Takayuki Terada

Clinical Significance of Serum Vascular Endothelial Growth Factor in Malignant Pleural Mesothelioma

Introduction: Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor of mesothelial origin associated with asbestos exposure. MPM has a limited response to conventional chemotherapy and radiotherapy so diagnosing MPM early is very important. Vascular endothelial growth factor (VEGF) is an autocrine growth factor for MPM. Here, we investigated the serum levels of VEGF in patients with MPM in comparison with a population that had been exposed to asbestos without developing MPM. Methods: Serum concentrations of VEGF were measured in 51 patients with MPM and 42 individuals with benign asbestos-related diseases (asbestosis or pleural plaques) or who were healthy despite asbestos exposure. Results: We demonstrated that patients with MPM had significantly higher serum levels of VEGF than a population who had been exposed to asbestos but had not developed MPM, and the patients with advanced stage MPM showed higher levels of VEGF than the early stage patients with MPM. The difference in overall survival between the groups with VEGF serum levels lower and higher than the assumed cutoff of 460 pg/ml was significant. Conclusions: Our data suggest that the VEGF serum concentration could be a useful marker for screening MPM among asbestos-exposed individuals and as a prognostic factor.

Serum thioredoxin-1 as a diagnostic marker for malignant peritoneal mesothelioma.

Background: Diffuse malignant peritoneal mesothelioma (DMPM) is an aggressive malignant tumor of mesothelial origin that shows a limited response to cytoreductive surgery along with intraperitoneal chemotherapy. Therefore, diagnosing DMPM early is very important. Reactive oxygen species play an important role in asbestos toxicity, which is associated with the pathogenesis of DMPM growth. Thioredoxin-1 (TRX) is a small redox-active protein that demonstrates antioxidative activity associated with tumor growth. Here, we investigated the serum levels of TRX in patients with DMPM and compared them with those of a population that had been exposed to asbestos but did not have DMPM. Study: The serum concentrations of TRX were measured in 15 DMPM patients and 34 individuals with benign asbestos-related diseases. Results: We demonstrated that the patients with DMPM had significantly higher serum levels of TRX than the population that had been exposed to asbestos but did not have DMPM. Conclusions: Our data suggest that serum TRX concentration is a useful serum marker for DMPM.

All-trans-retinoic acid inhibits tumour growth of malignant pleural mesothelioma in mice

Malignant pleural mesothelioma (MPM) is an aggressive malignant tumour of mesothelial origin associated with asbestos exposure. Because MPM has limited response to conventional chemotherapy and radiotherapy, the prognosis is very poor. Several researchers have reported that cytokines such as interleukin (IL)-6 play an important role in the growth of MPM. Previously, it was reported that all-trans-retinoic acid (ATRA) inhibited the production and function of IL-6 and transforming growth factor (TGF)-β1 in experiments using lung fibroblasts. We investigated whether ATRA had an inhibitory effect on the cell growth of MPM, the origin of which was mesenchymal cells similar to lung fibroblasts, using a subcutaneous xenograft mouse model. We estimated the tumour growth and performed quantitative measurements of IL-6, TGF-β1 and platelet-derived growth factor (PDGF) receptor (PDGFR)-β mRNA levels both of cultured MPM cells and cells grown in mice with or without the administration of ATRA. ATRA significantly inhibited MPM tumour growth. In vitro studies disclosed that the administration of ATRA reduced 1) mRNA levels of TGF-β1, TGF-β1 receptors and PDGFR-β, and 2) TGF-β1-dependent proliferation and PDGF-BB-dependent migration of MPM cells. These data may provide a rationale to explore the clinical use of ATRA for the treatment of MPM.

Heme Oxygenase-1 Promoter Polymorphism is Associated with Risk of Malignant Mesothelioma

BackgroundMalignant mesothelioma is an aggressive tumor of serosal surfaces that is closely associated with asbestos exposure which induces oxidative stress. Heme oxygenase (HO)-1, a rate-limiting enzyme of heme degradation, plays a protective role against oxidative stress. The HO-1 gene promoter carries (GT)n repeats whose number is inversely related to transcriptional activity of the HO-1 gene.MethodsTo investigate the relationship between the length polymorphism of (GT)n repeats and mesothelioma susceptibility, we analyzed the HO-1 promoter in 44 asbestos-exposed subjects without mesothelioma and 78 asbestos-exposed subjects with mesothelioma using PCR-based genotyping.ResultsThe number of repeats ranged from 16 to 38, with two peaks at 23 and 30 repeats. Polymorphisms of (GT)n repeats were grouped into two classes of alleles, short (S) (<24) and long (L) (≥24), and three genotypes: L/L, L/S, and S/S. The proportions of allele frequencies in class L as well as genotypic frequencies of L allele carriers (L/L and L/S) were significantly higher in the asbestos-exposed subjects with mesothelioma than in those without mesothelioma.ConclusionThe findings of this study suggest that long (GT)n repeats in the HO-1 gene promoter are associated with a higher risk of malignant mesothelioma in the Japanese population.

A novel clinical role for angiopoietin-1 in malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is an aggressive malignant tumour associated with asbestos exposure that has only a limited response to conventional therapy; therefore, diagnosing MPM early is very important. We have previously reported that angiopoietin (Ang)-1 was correlated with bleomycin-induced pulmonary fibrosis. Here, we investigated the association of Ang-1 with the development of MPM cells, which originate from mesenchymal cells similar to lung fibroblasts, and demonstrated that Ang-1 stimulated the growth and migration of MPM cells in vitro. We also demonstrated that patients with MPM had significantly higher serum levels of Ang-1 in comparison to a population who had been exposed to asbestos but had not developed MPM. The patients with advanced-stage MPM showed higher levels of Ang-1 than the early-stage MPM patients and the Kaplan–Meier method revealed a significant correlation between serum Ang-1 levels and survival. We propose the possibility that Ang-1 plays an important role in MPM tumour growth and our data suggest that the serum concentration of Ang-1 could be useful as prognostic factor.

A new prognostic index for overall survival in malignant pleural mesothelioma: the rPHS (regimen, PS, histology or stage) index.

OBJECTIVE Existing prognostic indices for malignant pleural mesothelioma do not incorporate the recent advances in oncology care. The purpose of this study was to provide a prognostic index for overall survival in malignant pleural mesothelioma patients treated with chemotherapy with pemetrexed or best supportive care in the recent clinical setting. METHODS A retrospective cohort study was performed in two hospitals in Japan (2007-13). The primary outcome was overall survival. The Cox proportional hazards model was used for multivariable analyses to identify prognostic factors. A final model was chosen based on both clinical and statistical significance. RESULTS A total of 283 patients (chemotherapy: n = 228, best supportive care: n = 55) were enrolled in the study. On multivariate analysis, regimen including platinum plus pemetrexed, a performance status >0, non-epithelial histological type and Stage IV disease predicted poor overall survival in chemotherapy patients. As hazard ratios of individual risk factors were approximately similar, a prognostic index for overall survival was constructed by counting the risk factors. Median overall survival in chemotherapy patients decreased by each one-point increase in this count: 1030 days for zero; 658 days for one; 373 days for two; 327 days for three; 125 days for four. Internal validation using the bootstrapping technique showed robustness of the model (c-index, 0.677; 95% confidence interval, 0.624-0.729). Further, the discrimination was consistent in best supportive care patients (c-index, 0.799; 95% confidence interval, 0.725-0.874). CONCLUSIONS This novel index can provide clinicians and malignant pleural mesothelioma patients with a better framework for discussing prognosis at the time of diagnosis.

Well-differentiated papillary mesothelioma with invasion to the chest wall.

Well-differentiated papillary mesothelioma (WDPM) is an uncommon tumor with a papillary architecture, bland cytologic features, a tendency toward superficial spread without invasion, and good prognosis with prolonged survival. WDPM occurs primarily in the peritoneum of women, but also rarely in the pleura. We here report a case of 48-year-old woman who developed WDPM in the pleura with no history of asbestos exposure. Tumors were multifocal and widespread with a velvety appearance on the surface of parietal and visceral pleurae resected by extrapleural pneumonectomy (EPP). Tumors showed papillary structures with fibrovascular cores and lined by epithelioid cells. Immunohistochemically, these epithelioid tumor cells were positive for epithelial membrane antigen (EMA), a marker of malignant mesothelioma, with more than 50% positive for p53. Tumor cells microinvaded into subpleural parenchyma of the lung and minimally spread to adipose tissues of the mediastinal lesion. In addition, tumor cells invaded into the chest wall with a trabecular or glandular architecture. Based on these findings, this case is pathologically considered as WDPM of the pleura with malignant potential.

Clinical Significance of Serum Angiopoietin-1 in Malignant Peritoneal Mesothelioma

We have previously reported that angiopoietin-1 was correlated with pulmonary fibrosis. Here, we investigated the serum levels of angiopoietin-1 in patients with malignant peritoneal mesothelioma, which originate from mesenchymal cells similar to lung fibroblasts. We showed that patients with peritoneal mesothelioma had significantly higher serum levels of angiopoietin-1 in comparison with a population with a history of asbestos exposure without peritoneal mesothelioma, and the Kaplan–Meier method revealed a significant correlation between serum angiopoietin-1 levels and survival. This is the first report about the relationship between angiopoietin-1 and peritoneal mesothelioma.

Sarcomatoid pleural mesothelioma with osteosarcomatous, chondrosarcomatous and rhabdomyoblastic elements: an extremely rare autopsy case.

To the Editor: Malignant mesotheliomas are rare but are now increasing in number, especially in Japan. The pathological classifications divide malignant mesothelioma into epithelioid, sarcomatoid, and biphasic types. In contrast to mesotheliomas with epithelioid component, the histological diagnosis of sarcomatoid mesotheliomas is often difficult. Furthermore, sarcomatoid mesotheliomas sometimes mimic true sarcomas, and the diagnosis of sarcomatoid mesotheliomas usually depends on clinical information in addition to the pathological findings. In the sarcomatoid type, there are very rare cases with heterologous elements. It is often difficult to discriminate between heterologous mesothelioma and extraskeletal osteosarcoma only by histological specimen. Identification of epithelioid component of mesothelioma, cytokeratin positivity in spindle cells and the unique anatomical localization favor the diagnosis of heterologous mesothelioma rather than extraskeletal osteosarcoma. Even if cytokeratins are negative for sarcomatoid tumor cells, the diagnosis of heterologous mesothelioma is preferred to that of matrix-producing sarcoma, especially in cases with typical distribution, for example, pleural spreading. We present here a unique autopsy case of sarcomatoid pleural mesothelioma with heterologous elements. A 70-year-old Japanese man with a smoking history went to a regional hospital with complaints of dyspnea on exertion and right chest pain. Chest roentgenogram and CT showed right pleural effusion and the right thoracic mass encasing the total right parietal pleura with massive calcification (Fig. 1a,b). He had a past history of asbestos exposure as a machinist for 12 years. For diagnostic purposes, a biopsy of the right parietal pleura was performed. The pathological diagnosis at that time was extraskeletal osteosarcoma. The patient was referred to Hyogo College of Medicine for treatment. Physical examination on admission revealed diminished breathing sound on the right thorax. Laboratory findings on admission were unremarkable except serum alkaline phosphatase (ALP) 542 U/L (normal range: 115–359 U/L). During his hospitalization, rather high ALP in the blood continued with a peak of 739 U/L, which might be related to osteogenesis. The concentration of hyaluronic acid in right pleural effusion was 125 000 ng/mL. Tumor markers (carcinoembryonic antigen (CEA), squamous cell carcinoma antigen, cytokeratin 19 fragment and progastrin releasing peptide) were all within normal range. Cytology of right pleural effusion revealed no malignant cells including epithelioid mesothelioma cells or carcinoma cells. After clinical examination, physicians strongly suspected malignant pleural mesothelioma rather than extraskeletal osteosarcoma. Two cycles of chemotherapy (carboplatin and pemetrexed) were done. However, successive chemotherapy was stopped due to the progression of the general fatigue and pain, and the patient went on to best supportive care. The patient died 5 months after the onset of the symptoms. An autopsy of the chest organs was performed to obtain a definitive diagnosis. Both surgical and autopsy specimens were evaluated. At autopsy, invasion of the right pleural tumor was seen to extensively infiltrate and tightly adhere to the chest wall, and the right anterior chest wall was dissected together with the pleural mass. After removal of the right anterior chest wall, calcified pleural mass was apparent (Fig. 1c). Coronal section of the right anterior chest wall clearly showed the tumor spreading throughout the right pleural surface (Fig. 1d). Although the tumor obviously invaded into the connective tissue between the ribs, it did not appear to originate from the ribs (Fig. 1b–d). Histologically there were no epithelioid cells, suggesting that this tumor is neither epithelioid mesothelioma nor carcinoma. Moreover, apparent tumors were not identified within the right lung, suggesting that the tumor originates from pleura. Sarcomatous cells were proliferating along the right parietal pleura (Fig. 2a) with focal expression of pankeratin (AE1/AE3, Leica, Wetzlar, Germany) (Fig. 2a inset), low molecular weight keratin (CAM5.2, Becton Dickinson, Franklin Lakes, NJ, USA) and epithelial membrane antigen (GP1.4, Leica). They were negative for calretinin (DAK Calret 1, Dako, Glostrup, Denmark), podoplanin (D2-40, DAKO), WT-1 (WT49, Leica), CEA (II-7, DAKO) and thyroid transcription factor-1 (TTF-1) (8G7G3/1, DAKO). Homozygous deletion of p16/CDKN2A was observed in 87% of the spindle cells (LSI Medience, cut off value 10%), which indicated the malignant nature of these cells. Matrix formation with osteosarcomatous and chondrosarcomatous differentiation was observed (Fig. 2b,c). Although enchondral ossification in chondrosarcomatous differentiation was seen, the chondrosarcomatous area was distinct from the osteosarcomatous area. In addition to the osteocartilaginous elements, so-called strap cells or rhabdomyoblasts were identified in a restricted area (Fig. 2d). These cells were positive for desmin (DE-R-II, Leica) and negative for myogenin (F5D, Santa Cruz, Dallas, TX, USA) and myoD1 (5.8A, DAKO). Although focal or faint immunoreactivity of muscle markers is sometimes encountered in sarcomatoid mesothelioma, marked atypia of rhabdoid cells and focal but definite staining for desmin favor Pathology International 2015; 65: 51–53 doi:10.1111/pin.12226 bs_bs_banner

Bevacizumab helped resolve pericardial and pleural effusion that was associated with malignant ovarian clear cell carcinoma

Highlights • An ovarian clear cell carcinoma patient showed malignant pericardial and pleural effusion.• She subsequently experienced pulmonary embolism due to cancer progression.• Pericardial and pleural effusion were successfully treated using bevacizumab.