Malignant mesothelioma is an aggressive tumor of serosal surfaces, such as the pleura and the peritoneum. This tumor was once rare, but its incidence is increasing worldwide, probably as a result of widespread exposure to asbestos, a factor with which it is associated. The authors review advances made in the past 5 to 10 years in the understanding, diagnosis, and management of mesothelioma.

Advances in Malignant Mesothelioma

Mesothelin is a cell-surface molecule over-expressed on a large fraction of carcinomas, and thus is an attractive target of immunotherapy. A molecularly targeted therapy for these cancers was created by engineering T cells to express a chimeric receptor with high affinity for human mesothelin. Lentiviral vectors were used to express a single-chain variable fragment that binds mesothelin and that is fused to signaling domains derived from T-cell receptor zeta, CD28, and CD137 (4–1BB). When stimulated by mesothelin, lentivirally transduced T cells were induced to proliferate, express the antiapoptotic gene Bcl-XL, and secrete multiple cytokines, all features characteristic of central memory T cells. When transferred intratumorally or intravenously into NOD/scid/IL2rγ−/− mice engrafted with large pre-established tumors, the engineered T cells reduced the tumor burden, and in some cases resulted in complete eradication of the tumors at low effector-to-target ratios. Incorporation of the CD137 signaling domain specifically reprogrammed cells for multifunctional cytokine secretion and enhanced persistence of T cells. These findings have important implications for adoptive immunotherapy of cancer, especially in the context of poorly immunogenic tumors. Genetically redirected T cells have promise of targeting T lymphocytes to tumor antigens, confer resistance to the tumor microenvironment, and providing immunosurveillance.

https://www.pnas.org/content/pnas/106/9/3360.full.pdf

Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains

Pleural effusions are a common medical problem with more than 50 recognised causes including disease local to the pleura or underlying lung, systemic conditions, organ dysfunction and drugs1

Pleural effusions occur as a result of increased fluid formation and/or reduced fluid resorption The precise pathophysiology of fluid accumulation varies according to underlying aetiologies As the differential diagnosis for a unilateral pleural effusion is wide, a systematic approach to investigation is necessary The aim is to establish a diagnosis swiftly while minimising unnecessary invasive investigations and facilitating treatment, avoiding the need for repeated therapeutic aspirations when possible

Since the 2003 guideline, several clinically relevant studies have been published, allowing new recommendations regarding image guidance of pleural procedures with clear benefits to patient comfort and safety, optimum pleural fluid sampling and processing and the particular value of thoracoscopic pleural biopsies This guideline also includes a review of recent evidence for the use of new biomarkers including N-terminal pro-brain natriuretic peptide (NT-proBNP), mesothelin and surrogate markers of tuberculous pleuritis

The history and physical examination of a patient with a pleural effusion may guide the clinician as to whether the effusion is a transudate or an exudate This critical distinction narrows the differential diagnosis and directs further investigation

Clinical assessment alone is often capable of identifying transudative effusions Therefore, in an appropriate clinical setting such as left ventricular failure with a confirmatory chest x-ray, such effusions do not need to be sampled unless there are atypical features or they fail to respond to treatment

Approximately 75% of patients with pulmonary embolism and …

https://thorax.bmj.com/content/thoraxjnl/65/Suppl_2/ii4.full.pdf

Investigation of a unilateral pleural effusion in adults: British Thoracic Society pleural disease guideline 2010

Malignant pleural mesothelioma (MPM) is a rare tumour but with increasing incidence and a poor prognosis. In 2008, the European Respiratory Society/European Society of Thoracic Surgeons Task Force brought together experts to propose practical and up-to-dated guidelines on the management of MPM.
To obtain an earlier and reliable diagnosis of MPM, the experts recommend performing thoracoscopy, except in cases of pre-operative contraindication or pleural symphysis. The standard staining procedures are insufficient in similar to 10% of cases. Therefore, we propose using specific immunohistochemistry markers on pleural biopsies. In the absence of a uniform, robust and validated staging system, we advice use of the most recent TNM based classification, and propose a three step pre-treatment assessment. Patient's performance status and histological subtype are currently the only prognostic factors of clinical importance in the management of MPM. Other potential parameters should be recorded at baseline and reported in clinical trials. MPM exhibits a high resistance to chemotherapy and only a few patients are candidates for radical surgery. New therapies and strategies have been reviewed.

Because of limited data on the best combination treatment, we emphasise that patients who are considered candidates for a multimodal approach should be included in a prospective trial at a specialised centre.

/pdf/guidelines-of-the-european-respiratory-society-and-the-1iaue8zr1p.pdf

Guidelines of the European Respiratory Society and the European Society of Thoracic Surgeons for the management of malignant pleural mesothelioma

Mesothelin is a differentiation antigen present on normal mesothelial cells and overexpressed in several human tumors, including mesothelioma and ovarian and pancreatic adenocarcinoma. The mesothelin gene encodes a precursor protein that is processed to yield the 40-kDa protein, mesothelin, attached to the cell membrane by a glycosylphosphatidyl inositol linkage and a 31-kDa shed fragment named megakaryocyte-potentiating factor. The biological function of mesothelin is not known. Mesothelin is a promising candidate for tumor-specific therapy, given its limited expression in normal tissues and high expression in several cancers. SS1(dsFv)PE38 is a recombinant anti-mesothelin immunotoxin that is undergoing clinical evaluation in patients with mesothelin-expressing tumors. There is evidence that mesothelin is an immunogenic protein and could be exploited as a therapeutic cancer vaccine. A soluble mesothelin variant has been identified and could be a useful tumor marker for malignant mesotheliomas.

https://clincancerres.aacrjournals.org/content/clincanres/10/12/3937.full.pdf

Mesothelin: A new target for immunotherapy

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140673603147940.pdf

Pernilla Winzell

Papers

Mesothelin-family proteins and diagnosis of mesothelioma.

Soluble mesothelin-related protein—A blood test for mesothelioma