Hyaluronan content in pleural fluid as a prognostic factor in patients with malignant pleural mesothelioma.

BACKGROUND: Regardless of the modality of therapy used, malignant pleural mesothelioma is a highly treatment-resistant and invariably fatal disease. Identification of prognostic variables are important for future investigational therapeutic studies. METHODS: The prognostic significance of various clinical variables, including hyaluronan levels in pleural fluid, was evaluated in a retrospective analysis in 100 patients with histologically confirmed malignant pleural mesothelioma. RESULTS: The overall median survival was 11.5 months. Univariate analyses identified histologic subtype, i.e., epithelial or mixed, and elevated content of hyaluronan in the pleural effusion as significant prognostic variables. A multivariate analysis confirmed the independent predictive power of histologic subtype, and an elevated concentration of hyaluronan in the pleural fluid also indicated longer survival in older patients and in patients receiving therapy other than supportive. CONCLUSIONS: The prognostic value of histologic subtype and the concentration of hyaluronan in pleural effusions should be considered when designing and evaluating treatment trials for patients with malignant pleural mesothelioma.

Hyaluronan in serum as an indicator of progressive disease in hyaluronan-producing malignant mesothelioma.

BACKGROUND: Malignant pleural mesothelioma is associated in up to 70% of cases with an elevated content of hyaluronan (HYA) in the pleural fluid. Increased levels of circulating HYA have also been described. The clinical course of the disease can be followed by computed tomography (CT), although there are disadvantages with serial CT scans. An easily analyzed blood test, such as HYA in serum, would be of value for clinical follow-up. The purpose of this study was to relate changes in serum HYA to changes in quantitative estimations of tumor volume in cases of mesothelioma. METHODS: The content of HYA in the pleural fluid was analyzed in 19 men with mesothelioma. CT scans were performed about every third month. The tumor volume was estimated on transilluminated CT scans with a digital planimeter. Blood samples for HYA analyses were drawn every month. The impact of the tumor burden on HYA in serum was indicated in statistical analysis by a straight line for each patient according to the restricted maximum likelihood method. RESULTS: An elevated content of HYA, i.e., >100 mg/L, in the pleural fluid was seen in 13 of 19 patients. There was a positive correlation, although low, between the initial level of HYA in serum and the concentration of HYA in pleural fluid. Increasing levels of circulating HYA were on average accompanied by an increase in tumor volume in the HYA-producing group of mesotheliomas (P = 0.01). This was not seen in the non-HYA-producing mesotheliomas (P = 0.10). CONCLUSIONS: These results provide evidence that it should be possible to follow the clinical course of malignant pleural mesothelioma patients by analysis of circulating HYA in the subgroup of HYA-synthesizing mesotheliomas.

Ifosfamide in malignant mesothelioma: a phase II study.

Malignant mesothelioma is a rare malignancy with a median survival, ranging from 4 to 18 months in untreated patients. In a phase II study of patients with mesothelioma, the efficacy and toxicity of ifosfamide and mesna was evaluated. Twenty-nine previously untreated patients, with histologically proven and unresectable mesothelioma, entered the study. Three patients were later excluded from the study due to revision of the diagnoses. The patients had to have bidimensionally measurable disease by CT scans and a WHO performance status < or = 3. Eligible patients received ifosfamide 3000 mg/m2 per day for 3 days as a 1-h infusion and mesna 1800 mg/m2 per day for 3 days every third week. Dose modifications were made according to the degree of hematologic, neurologic and renal toxicity. Response to treatment was evaluated in accordance with WHO criteria. The median age of patients was 59 years (range 39-68), 18 patients (69%) had a history of asbestos exposure and the median of treatment cycles was four (range 1-10). No complete responses were observed. One patient obtained a partial response after five cycles with a duration of response of 25 months. Nine patients (35%) had stable disease, while 13 (54%) progressed. The median survival for all patients was 10 months. The toxicity of the treatment was considerable. Thirteen patients (50%) had grade 4 leucopenia, ten patients (38%) had grade 3 or 4 reversible neurotoxicity and ten patients (38%) had grade 3 or 4 nausea and vomiting. Eleven patients (42%) went off the study due to the toxicity of the treatment. In conclusion, ifosfamide did not show any substantial activity of relevance in malignant mesothelioma at the dose level investigated, in spite of considerable toxicity.

Immunohistochemical differences between hyaluronan- and non-hyaluronan-producing malignant mesothelioma.

In many but not all cases, malignant mesothelioma is associated with an elevated content of hyaluronan in pleural fluid. The hyaluronan-producing mesothelioma has not yet been immunohistochemically characterized; therefore, the purpose of this study was to compare the immunohistochemical reactivity patterns in relation to the ability of this tumour to produce hyaluronan. Pleural fluid samples from 33 patients with malignant mesothelioma were analysed for content hyaluronan using a quantitative high performance liquid chromatographic method. Biopsy specimens from the patients were studied immunohistochemically, using monoclonal antibodies against carcinoembryonic antigen (CEA), epithelial membrane antigen (EMA), a low molecular weight cytokeratin antigen (CAM 5.2) and vimentin. An elevated hyaluronan content, i.e. > 100 mg.L-1, was noted in 23 patients (70%). There was no reactivity to the monoclonal antibody raised against CEA in any case. There was a significantly higher reactivity to EMA (p = 0.026), a higher reactivity to CAM 5.2 (p = 0.053) and a lower reactivity to vimentin (p = 0.057) in the hyaluronan-producing mesotheliomas as compared to those with normal levels of hyaluronan. Mesotheliomas that produced hyaluronan differed immunohistochemically from those that did not. The connection between the ability to produce different antigens and hyaluronan may relate to the degree of differentiation of the tumour. Both of these characteristics (immunophenotype and ability to produce hyaluronan) may, therefore, be of importance in studies concerning the prognosis and treatment of the malignant mesothelioma.

Clinical utility of liquid-chromatographic analysis of effusions for hyaluronate content.

A previously described HPLC method for determining hyaluronate in effusions was used to analyze a consecutive series of effusions from 1039 patients with pleural fluids and from 571 patients with peritoneal fluids. A mesothelioma was verified histologically in 50 of the cases. The results were used to estimate the clinical utility of the analysis. With a cutoff of 75 mg/L for hyaluronate-derived uronic acid, assay specificity for a malignant mesothelioma was 100% and the sensitivity 56%. Only 20% of the effusions from the mesothelioma patients showed no evidence of increased production of hyaluronate. Cytological smears from the associated cell pellets were evaluated as malignant or suspicious for malignancy in only 28% or in a further 46% of the mesothelioma cases, respectively, leaving 30% of the pellets as cytologically false-negative. We also analyzed effusions from selected cases submitted from other hospitals, 154 of which had been diagnosed histologically as mesotheliomas. Concentrations of hyaluronate were increased in these cases too, but a considerable proportion of the samples showed evidence of losses of hyaluronate; consequently, the sensitivity of the assay in these samples was lower.

The sensitivity of hyaluronan analysis of pleural fluid from patients with malignant mesothelioma and a comparison of different methods.

BACKGROUND: Hyaluronan may be used as a marker for malignant mesothelioma, thus indicating its mesodermal origin. METHODS: The sensitivity as a diagnostic test of three different methods for hyaluronan analyses of pleural fluid was examined in patients with biopsy-verified malignant pleural mesothelioma. RESULTS: A quantitative high-performance liquid-chromatography (HPLC) method was performed on fluids from 43 patients. Using a cutoff level of 100 mg/l, higher levels were noted in 30 (70%) patients, with a median value of 220 mg/l (mean, 560 mg/l; range, 20-6600 mg/l). An identical median value (220 mg/l) was obtained with a radioassay method when simultaneously performed on paired samples from 21 patients (correlation coefficient, 0.91). A qualitative precipitation test using 0.5% cetylpyridinium chloride combined with a quantitative viscosimetric method was significantly less sensitive (P < 0.01). CONCLUSION: Hyaluronan analyses is beneficial in distinguishing malignant mesothelioma if methods such as the evaluated HPLC or radioassay with a sensitivity of 70% toward mesothelioma are used and other known causes of elevated content are considered.