The most important causal factor for development of mesotheliomas is still asbestos, primarily amphibole asbestos. The recurring occurrence of mesotheliomas in younger people without known asbestos exposure needs the urgent investigation of other inducing factors for mesotheliomas.

Purpose Pemetrexed-based chemotherapy represents the standard of care in firstline-treatment of advanced malignant pleural mesothelioma (MPM). However, there are no established predictors of clinical benefit. Pemetrexed inhibits multiple enzymes involved in pyrimidine and purine synthesis, but the main target is thymidylate synthase (TS). Following cellular uptake pemetrexed is converted into more effective polyglutamated forms by folylpoly-γ-glutamate synthetase (FPGS). We hypothesized that FPGS and TS protein expression is associated with clinical outcome following pemetrexed-based chemotherapy. Patients and Methods Pretreatment tumor samples from 84 patients with histologically confirmed MPM, who received pemetrexed combined with platinum (79/84) or single-agent pemetrexed (5/84) as firstline treatment, were retrospectively analyzed. FPGS and TS protein expression was semiquantitatively assessed by using the H-Scoring system (range: 0–300). H-scores were correlated with radiological response according to modified RECIST, progression-free survival (PFS) and overall survival (OS). Results Median H-score of the entire cohort was 230 for FPGS (range: 100–300), and 210 for TS (range: 100–300). High FPGS protein expression was significantly associated with longer PFS (PCOX=0.0337), better objective tumor response (PR vs. SD + PD; PKW=0.003), and improved disease control rate (PR + SD vs. PD; PKW=0.0208), but not with OS. In addition, high TS protein expression was associated with PD under pemetrexed-based therapy (P=0.0383), and shorter OS (PCOX=0.0071), but no association with PFS was observed. Conclusion FPGS and TS expression were associated with clinical response and outcome to pemetrexed-based firstline chemotherapy in MPM. Prospective evaluation of FGPS and TS expression and their prognostic/predictive power in MPM patients is warranted.

Between 1987 and 2000, the German mesothelioma register recorded a total of 4,455 patients with malignant mesotheliomas. Survival times for 498 (11.2%) patients were available; 155 patients (study group, 3.5% of the total group) survived for more than 2 years and 343 patients (control group, 7.7% of the total group) survived for fewer than 24 months. Male patients were over-represented in both groups, with 13% of women in the study and 4.4% in the control group. The proportion of pleural mesotheliomas was more than 90% in both groups, with peritoneal cases comprising 6.5% in the study group and 3.2% in the control group. Histologically, the epithelioid subtype was represented in 58% of the study group, whereas the biphasic subtype predominated (67.6%) in the control group. Only 7% of tumours were of the sarcomatoid subtype. The average age of patients in the study group was 57.4 years, thus lower than in the control group (62.8 years). Lung dust analysis showed an increased pulmonary asbestos burden in 94% of all patients; significant differences between the study and control group were not observed. In the majority of the total group pleural effusions were the first symptoms. Therapeutic data were available in fewer than 40% of all cases. Surgical interventions were performed, partly in combination with radiation and chemotherapy and as alternative treatments. Significant deviations in survival time dependent on therapy applied could not be proved. By multivariate analysis (Cox proportional hazards regression model) favourable prognostic factors for long-term survival were epithelioid tumour subtype, comparatively young age (<60 years), and female gender ( P<0.05).

The incidence of mesothelioma is not expected to drop in the next few years. The available treatments are chemotherapy, surgery, and radiotherapy. Specialized treatment centers now increasingly provide multimodal therapy for treatment of mesothelioma.