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What is Immunotherapy and Gene Therapy in Mesothelioma

Immunotherapy
Both studies in animals and clinical trials of immunotherapy suggest that malignant mesothelioma is sensitive to immunotherapy. Trials of interferon alfa, intrapleural interleukin-2, and intratumoral granulocyte–
macrophage colony-stimulating factor have shown some tumor response, but nothing that warrants
widespread use of these agents.
Gene Therapy
Gene therapy for cancer generally involves the administration of engineered viruses to patients. In a small study, six patients with treatment-resistant malignant mesothelioma received intratumoral injections of a vaccinia vector containing the interleukin- 2 transgene in an attempt to modulate the
immune response. This treatment induced a lymphocytic infiltrate and a surprisingly persistent,
though low-level, expression of the transgene, with no major tumor regressions.93 “Suicide gene” therapy
 that is, delivery of a viral vector encoding a viral thymidine kinase, which renders the cell sensitive
to the drug ganciclovir by converting the drug to a toxic metabolite  has also induced some responses in patients with malignant mesothelioma.

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Chemotherapy and Radiotherapy for Mesothelioma

Chemotherapy
Until recently, all reviews of chemotherapy for malignant mesothelioma reported poor response rates
(typically less than 15 to 20 percent) and, because of these low rates, did not recommend a standard of
care.81 However, a number of multicenter studies are now under way, and several new therapeutic regimens
appear to be useful. Pemetrexed is a potent inhibitor of a number of proteins, including thymidylate synthase and dihydrofolate reductase, both of which are required for DNA synthesis. In a multicenter phase 3 study involving 448 patients, those treated with pemetrexed plus cisplatin had a longer overall median survival
(12.1 months) than those treated with cisplatin alone (9.3 months) and had an objective response
rate (shrinkage of the tumor by at least 50 percent) of 41 percent.82 Treatment with gemcitabine, a “false nucleotide” that is incorporated into DNA, plus cisplatin resulted in objective response rates of 48 percent and  percent in two studies, as well as symptomatic improvement and quality-of-life benefits.83 Imatinib
(Gleevec) and gefitinib (Iressa) block the platelet- derived growth factor and epidermal growth factor
signaling pathways, respectively. Both of these pathways are active in malignant mesothelioma.
Early studies of the treatment of mesothelioma with these compounds, however, have yielded no convincing
evidence of a response.
Radiotherapy:
Malignant mesothelioma is resistant to traditional radiotherapy.85 Local radiotherapy directed to surgical
sites prevents seeding of tumor, and radiotherapy can provide palliative relief of somatic chest-wall pain.85 The diffuse nature of the tumor, which often covers most of the lung and the interlobular fissures,
is the principal limitation to radiotherapy. However, even when the affected lung is removed,
radiotherapy is of limited effectiveness.86 The most successful fractionation method is intensity- modulated radiotherapy,86 a technique generally used after radical surgical resection of malignant mesothelioma. This approach controls local recurrence, but many patients die of metastatic disease.
 The use of radioactive colloids and other forms of brachytherapy in the pleural or peritoneal
cavity is logical, but the results have been disappointing.

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Palliation in Mesothelioma

Recurrent pleural effusions are best controlled by the removal of all fluid, with the use of suction when
required, followed by talc application or surgical pleurodesis. There are several types of pain in patients with
malignant mesothelioma.68 Local involvement of the chest wall causes somatic pain. Intercostal nerve
or vertebral invasion causes neuropathic pain. Organ invasion causes more diffuse visceral pain. Pain control can be difficult. Opiates should provide adequate pain relief for the duration of action of the drug (4 hours for liquid morphine and 12 hours for sustained-release morphine), without unnecessary
side effects. Somatic pain often responds to a nonsteroidal antiinflammatory drug given in addition to an opiate. Neuropathic pain requires the addition of an anticonvulsant, such as carbamazepine
or sodium valproate. Some patients require procedural pain relief, such as intrathecal analgesia or
nerve block. Dyspnea due to fluid accumulation or encasement of the lung by tumor is common.68 Opiates
are useful after any reversible causes of dyspnea, such as accumulation of fluid and anemia, have
been dealt with. Psychosocial factors are important in the palliation of malignant mesothelioma. Patients often express anger and fear, which are compounded by the medicolegal process. Involvement of a team of professional and community caregivers is very effective.

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Advances in Diagnosis of Mesothelioma

Accurate and rapid diagnosis of malignant mesothelioma is important for therapeutic and medicolegal
reasons. The most frequent diagnostic problem is the differentiation of malignant mesothelioma
from adenocarcinoma — a distinction that is particularly difficult to make when the tumor has invaded the pleur
Cytologic Analysis
Cytologic evidence of malignant mesothelioma in the pleural or ascitic fluid is found in 33 to 84 percent
of cases.In some patients, sampling by fineneedle aspiration of the tumor is required to make a diagnosis of malignant mesothelioma, particularly when there is no effusion. A group of immunohistochemical
markers is important in the differential diagnosis of malignant mesothelioma. As the first step, a marker such as calretinin or the Wilms’ tumor 1 antigen (WT1) is used to determine whether the tissue is mesothelial (Fig. 3A and 3B). The second step is to use a marker such as epithelial membrane membrane
antigen (EMA; also known as CA15-3  to determine whether the tissue is malignant. Staining for EMA in a thick peripheral distribution is highly suggestive of malignant mesothelioma Of the two anti-EMA antibodies, E29 has significantly greater specificity than MC-5.
In experienced hands, cytologic analysis is sufficient to make a diagnosis with a high level of confidence in approximately 80 percent of cases of malignant mesothelioma.histopathological analysis Because cytologic findings may be inconclusive or pleural or ascitic fluid may be absent altogether, tumor biopsy is often needed. Closed biopsy (e.g., with the use of an Abrams’ needle) is less likely than direct thoracoscopic biopsy to yield positive results. Immunohistochemical staining to show, for example, expression of epithelial membrane antigen on the luminal aspects of the tumor is essential in the
diagnostic process.Cytokeratin staining helps to confirm invasion and to distinguish malignant
mesothelioma from sarcoma and melanoma. Malignant mesothelioma is distinguished from adenocarcinoma
by the use of specific antibodies. Malignant mesothelioma is characterized by the presence of staining for EMA, calretinin, WT1, cytokeratin 5/6, HBME-1 (an anti–mesothelial cell antibody), or mesothelin (more than 85 percent of epithelioid

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Pathogenesis of Mesothelioma

Mesothelial cells normally facilitate the free movement of the pleural surfaces during respiration by
enmeshing lubricating glycoproteins. These cells readily proliferate in response to injury and growth factors.
Asbestos presumably induces mutations in many of the estimated 2 billion mesothelial cells
in adult humans.There are four principal processes by which asbestos affects the pleura. First, asbestos fibers may irritate the pleura. The shape of asbestos fibers, particularly the ratio of their length to their width,
determines how deeply into the lung they penetrate and their likelihood of inducing cancer. Fibers penetrating
the lung may enter or irritate the pleura and induce disease
 manifested by scarring (plaques) or a frank malignant process (malignant mesothelioma).
Second, asbestos fibers may sever or pierce the mitotic spindle of cells and thereby disrupt mitosis, resulting in aneuploidy and other forms of chromosomal damage.
Third, asbestos induces the generation of ironrelated reactive oxygen species that cause DNA damage.
Fourth, asbestos induces phosphorylation of the mitogen-activated protein (MAP) kinases and of extracellular signal–regulated kinases (ERK) 1 and 2. Phosphorylation of these kinases increases the expression of early-response proto-oncogenes that encode members of the Fos–Jun and activator
protein 1 families.
biology
Although the results are crude, conventional cytogenetic analysis has been used to investigate the
pathogenesis of malignant mesothelioma. Abnormal karyotypes, often with extensive aneuploidy and structural rearrangements, have been described for a number of genetic loci. Loss of chromosome 22
is the most common gross change, but structural rearrangements of 1p, 3p, 9p, and 6q are often
noted.

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Epidemiologic Features of Mesothelioma

The rising worldwide incidence of malignant mesothelioma is not expected to peak for another 10
to 20 years. It is possible that the disease has already reached its peak incidence in the United States,
whereas the anticipated peaks in Europe and Australia are not predicted to occur for another 10
to 15 years. Furthermore, in Japan and other non- Western countries, in which heavy use of asbestos
occurred later than in the Western world, there is a corresponding delay in the anticipated peak incidence
of mesothelioma (Table 1).
There is substantial concern that the increased use of asbestos in developing countries may result in an increase in the number of cases of malignant mesothelioma for many decades to come unless strong occupational health controls are put in place.Malignant mesothelioma has occurred in three principal cohorts of asbestos-exposed persons.
The initial cases occurred in people who were directly exposed to asbestos in their work, especially
those exposed to blue asbestos during its mining or milling. The clearest and best-studied example of
such exposure occurred at the blue-asbestos mine in Wittenoom, Australia, the site of one the worst
industrial disasters in history. Not only were the miners heavily exposed to asbestos, but the soft asbestos
tailings were used instead of grass to cover the schoolyards and playgrounds of the town, resulting
in a huge outbreak of mesotheliomas, many in young adults who had played in the asbestos dust
as children.Subsequently, asbestos-related diseases were noted in other workers who were exposed
later in the chain of manufacture and use of asbestos products, such as plumbers, carpenters,
defense personnel, and installers of asbestos insulation.A third group of affected people, accounting

for 20 to 30 percent of current cases of malignant mesothelioma, consists of those who were exposed to asbestos unknowingly and incidentally in the myriad situations in which asbestos fibers are released
into the atmosphere in industrialized countries. There have been several reports of familial clustering of malignant mesothelioma, including one cluster showing a possible autosomal dominant pattern in subjects studied in Cappadocia, Turkey

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