Advances in diagnosis and treatment of malignant mesothelioma

In late 1960’s, physician Dr. J. Stumphius identified twenty-five cases of a rare aggressive tumor known as mesothelioma among shipyard “Royal Schelde” workers due to asbestos exposure (1,2). Further observations showed an increase of mesothelioma cases among these workers. In 1974, the number of cases totaled 42; in 1978, the number rose to 57. The commercial use of asbestos in the Netherlands peaked in the 1970’s with the import of 50,000 tons of this ‘magic’ mineral and 150,000 tons of products annually (3). Five million tons of asbestos containing material still remains incorporated within our national infrastructure. Eternit, an asbestos cement factory in Goor processed asbestos until a ban on its use was introduced in 1993. For years, the factory dumped its asbestos-containing waste by simply putting the waste at the disposal of anyone who wanted to pave a road or a farmyard. So right now, there are miles of road paved around Goor with asbestos, exposing the local people to asbestos dust each time they use these roads. In The Netherlands, the public is getting increasingly familiar with the word asbestos and asbestos related disease, including mesothelioma. There is media interest during renovation, demolition or fire in buildings containing asbestos and the threat that the dust then poses to the public when carried by wind to surrounding areas. Also persons wearing respiratory and other personal protection equipment while removing asbestos containing materials can easily be encountered. Almost everyone who lives in industrialized areas of the western world has asbestos fibers in their lungs, and many can remember being exposed to asbestos incidentally. In the United States, the gray cloud that covered New York on September 11th, 2001, brought about much more awareness of the public to the word mesothelioma

Improving lung cancer survival; time to move on

Background: During the past decades, numerous efforts have been made to decrease the death rate among lung cancer patients. Nonetheless, the improvement in long-term survival has been limited and lung cancer is still a devastating disease.Discussion: With this article we would like to point out that survival of lung cancer could be strongly improved by controlling two pivotal prognostic factors: stage and treatment. This is corresponding with recent reports that show a decrease in lung cancer mortality by screening programs. In addition, modulation of the patient's immune system by immunotherapy either as monotherapy or combined with conventional cancer treatments offers the prospect of tailoring treatments much more precisely and has also been shown to lead to a better response to treatment and overall survival of non-small cell lung cancer patients.Summary: Since only small improvements in survival can be expected in advanced disease with the use of conventional therapies, more research should be focused on lung cancer screening programs and patient tailored immunotherapy with or without conventional therapies. If these approaches are clinically combined in a standard multidisciplinary policy we might be able to advance the survival of patients with lung cancer

Enhanced production of biologically active interleukin-1α and interleukin-1β by psoriatic epidermal cells ex vivo: Evidence of increased cytosolic interleukin-1β levels and facilitated interleukin-1 release

The expression of interleukin (IL)-1 is altered in psoriatic lesions. However, little is known about the actual production of IL-1α and IL-1β by psoriatic epidermal cells (EC). We monitored IL-1 in the extracellular, the membrane and the intracellular compartment of freshly isolated EC from untreated lesional psoriatic (PP) and normal healthy (NN) skin during non-stimulated short-term cultures, representing a psoriasis model ex vivo. Cytokines were measured using bioassays combined with neutralizing antibodies and enzyme-linked immunosorbent assay in parallel. PP EC released significantly increased amounts of biologically active IL-1α and IL-1β in a ratio of 3:1, whereas NN EC only released IL-1α. Also, the release of IL-6, but not of TNF-α, by PP EC was significantly increased. Membrane-associated IL-1 activity, analyzed using glutaraldehydefixed EC, was low and not unique to PP EC. The cytosol of PP EC contained significantly increased levels of immunoreactive IL-1β. Furthermore, PP EC displayed loss of membrane integrity, as determined by trypan blue exclusion and release of cytosolic lactate dehydrogenase. This facilitated release of intracellular IL-1. Depletion of CD45+ cells showed that intraepidermal leukocytes did not contribute to the production of IL-1. Our observations show that resident PP EC express enhanced IL-1 production ex vivo, which is due to an increased cytosolic IL-1β content and facilitated IL-1 release. This study provides the first evidence that PP EC can produce bioactive IL-1β

Prediction of response to pemetrexed in non-small-cell lung cancer with immunohistochemical phenotyping based on gene expression profiles

Figure S1. Scatter plots of gene expression levels of selected molecular markers and TS gene expression. Dot plots showing correlations between relative mRNA expression of TS and mRNA expression of TOP2A, MCM2, EZH2, CPA3, TPX2. Abbreviations: IHC, immunohistochemical; EZH2, Enhancer of zeste homolog; TOP2A, Topoisomerase II; TPX2, Microtubule Nucleation Factor; CPA3, Carboxypeptidase A3; MCM2, Minichromosome Maintenance Complex Component 2. (EPS 180 kb

TCR Gene Transfer: MAGE-C2/HLA-A2 and MAGE-A3/HLA-DP4 Epitopes as Melanoma-Specific Immune Targets

Adoptive therapy with TCR gene-engineered T cells provides an attractive and feasible treatment option for cancer patients. Further development of TCR gene therapy requires the implementation of T-cell target epitopes that prevent “on-target” reactivity towards healthy tissues and at the same time direct a clinically effective response towards tumor tissues. Candidate epitopes that meet these criteria are MAGE-C2336-344/HLA-A2 (MC2/A2) and MAGE-A3243-258/HLA-DP4 (MA3/DP4). We molecularly characterized TCRαβ genes of an MC2/A2-specific CD8 and MA3/DP4-specific CD4 T-cell clone derived from melanoma patients who responded clinically to MAGE vaccination. We identified MC2/A2 and MA3/DP4-specific TCR-Vα3/Vβ28 and TCR-Vα38/Vβ2 chains and validated these TCRs in vitro upon gene transfer into primary human T cells. The MC2 and MA3 TCR were surface-expressed and mediated CD8 T-cell functions towards melanoma cell lines and CD4 T-cell functions towards dendritic cells, respectively. We intend to start testing these MAGE-specific TCRs in phase I clinical trial

COX-2 inhibition improves immunotherapy and is associated with decreased numbers of myeloid-derived suppressor cells in mesothelioma. Celecoxib influences MDSC function

Background: Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature cells that accumulates in tumour-bearing hosts. These cells are induced by tumour-derived factors (e.g. prostaglandins) and have a critical role in immune suppression. MDSC suppress T and NK cell function via increased expression of arginase I and production of reactive oxygen species (ROS) and nitric oxide (NO). Immune suppression by MDSC was found to be one of the main factors for immunotherapy insufficiency. Here we investigate if the in vivo immunoregulatory function of MDSC can be reversed by inhibiting prostaglandin synthesis by specific COX-2 inhibition focussing on ROS production by MDSC subtypes. In addition, we determined if dietary celecoxib treatment leads to refinement of immunotherapeutic strategies.Methods: MDSC numbers and function were analysed during tumour progression in a murine model for mesothelioma. Mice were inoculated with mesothelioma tumour cells and treated with cyclooxygenase-2 (COX-2) inhibitor celecoxib, either as single agent or in combination with dendritic cell-based immunotherapy.Results: We found that large numbers of infiltrating MDSC co-localise with COX-2 expression in those areas where tumour growth takes place. Celecoxib reduced prostaglandin E2 levels in vitro and in vivo. Treatment of tumour-bearing mice with dietary celecoxib prevented the local and systemic expansion of all MDSC subtypes. T

COX-2 inhibition improves immunotherapy and is associated with decreased numbers of myeloid-derived suppressor cells in mesothelioma. Celecoxib influences MDSC function

Background: Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature cells that accumulates in tumour-bearing hosts. These cells are induced by tumour-derived factors (e.g. prostaglandins) and have a critical role in immune suppression. MDSC suppress T and NK cell function via increased expression of arginase I and production of reactive oxygen species (ROS) and nitric oxide (NO). Immune suppression by MDSC was found to be one of the main factors for immunotherapy insufficiency. Here we investigate if the in vivo immunoregulatory function of MDSC can be reversed by inhibiting prostaglandin synthesis by specific COX-2 inhibition focussing on ROS production by MDSC subtypes. In addition, we determined if dietary celecoxib treatment leads to refinement of immunotherapeutic strategies.Methods: MDSC numbers and function were analysed during tumour progression in a murine model for mesothelioma. Mice were inoculated with mesothelioma tumour cells and treated with cyclooxygenase-2 (COX-2) inhibitor celecoxib, either as single agent or in combination with dendritic cell-based immunotherapy.Results: We found that large numbers of infiltrating MDSC co-localise with COX-2 expression in those areas where tumour growth takes place. Celecoxib reduced prostaglandin E2 levels in vitro and in vivo. Treatment of tumour-bearing mice with dietary celecoxib prevented the local and systemic expansion of all MDSC subtypes. T