Kao SC, Yan TD, Lee K, Burn J, Henderson DW, Klebe S, Kennedy C, Vardy J, Clarke S, van Zandwijk N, McCaughan BC.

Asbestos Diseases Research Institute, Bernie Banton Centre, Sydney, Australia.

Abstract

Introduction: Histological subtype is an established prognostic factor in malignant pleural mesothelioma (MPM). We retrospectively investigated the accuracy of classifying histological subtype on diagnostic biopsies and examined the impact of different diagnostic procedures on the outcome.

Methods: Consecutive patients with histologically confirmed MPM who underwent extrapleural pneumonectomy (EPP) from 1994 to 2009 were included. Patient records were reviewed, and the initial diagnoses of histological subtype were obtained. The archival EPP specimens were reviewed by a panel of pathologists. The histological subtype obtained at review was compared with the initial diagnosis.

Results: Eighty-five patients underwent EPP. Two patients achieved a pathological complete response after neoadjuvant chemotherapy, leaving 83 patients to be included in this review. Different diagnostic methods were used before EPP: 81% thoracoscopy; 7% thoracotomy; 11% computed tomography-guided procedure; and 1% other. Patients determined to have an epithelial subtype (n = 64) at EPP were diagnosed correctly at initial diagnostic biopsy in 84% of cases, whereas patients considered to have a biphasic subtype (n = 19) at EPP were diagnosed correctly at diagnostic biopsy in 26% of cases. The sensitivity and specificity of diagnostic biopsy for epithelial MPM was 93% and 31%, respectively. The overall subtype misclassification rate was 20%. Biopsy by thoracotomy was most accurate in subtype classification (83%) compared with thoracoscopy (74%) and computed tomography-guided procedure (44%).

Conclusions: The determination of histological subtype from a diagnostic biopsy is difficult due to sampling error, but an adequate specimen obtained from surgical biopsy increases the accuracy of subtype classification compared with radiological-guided biopsies.

Greillier L, Marco S, Barlesi F.

Service d’Oncologie Multidisciplinaire et Innovations Thérapeutiques, Université de la Méditerranée-Assistance Publique Hôpitaux de Marseille, Marseille, France.

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis, whose exposure to asbestos fibers is the main etiology. The incidence of MPM is anticipated to increase worldwide during the first half of this century. MPM is notoriously refractory to most treatments, and the only standard of care is cisplatin and antifolate first-line chemotherapy. The urgent need for additional therapeutic agents, in parallel with advances in the knowledge of the molecular events of oncogenesis, has resulted in the development of the so-called ‘targeted agents’ that specifically inhibit critical pathways in malignant cells and in their microenvironment. We carried out a comprehensive review of the literature from January 2000 to May 2010 on studies that assessed targeted agents for the systemic treatment of MPM. Although tyrosine kinase inhibitors directed against the epidermal growth factor and the platelet-derived growth factor receptors did not show significant clinical activity in phase II studies, some other targeted therapies seemed promising, notably histone deacetylase inhibitors and antiangiogenic agents. However, none of these has yet reached daily practice. That is the reason why efforts must continue in the area of clinical and translational research for MPM.

Zucali PA, Giovannetti E, Destro A, Mencoboni M, Ceresoli GL, Gianoncelli L, Lorenzi E, De Vincenzo F, Simonelli M, Perrino M, Bruzzone A, Thunnissen E, Tunesi G, Giordano L, Roncalli M, Peters GJ, Santoro A.

Department of Oncology, Biostatistics Unit, Istituto Clinico Humanitas IRCCS, Rozzano, Milan, Italy. paolo.zucali@humanitas.it

Abstract

Purpose: The pemetrexed/platinum agent combination represents the standard of care in first-line treatment for malignant pleural mesothelioma (MPM). However, there are no established indicators of responsiveness that can be used to optimize the treatment. This retrospective study aimed to assess the role of excision repair cross-complementing group-1 (ERCC1) and thymidylate synthase (TS) in tumors, and correlate expression levels and polymorphisms of these key determinants of drug activity with the outcome of MPM patients treated with carboplatin/pemetrexed in first-line setting. Experimental design: Analysis of TS and ERCC1 polymorphisms, mRNA and protein expression was done by PCR and immunohistochemistry [with the H-score (histologic score)] in tumor specimens from 126 MPM patients, including 99 carboplatin-/pemetrexed-treated patients.

Results: A significant correlation between low TS protein expression and disease control (DC) to carboplatin/pemetrexed therapy (P = 0.027), longer progression-free survival (PFS; P = 0.017), and longer overall survival (OS; P = 0.022) was found when patients were categorized according to median H-score. However, patients with the higher tertile of TS mRNA expression correlated with higher risk of developing progressive disease (P = 0.022), shorter PFS (P < 0.001), and shorter OS (P < 0.001). At multivariate analysis, the higher tertile of TS mRNA level and TS H-score confirmed their independent prognostic role for DC, PFS, and OS. No significant associations were found among ERCC1 protein expression, TS and ERCC1 polymorphisms, and clinical outcome.

Conclusions: In our series of carboplatin-/pemetrexed-treated MPM patients, low TS protein and mRNA levels were significantly associated to DC, improved PFS, and OS. Prospective trials for the validation of the prognostic/predictive role of TS in MPM patients treated with pemetrexed-based regimens are warranted.

Demmy TL, Platis IE, Nwogu C, Yendamuri S.

Department of Thoracic Surgery, Roswell Park Cancer Institute, Buffalo, New York.

Abstract

Mesothelioma is the most common primary pleural malignancy. Surgical therapy offers limited cure benefits at the cost of high morbidity. Although technically challenging and performed rarely, a less invasive approach to extrapleural pneumonectomy was developed with the intent to speed convalescence, hasten adjuvant therapies, improve quality of life, and reduce wound surface area for possible tumor contamination.

Aldieri E, Riganti C, Silvagno F, Orecchia S, Betta PG, Doublier S, Gazzano E, Polimeni M, Bosia A, Ghigo D.

Genetics, Biology and Biochemistry, University of Turino, Turino, Italy; University of Torino, Interdepartmental Center "G. Scansetti" for Studies on Asbestos and Other Toxic Particulates, Torino, Italy; University of Torino, Research Center on Experimental Medicine (CeRMS), Torino, Italy.

Abstract

Rationale: Asbestos is a naturally occurring fibrous silicate, whose inhalation is highly related to the risk of developing malignant mesothelioma (MM), and crocidolite is one of its most oncogenic types. The mechanism by which asbestos may cause MM is still unclear. We have previously observed that crocidolite in human MM cells (HMM) induces NF-kB activation and stimulates the synthesis of nitric oxide by inhibiting the RhoA signaling pathway.

Methods: In primary human mesothelial cells (HMC) and HMM cells exposed to crocidolite asbestos, co-incubated or not with antioxidants, we evaluated both cytotoxicity and oxidative stress induction (lipid peroxidation), then the effect of asbestos on the RhoA signaling pathway (RhoA GTP binding, Rho kinase activity, RhoA prenylation, hydroxy-3-methylglutharyl-CoA reductase activity). Results. In this paper we show that the reactive oxygen species generated by the incubation of crocidolite with both primary HMC and three human MM cell lines mediate the inhibition of 3-hydroxy-3-methylglutharyl-CoA reductase (HMGCR). Indeed the co-incubation of HMC and HMM cells with crocidolite together with antioxidants, such as Tempol, Mn-porphyrin and the association of superoxide dismutase and catalase, completely prevented the cytotoxicity and lipoperoxidation caused by crocidolite alone, as well as the decrease of HMGCR activity, and restored the RhoA/ROCK activity and the RhoA prenylation. The same effect was observed when the oxidizing agent menadione was administrated to the cells in place of crocidolite.

Conclusions: Such a mechanism could at least partly explain the effects exerted by crocidolite fibers in mesothelial cells.

Foss KM, Sima C, Ugolini D, Neri M, Allen KE, Weiss GJ.

*Translational Genomics Research Institute, Phoenix, Arizona; †Department of Oncology, Biology and Genetics, University of Genoa, Genoa; ‡Unit of Epidemiology, Biostatistics and Clinical Trials, National Cancer Research Institute, Genoa; §Rehabilitative Pneumology, IRCCS San Raffaele Pisana, Rome, Italy; and ∥Virginia G. Piper Cancer Center at Scottsdale Healthcare, Scottsdale, Arizona.

Abstract

Introduction: The ability to diagnose non-small cell lung cancer (NSCLC) at an early stage may lead to improved survival. The aim of this study was to identify differentially expressed serum-based microRNAs (miRNAs) between patients with early-stage NSCLC and controls. These miRNAs may serve as biomarkers for NSCLC early detection.

Methods: miRNA profiling was performed on total RNA extracted from serum obtained from 22 individuals (11 controls and 11 patients with early-stage NSCLC). Quantitative polymerase chain reaction (qPCR) was used to validate the profiling results in the discovery set and in a validation set of 31 controls and 22 patients with early-stage NSCLC. Additionally, six matched plasma samples (four NSCLC cases and two controls) and three serum mesothelioma samples were analyzed by qPCR. Receiver operating characteristic curves were generated for each possible combination of the miRNAs measured by qPCR.

Results: The expression of hsa-miR-1254 and hsa-miR-574-5p was significantly increased in the early-stage NSCLC samples with respect to the controls. Receiver operating characteristic curves plotting these two miRNAs were able to discriminate early-stage NSCLC samples from controls with 82% and 77% of sensitivity and specificity, respectively, in the discovery cohort and with 73% and 71% of sensitivity and specificity, respectively, in the validation cohort. The mesothelioma and plasma samples did not seem to classify into either NSCLC or control groups.

Conclusions: Serum miRNAs are differentially expressed between patients with early-stage NSCLC and controls. The utility of miR-1254 and miR-574-5p serum-based biomarkers as minimally invasive screening and triage tools for subsequent diagnostic evaluation warrants additional validation.

Lee HE, Kim HR.

Occupational Safety and Health Research Institute, KOSHA, Inchoen, Korea.

Abstract

Malignant mesothelioma and lung cancer are representative examples of occupational cancer. Lung cancer is the leading cause of cancer death, and the incidence of malignant mesothelioma is expected to increase sharply in the near future. Although information about lung carcinogen exposure is limited, it is estimated that the number of workers exposed to carcinogens has declined. The first official case of occupational cancer was malignant mesothelioma caused by asbestos exposure in the asbestos textile industry in 1992. Since then, compensation for occupational respiratory cancer has increased. The majority of compensated lung cancer was due to underlying pneumoconiosis. Other main causative agents of occupational lung cancer included asbestos, hexavalent chromium, and crystalline silica. Related jobs included welders, foundry workers, platers, plumbers, and vehicle maintenance workers. Compensated malignant mesotheliomas were associated with asbestos exposure. Epidemiologic studies conducted in Korea have indicated an elevated risk of lung cancer in pneumoconiosis patients, foundry workers, and asbestos textile workers. Occupational respiratory cancer has increased during the last 10 to 20 yr though carcinogen-exposed population has declined in the same period. More efforts to advance the systems for the investigation, prevention and management of occupational respiratory cancer are needed.

Murakami H, Mizuno T, Taniguchi T, Fujii M, Ishiguro F, Fukui T, Akatsuka S, Horio Y, Hida T, Kondo Y, Toyokuni S, Osada H, Sekido Y.

Authors’ Affiliations: Division of Molecular Oncology, Aichi Cancer Center Research Institute; Departments of Thoracic Surgery and Thoracic Oncology, Aichi Cancer Center Hospital; Departments of Cardio-Thoracic Surgery and Cancer Genetics, Program in Function Construction Medicine, and Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Abstract

Malignant mesothelioma (MM) is an aggressive neoplasm associated with asbestos exposure. We carried out genome-wide array-based comparative genomic hybridization analysis with 14 MM cell lines. Three cell lines showed overlapping homozygous deletion at chromosome 13q12, which harbored the LATS2 (large tumor suppressor homolog 2) gene. With 6 other MM cell lines and 25 MM tumors, we found 10 inactivating homozygous deletions or mutations of LATS2 among 45 MMs. LATS2 encodes a serine/threonine kinase, a component of the Hippo tumor-suppressive signaling pathway, and we transduced LATS2 in MM cells with its mutation. Transduction of LATS2 inactivated oncoprotein YAP, a transcriptional coactivator, via phosphorylation, and inhibited MM cell growth. We also analyzed LATS2 immunohistochemically and found that 13 of 45 MM tumors had low expression of LATS2. Because NF2 is genetically mutated in 40% to 50% of MM, our data indicate that Hippo pathway dysregulation is frequent in MM cells with inactivation of LATS2 or an upstream regulator of this pathway, Merlin, which is encoded by NF2. Thus, our results suggest that the inactivation of LATS2 is one of the key mechanisms for constitutive activation of YAP, which induces deregulation of MM cell proliferation.

Ou WB, Hubert C, Corson JM, Bueno R, Flynn DL, Sugarbaker DJ, Fletcher JA.

Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA.

Abstract

The receptor tyrosine kinases (RTKs) epidermal growth factor receptor (EGFR) and MET are activated in subsets of mesothelioma, suggesting that these kinases might represent novel therapeutic targets in this notoriously chemotherapy-resistant cancer. However, clinical trials have shown little activity for EGFR inhibitors in mesothelioma. Despite the evidence for RTK activation in mesothelioma pathogenesis, it is unclear whether transforming activity is dependent on an individual kinase oncoprotein or the coordinated activity of multiple kinases. Using phospho-RTK and immunoblot assays, we herein demonstrate activation of multiple RTKs (EGFR, MET, AXL, and ERBB3) in individual mesothelioma cell lines but not in normal mesothelioma cells. Inhibition of mesothelioma multi-RTK signaling was accomplished using combinations of RTK direct inhibitors or by inhibition of the RTK chaperone, heat shock protein 90 (HSP90). Multi-RTK inhibition by the HSP90 inhibitor 17-allyloamino-17-demethoxygeldanamycin (17-AAG) had a substantially greater effect on mesothelioma proliferation and survival compared with inhibition of individual activated RTKs. HSP90 inhibition also suppressed phosphorylation of downstream signaling intermediates (AKT, mitogen-activated protein kinase, and S6); upregulated the p53, p21, and p27 cell cycle checkpoints; induced G(2) phase arrest; induced caspase 3/7 activity; and led to an increase in the sub-G(1) apoptotic population. These compelling proapoptotic and antiproliferative responses indicate that HSP90 inhibition warrants clinical evaluation as a novel therapeutic strategy in mesothelioma.

Zardo P, Zhang R, Wiegmann B, Haverich A, Fischer S.

Department of Thoracic Surgery and Lung Assist, Klinikum Ibbenbüren, Ibbenbüren, Germany.

Abstract

Background: We sought to analyze the efficacy of a bovine pericardial patch (PeriGuard®) for diaphragmatic repair.

Methods: Seven consecutive patients (6 males, median age 56 years) scheduled for diaphragmatic resection and/or repair were enrolled in this study. In all cases diaphragmatic repair was performed with a PeriGuard Repair Patch® (Synovis, St. Paul, MN, USA). At follow-up (median: 12 months; range: 6-18 months), quality of life, signs of reherniation and incorporation of mesh were assessed through clinical examination, blood samples and CT or MRT scan.

Results: Diagnosis on admission included sarcoma (n = 2), mesothelioma (n = 1), squamous cell carcinoma (n = 1), parachordoma (n = 1) and large congenital or posttraumatic herniation (n = 2). At follow-up successful diaphragmatic repair with no signs of reherniation, graft dehiscence or seroma formation was confirmed for all patients. Recorded inflammatory markers [C-reactive protein (CRP), white blood cell count (WBC) and procalcitonin (PCT)] reached their peak values between postoperative day (POD) 4 and POD 7. Values ranged from 122-282 mg/L for CRP, 0.4-4.6 µg/L for PCT and 6.2-15.6 Tsd/µL for WBC. Overall oncological results were good and 5 out of 6 survivors reported a fully reestablished quality of life.

Conclusion: We consider the PeriGuard Repair Patch® a viable alternative to synthetic materials for diaphragm replacement. Moreover, we advise carrying out cautious follow-up in patients undergoing extensive oncological resection to learn more about the biological behavior of the bovine PeriGuard Repair Patch® after diaphragmatic repair.