Aberrant splicing and protease involvement in mesothelin release from epithelioid mesothelioma cells.

Elevated amounts of soluble mesothelin-related proteins (SMRP) have already been reported in sera and pleural effusions from mesothelioma patients, providing a useful diagnostic marker for malignant pleural mesothelioma (MPM). However, the origin of SMRP is not yet understood. Production of SMRP could be related to abnormal splicing events leading to synthesis of a secreted protein (release) or to an enzymatic cleavage from membrane-bound mesothelin (ectodomain shedding). To test these hypotheses, we used a panel of mesothelioma cells established in culture from pleural effusions of MPM patients. Our in vitro results confirmed specific mesothelin expression and SMRP production in supernatants from epithelioid MPM cell lines, thus providing a relevant cellular model to study soluble mesothelin production mechanisms. The expression of mesothelin-encoding RNA variants was screened by reverse transcription-polymerase chain reaction experiments. Protease involvement in mesothelin cleavage from the cellular surface was investigated by treatment of MPM cells with GM6001, a broad-spectrum MMP- and ADAM-family inhibitor. GM6001 treatment significantly impaired SMRP production by MPM cell lines, in favor of an enzymatic-mediated shedding process. In addition, a splice variant transcript of mesothelin (variant 3) was detected in these MPM cell lines, in accordance with the release of a secreted part of the protein. Our results indicate that both mechanisms could be implicated in soluble mesothelin production by epithelioid mesothelioma cells.

Phase II study of vinflunine in malignant pleural mesothelioma.

PURPOSE: Malignant pleural mesothelioma (MPM) is a disease of increasing incidence for which treatment options are limited. This study reports the clinical efficacy data for vinflunine, a novel microtubule inhibitor, in MPM. PATIENTS AND METHODS: Patients with a histologically confirmed diagnosis of MPM were eligible for enrollment onto this multicenter phase II trial if they had not received prior chemotherapy or radiotherapy and had measurable lesions by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Vinflunine 320 mg/m2 by 10-minute intravenous infusion was administered on day 1 of 21-day cycles. Modifications of dose and schedule were made according to National Cancer Institute Common Toxicity Criteria version 2.0. Efficacy was assessed by an external, independent radiologist. The one-sample multiple testing procedure of Fleming was applied at the predetermined recruitment stages of 20 and 40 assessable patients. RESULTS: Sixty-seven patients were enrolled. Five patients were not assessable for tumor response. The response rate was 13.8% (95% CI, 6.5% to 24.7%). The median survival was 10.8 months (95% CI, 7.8 to 12.0 months). The most common adverse events were anemia, neutropenia, fatigue, constipation, and nausea. Of grade 3 and 4 toxicities, neutropenia and constipation were the most common (45% and 9% of patients, respectively). CONCLUSION: Vinflunine can be delivered with high-dose intensity in patients with MPM. The response rate and median survival are encouraging for a single agent. These data suggest that vinflunine should be further evaluated in the management of MPM.

[Improving organization of care could reduce referrals of cancer patients to the emergency department. Prospective analysis of 123 patients]. / Une meilleure organisation des soins pourrait diminuer le nombre des patients atteints de cancer adressés aux urgences. Analyse prospective de 123 patients.

OBJECTIVES: The objective of this prospective study was to analyze the profile of cancer patients admitted to an emergency department. METHODS: The study included all cancer patients admitted to the emergency department of our tertiary care hospital during a 47-day period in 2004 and analyzed their demographic and medical data. RESULTS: Patients were predominantly male (65%) with an average age of 62 years: 90% already knew their diagnosis. Most presented with immunodepression and severe deterioration of their general condition, in an advanced palliative stage (67%). They were referred mainly by their general practitioners (55%) and came from home (92%). In all, 81.3% were hospitalized. Follow-up at 3 months found 68.5% had died. DISCUSSION: Reasons for admissions were varied. The primary reasons were the unavailability of beds in specialized cancer units and limited home care due to poor hospital-community coordination and to a lack of social and psychological assistance. Management through the emergency care system proved satisfactory but earlier preadmission care could be improved by developing supportive care and providing education for general practitioners about pain control and palliative care.

Cytotoxic T cell responses against mesothelioma by apoptotic cell-pulsed dendritic cells.

Malignant pleural mesothelioma is an uncommon tumor largely confined to the thoracic cavity, which is resistant to conventional therapies, therefore prompting an intensive search for effective treatment alternatives. This study focuses on dendritic cell (DC) vaccination for malignant pleural mesothelioma and evaluates the in vitro efficacy of antigen-loaded DC-based vaccines for the induction of major histocompatibility complex Class I-restricted antimesothelioma cytotoxic T lymphocyte responses. The source of tumor-associated antigens for HLA-A2(+) DCs from healthy donors was apoptotic HLA-A2(-) mesothelioma cells either lacking or expressing heat shock protein 70 according to whether tumor cells were heat shocked or not before ultraviolet-mediated apoptosis. Our results show that both apoptotic preparations were equivalent regarding the responsiveness of DCs to combined treatment with tumor necrosis factor-alpha and poly(inosinic-cytidylic) acid, as determined by similar increased expression of costimulatory molecules and interleukin-12 production. However, only DCs loaded with apoptotic heat shock protein 70-expressing cells were found to be potent in vitro inducers of cytotoxic T lymphocyte activity against HLA-A2(+) mesothelioma cells. Such elicited cytotoxic T lymphocytes also exhibit cytotoxic activity against an HLA-A2(+) melanoma cell line, suggesting recognition of shared antigens. These findings therefore carry the potential of offering an alternative, promising approach for the therapy of patients with malignant pleural mesothelioma.