Home » Blog » Lawyer » Mesothelioma » DIAGNOSTIC AND THERAPEUTIC ASPECTS IN MALIGNANT Pleural mesothelioma

DIAGNOSTIC AND THERAPEUTIC ASPECTS IN MALIGNANT Pleural mesothelioma

2

162 3 Mesothelioma

Summary:

The diagnosis of mesothelioma requires a distinction between benign and malignant mesothelial involvement, and between malignant mesothelioma and metastatic carcinoma. For this, immunohistochemical techniques performed on large biopsies are necessary. Thoracoscopy is the technique of choice, although needle biopsy using real-time imaging techniques can be very useful if there is marked nodular thickening. Radical surgery (pleuropneumonectomy) is unlikely to be truly curative, so reduction of tumor mass by pleurectomy/decortication is gaining popularity, with the combination of chemotherapy and radiotherapy to surgery (multimodal therapy). When resection is not feasible, chemotherapy is considered, with pleurodesis or placement of a tunneled pleural catheter if control of the pleural effusion is required and radiation therapy is reserved to treat chest wall infiltration. Complete pain control (which takes on a particular role in this neoplasm) in specialized units is also essential.

Diagnosis of malignant pleural mesothelioma requires making the distinction between benign mesothelial hyperplasia and true mesothelioma, and between malignant mesothelioma and metastatic pleural adenocarcinoma. This involves immunohisto-chemical techniques applied on large biopsy specimens, and thoracoscopy is the best choice for obtaining them. A real-time image-guided needle biopsy can also be very helpful in presence of marked nodular pleural thickening. Radical surgery (ie, extrapleural pneumonectomy) is unlikely to cure completely the patient, and cytoreduction surgery with preservation of the underlying lung (pleurectomy/decortication), with the addition of chemo and radiation therapy (muiltimodal treatment), is gaining adepts in the last few years. When surgery is not feasible at all, early chemotherapy -with pleurodesis or placement of an indwelling pleural catheter (to control the effusion if necessary) – is advisable. Radiation therapy should be reserved to treat chest wall infiltration in those cases, and complete control of pain in specialized units is also essential in those patients.

INTRODUCTION

Mesothelioma was a rare tumor of the pleura until the first half of the 20th century and the uncertainty about its origin and histological characteristics meant that for years it was included in a group of tumors called “Endotheliomas” (whose origin was thought to be that resided in the endothelium of small vessels), and its mesodermal origin was later established. Since the 1950s, its association with asbestos ^{1 has been known} , particularly in its forms of “ blue asbestos ” (or crocidolite) and “ white asbestos ” ( chrysotile ), and its relationship with exposure is also well known. to erionite, which is a natural soil pollutant in various regions of the world, particularly in the Cappadocia region (Turkey), where a very high incidence of this tumor is observed, probably also associated with a certain genetic susceptibility ² . In approximately 80% of mesothelioma cases, there is a clear cause-effect relationship with occupational exposure to asbestos, with a wide spectrum of professions involved ³ . Possible environmental exposure must also be taken into account, generally due to proximity to mines or factories where the mineral is handled or due to contamination through the clothing of asbestos workers ⁴. A dose-response relationship has been demonstrated between cumulative exposure to asbestos (high levels of exposure, duration of exposure, or both) and malignant mesothelioma, and there is no threshold below which the risk of contracting the disease is ruled out 5 , 6 , 7 . Mesothelioma can appear in any of the structures of embryonic mesodermal origin (pleura, pericardium, peritoneum, “tunica vaginalis” and others) but the most frequent presentation -in more than 90% of cases- is pleural. However, its incidence is relatively low, ranging from seven cases per million inhabitants/year in Japan to 40 in Australia, depending mainly on the exposure to asbestos that has occurred in past decades in those countries.⁸ . In Europe, the incidence is estimated at 20 cases per million / year, with notable variation between countries (also in relation to the history of exposure to asbestos in the past), but in any case a global increase is expected, based on the long period latency between exposure and manifestation of the disease, which is around 40 years, with a wide margin between extreme values ​​(up to 75 years in the series by Bianchi et al.) ⁹ . Based on the consumption of asbestos, it has been estimated that the peak of maximum incidence of mesothelioma will be registered around the year 2020 in Europe, with marked differences between countries ¹⁰ .

DIAGNOSIS OF MALIGNANT PLEURAL MESOTHELIOMA

The initial symptoms of mesothelioma are usually of little clinical relevance, with the appearance of imprecise and persistent chest pain with little relation to respiratory movements. On occasions, dyspnea may occur, generally related to the presence of pleural effusion, and in early clinical stages, weight loss or any other symptoms are rare; Later, marked retraction of the hemithorax usually appears, and the pain acquires special intensity and persistence.

Imaging techniques for the diagnosis of pleural mesothelioma

First of all, chest radiography can provide us with information on the presence of diffuse pleural effusion and thickening or masses, but computed tomography (CT) – preferably with contrast – is essential for choosing the diagnostic steps to follow: thickening and diffuse pleural mesothelioma suggests nodular prominences, especially in a patient with a history of previous exposure to asbestos in all its forms ¹¹ . On the other hand, it has been suggested that the estimation of tumor volume by CT may be important for making therapeutic decisions ¹² . The nuclear magnetic resonance(NMR) provides a better contrast than CT for defining the invasion of the chest wall, but can not reliably detect the presence of metastatic disease in other parts ¹³ . On the other hand, CT is not very sensitive to assess a possible mediastinal lymph node involvement – which has a relevant prognostic value 14 , 15 – or the existence of contralateral or peritoneal pleural involvement. To investigate these aspects – and the presence of possible distant metastases – positron emission tomography ( PET ) is much more useful , especially when combined with CT (PET-CT) ¹⁶. PET-CT plays an important role in the preoperative staging of malignant pleural mesothelioma with a view to prognosis, 17 , 18 in the assessment of response to treatment and in the detection of possible recurrences, ¹⁹ but its sensitivity is relatively low for detecting disease N2 in this disease ²⁰ . On the other hand, false positives of PET can be seen in tuberculous pleurisy ²¹ , empyema ²² or in patients with a history of previous pleurodesis ²³ . In any case, the combination of several techniques can provide valuable information to establish the prognosis and the best therapeutic strategy ²⁴ .

Study of pleural fluid in mesothelioma

Thoracentesis can provide some suggestive -but rarely diagnostic- data of mesothelioma: high levels of hyaluronic acid ( > 100,000 ng / ml) are highly suggestive of malignant pleural mesothelioma ²⁵ , and a marked prognostic value is also attributed to this parameter, of Thus, a high hyaluronic acid is associated with better survival ²⁶ .

Elevated LDH values in pleural fluid have been correlated with a worse prognosis, ²⁷ with 500 U / L as cut-off point, but pH and glucose in pleural fluid seem to be more relevant : Low pH and glucose have been associated with shorter survival in carcinomatous pleural effusions 28 , 29 , 30 , 31 and also have prognostic value in mesotheliomas. It is important to note that pleural pH and glucose are significantly lower in mesotheliomas than in metastatic carcinomas, as can be seen in our series of malignant pleural effusions submitted to thoracoscopy (see Table 1 ).

Table 1 . Comparison between mesotheliomas and metastatic pleural carcinomas in our series of patients with malignant pleural effusion who underwent thoracoscopy.

(*) Data are presented as mean ± standard error of the mean.

(**) The quantification of tumor involvement was carried out following the methodology previously described by our Group (reference 30).

Adenosine deaminase (ADA) levels may be elevated in patients with mesothelioma ³² , but -before labeling them as false positives of the ADA- it must be taken into account that malignant mesothelioma and tuberculous pleurisy can sometimes coexist, and therefore it is recommended culture for M. tuberculosis in these cases ³³ .

The cytology of pleural fluid may suggest the presence of mesothelioma, but often poses problems between mesothelial hyperplasia benign and malignant ³⁴ and is also unable to demonstrate the invasiveness of the tumor (which is currently considered an essential feature for definitive diagnosis) ³⁵ . However, in most cases they can be combined cytology and imaging techniques to evaluate the invasion Extrapleural ³⁶ . On the other hand, immunocyte / histochemical techniques are always necessary to establish the distinction between mesothelioma and metastatic adenocarcinoma in the pleura ³⁷This requires tissue obtained by biopsy, or cell blocks prepared by inclusion of the cell button in paraffin after centrifugation of a sufficient volume of pleural fluid ( > 100  ml). The combination of all the following assumptions can provide the diagnosis of mesothelioma with sufficient reliability: atypical mesothelial proliferation in the pleural fluid + immunohistochemical studies compatible with mesothelioma in cell blocks + diffuse pleural thickening with nodulations + absence of masses in the lung or any other organ that suggest another primary tumor ³⁸. However , and especially the legal implications involved in the diagnosis of malignant mesothelioma in most cases and also when surgery poses, try to always get large tissue samples to establish more securely the tumor ³⁹ .

Histological aspects of malignant pleural mesothelioma

Epithelioid , sarcomatous, and biphasic types are distinguished in malignant pleural mesothelioma, but there are also rare subtypes, such as desmoplastic mesothelioma (which can be confused with benign fibrous pleurisy), small cell mesothelioma, and lymphohistiocytoid mesothelioma(which could be confused with a lymphoma), and immunohistochemical studies are key to distinguish between them. However, there is no marker with 100% sensitivity and specificity for mesothelioma and therefore it is essential to go to different panels of monoclonal antibodies, including at least two positive markers for mesothelioma, in the epithelioid subtype, calretinin would be preferable (particularly useful if it stains nucleus, in addition to the cytoplasm), WT-1, (Wilms tumor antigen 1) or EMA (epithelial membrane antigen) or broad-spectrum, low-molecular-weight cytokeratins , such as CK5 or CK6 – and two negative markers, such as Ber-EP4 (membrane marker) and TTF-1 ( thyroid transcription factor 1, nuclear marker). CEA ( carcinoembryonic antigen ) is very useful to distinguish metastatic carcinoma -especially of pulmonary origin- from mesothelioma (in which it is practically always negative), and in case of suspected mesothelioma in women it is convenient to also test the expression of ER ( endoplasmic reticulum ), which never appears in mesothelioma and does appear in metastatic breast tumors (see Table 2 ). When the tumor has a sarcomatous component, it is often necessary to distinguish it from metastatic tumors, such as squamous cell lung or transitional cell carcinoma. Although some of the antibodies used for epithelial mesothelioma are useful here, you often have to rely on different ones, such as p63 and MOC 31 (SeeTable 3 ).

Table 2 . Markers to differentiate epithelioid mesothelioma from other metastatic pleural tumors with immunohistochemical techniques

(WT-1 = Wilms tumor antigen 1, EMA = Epithelial membrane antigen, CEA = Carcinoembryonic antigen, TTF-1 = Thyroid transcription factor-1, ER = Endoplasmic reticulum marker). (Adapted from Scherpereel et al, reference 39) (See text).

Table 3 . Markers to differentiate sarcomatoid mesothelioma from other metastatic pleural tumors using immunohistochemical techniques

(WT-1 = Wilms tumor antigen 1) (Adapted from Scherpereel et al, reference 39) (See text).

Performance of pleural needle biopsy and thoracoscopy in the diagnosis of mesothelioma

The “blind” pleural biopsy (without the use of real-time imaging techniques) is unsatisfactory for the diagnosis of mesothelioma, not only due to the lack of control regarding the exact point from which the samples are obtained, but also due to the small size of these ⁴⁰ . When there is diffuse nodular pleural thickening, the performance of needle biopsy can be considerably improved if performed with the help of CT 41 , 42 or real-time ultrasound ⁴³ . Thoracoscopy (or pleuroscopy ) is much more cost-effective because it allows the collection of more and larger samples, it can be performed under local anesthesia and intravenous analgesia / sedation ⁴⁴, and we have diagnosed more than 80 pleural mesotheliomas with this method ⁴⁵ . VATS ( “video-assisted thoracoscopic surgery” ) allows better staging of the tumor (especially in the mediastinal area) and even pleurectomy / decortication in selected cases, but requires more resources, including general anesthesia and tracheal intubation ⁴⁶ . The performance of pleuroscopy (also called “medical thoracoscopy”) is suboptimal in mesothelioma with a sarcomatous component ⁴⁷ , and therefore it is preferable to obtain more representative samples by VATS or mini-thoracotomy ⁴⁸ .

Early diagnosis in malignant pleural mesothelioma

One of the main challenges we face in mesothelioma lies in the fact that, although we have identified the population at risk (individuals exposed in one way or another to asbestos), we lack the tools to achieve a sufficiently early diagnosis that allows apply radical treatment. This implies the need for biomarkers capable of detecting the disease before effusion or diffuse pleural thickening develops, and for now there are also no imaging techniques with sufficient sensitivity and specificity to achieve this objective.

Study of biomarkers in malignant pleural mesothelioma

The biomarker that has received the most attention in recent years is soluble mesothelin , which is closely correlated with tumor size and progression in epithelioid mesothelioma (non-sarcomatous, in which it is usually negative) ⁴⁹ . However, their values are influenced by renal function, and one of its biggest problems lies in the choice of a suitable cutting point to distinguish between benign and malignant pleural involvement ⁵⁰. In any case, it seems clear that mesothelin levels are more useful in pleural fluid than in serum, and this greatly limits its value for early diagnosis in subjects with a history of asbestos exposure but who do not present with pleural effusion. Given a low pre-test probability of suffering from mesothelioma, low levels of mesothelin can help to rule it out, while high levels reinforce the use of more invasive diagnostic techniques in a patient with suspected mesothelioma 51 , 52 , 53 . In any case, it seems that mesothelin is more useful for monitoring treatment than for differential diagnosis in pleural effusions ⁵⁴ .

Trying to overcome the problems of mesothelin and other markers, it has been recently published that fibulin-3 is able to distinguish between healthy people with a history of exposure to asbestos and patients with mesothelioma, and even between mesothelioma and other malignant or benign processes of pleura ⁵⁵. These excellent initial results have not been revalidated by another study recently carried out in Australia – a country with a high prevalence of mesothelioma – and in which mesothelin and fibulin-3 values ​​were compared in the same plasma and pleural fluid samples. In this study, a better diagnostic performance of mesothelin over fibulin-3 was confirmed, which did show a good predictive value of survival when its values ​​were high in the pleural fluid of patients with mesothelioma, especially in the sarcomatous or mixed ⁵⁶ .

THERAPEUTIC PERSPECTIVES OF MALIGNANT PLEURAL MESOTHELIOMA

Mesothelioma tends to have a poor response to chemotherapy and radiotherapy, and surgery is rarely curative, because the tumor is generally diagnosed too late, and therefore the careful evaluation of each patient before choosing the best treatment is especially important. If radical surgery is being considered, it is critical to assess lung and heart function, the presence of other comorbidity factors, and the physical and psychological state of the patient. The choice between the different therapeutic options is dictated by the clinical situation and the tumor extension studies (TNM) using imaging techniques. However, none of the currently available techniques is accurate enough to ensure the “T” and “N” in malignant pleural mesothelioma.⁵⁷ . Until a more robust TNM staging is achieved, it is advisable to follow that established by the UICC (“ Union Internationale contre le Cancer ”) ⁵⁸ (see Table 4 ).

Table 4 . TNM staging of malignant pleural mesothelioma

(Adapted from van Meerbeeck et al, reference 58).

Surgical Treatment

The principal goal of surgery is resected macroscopically throughout the tumor, thereby assuming better survival is obtained, and patients in which residues are macroscopically visible tumor survival is less ⁵⁹ . However, the currently accumulated evidence suggests that it is not possible to achieve a complete resection (macro and microscopic) in malignant pleural mesothelioma, regardless of the surgical technique that is applied and for this reason it is accepted today that the surgery is basically oriented to local control the disease, eliminate the pleural effusion, free the lung trapped by the tumor, improve ventilation / perfusion disorders and alleviate pain caused by invasion of the chest wall ⁶⁰. All these considerations apply especially to epithelioid type mesothelioma, since the sarcomatous or biphasic component has a worse prognosis and is consequently a worse candidate for any type of surgery ⁵⁷ .

Pleuropneumonectomy

It involves en bloc resection of the lung and parietal pleura, and is usually completed with pericardial and diaphragm resection on that side, in addition to systematic dissection of the mediastinal ganglion chains. Although perioperative mortality is around 5% in centers with extensive experience, it has high morbidity, including cardiac and respiratory complications (which may acquire special relevance due to the one-lung situation in which the patient remains after this intervention), bronchopleural fistula, empyema and bleeding, among others 61 , 62 . In any case, and due to the usual persistence of macro or microscopic tumor residues, this intervention must be considered within the framework of multimodal therapy, which is supported by the combined use of surgery, chemotherapy and radiotherapy ⁶³ . Occasionally hyperthermia – combined with chemotherapy – or local photodynamic therapy ⁶⁴ has also been used . In many protocols multimodal therapy chemotherapy given as induction therapy before surgery (neoadjuvant chemotherapy), and after resection radiation is applied on the affected hemithorax ⁶⁵ . However, the most recent clinical guidelines recommend ruling out surgery if progress of the disease is observed after neoadjuvant chemotherapy and, in any case, recommend that extrapleural pneumonectomy be performed only in the context of well-controlled clinical trials and by groups specialized in this technique 38, 39 .

Pleurectomy / decortication

Although it is associated with a greater risk of local recurrence than pleuropneumonectomy, it presents fewer complications than that ⁶⁶ , and is mainly aimed at freeing the lung and the chest wall from the constriction caused by the tumor. Patients with macroscopic diffuse presence of tumor in the parietal pleura, but only focal in the visceral, are the best candidates for this type of surgery. It can be performed using VATS , which has the advantage of minimizing the morbidity associated with thoracotomy 67 , 68 and pleurodesis can be done in the same act if complete resection is not feasible.

Although extrapleural pneumectomy is a more radical approach, its advantages over pleurectomy / decortication have been widely questioned in recent years 69 , 70 and in a recent randomized study in the United Kingdom (MARS study, “ Mesothelioma and Radical Surgery ”) The superiority of one over the other was not demonstrated ⁷¹ . On the other hand, the MARS study has been harshly criticized for the significant deviations that occurred from the protocol initially proposed and for the number of patients who were eventually included in each of the study branches ⁷². In any case, and although for some groups with extensive experience in both techniques it is considered inappropriate to leave macroscopically visible remains of the tumor (which leads to a worse prognosis), the idea of resecting the largest possible volume of the tumor while preserving the tumor is gaining adherents. underlying lung and in any case combining surgery with chemotherapy and radiotherapy, within the framework of trimodal therapy ⁷³ .

Radiation therapy in malignant pleural mesothelioma

Radical radiotherapy applied to an entire hemithorax is seriously limited by the risk of damaging critical organs such as the lung, liver, heart, spinal cord and esophagus, and to alleviate this, application techniques are being optimized ⁷⁴ , although there is no convincing evidence that alone prolongs the survival of patients with mesothelioma ⁷⁵ . On the other hand, palliative radiotherapy plays an important role in controlling pain caused by infiltration of the chest wall 76 , 77 . Classically, prophylactic radiotherapy has been recommended to avoid tumor seeding in thoracoscopy or thoracotomy scars 78 , 79but this practice is not supported by the available evidence and is currently discouraged 38 , 39 .

Chemotherapy, immunotherapy and other personalized therapies

Recent clinical guidelines recommend not delaying the administration of chemotherapy and it should be taken into consideration before functional deterioration of the patient appears 38 , 39 . The combination of several agents (including pemetrexed and platinum compounds) generally produces better results than monotherapy 80 , 81 . The current trend is aimed at investigating new therapeutic targets focused on controlling angiogenesis and apoptotic pathways through specific ligands, including PDGF (“ platelet derived growth factor ”, which is overexpressed quite frequently in mesothelioma and is associated with worse survival) and mesothelin(which is expressed only in the epithelial subtype) among others 82 , 83 . Also within multimodal therapy, immunotherapy can play an important role in the treatment of mesothelioma, because this tumor is capable of evading the immune system through T-regulatory cells ( Treg ) and M2 macrophages. For this reason, new therapeutic strategies that combine surgical cytoreduction, chemotherapy, immunotherapy and radiotherapy could achieve better control of the disease ⁸⁴. From passive immunotherapy (using specific cytokines or antibodies) to modulation of the immune response by dendritic cells or others, there is a wide spectrum of possibilities to achieve markedly synergistic antitumor effects 85 , 86 , 87 .

Pleurodesis

Control of pleural effusion is a priority in most patients with pleural tumors, including mesothelioma and talc pleurodesis may be a good option. However, in our experience, more pleurodesis failures tend to occur in this tumor than in others (see Table 5 ) and there are possible explanations for this:-

Difficulty adequately re-expanding the lung, cloistered by the tumor ⁸⁸ . Thus, previous studies by our Group show that the extension of the tumor in the pleural cavity has a negative influence on pleurodesis ⁸⁹ . The degree of involvement of the visceral pleura -which implies greater difficulty for lung re-expansion- is related in our series of malignant pleural effusions with the result of pleurodesis (see Table 5 ) and we observed a close correlation between this involvement and the pH of the pleural fluid (r = -0.402, p < 0.001), so that a low pH makes it more likely that the visceral pleura is diffusely affected.-

In addition to mechanical factors, it is likely that other biological factors not well known to date also influence pleurodesis. For several decades, low pH in pleural fluid has been associated with a worse prognosis in mesotheliomas ⁹⁰ -and also in other tumors- and with a worse response to any pleurodesis attempt ⁹¹ , although the biological mechanisms involved are not clear. In recent years, much attention has been paid to the regulation of intra and extracellular pH in tumors, especially in the most aggressive 92 , 93 , 94 and it seems that an acid extracellular pH (which is closely related to a context of tissue hypoxia) ⁹⁵it facilitates tumor aggressiveness through hypoxia-inducible factor-1 (HIF-1), whose over-expression triggers a series of suppressive mechanisms of apoptosis in tumor cells ⁹⁶ . The aquaporin-1 seems to be involved in regulation of this process ⁹⁷ and are already proposed some initiatives based on these new therapeutic targets ⁹⁸ .-

On the other hand, and according to recent experiments carried out ” in vitro ” by our Group, malignant mesothelial cells are more resistant to the action of talc than other cell lines, and this is evidenced both in the modulation / blocking of angiogenesis and in cell proliferation (unpublished data).

Table 5 . Differences Between Mesotheliomas and Metastatic Pleural Carcinomas in Our Series of Patients With Malignant Pleural Effusion Undergoing Thoracoscopy and Talc Pleurodesis

(*) Pleurodesis results: B (good) = Control of the pleural effusion during the entire follow-up of the patients, M (bad) = Recurrence of the pleural effusion at any time during the follow-up, requiring repeated evacuations. Partial = Recurrence of the pleural effusion at any time during the follow-up of the patients, but with a volume lower than that which existed prior to pleurodesis and without requiring evacuation. The pleurodesis results were significantly worse in mesotheliomas than in metastatic pleural carcinomas.

(**) The pH and pleural glucose were significantly higher in cases with effective pleurodesis (B), both in mesotheliomas and in metastatic carcinomas.

(***) The involvement of the visceral pleura was significantly less in the cases with a good pleurodesis result in both groups of tumors.

When pleurodesis fails, or if it is considered unlikely due to the presence of a lung massively trapped by the tumor, the best option is the insertion of a tunnelled pleural catheter , which allows the home evacuation of pleural fluid and induces spontaneous pleurodesis in a considerable proportion of cases 99 , 100 , 101 , 102 .

It is important to note that the performance of previous pleurodesis does not preclude surgical resection in the case of mesothelioma, regardless of the technique used (extrapleural pneumonectomy or pleurectomy / decortication) ⁶⁰ .

CONCLUSIONS AND FUTURE PERSPECTIVES

From what has been explained so far, it is clear that the diagnosis of malignant pleural mesothelioma is generally made too late to be able to apply a curative treatment, since in the vast majority of cases the surgery does not manage to eliminate all the tumor tissue and on the other hand part of the tumor is not very sensitive to chemo and radiotherapy. Therefore, there is a need to develop more sensitive and specific imaging techniques and biomarkers than those available up to now, and it is also necessary to optimize the therapeutic options, with the ultimate goal of completely eliminating the tumor in all its locations.

At the present time, it seems that the most realistic thing would be to search for detectable markers in peripheral blood -especially in people with a history of occupational or environmental exposure to asbestos- and who have adequate sensitivity and specificity to detect malignant mesothelioma early. Within this line, the most promising field of research is oriented – together with the development of better imaging techniques – to the exhaustive search for markers using proteomic techniques , which simultaneously analyze the profiles of a large number of proteins (more than 1000) and they will allow the preparation of panels configured to achieve the maximum diagnostic sensitivity and specificity 103 , 104 .

In recent years, intensive work has been done on gene expression studies in mesothelioma ¹⁰⁵ , and considerable emphasis is placed on the expression of certain proteins such as aquaporin-1 , which is related to the selective transport of water through the membrane and to cell proliferation 106 , 107 , 108 , and the study of micro-RNAs (miRNAs) in mesothelioma also stands out. MiRNAs are short RNAs (17 to 22 nucleotides) that do not encode proteins, which regulate gene expression and play an important role in oncogenesis ¹⁰⁹. They have high tissue specificity to detect the origin of a tumor and to distinguish mesothelioma other metastatic tumors of the pleura ¹¹⁰ . On the other hand, the detection of miRNAs in peripheral blood could make them excellent markers of mesothelioma in the near future ¹¹¹ .

In many cases, the use of gene therapy in mesothelioma has been considered to compensate for the limited efficacy of immunotherapy when the tumor is locally very advanced. To do this, different strategies are used, such as the use of “suicide genes” (which transfer to the tumor the ability to become sensitive to certain drugs), the administration of oncosuppressive genes or the transfer of immunomodulatory genes to the pleural space 112 , 113 , 114 , 115. Although its clinical application has so far obtained rather disappointing results, largely due to problems related to the vectors used and their relative inefficiency in controlling a large tumor mass, it is very likely that the inclusion of gene therapy in the multimodal strategy and its combination nanotechnology-based techniques contribute very significantly to improve the treatment prospects for malignant pleural mesothelioma in the future. Combining molecular biology and nanotechnology techniques, the concept of “ theranostics”, Which aims to combine diagnosis and treatment in the same procedure through the use of drugs specifically directed to each neoplasm phenotype. If the right ligands could be found, they could be applied for the early diagnosis of mesothelioma using PET or SPECT ( single photon emission computed tomography ) 116 , 117 , 118 . Probes combined with highly sensitive biofluorescent techniques have already been developed that are capable of detecting tumors in animal models 119 , 120 , and there are also techniques based on labeled antibodies, combined or not with nanoparticles, for use with nuclear magnetic resonance 121, 122 . All this presents a stimulating horizon for its application in humans in the not too distant future.

The author declares no conflicts of interest in relation to this article.

BIBLIOGRAPHIC REFERENCES

1JC Wagner , CA Sleggs , P. MarchandDiffuse pleural mesothelioma and asbestos exposure in the North Western Cape ProvinceBr J Ind Med , 17 ( 1960 Oct ) , pp. 260 – 271 View PDFCrossRefView Record in ScopusGoogle Scholar2I. Roushdy-Hammady , J. Siegel , S. Emri , et al.Genetic-susceptibility factor and malignant mesothelioma in the Cappadocian region of TurkeyLancet , 357 ( 2001 ) , pp. 444 – 445ArticleDownload PDFView Record in ScopusGoogle Scholar3I. Isidro Montes , K. Abu Shams , E. Alday , et al.Regulations on asbestos and its pleuropulmonary diseasesArch Bronconeumol , 41 ( 3 ) ( 2005 ) , pp. 153 – 168ArticleDownload PDFView Record in ScopusGoogle Scholar4J. Tarrés , R. Abós-Herrándiz , C. Albertí , et al.Asbestos disease in a town near a fiber cement factoryArch Bronconeumol , 45 ( 9 ) ( 2009 ) , pp. 429 – 434ArticleDownload PDFView Record in ScopusGoogle Scholar5Y. Iwatsubo , JC Pairon , C. Boutin , et al.Pleural mesothelioma: dose-response relation at low levels of asbestos exposure in a French population-based case-control studyAm J Epidemiol , 148 ( 1998 ) , pp. 133 – 142 View PDFCrossRefGoogle Scholar6G. Hillerdal , Mesothelioma:cases associated with non-occupational and low dose exposuresOccup Environ Med , 56 ( 1999 ) , pp. 505 – 513 View PDFCrossRefView Record in ScopusGoogle Scholar7M. Goldberg , D. LuceCan exposure to very low levels of asbestos induce pleural mesothelioma?Am J Respir Crit Care Med , 172 ( 8 ) ( 2005 Oct 15 ) , pp. 939 – 940 View PDFCrossRefView Record in ScopusGoogle Scholar8RT Lin , K. Takahashi , A. Karjalainen , et al.Ecological association between asbestos-related diseases and historical asbestos consumption: an international analysisLancet , 369 ( 2007 ) , pp. 844 – 849ArticleDownload PDFView Record in ScopusGoogle Scholar9C. Bianchi , T. Bianchi , S. BucconiMalignant mesothelioma of the pleura in nonagenarian patientsTumori Mar-Apr , 97 ( 2 ) ( 2011 ) , pp. 156 – 159 View PDFCrossRefView Record in ScopusGoogle Scholar10BW Robinson , RA LakeAdvances in malignant mesotheliomaN Engl J Med , 353 ( 2005 ) , pp. 1591 – 1603View Record in ScopusGoogle ScholarelevenZJ Wang , GP Reddy , MB Gotway , et al.Malignant pleural mesothelioma: evaluation with CTMR imaging, and PET Radiographics , 24 ( 2004 ) , pp. 105 – 119 View PDFCrossRefView Record in ScopusGoogle Scholar12RR Gill , WG Richards , BY Yeap , et al.Epithelial malignant pleural mesothelioma after extrapleural pneumonectomy: stratification of survival with CT-derived tumor volumeAJR , 198 ( 2012 ) , pp. 359 – 363 View PDFView Record in ScopusGoogle Scholar13C. Plathow , A. Staab , A. Schmaehl , et al.Computed tomography, positron emission tomography, positron emission tomography / computed tomography, and magnetic resonance imaging for staging of limited pleural mesothelioma: initial resultsInvest Radiol , 43 ( 2008 ) , pp. 737 – 744View Record in ScopusGoogle Scholar14DJ Sugarbaker , RM Flores , MT Jaklitsch , et al.Resection margins, extrapleural nodal status and cell type determine postoperative long term survival in trimodality therapy of malignant pleural mesothelioma: results in 183 patientsJ Thorac Cardiovasc Surg , 117 ( 1999 ) , pp. 54 – 65ArticleDownload PDFView Record in ScopusGoogle ScholarfifteenRM Flores , T. Routledge , VE Seshan , et al.The impact of lymph node station on survival in 348 patients with surgically resected malignant pleural mesothelioma: implications for revision of the American Joint Committee on Cancer staging systemJ Thorac Cardiovasc Surg , 136 ( 2008 ) , pp. 605 – 610ArticleDownload PDFCrossRefView Record in ScopusGoogle Scholar16S. Sharif , I. Zahid , T. Routledge , et al.Does positron emission tomography offer prognostic information in malignant pleural mesothelioma?Interact Cardiovasc Thorac Surg , 12 ( 2011 ) , pp. 806 – 811 View PDFCrossRefGoogle Scholar17RM Flores , T. Akhurst , M. Gonen , et al.Positron emission tomography predicts survival in malignant pleural mesotheliomaJ Thorac Cardiovasc Surg , 132 ( 2006 ) , pp. 763 – 768ArticleDownload PDFCrossRefView Record in ScopusGoogle Scholar18Klabatsa A1 , S. Chicklore , SF Barrington , V. Goh , L. Lang-Lazdunski , GJ CookThe association of 18F-FDG PET / CT parameters with survival in malignant pleural mesotheliomaEur J Nucl Med Mol Imaging , 41 ( 2 ) ( 2014 ) , pp. 276 – 282FebGoogle Scholar19S. Basu , B. Saboury , DA Torigian , A. AlaviCurrent evidence base of FDG-PET / CT imaging in the clinical management of malignant pleural mesothelioma: emerging significance of image segmentation and global disease assessmentMol Imaging Biol , 13 ( 2011 ) , pp. 801 – 811 View PDFCrossRefView Record in ScopusGoogle ScholartwentyI. Zahid , S. Sharif , T. Routledge , et al.What is the best way to diagnose and stage malignant pleural mesothelioma?Interact Cardiovasc Thorac Surg , 12 ( 2011 ) , pp. 254 – 259 View PDFCrossRefView Record in ScopusGoogle Scholartwenty-oneT. Shinohara , N. Shiota , M. Kume , N. Hamada , K. Naruse , F. OgushiAsymptomatic primary tuberculous pleurisy with intense 18-fluorodeoxyglucose uptake mimicking malignant mesotheliomaBMC Infect Dis , 13 ( 2013 ) , p. 12Jan 14 View PDFView Record in ScopusGoogle Scholar22Y. Abe , K. Tamura , I. Sakata , et al.Usefulness of (18) F-FDG positron emission tomography / computed tomography for the diagnosis of pyothorax-associated lymphoma: A report of three casesOncol Lett , 1 ( 5 ) ( 2010 ) , pp. 833 – 836Sep View PDFCrossRefView Record in ScopusGoogle Scholar2. 3T. Vandemoortele , S. Laroumagne , E. Roca , et al.Positive FDG-PET / CT of the pleura twenty years after talc pleurodesis: Three cases of benign talcomaRespiration , 87 ( 3 ) ( 2014 ) , pp. 243 – 248 View PDFCrossRefView Record in ScopusGoogle Scholar24SG Armato , ZE Labby , J. Coolen , et al.Imaging in pleural mesothelioma: a review of the 11th International Conference of the International Mesothelioma Interest GroupLung Cancer , 82 ( 2 ) ( 2013 ) , pp. 190 – 196Nov, 3rdArticleDownload PDFView Record in ScopusGoogle Scholar25N. Fujimoto , K. Gemba , M. Asano , et al.Hyaluronic acid in the pleural fluid of patients with malignant pleural mesotheliomaRespir Investig , 51 ( 2013 ) , pp. 92 – 97ArticleDownload PDFView Record in ScopusGoogle Scholar26J. Creaney , IM Dick , A. Segal , AW Musk , BW RobinsonPleural effusion hyaluronic acid as a prognostic marker in pleural malignant mesotheliomaLung Cancer , 82 ( 2013 ) , pp. 491 – 498ArticleDownload PDFView Record in ScopusGoogle Scholar27JE Herndon , MR Green , AP Chahinian , et al.Factors predictive of survival among 337 patients with mesothelioma treated between 1984 and 1994 by the Cancer and Leukemia Group BChest , 113 ( 1998 ) , pp. 723 – 731ArticleDownload PDFCrossRefView Record in ScopusGoogle Scholar28SA Sahn , JT GoodPleural fluid pH in malignant effusions: diagnostic, prognostic, and therapeutic implicationsAnn Intern Med , 108 ( 1988 ) , pp. 345 – 349 View PDFCrossRefView Record in ScopusGoogle Scholar29F. Rodriguez-Panadero , J. Lopez-MejiasSurvival time of patients with pleural metastatic carcinoma predicted by glucose and pH studiesChest , 95 ( 2 ) ( 1989 ) , pp. 320 – 324FebArticleDownload PDFCrossRefView Record in ScopusGoogle Scholar30A. Sanchez-Armengol , F. Rodriguez-PanaderoSurvival and talc pleurodesis in metastatic pleural carcinoma, revisitedReport of 125 cases Chest , 104 ( 5 ) ( 1993 Nov ) , pp. 1482 – 1485ArticleDownload PDFCrossRefView Record in ScopusGoogle Scholar31Fysh ET, Bielsa S, Budgeon CA, et al. Predictors of Clinical Use of Pleurodesis and / or Indwelling Pleural Catheter Therapy for Malignant Pleural Effusion. Chest. 2014 Dec 4. doi: 10.1378 / chest.14-1701. [Epub ahead of print].Google Scholar32Y. Ogata , K. Aoe , A. Hiraki , et al.Is adenosine deaminase in pleural fluid a useful marker for differentiating tuberculosis from lung cancer or mesothelioma in Japan, a country with intermediate incidence of tuberculosis?Acta Med Okayama , 65 ( 2011 ) , pp. 259 – 263Google Scholar33F. Rodríguez-Panadero , MA Pérez , MA Moya , MI CruzManagement of pleural pathologyArch Bronconeumol , 45 ( Suppl 3 ) ( 2009 ) , pp. 22 – 27ArticleDownload PDFView Record in ScopusGoogle Scholar3. 4DW Henderson , KB Shilkin , D. WhitakerReactive mesothelial hyperplasia vs mesothelioma, including mesothelioma in situ: a brief reviewAm J Clin Pathol , 110 ( 1998 ) , pp. 397 – 404 View PDFCrossRefView Record in ScopusGoogle Scholar35DW Henderson , G. Reid , SC Kao , N. van Zandwijk , S. KlebeChallenges and controversies in the diagnosis of mesothelioma: Part 1 Cytology-only diagnosis, biopsies, immunohistochemistry, discrimination between mesothelioma and reactive mesothelial hyperplasia, and biomarkersJ Clin Pathol , 66 ( 2013 ) , pp. 847 – 853 View PDFCrossRefView Record in ScopusGoogle Scholar36British Thoracic Society Standards of Care Committee BTS statement on malignant mesothelioma in the UK, 2007. Thorax. 2007; 62Suppl 2: ii1-ii19.Google Scholar37AN Husain , T. Colby , N. Ordonez , et al.Guidelines for pathologic diagnosis of malignant mesothelioma: 2012 update of the consensus statement from the International Mesothelioma Interest GroupArch Pathol Lab Med , 137 ( 2013 ) , pp. 647 – 667View Record in ScopusGoogle Scholar38N. van Zandwijk , C. Clarke , D. Henderson , et al.Guidelines for the diagnosis and treatment of malignant pleural mesotheliomaJ Thorac Dis , 5 ( 2013 ) , pp. E254 – E307 View PDFView Record in ScopusGoogle Scholar39A. Scherpereel , P. Astoul , P. Baas , et al.Guidelines of the European Respiratory Society and the European Society of Thoracic Surgeons for the management of malignant pleural mesotheliomaEur Respir J , 35 ( 2010 ) , pp. 479 – 495 View PDFCrossRefView Record in ScopusGoogle Scholar40RL Attanoos , AR GibbsThe comparative accuracy of different pleural biopsy techniques in the diagnosis of malignant mesotheliomaHistopathology , 53 ( 2008 ) , pp. 340 – 344 View PDFCrossRefView Record in ScopusGoogle Scholar41NA Maskell , FV Gleeson , RJ DaviesStandard pleural biopsy versus CT-guided cutting-needle biopsy for diagnosis of malignant disease in pleural effusions: a randomized controlled trialLancet , 361 ( 2003 ) , pp. 1326 – 1330ArticleDownload PDFView Record in ScopusGoogle Scholar42M. Metintas , G. Ak , E. Dundar , H. Yildirim , R. Ozkan , E. Kurt , et al.Medical thoracoscopy vs CT scan-guided Abrams pleural needle biopsy for diagnosis of patients with pleural effusions: a randomized, controlled trialChest , 137 ( 2010 ) , pp. 1362 – 1368ArticleDownload PDFCrossRefView Record in ScopusGoogle Scholar43JA Stigt , JE Boers , HJ GroenAnalysis of “dry” mesothelioma with ultrasound guided biopsiesLung Cancer , 78 ( 2012 ) , pp. 229 – 233ArticleDownload PDFView Record in ScopusGoogle Scholar44AR Medford , S. Agrawal , CM Free , JA BennettA local anesthetic video-assisted thoracoscopy service: prospective performance analysis in a UK tertiary respiratory centerLung Cancer , 66 ( 2009 ) , pp. 355 – 358ArticleDownload PDFView Record in ScopusGoogle ScholarFour. FiveF. Rodríguez-PanaderoMedical thoracoscopyRespiration , 76 ( 2008 ) , pp. 363 – 372 View PDFCrossRefView Record in ScopusGoogle Scholar46J. Walters , NA MaskellBiopsy techniques for the diagnosis of mesotheliomaRecent Results Cancer Res , 189 ( 2011 ) , pp. 45 – 55 View PDFCrossRefView Record in ScopusGoogle Scholar47L. Greillier , A. Cavailles , A. Fraticelli , et al.Accuracy of pleural biopsy using thoracoscopy for the diagnosis of histologic subtype in patients with malignant pleural mesotheliomaCancer , 110 ( 2007 ) , pp. 2248 – 2252 View PDFCrossRefView Record in ScopusGoogle Scholar48SC Kao , TD Yan , K. Lee , et al.Accuracy of diagnostic biopsy for the histological subtype of malignant pleural mesotheliomaJ Thorac Oncol , 6 ( 2011 ) , pp. 602 – 605ArticleDownload PDFCrossRefView Record in ScopusGoogle Scholar49J. Creaney , RJ Francis , IM Dick , et al.Soluble serum mesothelin concentrations in malignant pleural mesothelioma: relationship to tumor volume, clinical stage and changes in tumor burdenClin Cancer Res , 17 ( 2011 ) , pp. 1181 – 1189 View PDFView Record in ScopusGoogle ScholarfiftyJA Rodríguez PortalAsbestos-related disease: screening and diagnosisAdv Clin Chem , 57 ( 2012 ) , pp. 163 – 185ArticleDownload PDFView Record in ScopusGoogle Scholar51K. Hollevoet , JB Reitsma , J. Creaney , et al.Serum mesothelin for diagnosing malignant pleural mesothelioma: an individual patient data meta-analysisJ Clin Oncol , 30 ( 2012 ) , pp. 1541 – 1549 View PDFView Record in ScopusGoogle Scholar52CE Hooper , AJ Morley , P. Virgo , et al.A prospective trial evaluating the role of mesothelin in undiagnosed pleural effusionsEur Respir J , 41 ( 2013 ) , pp. 18 – 24 View PDFCrossRefView Record in ScopusGoogle Scholar53A. Cui , XG Jin , K. Zhai , ZH Tong , HZ ShiDiagnostic values ​​of soluble mesothelin-related peptides for malignant pleural mesothelioma: updated meta-analysisBMJ Open , 4 ( 2014 ) , p. e004145 View PDFCrossRefView Record in ScopusGoogle Scholar54I. Pantazopoulos , P. Boura , T. Xanthos , K. SyrigosEffectiveness of mesothelin family proteins and osteopontin for malignant mesotheliomaEur Respir J , 41 ( 2013 ) , pp. 706 – 715 View PDFCrossRefView Record in ScopusGoogle Scholar55HI Pass , SM Levin , MR Harbut , et al.Fibulin-3 as a blood and effusion biomarker for pleural mesotheliomaN Engl J Med , 367 ( 2012 ) , pp. 1417 – 1427View Record in ScopusGoogle Scholar56J. Creaney , IM Dick , TM Meniawy , et al.Comparison of fibulin-3 and mesothelin as markers in malignant mesotheliomaThorax , 69 ( 10 ) ( 2014 ) , pp. 895 – 902Oct View PDFCrossRefView Record in ScopusGoogle Scholar57VW Rusch , D. Giroux , C. Kennedy , et al.Initial analysis of the international association for the study of lung cancer mesothelioma databaseJ Thorac Oncol , 7 ( 2012 ) , p. 1631ArticleDownload PDFCrossRefView Record in ScopusGoogle Scholar58JP van Meerbeeck , A. Scherpereel , VF Surmont , P. BaasMalignant pleural mesothelioma: the standard of care and challenges for future managementCrit Rev Oncol Hematol , 78 ( 2011 ) , pp. 92 – 111ArticleDownload PDFView Record in ScopusGoogle Scholar59PM McCormack , F. Nagasaki , BS Hilaris , N. MartiniSurgical treatment of pleural mesotheliomaJ Thorac Cardiovasc Surg , 84 ( 1982 ) , pp. 834 – 842DecArticleDownload PDFView Record in ScopusGoogle Scholar60RM FloresSurgical options in malignant pleural mesothelioma: extrapleural pneumonectomy or pleurectomy / decorticationSemin Thorac Cardiovasc Surg , 21 ( 2009 ) , pp. 149 – 153ArticleDownload PDFView Record in ScopusGoogle Scholar61AS Wolf , J. Daniel , DJ SugarbakerSurgical techniques for multimodality treatment of malignant pleural mesothelioma: extrapleural pneumonectomy and pleurectomy / decorticationSemin Thorac Cardiovasc Surg , 21 ( 2009 ) , pp. 132 – 148ArticleDownload PDFView Record in ScopusGoogle Scholar62O. Rena , C. CasadioExtrapleural pneumonectomy for early stage malignant pleural mesothelioma: a harmful procedureLung cancer , 77 ( 2012 ) , pp. 151 – 155ArticleDownload PDFView Record in ScopusGoogle Scholar63DJ Sugarbaker , JP GarciaMultimodality therapy for malignant pleural mesotheliomaChest , 112 ( 1997 ) , pp. – 272 – 275SArticleDownload PDFCrossRefGoogle Scholar64WG Richards , L. Zellos , R. Bueno , et al.Phase I to II study of pleurectomy / decortication and intraoperative intracavitary hyperthermic cisplatin lavage for mesotheliomaJ Clin Oncol , 24 ( 2006 ) , pp. 1561 – 1567View Record in ScopusGoogle Scholar65PE Van Schil , P. Baas , R. Gaafar , et al.Trimodality therapy for malignant pleural mesothelioma: Results from an EORTC phase II multicentre trialEur Respir J , 36 ( 2010 ) , pp. 1362 – 1369 View PDFCrossRefView Record in ScopusGoogle Scholar66RM Flores , HI Pass , VE Seshan , et al.Extrapleural pneumonectomy versus pleurectomy / decortication in the surgical management of malignant pleural mesothelioma: results in 663 patientsJ Thorac Cardiovasc Surg , 135 ( 2008 ) , pp. 620 – 626 View PDFCrossRefView Record in ScopusGoogle Scholar67JC Halstead , E. Lim , RM Venkateswaran , SC Charman , M. Goddard , AJ RitchieImproved survival with VATS pleurectomy-decortication in advanced malignant mesotheliomaEur J Surg Oncol , 31 ( 2005 ) , pp. 314 – 320ArticleDownload PDFView Record in ScopusGoogle Scholar68V. Srivastava , J. Dunning , J. AuDoes video-assisted thoracoscopic decortication in advanced malignant mesothelioma improve prognosis?Interact Cardiovasc Thorac Surg , 8 ( 4 ) ( 2009 ) , pp. 454 – 456 View PDFCrossRefView Record in ScopusGoogle Scholar69MJ WeyantIs it time to consider pleurectomy and decortication as the only surgical treatment for malignant pleural mesothelioma?J Thorac Oncol , 7 ( 2012 ) , pp. 629 – 630ArticleDownload PDFCrossRefView Record in ScopusGoogle Scholar70AE Martin-Ucar , A. Nakas , JG Edwards , DA WallerCase-control study between extrapleural pneumonectomy and radical pleurectomy / decortication for pathological N2 malignant pleural mesotheliomaEur J Cardiothorac Surg , 31 ( 2007 ) , pp. 765 – 770may View PDFCrossRefView Record in ScopusGoogle Scholar71T. Treasure , L. Lang-Lazdunski , D. Waller , 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) randomized feasibility studyLancet Oncol , 12 ( 2011 ) , pp. 763 – 772ArticleDownload PDFView Record in ScopusGoogle Scholar72Weder W, Stahel RA, Baas P, et al. The MARS feasibility trial: conclusions not supported by data.Lancet Oncol. 2011; 12: 1093-4; author reply 4-5.Google Scholar73L. Lang-Lazdunski , A. Bille , R. Lal , et al.Pleurectomy / decortication is superior to extrapleural pneumonectomy in the multimodality management of patients with malignant pleural mesotheliomaJ Thorac Oncol , 7 ( 2012 ) , pp. 737 – 743ArticleDownload PDFCrossRefView Record in ScopusGoogle Scholar74E. Minatel , M. Trovo , J. Polesel , et al.Tomotherapy after pleurectomy / decortication or biopsy for malignant pleural mesothelioma allows the delivery of high dose of radiation in patients with intact lungJ Thorac Oncol , 7 ( 2012 ) , pp. 1862 – 1866ArticleDownload PDFCrossRefView Record in ScopusGoogle Scholar75A. PriceWhat is the role of radiotherapy in malignant pleural mesothelioma?Oncologist , 16 ( 2011 ) , pp. 359 – 365 View PDFCrossRefView Record in ScopusGoogle Scholar76L. de Graaf-Strukowska , J. van der Zee , W. van Putten , S. SenanFactors influencing the outcome of radiotherapy in malignant mesothelioma of the pleura – a single-institution experience with 189 patientsInt J Radiat Oncol Biol Phys , 43 ( 1999 ) , pp. 511 – 516ArticleDownload PDFView Record in ScopusGoogle Scholar77P. Jenkins , R. Milliner , C. SalmonRe-evaluating the role of palliative radiotherapy in malignant pleural mesotheliomaEur J Cancer , 47 ( 2011 ) , pp. 2143 – 2149ArticleDownload PDFView Record in ScopusGoogle Scholar78EM Low , GG Khoury , AW Matthews , E. NevillePrevention of tumor seeding following thoracoscopy in mesothelioma by prophylactic radiotherapyClin Oncol (R Coll Radiol) , 7 ( 1995 ) , pp. 317 – 318ArticleDownload PDFView Record in ScopusGoogle Scholar79D. De Ruysscher , B. SlotmanTreatment of intervention sites of malignant pleural mesothelioma with radiotherapy: a Dutch-Belgian surveyRadiother Oncol , 68 ( 2003 ) , pp. 299 – 302ArticleDownload PDFView Record in ScopusGoogle Scholar80DA Fennell , G. Gaudino , KJ O’Byrne , L. Mutti , J. van MeerbeeckAdvances in the systemic therapy of malignant pleural mesotheliomaNat Clin Pract Oncol , 5 ( 2008 ) , pp. 136 – 147 View PDFCrossRefView Record in ScopusGoogle Scholar81AK NowakChemotherapy for malignant pleural mesothelioma: a review of current management and a look to the futureAnn Cardiothorac Surg , 1 ( 2012 ) , pp. 508 – 515View Record in ScopusGoogle Scholar82JN Jakobsen , JB SorensenReview on clinical trials of targeted treatments in malignant mesotheliomaCancer Chemother Pharmacol , 68 ( 2011 ) , pp. 1 – 15 View PDFCrossRefView Record in ScopusGoogle Scholar83R. Hassan , E. Sharon , I. PastanMesothelin targeted chemo-immunotherapy for treatment of malignant mesothelioma and lung adenocarcinomaAnn Oncol , 21 ( 2010 ) , p. ii42View Record in ScopusGoogle Scholar84RM Wong , I. Ianculescu , S. Sharma , et al.Immunotherapy for malignant pleural mesothelioma Current status and future prospectsAm J Respir Cell Mol Biol , 50 ( 5 ) ( 2014 ) , pp. 870 – 875mayView Record in ScopusGoogle Scholar85JP Hegmans , JD Veltman , ME Lambers , et al.Consolidative dendritic cell-based immunotherapy elicits cytotoxicity against malignant mesotheliomaAm J Respir Crit Care Med , 181 ( 2010 ) , pp. 1383 – 1390View Record in ScopusGoogle Scholar86P. Astoul , E. Roca , F. Gallateau-Salle , A. ScherpereelMalignant pleural mesothelioma From the bench to the bedsideRespiration , 83 ( 2012 ) , pp. 481 – 493 View PDFCrossRefView Record in ScopusGoogle Scholar87H. Kim , W. Gao , M. HoNovel immunocytokine IL12-SS1 (Fv) inhibits mesothelioma tumor growth in nude micePLoS One , 8 ( 2013 ) , p. e81919 View PDFCrossRefView Record in ScopusGoogle Scholar88F. Rodriguez-Panadero , A. Montes-WorboysMechanisms of pleurodesisRespiration , 83 ( 2012 ) , pp. 91 – 98 View PDFCrossRefView Record in ScopusGoogle Scholar89S. Bielsa , P. Hernández , F. Rodriguez-Panadero , T. Taberner , A. Salud , JM PorcelTumor type influences the effectiveness of pleurodesis in malignant effusionsLung , 189 ( 2011 ) , pp. 151 – 155 View PDFCrossRefView Record in ScopusGoogle Scholar90Gottehrer A1 , DA Taryle , CE Reed , SA SahnPleural fluid analysis in malignant mesothelioma Prognostic implicationsChest , 100 ( 4 ) ( 1991 Oct ) , pp. 1003 – 1006Google Scholar91F. Rodríguez-Panadero , J. López MejíasLow glucose and pH levels in malignant pleural effusions Diagnostic significance and prognostic value in respect to pleurodesisAm Rev Respir Dis , 139 ( 3 ) ( 1989 ) , pp. 663 – 667Sea View PDFCrossRefView Record in ScopusGoogle Scholar92J. Chiche , K. Ilc , J. Laferrière , et al.Hypoxia-inducible carbonic anhydrase IX and XII promote tumor cell growth by counteracting acidosis through the regulation of the intracellular pHCancer Res , 69 ( 2009 ) , pp. 358 – 368 View PDFView Record in ScopusGoogle Scholar93RA Gatenby , ET Gawlinski , AF Gmitro , B. Kaylor , R. GilliesAcid-mediated tumor invasion: A multidisciplinary studyCancer Res , 66 ( 2006 ) , pp. 5216 – 5223 View PDFView Record in ScopusGoogle Scholar94RA Cardone , V. Casavola , SJ ReshkinThe role of disturbed pH dynamics and the Na + / H + exchanger in metastasisNat Rev Cancer , 5 ( 2005 ) , pp. 786 – 795 View PDFCrossRefView Record in ScopusGoogle Scholar95J. Chiche , C. Brahimi-Horn , J. PouysségurTumor hypoxia induces a metabolic shift causing acidosis: A common feature in cancerJ Cell Mol Med , 14 ( 4 ) ( 2010 ) , pp. 771 – 794 View PDFCrossRefView Record in ScopusGoogle Scholar96A. Klabatsa , MT Sheaff , JP Steele , MT Evans , RM Rudd , DA FennellExpression and prognostic significance of hypoxia-inducible factor 1alpha (HIF-1alpha) in malignant pleural mesothelioma (MPM)Lung Cancer , 51 ( 1 ) ( 2006 ) , pp. 53 – 59JanArticleDownload PDFView Record in ScopusGoogle Scholar97M. Echevarría , AM Muñoz-Cabello , R. Sánchez-Silva , JJ Toledo-Aral , J. López-BarneoDevelopment of cytosolic hypoxia and hypoxia-inducible factor stabilization are facilitated by aquaporin-1 expressionJ Biol Chem , 282 ( 2007 ) , pp. 30207 – 30215ArticleDownload PDFView Record in ScopusGoogle Scholar98Parks SK1 , J. Chiche , J. PouyssegurpH control mechanisms of tumor survival and growthJ Cell Physiol , 226 ( 2 ) ( 2011 ) , pp. 299 – 308FebGoogle Scholar99E. Cases , L. Seijo , C. Disdier , et al.Use of permanent pleural drainage in the outpatient management of recurrent malignant pleural effusionArch Bronconeumol , 45 ( 2009 ) , pp. 591 – 596ArticleDownload PDFView Record in ScopusGoogle Scholar100ME Van Meter , KY McKee , RJ KohlwesEfficacy and safety of tunneled pleural catheters in adults with malignant pleural effusions: a systematic reviewJ Gen Intern Med , 26 ( 2011 ) , pp. 70 – 76 View PDFCrossRefView Record in ScopusGoogle Scholar101HE Davies , EK Mishra , BC Kahan , et al.Effect of an indwelling pleural catheter vs chest tube and talc pleurodesis for relieving dyspnea in patients with malignant pleural effusion The TIME2 randomized controlled trialJAMA , 307 ( 2012 ) , pp. 2383 – 2389 View PDFCrossRefView Record in ScopusGoogle Scholar102MJ Lorenzo , M. Modesto , J. Pérez , et al.Quality-of-Life assessment in malignant pleural effusion treated with indwelling pleural catheter: A prospective studyPalliat Med , 28 ( 2014 ) , pp. 326 – 334 View PDFCrossRefView Record in ScopusGoogle Scholar103RM Ostroff , MR Mehan , A. Stewart , et al.Early detection of malignant pleural mesothelioma in asbestos-exposed individuals with a noninvasive proteomics-based surveillance toolPLoS One , 7 ( 2012 ) , p. e46091 View PDFCrossRefView Record in ScopusGoogle Scholar104F. Mundt , HJ Johansson , J. Forshed , et al.Proteome screening of pleural effusions identifies galectin 1 as a diagnostic biomarker and highlights several prognostic biomarkers for malignant mesotheliomaMol Cell Proteomics , 13 ( 2014 ) , pp. 701 – 715ArticleDownload PDFView Record in ScopusGoogle Scholar105F. Gueugnon , S. Leclercq , C. Blanquart , et al.Identification of novel markers for the diagnosis of malignant pleural mesotheliomaAm J Pathol , 178 ( 2011 ) , pp. 1033 – 1042ArticleDownload PDFView Record in ScopusGoogle Scholar106JL López-Campos , R. Sánchez Silva , L. Gómez Izquierdo , et al.Overexpression of Aquaporin-1 in lung adenocarcinomas and pleural mesotheliomasHistol Histopathol , 26 ( 4 ) ( 2011 ) , pp. 451 – 459AprView Record in ScopusGoogle Scholar107DW Henderson , G. Reid , SC Kao , N. van Zandwijk , S. KlebeChallenges 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 microRNAJ Clin Pathol , 66 ( 2013 ) , pp. 854 – 861 View PDFCrossRefView Record in ScopusGoogle Scholar108SC Kao , N. Armstrong , B. Condon , et al.Aquaporin 1 is an independent prognostic factor in pleural malignant mesotheliomaCancer , 118 ( 2012 ) , pp. 2952 – 2961 View PDFCrossRefView Record in ScopusGoogle Scholar109I. Bentwich , A. Avniel , Y. Karov , et al.Identification of hundreds of conserved and nonconserved human microRNAsNat Genet , 37 ( 7 ) ( 2005 ) , pp. 766 – 770Jul View PDFCrossRefView Record in ScopusGoogle Scholar110H. Benjamin , D. Lebanony , S. Rosenwald , et al.A diagnostic assay based on microRNA expression accurately identifies malignant pleural mesotheliomaJ Mol Diagn , 12 ( 2010 ) , pp. 771 – 779ArticleDownload PDFCrossRefView Record in ScopusGoogle Scholar111DG Weber , G. Johnen , O. Bryk , KH Jöckel , T. BrüningIdentification of miRNA-103 in the cellular fraction of human peripheral blood as a potential biomarker for malignant mesothelioma. A pilot studyPLoS One , 7 ( 2012 ) , p. e30221 View PDFCrossRefView Record in ScopusGoogle Scholar112A. Vachani , E. Moon , SM AlbeldaGene therapy for mesotheliomaCurr Treat Options Oncol , 12 ( 2011 ) , pp. 173 – 180 View PDFCrossRefView Record in ScopusGoogle Scholar113AR Haas , DH StermanNovel intrapleural therapies for malignant diseasesRespiration , 83 ( 2012 ) , pp. 277 – 292 View PDFCrossRefView Record in ScopusGoogle Scholar114Y. Tada , H. Shimada , K. Hiroshima , M. TagawaA potential therapeutic strategy for malignant mesothelioma with gene medicineBiomed Res Int , 2013 ( 2013 ) , p. 572609 View PDFView Record in ScopusGoogle Scholar115O. Melaiu , J. Stebbing , Y. Lombardo , et al.MSLN gene silencing has an anti-malignant effect on cell lines overexpressing mesothelin deriving from malignant pleural mesotheliomaPLoS One , 9 ( 2014 ) , p. e85935 View PDFCrossRefView Record in ScopusGoogle Scholar116C. AlbertiFrom molecular imaging in preclinical / clinical oncology to theranostic applications in targeted tumor therapyEur Rev Med Pharmacol Sci , 16 ( 2012 ) , pp. 1925 – 1933 View PDFView Record in ScopusGoogle Scholar117H. Zhang , M. Tian , E. Li , Y. Fujibayashi , LH Shen , DJ YangMolecular imaging-guided theranostics and personalized medicineJ Biomed Biotechnol , 2012 ( 2012 ) , p. 747416 View PDFView Record in ScopusGoogle Scholar118S. Bidlingmaier , J. He , Y. Wang , et al.Identification of MCAM / CD146 as the target antigen of a human monoclonal antibody that recognizes both epithelioid and sarcomatoid types of mesotheliomaCancer Res , 69 ( 2009 ) , pp. 1570 – 1577 View PDFView Record in ScopusGoogle Scholar119Y. Hama , Y. Urano , Y. Koyama , et al.A target cell-specific activatable fluorescence probe for in vivo molecular imaging of cancer based on a self-quenched Avidin-Rhodamine conjugateCancer Res , 67 ( 2007 ) , pp. 2791 – 2799 View PDFView Record in ScopusGoogle Scholar120V. Ntziachristos , C. Bremer , R. WeisslederFluorescence imaging with near-infrared light: new technological advances that enable in vivo molecular imagingEur Radiol , 13 ( 2003 ) , pp. 195 – 208 View PDFCrossRefView Record in ScopusGoogle Scholar121AM Morawski , PM Winter , KC Crowder , et al.Targeted nanoparticles for quantitative imaging of sparse molecular epitopes with MRIMagn Reson Med , 51 ( 2004 ) , pp. 480 – 486 View PDFView Record in ScopusGoogle Scholar122TK Nayak , M. Bernardo , DE Milenic , PL Choyke , MW BrechbielOrthotopic pleural mesothelioma in mice: SPECT / CT and MR imaging with HER1- and HER2-targeted radiolabeled antibodiesRadiology , 267 ( 1 ) ( 2013 ) , pp. 173 – 182Apr View PDFCrossRefView Record in ScopusGoogle ScholarCopyright © 2015 Published by Elsevier España, SL