is usually a standard chest X-ray, but this is not always conclusive, especially if the presence of pleural lesions is suspected.

Computed tomography
Because a chest X-Ray does not allow for a detailed examination of suspected pleural lesions, the first real in-depth examination for this disease should be computed tomography (CT). According to the AIOM national guidelines, the data obtained by CT analysis have demonstrated a specificity of 78% (95% CI, 72%-84%), but a sensitivity of only 68% (CI 95%, 62%-75%). This is necessary particularly in the differential diagnosis of pleural effusion with a negative CT scan that is negative for pleural lesions, in case you want to exclude the diagnosis of malignant disease.
Consequently, this often means subjecting the patient to an invasive diagnostic procedure, such as thoracentesis or a pleural biopsy. In these cases, the decision should be based on the clinical data rather than the negative CT scan (2).
If the thoracic CT scan shows evidence of MPM, the examination should be extended to the abdomen to exclude any secondary disease in the abdominal organs and the peritoneum in particular.

Ultrasonography
A simple ultrasound is one of the possible ultrasonography approaches to MPM, allowing us to analyze both the presence of pleural fluid and any parietal lesions. Ultrasound may also be used together with color Doppler or contrast media (CEUS). As such, ultrasonography allows us to easily identify pleurisy and pleural thickening and also determine any suspicious lesions due to malignancy based on their vascularization (3).

Magnetic resonance
Several studies have shown that nuclear magnetic resonance imaging (MRI) appears to be superior to CT in differentiating between benign and malignant pleural thickening, and particularly in assessing the possible infiltration of the chest wall and diaphragm (4). However, it is important to point out that the introduction of new generation and increasingly sophisticated TC equipment has greatly reduced this discrepancy. MRI could therefore be useful mainly to further the CT findings, particularly as an additional examination before performing an intervention. Preliminary studies also suggest the possibility of using MRI with special techniques, such as diffusion-weighted imaging (DWI), to assess the histology of patients with pleural mesothelioma using the apparent diffusion coefficient (ADC) (5). However, although the results are promising these methods are currently experimental.

Positron emission tomography
18-FDG PET-CT has been studied because it is a technique that helps to distinguish between benign and malignant pleural lesions (6). It is also used in the clinic for staging, in other words to identify metastatic sites not shown by other radiological procedures.
This metabolic method has demonstrated greater sensitivity, specificity and accuracy in lymph node staging (7). However, the reliability of the method is limited due to the possibility of false negatives (especially in the presence of micrometastases <4 mm) and false positives (very often related to non-necrotizing granulomatous reactions) (8). However, the gold standard for the most accurate pleural staging remains the thoracoscopy, as suggested by at least one study which compared metabolic imaging with this procedure (9).
A total body 18-FDG PET-CT is recommended for the staging of patients eligible for multimodal treatment due to its greater accuracy in extra-thoracic and lymphatic staging compared to a CT scan. The optimal timing for performing this procedure is before conducting any invasive procedures such as pleurodesis due to the risk of subsequent false positive results due to the procedure (10, 11). Precisely because of the above limitations, the use of this method for evaluating response to treatment is still being studied and it is not recommended for routine use (12).
Metabolic assessments could be used not only in the diagnosis and staging of the disease but also for monitoring the malignant lesions during antiblastic therapy. In fact, a recent study suggests that there is a possible role for metabolic imaging to identify the non-responders among patients with stable disease according to mRECIST criteria. In this subgroup of patients, a ≥ 25% increase of SUVmax compared to baseline was associated with a statistically significant reduction in median time to progression (10.0 vs 13.7 months, p <0.001). (13)

RECIST criteria
The radiological criteria usually evaluated are known as RECIST (Response Evaluation Criteria in Solid Tumor), which were updated and published in 2004 ("modified RECIST"). However, the use of these criteria for evaluating response in mesothelioma is rather complex. The modified RECIST1 system published in 2004 allows for more accurate measurements. Even though this has led to an improvement over the initial RECIST criteria, the rate of variability and inaccuracy of the measures remains very high. It is important to point out that compliance of the radiology specialists with the correct method greatly influences the evaluation of disease response to treatment.
Currently the modified RECIST criteria are based on the CT measurement of the thickness of the neoplasm perpendicular to the chest wall or the mediastinum at three different levels, so as to take into account the irregularity of the tumor (Tables 1 and 2) (14). These criteria are the diagnostic standard, since the response evaluated with these tools has shown a statistically significant correlation with overall survival and respiratory function.

Studying volumetric variation using CT is a promising approach in this area, considering also the potential correlation with survival, if analyzed together with several clinical parameters (15).
An article was also recently published proposing further modifications to the modified RECIST version 1.0, with a recommendation to adopt a new RECIST version 1.1 (16). Specifically, the continuous updating of the RECIST criteria evaluates different approaches that are reflected in clinical practice. The main ones are as follows:

  • Definition of measurable lesions
  • Evaluation of non-pleural lesions
  • Characterization of non-measurable pleural disease
  • Definition of pathological lymph nodes
  • Definition of disease progression

CONCLUSIONS

Radiology plays a fundamental role for malignant pleural mesothelioma and is useful for diagnosing, staging and, more importantly, for monitoring the disease during specific antiblastic treatment.
However, continuous updates are needed specifically in this area and the role of the radiology specialist in this field is increasingly necessary.
The FBU, which has always been involved in the diagnosis and treatment of MPM, also wished to contribute to this sector by funding a radiology specialist dedicated to this neoplasm.

BIBLIOGRAPHY

1. Surea B, Thukral BB, Mittal MK, Mittal A, Sinha M. Radiological review of pleural tumors. Indina J Radiol Imaging. 2013;23:313-20
2. Hallifax RJ, Haris M , Corcoran JP, Leyakathaliakn S, Brown E, Srikantharaja D, Manuel A, Gleeson FV, Munavvar M, Rahman NM. Role of CT in assessing pleural malignancy prior to thoracoscopy. Thorax. 2015;70:192-3
3. Sartori S, Postorivo S, Vede FD, Ermili F, Tassinari D, Tombesi P. Contrast-enhanced ultrasonography in peripheral lung consolidations: what’s its actual role? World J radiol. 2013;5:372-80
4. Gill RR, Gerbaudo VH, Jacobson FL, Trotman-Dickenson B, Matsuoka S, Hunsaker A, Sugarbaker DJ, Hatabu H. MR imaging of benign and malignant pleural disease. Magn Reson Imaging Clin N Am; 16(2008) 319-339
5. Gill RR, Umeoka S, Mamata H, Tilleman TR, Stanwell P, Woodhams R, Padera RF, Sugarbaker Dj, Habau H. Diffusion-weighted MRI of malignant pleural mesothelioma: preliminary assessment of apparent diffusion coefficient in histologic subtypes. AJR Am J Roentgenol 2010;195(2):W125-30
6. Yildirim H, Metintas M, Entok E, et al. Clinical value of fluorodeoxyglucose-positron emission tomography/computed tomography in differentiation of malignant mesothelioma from asbestos related bening pleural disease: an observational pilot study. J Thorac Oncol 2009;4:1480-84
7. Zahid I, Sharif S, Routledge T, Scarci M. What is the best way to diagnose and stage malignant pleural mesothelioma? Interact Cardiovasc Thorac Surg. 2011;12:254-9
Sørensen JB1, Ravn J, Loft A, Brenøe J, Berthelsen AK for the Nordic Mesothelioma Group. Preoperative staging of mesothelioma by 18F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography fused imaging and mediastinoscopy compared to pathological findings after extrapleural pneumonectomy. Eur. J. Cardiothorac. Surg. 2008;34: 1090-6
9. Pinelli V, Roca E, Lucchini S, et al. Positron emission tomography/computed tomography for the pleural staging of malignant pleural mesothelioma: how accurate is it?. Respiration 2015;89:558-64
10. Murray JG, Erasmus JJ, Bahtiarian EA, Goodman PC. Talc pleurodesis simulating pleural metastases on 18Ffluorodeoxyglucose positron emission tomography. AJR Am J Roentgenol 1997; 168:359-60
11. Nguyen NC, Tran I, Hueser CN, et al. F-18 FDG PET/CT characterization of talc pleurodesis induced pleural changes over time: a retrospective study. Clin Nucl Med 2009;34:886-90
12. Schaefer NG, Veit-Heibach P, Soyka JD, et al. Continued pemetrexed and platin-based chemotherapy in patients with malignant pleural mesothelioma (MPM): value of 18F-FDG.PET/CT.Eur J Radiol 2012;81:e19-25
13. Kanemura S, Kuribayashi K, Funaguchi N, et al. Metabolic response assessment with 18F-FDG PET/CT is superior to modified RECIST for the evaluation of response to platinum-based doublet chemotherapy in malignant pleural mesothelioma. Eur J Radiol 2017;86:92-98
14. Byrne M.J., Nowak A.K.. Modified RECIST criteria for assessment of response inmalignant pleural mesothelioma, Ann. Oncol. 15 (2004) 257–260
15. Labby ZE, Nowak KA, Dignam JJ, Straus C, Kindler HL, Armato III SG. Disease volumes as a marker for patient response in malignant pleural mesothelioma. Ann Oncol 2013;24(4):999-1005
16. Armato SG 3rd, Nowak AK. Revised modified response evaluation criteria in solid tumors for assessment of response in malignant pleural mesothelioma (version 1.1). J Thorac Oncol. 2018;13:1012–1021.

ADDITIONAL REFERENCES

■ Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L,Verweij J, van Glabbeke M, van Oosteron AT, Christian MC, Gwyther SG: New guidelines to evaluate the response to treatment in solid tumors. Journal of the National Cancer Institute 92: 205–216, 2000.
■ Byrne MJ, Nowak AK; Modified RECIST criteria for assessment of response in malignant pleural mesothelioma. Annals of Oncology 15: 257–260, 2004.
■ Zalcman G, Mazieres J, Margery J, Greillier L, Audigier-Valette C, Moro-Sibilot D, Molinier O, Corre R, Monnet I, Gounant V, Rivière F, Janicot H, Gervais R, Locher C, Milleron B, Tran Q, Lebitasy MP, Morin F, Creveuil C, Parienti JJ, Scherpereel A; French Cooperative Thoracic Intergroup (IFCT): Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): A randomised, controlled, open-label, phase 3 trial. Lancet 387: 1405–1414, 2016.

■ Calabrò L, Morra A, Fonsatti E, Cutaia O, Amato G, Giannarelli D, Di Giacomo AM, Danielli R, Altomonte M, Mutti L, Maio M: Tremelimumab for patients with chemotherapyresistant advanced malignant mesothelioma: An open-label, single-arm, phase 2 trial. Lancet Oncol 14: 1104–1111, 2013.
■ Calabrò L, Morra A, Fonsatti E, Cutaia O, Fazio C, Annesi D, Lenoci M, Amato G, Danielli R, Altomonte M, Giannarelli D, Di Giacomo AM, Maio M. Efficacy and safety of an intensified schedule of tremelimumab for chemotherapy-resistant malignant mesothelioma: An open-label, single-arm, phase 2 study. Lancet Respir Med 3: 301–309, 2015.
■ Maio M, Scherpereel A, Calabrò L, Aerts J, Perez SC, Bearz A, Nackaerts K, Fennell DA, Kowalski D, Tsao AS, Taylor P, Grosso F, Antonia SJ, Nowak AK, Taboada M, Puglisi M, Stockman PK, Kindler HL. Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): A multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial. Lancet Oncol 18: 1261-1273, 2017.
■ Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J: New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). European Journal of Cancer 45: 228-247, 2009.
■ Byrne MJ, Davidson JA, Musk AW et al.: Cisplatin and gemcitabine treatment for malignant mesothelioma: a phase II study. J Clin Oncol 17: 25–30, 1999.
■ Nowak AK, Byrne MJ, Williamson R et al.: A multicentre phase II study of cisplatin and gemcitabine for malignant mesothelioma. Br J Cancer 87: 491–496, 2002.
■ Oxnard GR, Zhao B, Sima CS, Ginsberg MS, James LP, Lefkowitz RA, Guo P, Kris MG, Schwartz LH, Riely GJ: Variability of lung tumor measurements on repeat computed tomography scans taken within 15 minutes. J Clin Oncol 29: 3114–3119, 2011.
■ Armato SG III, Nowak AK, Francis RJ, Kocherginsky M, Byrne MJ: Observer variability in mesothelioma tumor thickness measurements: Defining minimally measurable lesions. Journal of Thoracic Oncology 9: 1187–1194, 2014.
■ Oxnard GR, Armato SG III, Kindler HL: Modeling of mesothelioma growth demonstrates weaknesses of current response criteria. Lung Cancer 52: 141–148, 2006.
■ Armato SG III, Oxnard GR, MacMahon H, Vogelzang NJ, Kindler HL, Kocherginsky M, Starkey A: Measurement of mesothelioma on thoracic CT scans: A comparison of manual and computer-assisted techniques. Medical Physics 31: 1105–1115, 2004.
■ Armato SG III, Oxnard GR, Kocherginsky M, Vogelzang NJ, Kindler HL, MacMahon H: Evaluation of semi-automated measurements of mesothelioma tumor thickness on CT scans. Academic Radiology 12: 1301–1309, 2005.
■ Sensakovic WF, Armato SG III, Starkey A, Ogarek JL: Automated matching of temporally sequential CT sections. Medical Physics 31: 3417–3424, 2004.
■ Armato SG III, Ogarek JL, Starkey A, Vogelzang NJ, Kindler HL, Kocherginsky M, MacMahon H: Variability in mesothelioma tumor response classification. American Journal of Roentgenology 186: 1000–1006, 2006.
■ Oxnard GR, Armato SG III, Kindler HL: Modeling of mesothelioma growth demonstrates weaknesses of current response criteria. Lung Cancer 52: 141–148, 2006.
■ Labby ZE, Armato SG III, Kindler HL, Dignam JJ, Hasani A, Nowak AK: Optimization of response classification criteria for patients with malignant mesothelioma. Journal of Thoracic Oncology 7: 1728–1734, 2012.
■ Schwartz LH, Bogaerts J, Ford R, Shankar L, Therasse P, Gwyther S, Eisenhauer EA: Evaluation of lymph nodes with RECIST 1.1. European Journal of Cancer 45: 261-267, 2009.
■ Miller AB, Hogestraeten B, Staquet M, Winkler A: Reporting results of cancer treatment. Cancer 47: 207–214, 1981. Labby ZE, Armato SG III, Dignam JJ, Straus C, Kindler HL, Nowak AK: Lung volume measurements as a surrogate marker for patient response in malignant pleural mesothelioma. Journal of Thoracic Oncology 8: 478–486, 2013.
■ de Perrot M, Dong Z, Bradbury P, Patsios D, Keshavjee S, Leighl NB, Hope A, Feld A, Cho J: Impact of tumour thickness on survival after radical radiation and surgery in malignant pleural mesothelioma. European Respiratory Journal 49: 1601428, 2017.
■ Nowak AK, Chansky K, Rice DC, Pass HI, Kindler HL, Shemanski L, Billé A, Rintoul RC, Batirel HF, Thomas CF, Friedberg J, Cedres S, de Perrot M, Rusch VW, the Staging and Prognostic Factors Committee, Advisory Boards and Participating Institutions: The IASLC Mesothelioma Staging Project: Proposals for revisions of the T descriptors in the forthcoming eighth edition of the TNM classification for pleural mesothelioma. Journal of Thoracic Oncology 11: 2089-2099, 2016.
■ Corson N, Sensakovic WF, Straus C, Starkey A, Armato SG III: Characterization of mesothelioma and tissues present in contrast-enhanced thoracic CT scans. Medical Physics 38: 942–947, 2011.
■ Gill RR, Naidich DP, Mitchell A, Ginsberg M, Erasmus J, Armato SG III, Straus C, Katz S, Pastios D, Richards WG, Rusch VW: North American multicenter volumetric CT study for clinical staging of malignant pleural mesothelioma: Feasibility and logistics of setting up a quantitative imaging study. Journal of Thoracic Oncology 11: 1335–1344, 2016.
■ Sullivan DC, Obuchowski NA, Kessler LG, Raunig DL, Gatsonis C, Huang EP, Kondratovich M, McShane LM, Reeves AP, Barboriak DP, Guimaraes AR, Wahl RL, RSNA-QIBA Metrology Working Group: Metrology standards for quantitative imaging biomarkers. Radiology 277:813–285, 2015.
■ Plathow C, Klopp M, Thieke C, et al. Therapy response in malignant pleural mesothelioma-role of MRI using RECIST, modified RECIST and volumetric approaches in comparison with CT. Eur Radiol. 2008;18:1635–1643.
■ 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;48:1449–1458.
■ Alley EW, Lopez J, Santoro A, Morosky A, Saraf S, Piperdi B, van Brummelen E: Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): Preliminary results from a non-randomised, open-label, phase 1b trial. Lancet Oncology 17: 30169-9, 2017.
■ Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, Lin NU, Litière S, Dancey J, Chen A, Hodi FS, Therasse P, Hoekstra OS, Shankar LK, Wolchok JD, Ballinger M, Caramella C, de Vries EGE, RECIST Working Group: iRECIST: Guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncology 18: e143– 52, 2017.
■ Ceresoli GL, Chiti A, Zucali PA, Rodari M, Lutman RF, Salamina S, Incarbone M, Alloisio M, Santoro A: Early response evaluation in malignant pleural mesothelioma by positron emission tomography with [18F]fluorodeoxyglucose. Journal of Clinical Oncology 24: 4587-4593, 2006.
■ Francis RJ, Byrne MJ, van der Schaaf AA, Boucek JA, Nowak AK, Phillips M, Price R, Patrikeos AP, Musk AW, Millward MJ: 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. Journal of Nuclear Medicine 48: 1449- 1458, 2007. Veit-Haibach P, Schaefer NG, Steinert HC, Soyka JD, Seifert B, Stahel RA: Combined FDG-PET/CT in response evaluation of malignant pleural mesothelioma. Lung Cancer 67: 311-317, 2010.
■ Genestreti G, Moretti A, Piciucchi S, Giovannini N, Galassi R, Scarpi E, Burgio MA, Amadori D, Sanna S, Poletti V, Matteucci F, Gavelli G: FDG PET/CT response evaluation in malignant pleural mesothelioma patients treated with talc pleurodesis and chemotherapy. Journal of Cancer 3: 241-245, 2012.
■ Kwek BH, Aquino SL, Fischman AJ: Fluorodeoxyglucose positron emission tomography and CT after talc pleurodesis. Chest 125: 2356-2360, 2004.
■ Nowak AK, Francis RJ, Phillips MJ, Millward MJ, van der Schaaf AA, Boucek J, Musk AW, McCoy MJ, Segal A, Robins P, Byrne MJ: A novel prognostic model for malignant mesothelioma incorporating quantitative FDG-PET imaging with clinical parameters. Clinical Cancer Research 16: 2409-2417, 2010