Journal of Thoracic Oncology

About the journal

Publisher: Elsevier
Published: 2006 to the present, United States
Language: English
ISSN: 1556-0864 (print), 1556-1380 (electronic)
Its record in the NLM Catalog

2020s

Advances in the Basic Sciences in Thoracic Oncology in the Last 20 Years and Their Translational Impact. M. Carbone, C. Amos, R.L. Attanoos, et al. 2026;21(1):41-76. Review PubMed · Publisher · Free full text

Abstract

In this article, we summarize the progress made in lung cancer, mesothelioma, and thymic epithelial malignancy during the period 2005-2025. We enlisted multidisciplinary thoracic oncologic experts to tackle this task. The main focus of the article concerns how basic science with translational impact has improved the diagnosis, prognosis, and therapy of these cancers. During the past 20 years, we have come to the realization that "lung cancer" is a name that encompasses tumors with vast histologic, immune, and genomic differences that in turn influence prognosis and response to therapy. For example, programmed death-ligand 1 levels are being used as an immune signature which guides the use of immunotherapy. There is an 85% higher risk for developing lung cancer among first-degree relatives of patients with lung cancer. Accordingly, an increasing number of lung cancers are being identified in carriers of predisposing germline pathogenic inactivating mutations, suggesting that screening programs for early lung cancer detection may benefit family members. Underscoring the role of genetics, and the importance of germline testing, a different variant of mesothelioma has been identified developing in carriers of inactivating heterozygous germline mutations of BAP1 and of other tumor suppressor genes, including a new variant of mesothelioma caused by fusion genes. These variants of mesothelioma are characterized by specific histologic and molecular genetic alterations. These patients benefit from screening programs as they are at risk of multiple malignancies, their tumors are usually much less aggressive, and they are more responsive to therapy compared with sporadic, asbestos-induced mesotheliomas. Thus, the tailored therapeutic approach that is described here for lung cancer may extend to patients with mesothelioma, rather than the previous "one therapy fits all" approach. Progress in the rare thymic epithelial tumors has been less marked; however, recent insights into the biology of thymic tumors have resulted in the development of clinically relevant interventions.

Copyright © 2025 International Association for the Study of Lung Cancer. All rights reserved.
Amivantamab Induces Immune-Mediated Cytotoxicity in Mesothelioma Through EGFR and MET Engagement. S. Suzuki, K. Parikh, E. Tolosa, et al. 2026;21(11):103993. PubMed · Publisher · Free full text

Abstract

Introduction: Diffuse pleural mesothelioma (DPM) is a lethal malignancy with no approved therapies directly targeting tumor cells. Based on reports that EGFR and MET are frequently expressed in DPM, we sought to systematically assess their co-expression and determine the preclinical activity of amivantamab, a bispecific antibody that targets EGFR and MET.

Methods: We evaluated EGFR and MET expression in patient cohorts and cell lines using transcriptomic analysis, immunohistochemistry, and biochemical assays. The mechanistic actions of amivantamab, including receptor internalization, signaling blockade, and immune-mediated cytotoxicity, were assessed using in vitro co-culture systems with peripheral blood mononuclear cells and natural killer (NK) cells. In vivo efficacy was evaluated in mesothelioma patient-derived xenograft models using immunodeficient mice reconstituted with human NK cells.

Results: Transcriptomic and single-cell RNA-sequencing analyses of DPM patient cohorts revealed frequent co-expression of EGFR and MET, predominantly in malignant cells. Immunohistochemical analyses confirmed EGFR and MET protein expression across mesothelioma histologic subtypes. In vitro, amivantamab preferentially bound to DPM cells, inhibited ligand-induced EGFR and MET signaling, and promoted receptor internalization. Co-culture experiments demonstrated that amivantamab induced dose-dependent cytotoxicity through NK cell-mediated antibody-dependent cellular cytotoxicity. In multiple mesothelioma patient-derived xenograft models, the combination of amivantamab and NK cells significantly reduced tumor growth without overt toxicity.

Conclusions: Amivantamab demonstrates robust preclinical antitumor activity in mesothelioma, primarily through innate immune-mediated cytotoxicity associated with EGFR and MET engagement. These findings support the clinical evaluation of bispecific EGFR/MET-targeting antibodies in mesothelioma.

Copyright © 2026 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Moving Beyond Morphology: Toward a Morpho-Molecular Classification of Pleural Mesothelioma. G. Drevet, L. Kalson, L. Mangé, et al. 2026;21(5):103551. Review PubMed · Publisher · Free full text

Abstract

Despite recent advances in the treatment of pleural mesothelioma, it remains a challenging and heterogeneous disease, with limited options for patients. Survival rates have only marginally improved in the past years, highlighting the need for a better biological understanding of the disease for the translation into clinical practice. Although recent years have seen substantial progress in genomics and molecular pathology, much of the existing literature has focused on morphology-correlated changes, with molecular, immunohistochemical, clinical, and blood biomarkers largely studied in a correlative framework. Despite these efforts, TNM classification remains the most powerful predictor of survival and one of the most important parameters to guide therapy in clinical practice. However, emerging evidence reveals that histology alone fails to capture the full heterogeneity of the disease, leading to suboptimal diagnostic, prognostic, and therapeutic approaches. This review summarizes recent major molecular findings relating not only to histology but also ploidy, tumor microenvironment, and methylation-which together offer a more comprehensive understanding of interpatient heterogeneity. In light of these results, we discuss the potential for a new morpho-molecular classification based on these molecular findings to overcome the current clinical challenges. Future directions for the field are also proposed, including the potential for emerging technologies such as single-cell, spatial omics, and artificial intelligence to fill in the gaps of bulk studies and unveil clinically relevant information about pleural mesothelioma tumor heterogeneity.

Copyright © 2026 World Health Organization,. Published by Elsevier Inc. All rights reserved.
Multiomic, Histologic, and scRNA-seq Profiling of Pleural Mesothelioma Reveals Negative Prognosis Associated With a Novel Uncommitted Molecular Phenotype. D.T. Severson, S. Freyaldenhoven, B. Wadowski, et al. 2026;21(4):103529. PubMed · Publisher · Free full text

Abstract

Introduction: Multiomics pleural mesothelioma (PM) studies have identified prognostic molecular subsets of PM histologic types, epithelioid (ePM), biphasic (bPM), and sarcomatoid (sPM), defined by relative tumor cell content. However, the underlying biology modulating survival remains unknown.

Methods: Using 93 samples from 40 patients, we performed single-cell RNA sequencing (scRNA-seq), bulk exome and RNA sequencing, optical genome mapping, spatial transcriptomics, and histologic analyses to identify candidate drivers and prognostic biomarkers of malignant cell (MC) state.

Results: We identified a novel uncommitted MC state enriched in bPM tumors. Using inferred copy number variants, we observed all three MC states within individual clones suggesting MC state is not clonally restricted. We identified TGF-β and GAS6-AXL signaling as candidate MC state drivers for further study. Finally, we validated two prognostic MC state immunohistochemistry biomarkers, MEST (uncommitted) and MSLN (epithelioid).

Conclusions: These multiomic, scRNA-seq analyses of primary patient tissues provide new candidate drivers of MC state and novel biomarkers to improve patient stratification. Further experimental exploration and clinical validation of these findings may reveal new treatment strategies and refine current clinical decision-making in PM.

Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.
Clinical and Pathologic Phenotyping of Mesotheliomas Developing in Carriers of Germline BAP1 Mutations. M. Carbone, M. Minaai, M. Kittaneh, et al. 2025;20(11):1683-1698. PubMed · Publisher · Free full text

Abstract

Introduction: Mesothelioma is frequent among carriers of inactivating heterozygous germline BAP1 mutations (BAP1+/-). We studied whether the natural history and the pathology of mesotheliomas in BAP1+/- carriers differed from sporadic, not genetically related, mesotheliomas.

Methods: During 1999 to 2024, we studied 47 families carrying BAP1+/- transmitted in a Mendelian fashion. We characterized these mutations, collected family history, clinical records, prepared family pedigrees, and diagnosed their mesotheliomas.

Results: We identified 34 different germline inactivating mutations. Among 238 BAP1+/- carriers aged 27 to 81 years, 84 were diagnosed with mesothelioma (35%) and one of 84 had evidence of asbestos exposure. No mesothelioma was recorded among 123 siblings, first- or second-degree relatives who did not inherit BAP1+/- (p < 0.0001). The 84 patients with BAP1+/- developed mesothelioma at a relatively young age; 45.2% developed multiple cancers. Patients with BAP1+/- had a florid, diffuse mesothelial hyperplasia often present in both pleural cavities, peritoneum and pericardium. Thoracoscopy and laparoscopy results revealed several multicavity approximately 1 to 3 mm whitish flat lesions, but imaging result was usually negative for cancer. Histology results revealed epithelioid cells lacking BAP1 nuclear staining arranged in tubulopapillary and trabecular architectures, focally invading submesothelial adipose tissue. These findings may lead to the diagnosis of stage IV metastatic mesothelioma. However, we found that these tumors remain indolent for years, and, at this early stage, patients do not require aggressive therapy. We refer to these tumors as "low-grade-germline-mutant-BAP1-associated-mesotheliomas, L-BAM" to distinguish them from aggressive, therapy-resistant, sporadic mesotheliomas. For the 1/3 of patients who developed lesions visible by imaging, surgery, chemotherapy, or a combination of both led to survival of several years, and some were cured. Deep invasion by mesothelioma cells with a solid architecture is rare: these cases have poor survival.

Conclusions: Compared with sporadic mesotheliomas, mesotheliomas developing in BAP1+/- carriers are a different disease, biologically, histologically, and clinically; these patients require a tailored clinical approach.

Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.
Interferon Epsilon Loss Is Elusive 9p21 Link to Immune-Cold Tumors, Resistant to Immune Checkpoint Therapy, and Endogenous CXCL9/10 Induction. X. Zhao, B. Liu, W.N. William, et al. 2025;20(9):1177-1236. Review PubMed · Publisher · Free full text

Abstract

Introduction: Copy number alterations of chromosome 9p, or parts thereof, impair immune response and confer immune-checkpoint therapy (ICT) resistance by direct elimination of immune-regulatory genes on this arm, notably interferon (IFN)-γ (at 9p24.1) and type I IFN (IFN-I) cluster (9p21.3) genes. Nevertheless, the primary 9p-loss human tumor immune readout is indirect (CXCL9/10 depletion at 4q21.1), and molecular alteration of chromosomes with engineered tandem elements-engineered 9p21.3-syntenic deletions in mice, Cdkn2a/b±Mtap (ΔS) versus larger Cdkn2a/b+Mtap+IFN-I (ΔL), revealed the causal link of IFN-I, primarily IFNϵ, to immune evasion.

Methods: This report updates and explicates the rapidly emerging body of clinical 9p ICT-cohort data and executes human (tumor, cell line) and mouse-model intrinsic 9p, IFN-I, and tumor-immune microenvironment CXCL9/10 deconvolution, mediation, and experimental studies. We analyzed CXCL9/10-CXCR3 cell sources and regulation by 9p deletion (size and depth) and mouse spatial single-cell RNA sequencing (scRNA-seq) syntenic chr4qC4 IFN-I (ΔS versus ΔL immune-evasive model) studies of immune-cell type, subtype, and subcluster Cxcl9/10+ numbers, fractions, and per-cell expression.

Results: Chr9p (9p, 9p21.3, 9p24.1) copy number loss is associated with immune-cold, programmed cell death protein 1 axis ICT-resistant human papillomavirus-negative head and neck squamous cancer, nonsquamous NSCLC, melanoma, urothelial cancer, and mesothelioma (13 reports, 36 ICT cohorts; <4 y). IFN-I has been associated with IFNα and ICT resistance. In human papillomavirus-negative head and neck squamous cancer, IFNE was the most highly expressed (and suppressed in 9p loss) IFN-I gene in tumors and cell lines, driven by 9p21.3 (q = 0.03; versus 9p24.1, q = 0.27); direct link to effector T-cell suppression (CD8 strongest, p = 0.006; mediation analysis), exhibited striking TP53 mutation co-occurrence and IFN-response pathway depletion. Progressively deep 9p21.3 loss (wild-type, shallow, deep) correlated with progressive IFNE and CXCL9/10-CXCR3 suppression; 9p21.3 ΔS (versus ΔL) IFN-I impact on CD8, NK (CD4, B, CD103) levels. Pan-tumor IFNE loss/tumor-immune microenvironment patterns were profoundly tissue-specific (Z ≤ 1.95 in 4/34 tumor types). IFN-intact ΔS (versus ΔL) KPC pancreatic model was linked to Cxcl9/10+ dendritic cell (DC), macrophage, and neutrophil number (confirmed in KPL-3M nonsquamous NSCLC), and macrophage per-cell expression. DC and macrophage subclustering revealed heterogeneity at the level of M1, Ccl5, and conventional type 1 DC (cDC1), particularly high in ΔS.

Conclusion: IFNϵ is the elusive, cell-intrinsic 9p21 IFN-I signal to human CD8 T-cell, myeloid DC, CXCL9/10, murine DC, and macrophage subtype and subcluster Cxcl9/10 expression. 9p-loss IFN-I and IFN-γ pathway (e.g., JAK2) genes at p21 and p24 lack the capacity of endogenous CXCL9/10 induction in an immune-desert, ICT-resistant state. These findings, 9p-loss/ICT-resistance data, and DC vaccine lung trials have led to a DC-CXCL9/10 vaccine, designed to bypass the severe chemokine deficit in 9p-loss tumors.

Copyright © 2024. Published by Elsevier Inc.
Prospective Analysis of Mesotheliomas in Subjects With BAP1 Cancer Syndrome: Clinical Characteristics and Epigenetic Correlates of Disease. X. Wu, F.V. Hernandez, H. Wang, et al. 2025;20(11):1699-1715. PubMed · Publisher · Free full text

Abstract

Introduction: Although mesotheliomas are the most common malignancies identified in BAP1 cancer syndrome (BCS), the prevalence and natural history of the neoplasms have not been elucidated. Protocol NCT04431024 was initiated to prospectively evaluate whether high-resolution computed tomography (CT) imaging and minimally invasive surgical evaluation could facilitate detection and surveillance of mesotheliomas in subjects with germline BAP1 mutations.

Methods: Subjects above or equal to 33 years of age with or without prior malignancies underwent CT imaging followed by bilateral thoracoscopies and laparoscopies. CT imaging and intraoperative findings were objectively scored; surgical biopsies were interpreted by two expert pathologists. Skin, peripheral blood mononuclear cells, plasma, serum, and tumor biopsies were collected for correlative research studies.

Results: A total of 50 subjects with 32 germline BAP1 mutations were enrolled between March 2021 and July 2024. Median follow-up was 21.8 months (range: 1.7-41.1 mo). Furthermore, 16 sites of prior mesothelioma in 15 patients were excluded from the analysis. Surgical evaluation identified diffuse mesotheliomas in 39 of 45 subjects (87%), affecting 63 of 81 hemi-thoraces (78%) and 27 of 32 peritoneal cavities (84%); these mesotheliomas exhibited unique histologic features and slow clinical progression without therapeutic interventions. CT scans were unreliable for detecting or ruling out these mesotheliomas. Common and mutation specific, cancer-associated epigenomic alterations were identified in dermal fibroblasts and peripheral blood mononuclear cells, which correlated with cancer predilection in subjects with BCS.

Conclusions: Adult subjects with germline BAP1 mutations exhibit a high prevalence of subclinical, multicompartment mesotheliomas, which may be manifestations of systemic epigenetic burdens. These findings establish a paradigm for longitudinal assessment of subjects with BCS and support further efforts to identify and validate epigenetic biomarkers for the detection and surveillance of mesotheliomas and other malignancies arising in these individuals.

Published by Elsevier Inc.
Brief Report: Real-World Toxicity and Survival of Combination Immunotherapy in Pleural Mesothelioma-RIOMeso. N. McNamee, C. Harvey, L. Gray, et al. 2024;19(4):636-642. PubMed · Publisher

Abstract

Background: Australia has one of the highest rates of asbestos-associated diseases. Mesothelioma remains an area of unmet need with a 5-year overall survival of 10%. First-line immunotherapy with ipilimumab and nivolumab is now a standard of care for unresectable pleural mesothelioma following the CheckMate 743 trial, with supportive data from the later line single-arm MAPS2 trial. RIOMeso evaluates survival and toxicity of this regimen in real-world practice.

Methods: Demographic and clinicopathologic data of Australian patients treated with ipilimumab and nivolumab in first- and subsequent-line settings for pleural mesothelioma were collected retrospectively. Survival was reported using the Kaplan-Meier method and compared between subgroups with the log-rank test. Toxicity was investigator assessed using Common Terminology Criteria for Adverse Events version 5.0.

Results: A total of 119 patients were identified from 11 centers. The median age was 72 years, 83% were male, 92% had Eastern Cooperative Oncology Group less than or equal to 1, 50% were past or current smokers, and 78% had known asbestos exposure. In addition, 50% were epithelioid, 19% sarcomatoid, 14% biphasic, and 17% unavailable. Ipilimumab and nivolumab were used first line in 75% of patients. Median overall survival (mOS) was 14.5 months (95% confidence interval [CI]: 13.0-not reached [NR]) for the entire cohort. For patients treated first line, mOS was 14.5 months (95% CI: 12.5-NR) and in second- or later-line patients was 15.4 months (95% CI: 11.2-NR). There was no statistically significant difference in mOS for epithelioid patients compared with nonepithelioid (19.1 mo [95% CI: 15.4-NR] versus 13.0 mo [95% CI: 9.7-NR], respectively, p = 0.064). Furthermore, 24% of the patients had a Common Terminology Criteria for Adverse Events grade greater than or equal to 3 adverse events, including three treatment-related deaths. Colitis was the most frequent adverse event.

Conclusions: Combination immunotherapy in real-world practice has poorer survival outcomes and seems more toxic compared with clinical trial data. This is the first detailed report of real-world survival and toxicity outcomes using ipilimumab and nivolumab treatment of pleural mesothelioma.

Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
The International Association for the Study of Lung Cancer Mesothelioma Staging Project: Proposals for Revisions of the "T" Descriptors in the Forthcoming Ninth Edition of the TNM Classification for Pleural Mesothelioma. R.R. Gill, A.K. Nowak, D.J. Giroux, et al. 2024;19(9):1310-1325. PubMed · Publisher · Free full text

Abstract

Introduction: The primary tumor (T) component in the eighth edition of pleural mesothelioma (PM) staging system is based on pleural involvement and extent of invasion. Quantitative assessment of pleural tumor has been found to be prognostic. We explored quantitative and qualitative metrics to develop recommendations for T descriptors in the upcoming ninth edition of the PM staging system.

Methods: The International Association for the Study of Lung Cancer prospectively collected data on patients with PM. Sum of maximum pleural thickness (Psum) was recorded. Optimal combinations of Psum and eighth edition cT descriptors were assessed using recursive binary splitting algorithm, with bootstrap resampling to correct for the adaptive nature of the splitting algorithm, and validated in the eighth edition data. Overall survival (OS) was calculated by the Kaplan-Meier method and differences in OS assessed by the log-rank test.

Results: Of 7338 patients submitted, 3598 were eligible for cT analysis and 1790 had Psum measurements. Recursive partitioning identified optimal cutpoints of Psum at 12 and 30 mm, which, in combination with extent of invasion, yielded four prognostic groups for OS. Fmax greater than 5 mm indicated poor prognosis. cT4 category (based on invasion) revealed similar performance to eighth edition. Three eighth edition descriptors were eliminated based on low predictive accuracy. Eighth edition pT descriptors remained valid in ninth edition analyses.

Conclusion: Given reproducible prognostication by Psum, size criteria will be incorporated into cT1 to T3 categories in the ninth edition. Current cT4 category and all pT descriptors will be maintained, with reclassification of fissural invasion as pT2.

Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
The International Association for the Study of Lung Cancer Mesothelioma Staging Project: Proposals for the "N" Descriptors in the Forthcoming Ninth Edition of the TNM Classification for Pleural Mesothelioma. A. Bille, R.T. Ripley, D.J. Giroux, et al. 2024;19(9):1326-1338. PubMed · Publisher · Free full text

Abstract

Introduction: The International Association for the Study of Lung Cancer developed an international database to inform potential revisions in the ninth edition of the TNM classification of diffuse pleural mesothelioma (PM). This study analyzed the clinical and pathologic N categories to determine whether revisions were indicated relative to the eighth edition staging system.

Methods: Of 7338 PM cases diagnosed from 2013 to 2022 and 3598 met all inclusion criteria for planned analyses. Data on 2836 patients without metastases were included in this study. Overall survival (OS) was measured from date of diagnosis. Patients were included regardless of whether they received neoadjuvant treatment. For the pathologic N analysis, patients who underwent resection (extrapleural pneumonectomy or pleurectomy/decortication) were included. N subgroups were analyzed and OS assessed by the Kaplan-Meier method.

Results: The existing eighth edition N categories were performed adequately in the ninth edition data set. A median OS advantage was noted for clinical and pathologic N0 versus N1 patients: 23.2 versus 18.5 and 33.8 versus 25.0 months, respectively. Patients with resected pN0 had a 3-year OS of 48%. No difference in OS was noted for single- versus multiple-station nodal metastases. The number of nodal stations sampled at the time of resection was not associated with a difference in OS.

Conclusions: Data regarding clinical and pathologic N categories corroborate those used in the eighth edition. No changes in the N categories are recommended in the ninth edition of PM staging system.

Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
The International Association for the Study of Lung Cancer Mesothelioma Staging Project: Proposals for the M Descriptors in the Forthcoming Ninth Edition of the TNM Classification for Pleural Mesothelioma. H.L. Kindler, A. Rosenthal, D.J. Giroux, et al. 2024;19(11):1564-1577. PubMed · Publisher · Free full text

Abstract

Introduction: The International Association for the Study of Lung Cancer developed a global multicenter database to propose evidence-based revisions for the ninth edition of the TNM classification of pleural mesothelioma (PM). This study analyzes the M category to validate eighth edition M category recommendations.

Methods: Cases were submitted electronically or by transfer of existing institutional databases for patients with histologically or cytologically confirmed PM. The presence and number of metastases (single versus multiple) in each of eight organ systems were reported for patients with M1 disease at diagnosis. Overall survival (OS) was calculated by the Kaplan-Meier method. Differences in OS were assessed by log-rank test.

Results: Of 7338 submitted cases, 3598 were eligible and 3221 had sufficient data for clinical staging; 228 cases (7%) were M1. Median overall estimated survival was inferior for M1 compared with M0 patients: 10.5 months versus 21.5 months, respectively (p < 0.0001); estimated 1-year survival was 46% versus 71%, respectively. OS differences between M categories were preserved within histologic subgroups. Among 158 patients with organ-specific documentation of M1 disease, there was no statistically significant difference in OS between those with intrathoracic versus more distant metastatic disease (14.4 mo versus 10.9 mo, p = 0.64). No significant survival difference was detected between patients with metastatic disease in a single-organ system versus multiple-organ systems (12.6 mo versus 8.8 mo, p = 0.45).

Conclusions: This evidence-based analysis of the M category for PM conforms with the eighth edition M descriptors. No changes are proposed in the ninth edition of the mesothelioma M category.

Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
The International Association for the Study of Lung Cancer Pleural Mesothelioma Staging Project: Expanded Database to Inform Revisions in the Ninth Edition of the TNM Classification of Pleural Mesothelioma. A.S. Wolf, M. Eisele, D.J. Giroux, et al. 2024;19(8):1242-1252. PubMed · Publisher · Free full text

Abstract

The International Association for the Study of Lung Cancer collaborated with the International Mesothelioma Interest Group to propose the first TNM stage classification system for diffuse pleural mesothelioma in 1995, accepted by the Union for International Cancer Control and the American Joint Committee on Cancer for the sixth and seventh edition stage classification manuals. The International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee Mesothelioma Domain developed and analyzed an international registry of patients with pleural mesothelioma and updated TNM descriptors for the eighth edition of the stage classification system. To inform revisions for the forthcoming ninth edition of the TNM stage classification system, data submission was solicited for patients diagnosed between 2013 and 2022 with expanded data elements on the basis of the first project's exploratory analyses, including pleural thickness measurements, updated surgical nomenclature, and molecular markers. The resulting database consisted of a total of 3598 analyzable cases from Europe, Australia, Asia, North America, and South America, with a median age of 71 years (range: 18-99 y), 2775 (77.1%) of whom were men. With only 1310 patients (36.4%) undergoing curative-intent operations, this iteration of the database includes far more patients treated nonsurgically compared with prior. Four separate manuscripts on T, N, M, and stage groupings submitted to this journal will summarize analyses of these data and will serve collectively as the primary source of the proposed changes to the upcoming ninth edition of the pleural mesothelioma stage classification system.

Copyright © 2024. Published by Elsevier Inc.
The Interplay Between the Immune System, Tumor Suppressor Genes, and Immune Senescence in Mesothelioma Development and Response to Immunotherapy. A.E. Nel, E.N. Pavlisko, V.L. Roggli. 2024;19(4):551-564. Review PubMed · Publisher

Abstract

Despite efforts to ban asbestos mining and manufacturing, mesothelioma deaths in the United States have remained stable at approximately 2500 cases annually. This trend is not unique to the United States but is also a global phenomenon, associated with increased aging of populations worldwide. Although geoeconomic factors such as lack of regulations and continued asbestos manufacturing in resource-poor countries play a role, it is essential to consider biological factors such as immune senescence and increased genetic instability associated with aging. Recognizing that mesothelioma shares genetic instability and immune system effects with other age-related cancers is crucial because the impact of aging on mesothelioma is frequently assessed in the context of disease latency after asbestos exposure. Nevertheless, the long latency period, often cited as a reason for mesothelioma's elderly predominance, should not overshadow the shared mechanisms. This communication focuses on the role of immune surveillance in mesothelioma, particularly exploring the impact of immune escape resulting from altered TSG function during aging, contributing to the phylogenetic development of gene mutations and mesothelioma oncogenesis. The interplay between the immune system, TSGs, and aging not only shapes the immune landscape in mesothelioma but also contributes to the development of heterogeneous tumor microenvironments, significantly influencing responses to immunotherapy approaches and survival rates. By understanding the complex interplay between aging, TSG decline, and immune senescence, health care professionals can pave the way for more effective and personalized immunotherapies, ultimately offering hope for better outcomes in the fight against mesothelioma.

Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Did the Ban on Asbestos Reduce the Incidence of Mesothelioma?. M. Carbone, H. Yang, H.I. Pass, et al. 2023;18(6):694-697. Editorial · Comment PubMed · Publisher
Global Incidence, Risk Factors, and Temporal Trends of Mesothelioma: A Population-Based Study. J. Huang, S.C. Chan, W.S. Pang, et al. 2023;18(6):792-802. PubMed · Publisher

Abstract

Introduction: Mesothelioma is an uncommon type of cancer which has received little attention. This study aims to evaluate the global disease burden; trends of mesothelioma by age, sex, and geographic locations; and its risk factors on the population level.

Methods: The Global Cancer Observatory, Cancer Incidence in Five Continents Plus, and Global Burden of Disease were accessed for mesothelioma incidence and its risk factors worldwide. The associations between mesothelioma incidence and asbestos were evaluated for each country by multivariable linear regression analysis by sex and age. Average annual percentage change (AAPC) was calculated using Joinpoint regression to evaluate the epidemiologic trends of mesothelioma.

Results: The age-standardized rate of mesothelioma was 0.30 per 100,000 persons with Northern Europe reporting the highest incidence rates. The incidence rate of the male population was much higher than that of the females. Countries with higher human development index (β = 0.119, confidence interval [CI]: 0.073-0.166, p < 0.001), gross domestic product per capita (β = 0.133, CI: 0.106-0.161, p < 0.001), and asbestos exposure (β = 0.087, CI: 0.073-0.102, p < 0.001) had higher mesothelioma. The overall trend of mesothelioma incidence was decreasing, although an increase was observed in Bulgaria (AAPC: 5.56, 95% CI: 2.94-8.24, p = 0.001) and Korea (AAPC: 3.24, 95% CI: 0.08-6.49, p = 0.045).

Conclusions: There was a substantial declining incidence trend of mesothelioma in the past decade possibly related to the restriction of the use of asbestos in some countries. Meanwhile, the increasing trend in mesothelioma incidence observed in females might be indicative of an increase in environmental exposure to mineral fibers.

Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
The International Association for the Study of Lung Cancer Pleural Mesothelioma Staging Project: Updated Modeling of Prognostic Factors in Pleural Mesothelioma. A.S. Wolf, A. Rosenthal, D.J. Giroux, et al. 2023;18(12):1689-1702. PubMed · Publisher · Free full text

Abstract

Introduction: The International Association for the Study of Lung Cancer developed an international pleural mesothelioma database to improve staging. Data entered from 1995 to 2009 (training data set) were analyzed previously to evaluate supplemental prognostic factors. We evaluated these factors with new clinical data to determine whether the previous models could be improved.

Methods: Patients entered into the database from 2009 to 2019 (validation cohort) were assessed for the association between previous prognosticators and overall survival using Cox proportional hazards regression with bidirectional stepwise selection. Additional variables were analyzed and models were compared using Harrell's C-index.

Results: The training data set included 3101 patients and the validation cohort, 1733 patients. For the multivariable pathologic staging model applied to the training cohort, C-index was 0.68 (95% confidence interval [CI]: 0.656-0.705). For the validation data set (n = 497), C-index was 0.650 (95% CI: 0.614-0.685), and pathologic stage, histologic diagnosis, sex, adjuvant therapy, and platelet count were independently associated with survival. Adding anemia to the model increased the C-index to 0.652 (95% CI: 0.618-0.686). A basic presentation model including all parameters before staging yielded a C-index of 0.668 (95% CI: 0.641-0.695). In comparison, the European Organization for Research and Treatment of Cancer model yielded C-indices of 0.550 (95% CI: 0.511-0.589) and 0.577 (95% CI: 0.550-0.604) for pathologic staging and presentation models, respectively.

Conclusions: Although significant predictors differed slightly, the International Association for the Study of Lung Cancer training model performed well in the validation set and better than the model of the European Organization for Research and Treatment of Cancer. International collaboration is critical to improve outcomes in this rare disease.

Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Asbestos Lung Burden Does Not Predict Survival in Malignant Pleural Mesothelioma: A Necropsy-Based Study of 185 Cases. P.G. Barbieri, D. Consonni, A. Somigliana. 2022;17(8):1042-1049. PubMed · Publisher

Abstract

Introduction: Malignant pleural mesothelioma is an asbestos-related disease with poor survival. The prognostic role of histologic subtype is well established. Some studies (without a biological hypothesis) suggested that higher asbestos lung burden is associated with reduced survival.

Methods: We selected subjects from two series of necropsies: residents in Brescia province (North-West Italy) and workers (or persons living with them) employed in the Monfalcone shipyards (North-East Italy). Asbestos fibers and asbestos bodies in lung samples were counted using a scanning electron and an optical microscope, respectively. Separately in the two series, we analyzed median survival time and fitted multivariable Cox regression models (adjusted for sex, period and age at diagnosis, and histopatholocical diagnosis) to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for three levels of asbestos fiber counts (reference: <1 million fibers/g of dry lung tissue).

Results: We analyzed 185 necropsies, 83 in Brescia and 102 in Monfalcone. Despite a much higher lung burden in Monfalcone patients, median survival was slightly shorter in Brescia (8.3 mo) than in Monfalcone (10.2 mo). In Brescia, medium (1.0-9.9) and high (10+) fiber burden HRs were 0.91 (95% CI: 0.54-1.53) and 1.23 (95% CI: 0.41-3.70), respectively. In Monfalcone, the corresponding HRs were 1.18 (95% CI: 0.59-2.35) and 1.63 (95% CI: 0.77-3.45), respectively.

Conclusions: No relationship between asbestos lung burden and survival was found. Histologic subtype was the strongest prognostic determinant.

Copyright © 2022. Published by Elsevier Inc.
BAP1 Loss by Immunohistochemistry Predicts Improved Survival to First-Line Platinum and Pemetrexed Chemotherapy for Patients With Pleural Mesothelioma: A Validation Study. A. Louw, V. Panou, W.M. Szejniuk, et al. 2022;17(7):921-930. PubMed · Publisher

Abstract

Introduction: Pleural mesothelioma (PM) is an aggressive malignancy with no identified predictive biomarkers. We assessed whether tumor BAP1 status is a predictive biomarker for survival in patients receiving first-line combination platinum and pemetrexed therapy.

Methods: PM cases (n = 114) from Aalborg, Denmark, were stained for BAP1 on tissue microarrays. Demographic, clinical, and survival data were extracted from registries and medical records. Surgical cases were excluded. BAP1 status was associated with overall survival (OS) by Cox regression and Kaplan-Meier methods. Results were validated in an independent cohort from Perth, Australia (n = 234).

Results: BAP1 loss was found in 62% and 60.3% of all Danish and Australian samples, respectively. BAP1 loss was an independent predictor of OS in multivariate analyses corrected for histological subtype, performance status, age, sex, and treatment (hazard ratio = 2.49, p < 0.001, and 1.48, p = 0.01, respectively). First-line platinum and pemetrexed-treated patients with BAP1 loss had significantly longer median survival than those with retained BAP1 in both the Danish (20.1 versus 7.3 mo, p < 0.001) and Australian cohorts (19.6 versus 11.1 mo, p < 0.01). Survival in patients with BAP1 retained and treated with platinum and pemetrexed was similar as in those with best supportive care. There was a higher OS in patients with best supportive care with BAP1 loss, but it was significant only in the Australian cohort (16.8 versus 8.3 mo, p < 0.01).

Conclusions: BAP1 is a predictive biomarker for survival after first-line combination platinum and pemetrexed chemotherapy and a potential prognostic marker in PM. BAP1 in tumor is a promising clinical tool for treatment stratification.

Copyright © 2022 International Association for the Study of Lung Cancer. All rights reserved.
Does the Amount of Asbestos Exposure Influence Prognosis?. H. Yang, G. Gaudino, F. Bardelli, et al. 2022;17(8):949-952. Editorial · Comment PubMed · Publisher
Medical and Surgical Care of Patients With Mesothelioma and Their Relatives Carrying Germline BAP1 Mutations. M. Carbone, H.I. Pass, G. Ak, et al. 2022;17(7):873-889. Review PubMed · Publisher · Free full text

Abstract

The most common malignancies that develop in carriers of BAP1 germline mutations include diffuse malignant mesothelioma, uveal and cutaneous melanoma, renal cell carcinoma, and less frequently, breast cancer, several types of skin carcinomas, and other tumor types. Mesotheliomas in these patients are significantly less aggressive, and patients require a multidisciplinary approach that involves genetic counseling, medical genetics, pathology, surgical, medical, and radiation oncology expertise. Some BAP1 carriers have asymptomatic mesothelioma that can be followed by close clinical observation without apparent adverse outcomes: they may survive many years without therapy. Others may grow aggressively but very often respond to therapy. Detecting BAP1 germline mutations has, therefore, substantial medical, social, and economic impact. Close monitoring of these patients and their relatives is expected to result in prolonged life expectancy, improved quality of life, and being cost-effective. The co-authors of this paper are those who have published the vast majority of cases of mesothelioma occurring in patients carrying inactivating germline BAP1 mutations and who have studied the families affected by the BAP1 cancer syndrome for many years. This paper reports our experience. It is intended to be a source of information for all physicians who care for patients carrying germline BAP1 mutations. We discuss the clinical presentation, diagnostic and treatment challenges, and our recommendations of how to best care for these patients and their family members, including the potential economic and psychosocial impact.

Copyright © 2022 International Association for the Study of Lung Cancer. All rights reserved.
Meningiomas in Patients With Malignant Pleural Mesothelioma Harboring Germline BAP1 Mutations. Z.I. Hu, M. Miettinen, M. Quezado, et al. 2022;17(3):461-466. PubMed · Publisher · Free full text

Abstract

BAP1 is a tumor suppressor gene implicated in DNA repair and cell growth. Individuals with germline BAP1 mutations are at a significantly increased risk for developing many different cancers including malignant mesothelioma, uveal melanomas, cutaneous melanomas and renal clear cell carcinomas. Meningiomas with absent BAP1 expression have been reported to be more aggressive and present often with rhabdoid features. Here, we report the co-occurrence of pleural mesotheliomas and meningiomas in patients with germline BAP1 mutations. We describe the cancer history, family pedigrees, clinical management, and outcomes of four BAP1 germline mutation carrier families with a history of malignant mesothelioma and meningioma.

Copyright © 2021. Published by Elsevier Inc.
Molecular Characterization of Peritoneal Mesotheliomas. M. Offin, S.R. Yang, J. Egger, et al. 2022;17(3):455-460. PubMed · Publisher · Free full text

Abstract

Introduction: Malignant peritoneal mesothelioma (MPeM) is clinically distinct and less studied than malignant pleural mesothelioma. We report the genomic and immunophenotypic features of a prospectively collected MPeM cohort.

Methods: Next-generation sequencing (NGS) was performed on MPeM tumors. Genomic near-haploidization (GNH) was assessed. WT1, BAP1, mesothelin, VISTA, and programmed death-ligand 1 were evaluated by immunohistochemistry (IHC) when tissue was available. Overall survival was stratified by selected genomic and IHC features.

Results: A total of 50 consented patients with MPeM (45 epithelioid, 5 nonepithelioid) were studied exhibiting common alterations in BAP1 (60%; 30 of 50), NF2 (24%; 12 of 50) SETD2 (22%; 11 of 50), and TP53 (16%; 8 of 50). A total of 76% (38 of 50) of specimens were assessable for allele-specific copy number analysis; 8% (3 of 38) had GNH. IHC positivity rates were 93% (37 of 40) for mesothelin, 96% (46 of 48) for WT1, 50% (19 of 38) for programmed death-ligand 1, and 89% (34 of 38) for VISTA. BAP1 loss by IHC was observed in 76% (29 of 38), including five wild-type on NGS. Combining NGS and IHC for BAP1, overall survival was worse with alteration or loss compared with wild-type or retained in all patients (n = 37 versus 13, 43.8 versus 117.3 mo, p = 0.04) Three of 30 patients had a pathogenic germline variant: POT1 I78T, MUTYH R109Y, and BAP1 E402∗.

Conclusions: MPeM has distinct biology and genomic composition. CDKN2A/B alterations were rare in MPeM, whereas BAP1, NF2, TP53, SETD2, and LATS2 were common. BAP1 alteration/loss was associated with shorter survival when all patients were included. A notable minority of specimens had GNH associated with NF2, TP53, and SETDB1 mutations. Pathogenic germline mutations were found in 3 of 30 patients.

Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Multimodality Therapy in Patients With Primary Pericardial Mesothelioma. M. Offin, D.L. De Silva, J.L. Sauter, et al. 2022;17(12):1428-1432. PubMed · Publisher · Free full text

Abstract

Introduction: Primary pericardial mesothelioma (PPM) has no accepted standard-of-care treatment options with management and outcomes often extrapolated from diffuse pleural mesothelioma. Disease-specific research is needed to better define PPM. We report our institutional experience with PPM highlighting the potential role for multimodality therapy.

Methods: Patients with PPM diagnosed by a multidisciplinary team of medical oncologists, thoracic surgeons, thoracic pathologists, and radiologists between January 2011 and January 2022 were followed to February 2022. Clinicopathologic features and treatment outcomes were annotated. Overall survival (OS) was defined from the date of pathologic diagnosis.

Results: The median age at diagnosis of the 12 patients identified with having PPM was 51 (range: 21-71) years old. Most patients were of female sex (n = 8; 67%), 75% of the samples were epithelioid (n = 9), and 25% were nonepithelioid (two sarcomatoid and one biphasic). Most cases (92%, 11 of 12) had expression of at least two mesothelial markers on immunohistochemistry. The median OS of the cohort was 25.9 months. Five patients had an OS greater than 12 months; four of whom received pericardial radiation. Three of the patients who received radiation did so as part of a trimodality approach (surgical resection, adjuvant chemotherapy, and radiation); the OS for patients who received trimodality therapy was 70.3 months versus 8.2 months for those who did not.

Conclusions: PPM represents a distinct disease with no universally accepted treatment options. Our findings suggest that trimodality therapy may improve outcomes in selected patients with PPM.

Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Pulmonary Asbestos Fiber Burden Is Related to Patient Survival in Malignant Pleural Mesothelioma. S. Laaksonen, E. Kettunen, E. Sutinen, et al. 2022;17(8):1032-1041. PubMed · Publisher

Abstract

Introduction: Malignant pleural mesothelioma (MPM) is associated with poor prognosis and is strongly associated with occupational asbestos exposure. Given the importance of asbestos exposure in MPM pathogenesis, we retrospectively analyzed the types and concentrations of asbestos fibers within the lung tissues of patients with MPM and investigated their effects on all-cause mortality.

Methods: We formed a national data set of patients with MPM identified from the Finnish Cancer Registry and Statistics Finland. These data were merged with pulmonary asbestos fiber analysis results received from the Finnish Institute of Occupational Health.

Results: We identified 590 patients with MPM who underwent pulmonary asbestos fiber analysis. The median asbestos concentration within dry lung tissue was 3.20 million fibers/gram (range: 0 - 1700 million fibers/gram). Crocidolite and anthophyllite were the most prevalent asbestos fiber types detected in lung tissue. The multivariable risk of death analyses, where changes over time were accounted for, revealed that total asbestos fiber concentration was associated with increased mortality. Nevertheless, no difference in mortality was noted between different fiber types.

Conclusions: Our study revealed that pulmonary fiber concentrations correlated with the manner of asbestos usage. Anthophyllite was identified as the sole fiber in a sizable proportion of cases, supporting its independent role in the pathogenesis of MPM. Our findings suggest that asbestos fiber burden, but not fiber type, may have an impact on the prognosis of MPM.

Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Response to "Revisiting 'BAP1ness' in Malignant Pleural Mesothelioma". O.D. Røe, J. Creaney, BAP1 Study Group. 2022;17(8):e69-e70. Letter · Comment PubMed · Publisher
Tumor Junction Burden and Antigen Presentation as Predictors of Survival in Mesothelioma Treated With Immune Checkpoint Inhibitors. F. Kosari, M. Disselhorst, J. Yin, et al. 2022;17(3):446-454. PubMed · Publisher · Free full text

Abstract

Introduction: The favorable outcomes with immunotherapy for mesothelioma were somewhat unexpected because this tumor has a low tumor mutation burden which has been associated with benefit in other cancers. Because chromosomal rearrangements are common in mesothelioma and have neoantigenic potential, we sought to determine whether they are associated with survival in patients treated with immunotherapy.

Methods: Pleural biopsies of mesothelioma after at least one line of therapy were obtained from patients (n = 44) before treatment with nivolumab alone (NCT29908324) or in combination with ipilimumab (NCT30660511). RNA and whole-genome sequencing were performed to identify the junctions resulting from chromosomal rearrangements and antigen processing and presentation gene set expression. Associations with overall survival (OS) were estimated using Cox models. An OS cutoff of 1.5 years was used to distinguish patients with and without durable benefit for use in receiving operating characteristic curves.

Results: Although tumor junction burdens were not predictive of OS, we identified significant interactions between the junction burdens and multiple antigen processing and presentation gene sets. The "regulation of antigen processing and presentation of peptide antigen" gene set revealed an interaction with tumor junction burden and was predictive of OS. This interaction also predicted 1.5-year or greater survival with an area under the receiving operating characteristic curve of 0.83. This interaction was not predictive of survival in a separate cohort of patients with mesothelioma who did not receive immune checkpoint inhibitors.

Conclusions: Analysis of structural variants and antigen presentation gene set expression may facilitate patient selection for immune checkpoint inhibitors.

Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
DNA Methylation as a Diagnostic Biomarker for Malignant Mesothelioma: A Systematic Review and Meta-Analysis. J. Vandenhoeck, J.P. van Meerbeeck, E. Fransen, et al. 2021;16(9):1461-1478. Meta-analysis · Systematic review PubMed · Publisher

Abstract

Malignant mesothelioma is an aggressive cancer type linked to asbestos exposure. Because of several intrinsic challenges, mesothelioma is often diagnosed in an advanced disease stage. Therefore, there is a need for diagnostic biomarkers that may contribute to early detection. Recently, the epigenome of tumors is being extensively investigated to identify biomarkers. This manuscript is a systematic review summarizing the state-of-the-art research investigating DNA methylation in mesothelioma. Four literature databases (PubMed, Scopus, Web of Science, MEDLINE) were systematically searched for studies investigating DNA methylation in mesothelioma up to October 16, 2020. A meta-analysis was performed per gene investigated in at least two independent studies. A total of 53 studies investigated DNA methylation of 97 genes in mesothelioma and are described in a qualitative overview. Furthermore, ten studies investigating 13 genes (APC, CDH1, CDKN2A, DAPK, ESR1, MGMT, miR-34b/c, PGR, RARβ, RASSF1, SFRP1, SFRP4, WIF1) were included in the quantitative meta-analysis. In this meta-analysis, the APC gene is significantly hypomethylated in mesothelioma, whereas CDH1, ESR1, miR-34b/c, PGR, RARβ, SFRP1, and WIF1 are significantly hypermethylated in mesothelioma. The three genes that are the most appropriate candidate biomarkers from this meta-analysis are APC, miR-34b/c, and WIF1. Nevertheless, both study number and study objects comprised in this meta-analysis are too low to draw final conclusions on their clinical applications. The elucidation of the genome-wide DNA methylation profile of mesothelioma is desirable in the future, using a standardized genome-wide methylation analysis approach. The most informative CpG sites from this signature could then form the basis of a panel of highly sensitive and specific biomarkers that can be used for the diagnosis of mesothelioma and even for the screening of an at high-risk population of asbestos-exposed individuals.

Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Mesothelioma Risk Score: A New Prognostic Pretreatment, Clinical-Molecular Algorithm for Malignant Pleural Mesothelioma. B.Y. Yeap, A. De Rienzo, R.R. Gill, et al. 2021;16(11):1925-1935. PubMed · Publisher · Free full text

Abstract

Introduction: Prognostic models for malignant pleural mesothelioma have been limited to demographics, symptoms, and laboratory values. We hypothesize higher accuracy using both tumor and patient characteristics. The mesothelioma prognostic test (MPT) and molecular subtype based on claudin-15-to-vimentin expression ratio are molecular signatures associated with survival. Tumor volume (TV) has improved performance compared with clinical staging, whereas neutrophil-to-lymphocyte ratio (NLR) is prognostic for malignant pleural mesothelioma.

Methods: Tumor specimens and clinical data were collected prospectively from patients who underwent extrapleural pneumonectomy (EPP) or pleurectomy and decortication (PD) during 2007 to 2014. MPT and claudin-15-to-vimentin ratio were determined by real-time quantitative polymerase chain reaction, whereas TV was assessed from preoperative scans. Risk groups were derived from combinations of adverse factors on the basis of the Cox model. Predictive accuracy was assessed using Harrell's c-index.

Results: MPT, molecular subtype, TV, and NLR were independently prognostic in patients with EPP (N = 191), suggesting equal weighting in a final three-group model (c = 0.644). In the PD cohort (N = 193), MPT poor risk combined with TV greater than 200 cm3 was associated with triple the risk compared with other subgroups (hazard ratio = 2.94, 95% confidence interval: 1.70-5.09, p < 0.001) persisting when adjusted for molecular subtype, NLR, performance status, and serum albumin to yield a final three-group model (c = 0.641). The EPP and PD models achieved higher accuracy than published models (c ≤ 0.584, c ≤ 0.575) and pathologic staging (c = 0.554, c = 0.571).

Conclusions: The novel models use pretreatment parameters obtained from minimally invasive biopsy, imaging, and blood tests to evaluate the expected outcome of each type of surgery in newly diagnosed patients and improve stratification on clinical trials.

Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Serum Proteomics and Plasma Fibulin-3 in Differentiation of Mesothelioma From Asbestos-Exposed Controls and Patients With Other Pleural Diseases. S. Tsim, L. Alexander, C. Kelly, et al. 2021;16(10):1705-1717. PubMed · Publisher · Free full text

Abstract

Introduction: Malignant pleural mesothelioma (MPM) is difficult to diagnose. An accurate blood biomarker could prompt specialist referral or be deployed in future screening. In earlier retrospective studies, SOMAscan proteomics (Somalogic, Boulder, CO) and fibulin-3 seemed highly accurate, but SOMAscan has not been validated prospectively and subsequent fibulin-3 data have been contradictory.

Methods: A multicenter prospective observational study was performed in 22 centers, generating a large intention-to-diagnose cohort. Blood sampling, processing, and diagnostic assessment were standardized, including a 1-year follow-up. Plasma fibulin-3 was measured using two enzyme-linked immunosorbent assays (CloudClone [used in previous studies] and BosterBio, Pleasanton, CA). Serum proteomics was measured using the SOMAscan assay. Diagnostic performance (sensitivity at 95% specificity, area under the curve [AUC]) was benchmarked against serum mesothelin (Mesomark, Fujirebio Diagnostics, Malvern, PA). Biomarkers were correlated against primary tumor volume, inflammatory markers, and asbestos exposure.

Results: A total of 638 patients with suspected pleural malignancy (SPM) and 110 asbestos-exposed controls (AECs) were recruited. SOMAscan reliably differentiated MPM from AECs (75% sensitivity, 88.2% specificity, validation cohort AUC 0.855) but was not useful in patients with differentiating non-MPM SPM. Fibulin-3 (by BosterBio after failed CloudClone validation) revealed 7.4% and 11.9% sensitivity at 95% specificity in MPM versus non-MPM SPM and AECs, respectively (associated AUCs 0.611 [0.557-0.664], p = 0.0015) and 0.516 [0.443-0.589], p = 0.671), both inferior to mesothelin. SOMAscan proteins correlated with inflammatory markers but not with asbestos exposure. Neither biomarker correlated with tumor volume.

Conclusions: SOMAscan may prove useful as a future screening test for MPM in asbestos-exposed persons. Neither fibulin-3 nor SOMAscan should be used for diagnosis or pathway stratification.

Copyright © 2021 International Association for the Study of Lung Cancer. All rights reserved.
UHRF1 Is a Novel Druggable Epigenetic Target in Malignant Pleural Mesothelioma. E.S. Reardon, V. Shukla, S. Xi, et al. 2021;16(1):89-103. PubMed · Publisher · Free full text

Abstract

Introduction: Ubiquitin-like with plant homeodomain and ring finger domains 1 (UHRF1) encodes a master regulator of DNA methylation that has emerged as an epigenetic driver in human cancers. To date, no studies have evaluated UHRF1 expression in malignant pleural mesothelioma (MPM). This study was undertaken to explore the therapeutic potential of targeting UHRF1 in MPM.

Methods: Microarray, real-time quantitative reverse transcription-polymerase chain reaction, immunoblot, and immunohistochemistry techniques were used to evaluate UHRF1 expression in normal mesothelial cells (NMCs) cultured with or without asbestos, MPM lines, normal pleura, and primary MPM specimens. The impact of UHRF1 expression on MPM patient survival was evaluated using two independent databases. RNA-sequencing, proliferation, invasion, and colony formation assays, and murine xenograft experiments were performed to evaluate gene expression and growth of MPM cells after biochemical or pharmacologic inhibition of UHRF1 expression.

Results: UHRF1 expression was significantly higher in MPM lines and specimens relative to NMC and normal pleura. Asbestos induced UHRF1 expression in NMC. The overexpression of UHRF1 was associated with decreased overall survival in patients with MPM. UHRF1 knockdown reversed genomewide DNA hypomethylation, and inhibited proliferation, invasion, and clonogenicity of MPM cells, and growth of MPM xenografts. These effects were phenocopied by the repurposed chemotherapeutic agent, mithramycin. Biochemical or pharmacologic up-regulation of p53 significantly reduced UHRF1 expression in MPM cells. RNA-sequencing experiments exhibited the pleiotropic effects of UHRF1 down-regulation and identified novel, clinically relevant biomarkers of UHRF1 expression in MPM.

Conclusions: UHRF1 is an epigenetic driver in MPM. These findings support the efforts to target UHRF1 expression or activity for mesothelioma therapy.

Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Anaplastic Lymphoma Kinase Gene Rearrangement in Children and Young Adults With Mesothelioma. I. Mian, Z. Abdullaev, B. Morrow, et al. 2020;15(3):457-461. Case report PubMed · Publisher · Free full text

Abstract

Introduction: Children and young adults diagnosed with malignant mesothelioma may have unique genetic characteristics. In this study, we evaluated for the presence of the anaplastic lymphoma kinase (ALK) translocations in these patients.

Methods: In a prospective study of mesothelioma natural history (ClinicalTrials.gov number NCT01950572), we assessed for the presence of the ALK translocation in patients younger than 40 years, irrespective of the site of disease. The presence of this translocation was assessed by means of fluorescence in situ hybridization (FISH). If the patients tested positive for the ALK translocation, both immunohistochemistry and RNA sequencing were performed on the tumor specimen.

Results: Between September 2013 and December 2018, 373 patients were enrolled in the mesothelioma natural history study, of which 32 patients were 40 years old or younger at the time of their mesothelioma diagnosis. There were 25 patients with peritoneal mesothelioma, five with pleural mesothelioma, one with pericardial mesothelioma, and one with bicompartmental mesothelioma. Presence of an ALK translocation by FISH was seen in two of the 32 patients (6%) with mesothelioma. Both patients, a 14-year-old female and a 27-year-old male, had peritoneal mesothelioma and had no history of asbestos exposure, prior radiation therapy, or predisposing germline mutations. Neither had detectable ALK expression by immunohistochemistry. RNA sequencing revealed the presence of an STRN fusion partner in the female patient but failed to identify any fusion protein in the male patient.

Conclusions: Young patients with peritoneal mesothelioma should be evaluated for the presence of ALK translocations. Presence of this translocation should be assessed by FISH and these patients could potentially benefit from tyrosine kinase inhibitors targeting ALK.

Published by Elsevier Inc.
Comprehensive Molecular and Pathologic Evaluation of Transitional Mesothelioma Assisted by Deep Learning Approach: A Multi-Institutional Study of the International Mesothelioma Panel from the MESOPATH Reference Center. F. Galateau Salle, N. Le Stang, F. Tirode, et al. 2020;15(6):1037-1053. PubMed · Publisher · Free full text

Abstract

Introduction: Histologic subtypes of malignant pleural mesothelioma are a major prognostic indicator and decision denominator for all therapeutic strategies. In an ambiguous case, a rare transitional mesothelioma (TM) pattern may be diagnosed by pathologists either as epithelioid mesothelioma (EM), biphasic mesothelioma (BM), or sarcomatoid mesothelioma (SM). This study aimed to better characterize the TM subtype from a histological, immunohistochemical, and molecular standpoint. Deep learning of pathologic slides was applied to this cohort.

Methods: A random selection of 49 representative digitalized sections from surgical biopsies of TM was reviewed by 16 panelists. We evaluated BAP1 expression and CDKN2A (p16) homozygous deletion. We conducted a comprehensive, integrated, transcriptomic analysis. An unsupervised deep learning algorithm was trained to classify tumors.

Results: The 16 panelists recorded 784 diagnoses on the 49 cases. Even though a Kappa value of 0.42 is moderate, the presence of a TM component was diagnosed in 51%. In 49% of the histological evaluation, the reviewers classified the lesion as EM in 53%, SM in 33%, or BM in 14%. Median survival was 6.7 months. Loss of BAP1 observed in 44% was less frequent in TM than in EM and BM. p16 homozygous deletion was higher in TM (73%), followed by BM (63%) and SM (46%). RNA sequencing unsupervised clustering analysis revealed that TM grouped together and were closer to SM than to EM. Deep learning analysis achieved 94% accuracy for TM identification.

Conclusion: These results revealed that the TM pattern should be classified as non-EM or at minimum as a subgroup of the SM type.

Copyright © 2020. Published by Elsevier Inc.
Frequent Homozygous Deletions of Type I Interferon Genes in Pleural Mesothelioma Confer Sensitivity to Oncolytic Measles Virus. T. Delaunay, C. Achard, N. Boisgerault, et al. 2020;15(5):827-842. PubMed · Publisher

Abstract

Introduction: Oncolytic immunotherapy is based on the use of nonpathogenic replicative oncolytic viruses that infect and kill tumor cells exclusively. Recently, we found that the spontaneous oncolytic activity of the Schwarz strain of measles virus (MV) against human malignant pleural mesothelioma (MPM) depends on defects in the antiviral type I interferon (IFN-I) response in tumor cells.

Methods: In this study, we studied three independent human MPM bio-collections to identify the defects in the IFN-I responses in tumor cells.

Results: We show that the most frequent defect is the homozygous deletions (HDs) of all the 14 IFN-I genes (IFN-α and IFN-β) that we found in more than half of MV-sensitive MPM cell lines. These HDs occur together with the HDs of the tumor suppressor gene CDKN2A also located in the 9p21.3 chromosome region. Therefore, the IFN-I-/- MPM cell lines develop a partial and weak IFN-I response when they are exposed to the virus compared with that of normal cells and MV-resistant MPM cell lines. This response consists of the expression of a restricted number of IFN-stimulated genes that do not depend on the presence of IFN-I. In addition, the IFN-I-/- MPM cell lines infected by MV also develop a pro-inflammatory response associated with stress of the endoplasmic reticulum.

Conclusion: Our study emphasizes the link between HDs of IFN-I encoding genes and the CDKN2A gene in MPM and sensitivity to MV oncolytic immunotherapy.

Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
In Reply. A.G. Nicholson, J.L. Sauter, F. Galateau-Salle. 2020;15(6):e94-e95. Letter · Comment PubMed · Publisher
Is the Deciduoid Variant of Pleural Mesothelioma Significant?. A. Aujayeb, L. Taylor. 2020;15(6):e94. Letter · Comment PubMed · Publisher
Novel Germline Mutations in DNA Damage Repair in Patients with Malignant Pleural Mesotheliomas. R. Guo, M. DuBoff, G. Jayakumaran, et al. 2020;15(4):655-660. PubMed · Publisher · Free full text

Abstract

Introduction: Although next-generation sequencing (NGS) has brought insight into critical mutations or pathways (e.g., DNA damage sensing and repair) involved in the etiology of many cancers and has directed new screening, prevention, and therapeutic approaches for patients and families, it has only recently been used in malignant pleural mesotheliomas (MPMs).

Methods: We analyzed the blood samples from patients with MPM using the NGS platform MSK-IMPACT to explore cancer-predisposing genes. The loss-of-function variants or pathogenic entries were identified, and clinicopathologic information was collected.

Results: Of 84 patients with MPM, 12% (10 of 84) had pathogenic variants. Clinical characteristics were similar between cohorts, although patients with germline pathogenic variants were more likely to have more than two first-degree family members with cancer than those without germline mutations (40% versus 12%; Fisher's exact test, p < 0.05). Novel, deleterious variants in mesotheliomas included MutS homolog 3 (1% [one of 84]; 95% confidence interval [CI]: 0%-7%), breast cancer gene 1-associated ring domain 1 (1% [one of 84]; 95% CI: 0%-7%), and RecQ-like helicase 4 (2% [two of 84]; 95% CI: 0%-9%). Pathogenic variants previously reported on germline testing in patients with mesotheliomas were breast cancer gene 1-associated protein 1 (4% [three of 84]; 95% CI: 1%-10%), breast cancer gene 2 (1% [one of 84]; 95% CI: 0%-7%), and MRE11 homolog, double strand break repair nuclease (1% [one of 84]; 95% CI: 0%-7%). One patient (1% [one of 84]; 95% CI: 0%-7%) had a likely pathogenic alteration in SHQ1, H/ACA ribonucleoprotein assembly factor that has not been associated with a heritable susceptibility to cancer.

Conclusions: Our study lends further support for the role of aberrations in DNA damage repair genes in the pathogenesis of MPMs and suggests that targeting the members of these pathways for screening and treatment warrants further study.

Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Oncolytic Viral Therapy for Malignant Pleural Mesothelioma. H. Yang, D. Xu, Y. Gao, et al. 2020;15(7):e111-e113. Letter · Comment PubMed · Publisher

Summary

In this letter to the editor, the authors commented on a study by Delaunay et al. reporting that homozygous deletions (HDs) of type I interferon (IFN-I) genes were frequent in malignant pleural mesothelioma (MPM), co-occurred with HDs of CDKN2A, and were associated with sensitivity to oncolytic measles virus (MV) therapy. The authors noted that not all MV-sensitive cell lines in that study had an HD of IFNB1 (the letter cites "eight of 15"). They also noted that three of four MV-resistant cell lines had a CDKN2A HD. They took this to mean that other mechanisms were involved. Using data on The Cancer Genome Atlas (TCGA) pleural mesothelioma cohort (n = 81) from cBioPortal, they described the frequency and overlap of alterations in CDKN2A/B, BAP1, NF2 and TP53. Of the samples with CDKN2A HDs, 46.9% had a co-occurring BAP1 alteration. They identified genes correlated with BAP1 mRNA level and performed Gene Ontology and Reactome enrichment analysis. Genes highly negatively correlated with BAP1 expression (Spearman's r < -0.4, q-value < 0.01) were significantly enriched in the IFN-I pathway, but positively correlated genes were not. The authors suggested that MPM with BAP1 loss of function might be correlated with resistance to oncolytic viral therapy, and MPM with regular or high BAP1 expression with sensitivity. They concluded that combining CDKN2A and BAP1 status might be needed to select patients, and that further studies were warranted.

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Personalized Oncolytic Therapy: The Next Step Toward the Successful Clinical Application of Vaccine-Strain Measles Viruses for Cancer Therapy?. T. Peikert. 2020;15(5):689-691. Editorial · Comment PubMed · Publisher
Reply to Waller et al. Standardizing Surgical Treatment for Mesothelioma. J.S. Friedberg, M.J. Culligan, A.S. Tsao, et al. 2020;15(5):e75-e77. Letter · Comment PubMed · Publisher
Reply to: Oncolytic Viral Therapy for Malignant Pleural Mesothelioma. D. Jean, T. Delaunay, C. Meiller, et al. 2020;15(7):e113-e116. Letter · Comment PubMed · Publisher
Response to Letter to Editor by Cornelissen et al. R. Hassan, M. Miettinen. 2020;15(10):e169-e170. Letter · Comment PubMed · Publisher · Free full text
Response to Letter to the Editor by Yang et al. R. Hassan, M. Sengupta, J. Murai, et al. 2020;15(6):e91. Letter · Comment PubMed · Publisher
Sensitivity of Mesothelioma Cells to PARP Inhibitors Is Not Dependent on BAP1 but Is Enhanced by Temozolomide in Cells With High-Schlafen 11 and Low-O6-methylguanine-DNA Methyltransferase Expression. D. Rathkey, M. Khanal, J. Murai, et al. 2020;15(5):843-859. PubMed · Publisher · Free full text

Abstract

Introduction: BRCA1-associated protein-1 (BAP1), a nuclear deubiquitinase thought to be involved in DNA double-strand break repair, is frequently mutated in mesothelioma. Because poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPIs) induce synthetic lethality in BRCA1/2 mutant cancers, we evaluated whether BAP1 inactivating mutations confer sensitivity to PARPIs in mesothelioma and if combination therapy with temozolomide (TMZ) would be beneficial.

Methods: A total of 10 patient-derived mesothelioma cell lines were generated and characterized for BAP1 mutation status, protein expression, nuclear localization, and sensitivity to the PARPIs, olaparib, and talazoparib, alone or in combination with TMZ. BAP1 deubiquitinase (DUB) activity was evaluated by ubiquitin with 7-amido-4-methylcoumarin assay. BAP1 knockout mesothelioma cell lines were generated by CRISPR-Cas9. Because Schlafen 11 (SLFN11) and O6-methylguanine-DNA methyltransferase also drive response to TMZ and PARPIs, we tested their expression and relationship with drug response.

Results: BAP1 mutations or copy-number alterations, or both were present in all 10 cell lines. Nonetheless, four cell lines exhibited intact DUB activity and two had nuclear BAP1 localization. Half maximal-inhibitory concentrations of olaparib and talazoparib ranged from 4.8 μM to greater than 50 μM and 0.039 μM to greater than 5 μM, respectively, classifying them into sensitive (two) or resistant (seven) cells, independent of their BAP1 status. Cell lines with BAP1 knockout resulted in the loss of BAP1 DUB activity but did not increase sensitivity to talazoparib. Response to PARPI tended to be associated with high SLFN11 expression, and combination with temozolomide increased sensitivity of cells with low or no MGMT expression.

Conclusions: BAP1 status does not determine sensitivity to PARPIs in patient-derived mesothelioma cell lines. Combination of PARPI with TMZ may be beneficial for patients whose tumors have high SLFN11 and low or no MGMT expression.

Published by Elsevier Inc.
Standardizing Surgical Treatment of Malignant Pleural Mesothelioma. D.A. Waller, R. Bilancia, A. Bille, et al. 2020;15(5):e73-e74. Letter · Comment PubMed · Publisher
The Association of BAP1 Loss-of-Function With the Defect in Homologous Recombination Repair and Sensitivity to PARP-Targeted Therapy. H. Yang, D. Xu, Y. Gao, et al. 2020;15(6):e88-e90. Letter · Comment PubMed · Publisher

Summary

In this letter to the editor, the authors responded to a recent study by Rathkey et al., which reported that the sensitivity of patient-derived malignant pleural mesothelioma (MPM) cells to PARP inhibitors did not depend on BAP1 mutational status. Earlier studies had linked BAP1 loss-of-function to defects in DNA double-strand break repair and to susceptibility to PARP-targeted therapy. To cross-validate the Rathkey findings, the authors reanalysed public data. They took drug screening results from the Genomics of Drug Sensitivity in Cancer database and genetic data from the Cancer Cell Line Encyclopedia for 20 MPM cell lines, 8 with and 12 without BAP1 mutations. They also used data on The Cancer Genome Atlas pleural mesothelioma cohort (n = 82) from cBioPortal. Some BAP1-altered lines (H2804, IST-MES1, H2795) and some wild-type lines (H2803, MSTO-211H) were particularly sensitive to PARP inhibitors (talazoparib, olaparib, veliparib, rucaparib), based on low IC50 z-scores. Other BAP1-mutant lines (H2452, H2731, H2722) were highly resistant. The authors proposed four possible explanations for this heterogeneity: co-occurring mutations, BAP1 splice isoforms, BAP1 functions beyond DNA repair, and cell lineage. They concluded that BAP1 mutational status in MPM does not seem to affect sensitivity to PARP-targeted therapy and that further studies are required.

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Transitional Mesothelioma and Artificial Intelligence: Do We Need One More Subtype? and Do We Need Computers to Identify Them?. M. Carbone. 2020;15(6):884-887. Editorial · Comment PubMed · Publisher

2010s

A Proposed System Toward Standardizing Surgical-Based Treatments for Malignant Pleural Mesothelioma, From the Joint National Cancer Institute-International Association for the Study of Lung Cancer-Mesothelioma Applied Research Foundation Taskforce. J.S. Friedberg, M.J. Culligan, A.S. Tsao, et al. 2019;14(8):1343-1353. Review PubMed · Publisher

Abstract

This article is a joint effort arising from a task force formed at a National Cancer Institute-International Association for the Study of Lung Cancer-Mesothelioma Applied Research Foundation Mesothelioma Clinical Trials Planning Meeting, held at the NIH in March 2017. Malignant pleural mesothelioma remains one of the most virulent and recalcitrant malignancies, still considered incurable, and in desperate need of clinical trials in order to make progress for our patients. Although not standard of care, there is compelling evidence that a select subgroup of mesothelioma patients benefit from a surgery-based multimodal approach. As it is not possible to achieve a microscopically complete resection with mesothelioma, there appears to be no role for surgery alone. Thus, it is anticipated that significant strides in the surgery-based treatment of this cancer will require trials that determine which complementary treatments best augment the cytoreductive efficacy of surgery. Although lung-sacrificing surgery for mesothelioma is fairly standardized, approaches to lung-sparing surgery are highly variable and lung sparing surgery is emerging internationally as the dominant extirpative procedure for this cancer. It is not currently possible to rigorously assess the contribution of the adjuvant treatments combined with surgery because of the variability in procedures used to debulk this cancer, the extreme variability of the cancer itself, the variability in patient selection, the variability in treatment of the inevitable recurrence, and even the variability in follow up schedules. This article is an effort to address these problems by suggesting a more uniform approach to the surgical procedure and also proposing a series of data collection forms that could be adopted immediately, with any eye toward collecting the information that will be necessary to facilitate patient selection and determine which aspects of mesothelioma surgery can and should be standardized - with the goal being extension of life while maintaining quality of life as an equal priority. Furthermore, a completely original contribution in this manuscript is the proposal of a grading system that takes the information from the surgical procedure data forms and generates a completeness of resection score. This is the initial effort to establish a common denominator for mesothelioma surgery that will allow for more accurate comparison between surgical series and better assessment of the impact of the treatments combined with surgery.

Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.
Does Chromothripsis Make Mesothelioma an Immunogenic Cancer?. M. Carbone, H. Yang, G. Gaudino. 2019;14(2):157-159. Editorial · Comment PubMed · Publisher · Free full text

Summary

This editorial commented on a study by Mansfield et al., published in the same journal issue, that used mate-pair sequencing and RNA sequencing on tumors from 28 treatment-naive patients with malignant mesothelioma (MM). That study found chromosomal rearrangements, often with a pattern of chromothripsis or chromoplexy, across tumor subtypes. The editorial authors noted that earlier next-generation sequencing (NGS) studies had reported a low mutation burden in MM, averaging 23 mutations per biopsy specimen (range 2 to 51). This was hard to reconcile with older cytogenetic findings of many chromosomal abnormalities. They explained that NGS cannot reliably detect copy number changes, and that Mansfield et al. and an earlier study by Yoshikawa et al. found far more genetic alterations and identified chromothripsis as one cause. They described chromothripsis and stated that DNA damage in MM is enhanced by germline mutations and/or by exposure to asbestos and other carcinogenic fibers. They suggested that a higher-than-expected mutational burden might explain encouraging preliminary results with nivolumab. Mansfield et al. predicted neoantigens from the rearrangements and tested three synthetic peptides, linking predicted neoantigens to clonal expansion of tumor-infiltrating T cells. The editorial authors concluded that MM may be immunogenic. However, they cautioned that the advantage of immunotherapy over chemotherapy has not been demonstrated and that the existence of these neoantigens remains an unproven hypothesis.

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Effectiveness of Nivolumab on Sarcomatoid Malignant Pleural Mesothelioma With Eosinophilia and Eosinophilic Pleural Effusion. M. Yamazoe, H. Ozasa, Y.H. Kim. 2019;14(11):e251-e253. Case report · Letter PubMed · Publisher
Fatal Anti-Ma2 Encephalitis Related to Treatment of Malignant Pleural Mesothelioma With a Combination of Anti-Programmed Death 1 and Anti-Cytotoxic T-Lymphocyte Associated Protein 4 Antibodies. P. Du Rusquec, A. Peyre, F. Toulgoat, et al. 2019;14(8):e174-e176. Letter PubMed · Publisher

Summary

This letter reported a case of fatal anti-Ma2 encephalitis in a patient receiving immune checkpoint inhibitor (ICI) therapy for malignant pleural mesothelioma (MPM). A 70-year-old man with prior asbestos exposure and histologically confirmed unresectable MPM was treated with an anti-programmed death 1 (PD-1) antibody (3 mg/kg every 2 weeks) combined with an anti-CTLA4 antibody (1 mg/kg every 6 weeks). After 12 cycles of anti-PD-1 and 4 cycles of anti-CTLA4, and despite a partial response, he developed weight gain, excessive daytime sleepiness and depressive disorder, followed by narcolepsy-cataplexy. Brain MRI showed increased signal in both mesial temporal lobes and the hypothalamus region. Cerebrospinal fluid showed elevated protein, oligoclonal bands and a low hypocretin level (<50 ng/mL). Anti-Ma2 antibodies were positive in blood and cerebrospinal fluid, and also in serum collected before ICI treatment. Methylprednisolone, paroxetine and rituximab improved his symptoms. One month after steroids were stopped, the symptoms relapsed with hallucinations and cognitive decline. He died despite resumed methylprednisolone. CT showed no thoracic cancer relapse. The authors described this as the first reported case of anti-Ma2 encephalitis with limbic and diencephalic dysfunction after ICI combination therapy. They proposed that the patient had already developed an anti-Ma2 immune reaction that the ICIs triggered against the nervous system. They advised physicians to watch for encephalitis symptoms because early treatment could improve them.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.
Neoantigenic Potential of Complex Chromosomal Rearrangements in Mesothelioma. A.S. Mansfield, T. Peikert, J.B. Smadbeck, et al. 2019;14(2):276-287. PubMed · Publisher · Free full text

Abstract

Introduction: Malignant pleural mesothelioma is a disease primarily associated with exposure to the carcinogen asbestos. Whereas other carcinogen-related tumors are associated with a high tumor mutation burden, mesothelioma is not. We sought to resolve this discrepancy.

Methods: We used mate-pair (n = 22), RNA (n = 28), and T cell receptor sequencing along with in silico predictions and immunologic assays to understand how structural variants of chromosomes affect the transcriptome.

Results: We observed that inter- or intrachromosomal rearrangements were present in every specimen and were frequently in a pattern of chromoanagenesis such as chromoplexy or chromothripsis. Transcription of rearrangement-related junctions was predicted to result in many potential neoantigens, some of which were proven to bind patient-specific major histocompatibility complex molecules and to expand intratumoral T cell clones. T cells responsive to these predicted neoantigens were also present in a patient's circulating T cell repertoire. Analysis of genomic array data from the mesothelioma cohort in The Cancer Genome Atlas suggested that multiple chromothriptic-like events negatively impact survival.

Conclusions: Our findings represent the discovery of potential neoantigen expression driven by structural chromosomal rearrangements. These results may have implications for the development of novel immunotherapeutic strategies and the selection of patients to receive immunotherapies.

Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Pathologic Considerations and Standardization in Mesothelioma Clinical Trials. M.S. Tsao, M. Carbone, F. Galateau-Salle, et al. 2019;14(10):1704-1717. PubMed · Publisher

Abstract

The accurate diagnosis of mesothelioma is critical for the appropriate clinical management of this cancer. Many issues complicate making the diagnosis of mesothelioma including the presence of reactive mesothelial cells in benign pleural effusions, the heterogeneity of mesothelioma histopathology, the relatively high incidence of other epithelial malignancies that metastasize to the pleura, and primary sarcomas that arise within the pleura. Given the rapidly evolving field of molecular profiling and the need for translational correlates in mesothelioma clinical trials, the National Cancer Institute (NCI)-International Association for the Study of Lung Cancer-Mesothelioma Applied Research Foundation Clinical Trials Planning Meeting was convened in March 2017 to develop a consensus on standard pathology guidelines for future NCI-sponsored clinical trials in mesothelioma. This consensus statement covers recommendations for specimen handling, pathologic classification and diagnosis, biobanking, and tissue correlative studies.

Copyright © 2019 International Association for the Study of Lung Cancer. All rights reserved.
Peripheral Blood DNA Methylation as Potential Biomarker of Malignant Pleural Mesothelioma in Asbestos-Exposed Subjects. S. Guarrera, C. Viberti, G. Cugliari, et al. 2019;14(3):527-539. PubMed · Publisher

Abstract

Introduction: Malignant pleural mesothelioma (MPM) is an aggressive tumor strongly associated with asbestos exposure. Patients are usually diagnosed when current treatments have limited benefits, highlighting the need for noninvasive early diagnostic tests to monitor asbestos-exposed people.

Methods: We used a genome-wide methylation array to identify, in asbestos-exposed subjects, novel blood DNA methylation markers of MPM in 163 MPM cases and 137 cancer-free controls (82 MPM cases and 68 controls, training set; replication in 81 MPM cases and 69 controls, test set) sampled from the same areas.

Results: Evidence of differential methylation between MPM cases and controls was found (more than 800 cytosine-guanine dinucleotide sites, false discovery rate p value (pfdr) < 0.05), mainly in immune system-related genes. Considering the top differentially methylated signals, seven single- cytosine-guanine dinucleotides and five genomic regions of coordinated methylation replicated with similar effect size in the test set (pfdr < 0.05). The top hypomethylated single-CpG (cases versus controls effect size less than -0.15, pfdr < 0.05 in both the training and test sets) was detected in FOXK1 (Forkhead-box K1) gene, an interactor of BAP1 which was found mutated in MPM tissue and as germline mutation in familial MPM. In the test set, comparison of receiver operating characteristic curves and the area under the curve (AUC) of two models, including or excluding methylation, showed a significant increase in case/control discrimination when considering DNA methylation together with asbestos exposure (AUC = 0.81 versus AUC = 0.89, DeLong's test p = 0.0013).

Conclusions: We identified signatures of differential methylation in DNA from whole blood between asbestos exposed MPM cases and controls. Our results provide the rationale to further investigate, in prospective studies, the potential use of blood DNA methylation profiles for the identification of early changes related to the MPM carcinogenic process.

Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Potential Diagnostic and Prognostic Role of Microenvironment in Malignant Pleural Mesothelioma. I.C. Salaroglio, J. Kopecka, F. Napoli, et al. 2019;14(8):1458-1471. PubMed · Publisher

Abstract

Introduction: A comprehensive analysis of the immune cell infiltrate collected from pleural fluid and from biopsy specimens of malignant pleural mesothelioma (MPM) may contribute to understanding the immune-evasion mechanisms related to tumor progression, aiding in differential diagnosis and potential prognostic stratification. Until now such approach has not routinely been verified.

Methods: We enrolled 275 patients with an initial clinical diagnosis of pleural effusion. Specimens of pleural fluids and pleural biopsy samples used for the pathologic diagnosis and the immune phenotype analyses were blindly investigated by multiparametric flow cytometry. The results were analyzed using the Kruskal-Wallis test. The Kaplan-Meier and log-rank tests were used to correlate immune phenotype data with patients' outcome.

Results: The cutoffs of intratumor T-regulatory (>1.1%) cells, M2-macrophages (>36%), granulocytic and monocytic myeloid-derived suppressor cells (MDSC; >5.1% and 4.2%, respectively), CD4 molecule-positive (CD4+) programmed death 1-positive (PD-1+) (>5.2%) and CD8+PD-1+ (6.4%) cells, CD4+ lymphocyte activating 3-positive (LAG-3+) (>2.8% ) and CD8+LAG-3+ (>2.8%) cells, CD4+ T cell immunoglobulin and mucin domain 3-positive (TIM-3+) (>2.5%), and CD8+TIM-3+ (>2.6%) cells discriminated MPM from pleuritis with 100% sensitivity and 89% specificity. The presence of intratumor MDSC contributed to the anergy of tumor-infiltrating lymphocytes. The immune phenotype of pleural fluid cells had no prognostic significance. By contrast, the intratumor T-regulatory and MDSC levels significantly correlated with progression-free and overall survival, the PD-1+/LAG-3+/TIM-3+ CD4+ tumor-infiltrating lymphocytes correlated with overall survival.

Conclusions: A clear immune signature of pleural fluids and tissues of MPM patients may contribute to better predict patients' outcome.

Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Prediction modelling using routine clinical parameters to stratify survival in Malignant Pleural Mesothelioma patients undergoing cytoreductive surgery. E.J.A. Harris, S. Kao, B. McCaughan, et al. 2019;14(2):288-293. PubMed · Publisher

Abstract

Introduction: Malignant pleural mesothelioma (MPM) is an uncommon cancer with a poor prognosis and heterogeneous survival. Surgery for MPM is offered in some specialist centers to highly selected patients. A previously described classification and regression tree (CART) model stratified survival in unselected MPM patients using routinely collected clinical data. This study aimed to examine the performance of this CART model on a highly selected surgical population.

Methods: Data were collected from subjects undergoing cytoreductive surgery for MPM from specialist centers in Hyõgo, Japan, and Sydney, Australia, between 1991 and 2016. The CART model was applied using the combination of clinical variables to stratify subjects into risk groups (1 through 4); survival characteristics were then compared.

Results: Two hundred eighty-nine cases were included (205 from Australia, 84 from Japan). Overall median survival was 34.6 (interquartile range: 17.5-56.1) months; median age was 63.0 (interquartile range: 57.0-67.8) years, and 83.0% (n = 240) were male. There were no clinically meaningful differences between the two cohorts. Survival across the four risk groups was significantly different (p < 0.0001); the model stratified survival well with a Harrell's concordance statistic of 0.62 (95% confidence interval: 0.57-0.66) at 36 months. The group with the longest survival (median, 82.5 months) had: no weight loss, hemoglobin > 153 g/L and serum albumin > 43 g/L at time of referral to the surgical center.

Conclusions: Using routinely available clinical variables, the CART model was able to stratify surgical patients into risk groups with statistically different survival characteristics with fair to good performance. Presence of weight loss, anemia, and low albumin should confer caution when considering surgical therapy for MPM.

Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Prevalence and Preliminary Validation of Screening Criteria to Identify Carriers of Germline BAP1 Mutations. M.G. Zauderer, G. Jayakumaran, M. DuBoff, et al. 2019;14(11):1989-1994. PubMed · Publisher · Free full text

Abstract

Introduction: Inherited mutations are easily detected factors that influence the disease courses and optimal treatment strategies of some cancers. Germline mutations in BRCA1 associated protein 1 (BAP1) are associated with unique disease profiles in mesothelioma, atypical spitz nevi, and uveal melanoma, but the patient characteristics of an unselected population of BAP1 carriers identified by an ascertainment prevalence study are unknown.

Methods: We collected blood samples, cancer histories, and occupational exposures from 183 unselected patients with BAP1-related diseases. Clinical information for each patient was obtained from medical records. Germline DNA was extracted from blood samples and sequenced using a next-generation sequencing assay. We tested screening criteria developed to identify patients with a possible germline BAP1 mutation.

Results: Pathogenic or likely pathogenic germline BAP1 mutations were observed in 5 of 180 sequenced specimens and were exclusively found in patients identified by our screening criteria. Several patients with characteristics suspicious for a heritable deleterious mutation did not have a germline BAP1 mutation. The prevalence of pathogenic germline BAP1 mutations in patients with mesothelioma was 4.4% (95% confidence interval 1.1-11.1).

Conclusions: Results from the first unselected prevalence ascertainment study of germline BAP1 alterations suggest that the frequency of this mutation is low among patients with mesothelioma. The proposed screening criteria successfully identified all patients with germline BAP1-mutant mesothelioma. These screening guidelines may assist physicians in selecting patients who would benefit from genetic testing. Future efforts should validate and refine these criteria and search for other germline mutations associated with mesothelioma and related diseases.

Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Proton Beam Therapy and Immune Checkpoint Inhibitors in Malignant Pleural Mesothelioma. M.G. McCusker, K.A. Scilla, C.B. Simone, et al. 2019;14(9):e185-e187. Case report PubMed · Publisher

Summary

The authors described a patient with malignant pleural mesothelioma (MPM) who developed life-threatening toxicities after proton beam therapy was followed by an immune checkpoint inhibitor. The patient was a 69-year-old woman who had never smoked, with unresectable stage IV biphasic MPM. She received carboplatin and pemetrexed. After cycle three, imaging showed persistent bulky pleural disease and new right lung progression. Chemotherapy was stopped, and pencil beam scanning proton therapy was given to the entire pleura, to a total dose of 54 Gy to bulky disease sites. She tolerated it well, with near total pain control and grade 2 nausea and esophagitis that resolved. Three months later there was a strong right hemithorax response, but new metastatic foci had appeared in the right triceps and left pelvis. Thirty weeks after proton therapy her disease progressed, and nivolumab 240 mg was started on compassionate use. Two weeks after the first dose she had shortness of breath, grade 3 hypotension, tachycardia and hypoxia. Tests found a large pericardial effusion with grade 4 cardiac tamponade and grade 3 pneumonitis limited to the right lung. Pericardiocentesis removed 240 mL of fluid without malignant cells, and a biopsy showed alveolar injury. Corticosteroids led to rapid symptom resolution. The authors hypothesized that proton therapy caused immune "priming" and a later "recall" reaction. They concluded that the combination, particularly with very large treatment volumes, may worsen immune-related adverse events and needs further study.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.
Radiologic Considerations and Standardization of Malignant Pleural Mesothelioma Imaging Within Clinical Trials: Consensus Statement from the NCI Thoracic Malignancy Steering Committee - International Association for the Study of Lung Cancer - Mesothelioma Applied Research Foundation Clinical Trials Planning Meeting. R.R. Gill, A.S. Tsao, H.L. Kindler, et al. 2019;14(10):1718-1731. Consensus statement PubMed · Publisher

Abstract

Detailed guidelines pertaining to radiological assessment of malignant pleural mesothelioma are currently lacking due to the rarity of the disease, complex morphology, propensity to invade multiple planes simultaneously, and lack of specific recommendations within the radiology community about assessment, reporting, and follow-up. In March 2017, a multidisciplinary meeting of mesothelioma experts was co-sponsored by the National Cancer Institute Thoracic Malignancy Steering Committee, International Association for the Study of Lung Cancer, and the Mesothelioma Applied Research Foundation. One of the outcomes of this conference was the foundation of detailed, multidisciplinary consensus imaging and management guidelines. Here, we present the recommendations for radiologic assessment of malignant pleural mesothelioma in the setting of clinical trial enrollment. We discuss optimization of imaging parameters across modalities, standardized reporting, and response assessment within clinical trials.

Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
The Correlation of Serum Mesothelin Level With Pleural Thickness in Malignant Pleural Mesothelioma Makes it a Valuable Tool for Monitoring Tumor Progression. V. Fontana, A. Vigani, M.P. Pistillo, et al. 2019;14(5):e92-e94. Letter PubMed · Publisher

Summary

In this letter, the authors extended an earlier single-case report and examined whether serum soluble mesothelin-related peptide (Se-SMRP) levels tracked pleural thickness measured by computed tomography (CT) in malignant pleural mesothelioma (MPM). They analyzed 10 MPM patients (6 epithelioid, 3 sarcomatoid, 1 biphasic; 9 male; median age 67.5 years) recruited at the Oncology Division, ASL5 La Spezia, Italy, between March 2011 and May 2017. Pleural effusion was present at diagnosis in eight patients and appeared later in two. Se-SMRP was measured in duplicate with an enzyme-linked immunosorbent assay on blood taken at diagnosis, before therapy and during follow-up. Costal pleural thickness was measured on repeated CT scans by the same two thoracic radiologists. The association was analyzed with mixed-effects regression on log-transformed values, adjusted for age and disease stage at diagnosis. Se-SMRP and pleural thickness showed very similar trends, most closely in seven patients. In three patients, the trends diverged at time points when pleural effusion strongly increased or newly appeared. Pleural thickness showed a statistically significant geometric mean increase of 110% (95% CI 16%–280%, p = 0.014) per unit increase in log-SMRP. The authors concluded that the study confirmed a strong positive association. They noted that Se-SMRP levels could be influenced by new or changing pleural effusion, and suggested that Se-SMRP testing could be performed routinely and integrated with CT to monitor MPM progression.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.
The Use of Radiation Therapy for the Treatment of Malignant Pleural Mesothelioma: Expert Opinion from the National Cancer Institute Thoracic Malignancy Steering Committee, International Association for the Study of Lung Cancer, and Mesothelioma Applied Research Foundation. D.R. Gomez, A. Rimner, C.B. Simone, et al. 2019;14(7):1172-1183. Review · Consensus statement PubMed · Publisher

Abstract

Introduction: Detailed guidelines regarding the use of radiation therapy for malignant pleural mesothelioma (MPM) are currently lacking because of the rarity of the disease, the wide spectrum of clinical presentations, and the paucity of high-level data on individual treatment approaches.

Methods: In March 2017, a multidisciplinary meeting of mesothelioma experts was cosponsored by the U.S. National Cancer Institute, International Association for the Study of Lung Cancer Research, and Mesothelioma Applied Research Foundation. Among the outcomes of this conference was the foundation of detailed, multidisciplinary consensus guidelines.

Results: Here we present consensus recommendations on the use of radiation therapy for MPM in three discrete scenarios: (1) hemithoracic radiation therapy to be used before or after extrapleural pneumonectomy; (2) hemithoracic radiation to be used as an adjuvant to lung-sparing procedures (i.e., without pneumonectomy); and (3) palliative radiation therapy for focal symptoms caused by the disease. We discuss appropriate simulation techniques, treatment volumes, dose fractionation regimens, and normal tissue constraints. We also assess the role of particle beam therapy, specifically, proton beam therapy, for MPM.

Conclusion: The recommendations provided in this consensus statement should serve as important guidelines for developing future clinical trials of treatment approaches for MPM.

Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
A Phase I Trial of Surgical Resection and Intraoperative Hyperthermic Cisplatin and Gemcitabine for Pleural Mesothelioma. B.M. Burt, W.G. Richards, H.S. Lee, et al. 2018;13(9):1400-1409. PubMed · Publisher

Abstract

Introduction: The primary objective of this single-institution phase I clinical trial was to establish the maximum tolerated dose of gemcitabine added to cisplatin and delivered as heated intraoperative chemotherapy after resection of malignant pleural mesothelioma.

Methods: The extrapleural pneumonectomy (EPP) and pleurectomy/decortication (P/D) treatment arms were based on investigators' assessment of patient fitness and potential for macroscopic complete resection. Previously established intracavitary dosing of cisplatin (range 175-225 mg/m2) with systemic cytoprotection was used in combination with escalating doses of gemcitabine, following a 3-plus-3 design from 100 mg/m2 in 100-mg increments.

Results: From 2007 to 2011, 141 patients were enrolled and 104 completed treatment. The median age of those completing treatment was 65 years (range 43-85 years), and 22 (21%) were female. In the EPP arm (n = 59), 31 patients (53%) had the epithelioid histologic type and the median radiographic tumor volume was 236 cm3 (range 16-4285 cm3). In the P/D arm (n = 41), 29 patients (71%) had the epithelioid histologic type and the median tumor volume was 79 cm3 (range 6-1107 cm3). The operative mortality rate was 2%, and 35 and 22 serious adverse events were encountered among 27 patients (46%) and 16 patients (39%) in the EPP and P/D arms, respectively. Dose-limiting toxicity (grade 3 leukopenia) was observed in two patients who were receiving 1100 mg/m2 of gemcitabine, thus establishing the maximum tolerated dose at 1000 mg/m2, in combination with 175 mg/m2 of cisplatin. The median overall and recurrence-free survival times in treated patients were 20.3 and 10.7 months, respectively.

Conclusions: Combination cisplatin and gemcitabine heated intraoperative chemotherapy can be administered safely and feasibly in the context of complete surgical resection of malignant pleural mesothelioma by EPP or P/D.

Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Biomarker-Integrated Neoadjuvant Dasatinib Trial in Resectable Malignant Pleural Mesothelioma. A.S. Tsao, H. Lin, B.W. Carter, et al. 2018;13(2):246-257. PubMed · Publisher

Abstract

Introduction: Window of opportunity trials in malignant pleural mesothelioma (MPM) are challenging but can yield important translational information about a novel agent.

Methods: We treated patients with MPM (N = 24) with 4 weeks of oral dasatinib followed by surgery with or without radiotherapy and then an optional 2 years of maintenance dasatinib. The primary end point was biomarker modulation of phosphorylated (p) SrcTyr419.

Results: For all patients, the median progression-free survival (PFS) was 7.5 months and the median overall survival was 19.1 months. No significant responses were seen after 4 weeks of dasatinib therapy; however, modulation of median p-SrcTyr419 immunohistochemistry (IHC) scores was seen: the median pretreatment score was 70 (interquartile range 37.5-110), and the median posttreatment score was 41.9 (interquartile range 4.2-60) (p = 0.004). A decrease in p-SrcTyr419 levels after dasatinib correlated with improved median PFS (6.9 months versus 0.94 months [p = 0.03]), suggesting that p-SrcTyr419 is a viable pharmacodynamic biomarker for dasatinib in MPM. Platelet-derived growth factor receptor (PDGFR) pathway analysis correlated high PDGFR beta [PDGFRB) level (in the cytoplasm [hazard ratio] (HR) = 2.54, p = 0.05], stroma [HR = 2.79, p = 0.03], and nucleus [HR = 6.79, p = 0.023]) with a shorter PFS. Low (less than the median) cytoplasmic p-PDGFR alpha IHC levels were predictive of a decrease in positron emission tomography/computed tomography standard uptake values levels after dasatinib therapy (p = 0.04), whereas higher-than-median IHC scores of PDGFRB (cytoplasmic [HR = 2.8, p = 0.03] and nuclear [HR = 6.795, p = 0.02]) were correlated with rising standard uptake values levels.

Conclusions: In conclusion, there was no significant efficacy signal, and dasatinib monotherapy will not continue to be studied in MPM. However, our study demonstrated that PDGFR subtypes (platelet-derived growth factor receptor alpha and PDGFRB) may have differential roles in prognosis and resistance to antiangiogenic tyrosine kinase inhibitors and are important potential therapeutic targets that require further investigation.

Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Breast Metastasis from Malignant Pleural Mesothelioma: A Rare Challenging Entity. A. Catino, D. La Forgia, A. Scattone, et al. 2018;13(7):e117-e118. Case report · Letter PubMed · Publisher
Chimeric Antigen Receptor (CAR) T-Cell Therapy for Thoracic Malignancies. S. Kiesgen, L. Chicaybam, N.K. Chintala, et al. 2018;13(1):16-26. Review PubMed · Publisher · Free full text

Abstract

Chimeric antigen receptor (CAR) T cells are patient T cells that are transduced with genetically engineered synthetic receptors to target a cancer cell surface antigen. The remarkable clinical response rates achieved by adoptive transfer of T cells that target CD19 in patients with leukemia and lymphoma have led to a growing number of clinical trials exploring CAR T-cell therapy for solid tumors. Herein, we review the evolution of adoptive T-cell therapy; highlight advances in CAR T-cell therapy for thoracic malignancies; and summarize the targets being investigated in clinical trials for patients with lung cancer, malignant pleural mesothelioma, and esophageal cancer. We further discuss the barriers to successfully translating CAR T-cell therapy for solid tumors and present strategies that have been investigated to overcome these hurdles.

Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Current and Future Management of Malignant Mesothelioma: A Consensus Report from the National Cancer Institute Thoracic Malignancy Steering Committee, International Association for the Study of Lung Cancer, and Mesothelioma Applied Research Foundation. A.S. Tsao, O.W. Lindwasser, A.A. Adjei, et al. 2018;13(11):1655-1667. PubMed · Publisher

Abstract

On March 28- 29, 2017, the National Cancer Institute (NCI) Thoracic Malignacy Steering Committee, International Association for the Study of Lung Cancer, and Mesothelioma Applied Research Foundation convened the NCI-International Association for the Study of Lung Cancer- Mesothelioma Applied Research Foundation Mesothelioma Clinical Trials Planning Meeting in Bethesda, Maryland. The goal of the meeting was to bring together lead academicians, clinicians, scientists, and the U.S. Food and Drug Administration to focus on the development of clinical trials for patients in whom malignant pleural mesothelioma has been diagnosed. In light of the discovery of new cancer targets affecting the clinical development of novel agents and immunotherapies in malignant mesothelioma, the objective of this meeting was to assemble a consensus on at least two or three practice-changing multimodality clinical trials to be conducted through NCI's National Clinical Trials Network.

Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved.
Dysregulated Expression of the MicroRNA miR-137 and Its Target YBX1 Contribute to the Invasive Characteristics of Malignant Pleural Mesothelioma. T.G. Johnson, K. Schelch, Y.Y. Cheng, et al. 2018;13(2):258-272. PubMed · Publisher

Abstract

Introduction: Malignant pleural mesothelioma (MPM) is an aggressive malignancy linked to asbestos exposure. On a genomic level, MPM is characterized by frequent chromosomal deletions of tumor suppressors, including microRNAs. MiR-137 plays a tumor suppressor role in other cancers, so the aim of this study was to characterize it and its target Y-box binding protein 1 (YBX1) in MPM.

Methods: Expression, methylation, and copy number status of miR-137 and its host gene MIR137HG were assessed by polymerase chain reaction. Luciferase reporter assays confirmed a direct interaction between miR-137 and Y-box binding protein 1 gene (YBX1). Cells were transfected with a miR-137 inhibitor, miR-137 mimic, and/or YBX1 small interfering RNA, and growth, colony formation, migration and invasion assays were conducted.

Results: MiR-137 expression varied among MPM cell lines and tissue specimens, which was associated with copy number variation and promoter hypermethylation. High miR-137 expression was linked to poor patient survival. The miR-137 inhibitor did not affect target levels or growth, but interestingly, it increased miR-137 levels by means of mimic transfection suppressed growth, migration, and invasion, which was linked to direct YBX1 downregulation. YBX1 was overexpressed in MPM cell lines and inversely correlated with miR-137. RNA interference-mediated YBX1 knockdown significantly reduced cell growth, migration, and invasion.

Conclusions: MiR-137 can exhibit a tumor-suppressive function in MPM by targeting YBX1. YBX1 knockdown significantly reduces tumor growth, migration, and invasion of MPM cells. Therefore, YBX1 represents a potential target for novel MPM treatment strategies.

Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Evaluation of RET Gene Rearrangement by Fluorescence In Situ Hybridization in Malignant Mesothelioma. S. Salvi, J.L. Ravetti, G. Arena, et al. 2018;13(1):e12-e14. Letter PubMed · Publisher

Summary

In this letter, the authors asked whether malignant mesothelioma (MM) carries rearrangements of the RET gene. RET is a tyrosine kinase receptor targeted by drugs such as vandetanib, sunitinib and sorafenib, mainly in RET-rearranged thyroid carcinoma and non-small cell lung cancer. In a retrospective study approved by the Liguria Region Ethics Committee, they examined formalin-fixed paraffin-embedded tissue from 106 MMs (60 epithelioid, 34 sarcomatoid and 12 biphasic). Of these, 79 came from two commercial tissue microarrays (US Biomax), 16 from Ospedale Policlinico San Martino in Genoa and 11 from ASL 5 in La Spezia, Italy. RET status was assessed by fluorescence in situ hybridization (FISH) with a dual-color break-apart probe. A papillary thyroid carcinoma served as a positive control. Signals were counted in almost 50 nuclei per slide, and a case was considered rearranged if more than 15% of cells showed split signals. Two pathologists read the slides independently. None of the 106 MM samples showed a RET rearrangement. The authors described this as, to their knowledge, the first report on RET gene status in MM. They concluded that anti-RET tyrosine kinase inhibitor therapy does not appear applicable in MM. They noted that RET rearrangement in a very small subset of cases cannot be excluded with absolute certainty, and that further studies using other molecular methods are needed.

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Mismatch Repair Protein Defects and Microsatellite Instability in Malignant Pleural Mesothelioma. S. Arulananda, B. Thapa, M. Walkiewicz, et al. 2018;13(10):1588-1594. PubMed · Publisher

Abstract

Introduction: Malignant pleural mesothelioma is an aggressive malignancy with limited systemic therapy options. Promising results have been reported with use of anti-programmed cell death 1 therapy; however, its benefits appear to be confined to a subgroup of patients. Microsatellite instability (MSI) results from the inactivation of DNA mismatch repair genes and results in a high tumor mutational burden, a phenomenon that has not been seen with mesothelioma. MSI and protein absence have been shown to correlate in colorectal cancer, such that most centers have adopted immunohistochemistry (IHC) to screen for MSI-high colorectal cancers. We profiled a large cohort of patients with mesothelioma to determine the rate of negative IHC staining results the four common mismatch repair proteins.

Design: A tissue microarray comprising 335 patients with malignant pleural mesothelioma were used. IHC for the four common mismatch repair proteins (mutL homolog 1; PMS1 homolog 2, mismatch repair system component; mutS homolog 2; and mutS homolog 6) was performed. Programmed death ligand 1 IHC staining with the E1L3N clone was also performed. DNA was isolated from IHC equivocal samples and analyzed for microsatellite instability by using the Promega MSI Analysis System (version 1.2, Promega, Madison, WI).

Results: Of the patients profiled, 329 had intact mismatch repair proteins by IHC. Six samples with IHC testing results indicating absent mismatch repair protein were analyzed for MSI and confirmed to be negative. Of the six IHC-negative samples, five were negative for programmed death ligand 1 staining and one sample had more than 5% staining.

Conclusion: In this large retrospective series, we were unable to identify any patients with malignant pleural mesothelioma with microsatellite instability. Response to anti-programmed cell death 1-based immunotherapy may be driven by other mechanisms.

Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Molecular and Histopathological Characterization of the Tumor Immune Microenvironment in Advanced Stage of Malignant Pleural Mesothelioma. N.S. Patil, L. Righi, H. Koeppen, et al. 2018;13(1):124-133. PubMed · Publisher

Abstract

Introduction: Malignant pleural mesothelioma (MPM) is a rare, highly aggressive, and relatively chemoresistant and radioresistant malignancy with limited therapeutic options. Our objective was to investigate the prevalence of programmed death ligand 1 (PD-L1) and the characteristics of the immune environment in this disease.

Methods: A total of 99 archival tumors from advanced-stage MPM were immunohistochemically tested in parallel for PD-L1 in two different laboratories, and 87 of them were profiled for immune gene expression by NanoString analysis for 800 genes. A prior study on the same samples indicated a low mutational load with a complex mutational landscape of genetic variations more frequently associated with the p53/DNA repair and phosphoinisitide-3-kinase pathways.

Results: PD-L1 expression was found in 16% of the MPM tumor samples, either in the tumor cells or the infiltrating immune cells. Gene expression analysis suggested that MPM is an inflamed tumor type and can be classified into three different subgroups on the basis of the different expression profiles of immune-related genes, of which two groups showed varying degrees of expression of immune-related genes. Overall, these molecular findings suggest that these subgroups of MPM associated with PD-L1 positivity and expression of immune-related genes accounting for 60% of MPMs represent a candidate subtype that may respond to cancer immunotherapy.

Conclusions: These data suggest that 60% of patients with MPM characterized by either PD-L1 expression or an inflamed status are attractive candidates for cancer immunotherapeutic options.

Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
National Cancer Database Report on Pneumonectomy Versus Lung-Sparing Surgery for Malignant Pleural Mesothelioma. Z.M. Abdelsattar, S.A. Saddoughi, S.H. Blackmon. 2018;13(4):e64-e65. Letter · Comment PubMed · Publisher
New Insights on Diagnostic Reproducibility of Biphasic Mesotheliomas: A Multi-Institutional Evaluation by the International Mesothelioma Panel From the MESOPATH Reference Center. F. Galateau Salle, N. Le Stang, A.G. Nicholson, et al. 2018;13(8):1189-1203. PubMed · Publisher · Free full text

Abstract

Introduction: The 2015 WHO classification of tumors categorized malignant mesothelioma into epithelioid, biphasic (BMM), and sarcomatoid (SMM) for prognostic relevance and treatment decisions. The survival of BMM is suspected to correlate with the amount of the sarcomatoid component. The criteria for a sarcomatoid component and the interobserver variability between pathologists for identifying this component are not well described. In ambiguous cases, a "transitional" (TMM) subtype has been proposed but was not accepted as a specific subtype in the 2015 WHO classification. The aims of this study were to evaluate the interobserver agreement in the diagnosis of BMM, to determine the nature and the significance of TMM subtype, and to relate the percentage of sarcomatoid component with survival. The value of staining for BRCA-1-associated protein (BAP1) and CDKN2A(p16) fluorescence in situ hybridization (FISH) were also assessed with respect to each of the tumoral components.

Methods: The study was conducted by the International Mesothelioma Panel supported by the French National Cancer Institute, the network of rare cancer (EURACAN) and in collaboration with the International Association for the Study of Lung Cancer (IASLC). The patient cases include a random group of 42 surgical biopsy samples diagnosed as BMM with evaluation of SMM component by the French Panel of MESOPATH experts was selected from the total series of 971 BMM cases collected from 1998 to 2016. Fourteen international pathologists with expertise in mesothelioma reviewed digitally scanned slides (hematoxylin and eosin - stained and pan-cytokeratin) without knowledge of prior diagnosis or outcome. Cases with at least 7 of 14 pathologists recognizing TMM features were selected as a TMM group. Demographic, clinical, histopathologic, treatment, and follow-up data were retrieved from the MESOBANK database. BAP1 (clone C-4) loss and CDKN2A(p16) homozygous deletion (HD) were assessed by immunohistochemistry (IHC) and FISH, respectively. Kappa statistics were applied for interobserver agreement and multivariate analysis with Cox regression adjusted for age and gender was performed for survival analysis.

Results: The 14 panelists recorded a total of 544 diagnoses. The interobserver correlation was moderate (weighted Kappa = 0.45). Of the cases originally classified as BMM by MESOPATH, the reviewers agreed in 71% of cases (385 of 544 opinions), with cases classified as pure epithelioid in 17% (93 of 544), and pure sarcomatoid in 12% (66 of 544 opinions). Diagnosis of BMM was made on morphology or IHC alone in 23% of the cases and with additional assessment of IHC in 77% (402 of 544). The median overall survival (OS) of the 42 BMM cases was 8 months. The OS for BMM was significantly different from SMM and epithelioid malignant mesothelioma (p < 0.0001). In BMM, a sarcomatoid component of less than 80% correlated with a better survival (p = 0.02). There was a significant difference in survival between BMM with TMM showing a median survival at 6 months compared to 12 months for those without TMM (p < 0.0001). BAP1 loss was observed in 50% (21 of 42) of the total cases and in both components in 26%. We also compared the TMM group to that of more aggressive patterns of epithelioid subtypes of mesothelioma (solid and pleomorphic of our large MESOPATH cohort). The curve of transitional type was persistently close to the OS curve of the sarcomatoid component. The group of sarcomatoid, transitional, and pleomorphic mesothelioma were very close to each other. We then considered the contribution of BAP1 immunostaining and loss of CDKN2A(p16) by FISH. BAP1 loss was observed in 50% (21 of 41) of the total cases and in both component in 27% of the cases (11 of 41). There was no significant difference in BAP1 loss between the TMM and non-TMM groups. HD CDKN2A(p16) was detected in 74% of the total cases with no significant difference between the TMM and non-TMM groups. In multivariate analysis, TMM morphology was an indicator of poor prognosis with a hazard ratio = 3.2; 95% confidence interval: 1.6 - 8.0; and p = 0.003 even when compared to the presence of HD CDKN2A(p16) on sarcomatoid component (hazard ratio = 4.5; 95% confidence interval: 1.2 - 16.3, p = 0.02).

Conclusions: The interobserver concordance among the international mesothelioma and French mesothelioma panel suggests clinical utility for an updated definition of biphasic mesothelioma that allows better stratification of patients into risk groups for treatment decisions, systemic anticancer therapy, or selection for surgery or palliation. We also have shown the usefulness of FISH detection of CDKN2A(p16) HD compared to BAP1 loss on the spindle cell component for the separation in ambiguous cases between benign florid stromal reaction from true sarcomatoid component of biphasic mesothelioma. Taken together our results further validate the concept of transitional pattern as a poor prognostic indicator.

Copyright © 2018 International Association for the Study of Lung Cancer. All rights reserved.
Pathologic Grading of Malignant Pleural Mesothelioma: An Evidence-Based Proposal. G. Pelosi, M. Papotti, L. Righi, et al. 2018;13(11):1750-1761. PubMed · Publisher

Abstract

Introduction: A pathologic grading system (PGS) for malignant pleural mesothelioma (MPM) is warranted to better identify different risk categories of patients, plan therapeutic options, and activate clinical trials.

Methods: A series of 940 patients with MPM (328 in a training set and 612 in a validation set) that was diagnosed between October 1980 and June 2015 at the participant institutions was retrospectively assembled. A PGS was constructed by attributing to each histologic parameter, independent at multivariate analysis with excellent reproducibility (κ > 0.75), different scores based on the increase in corresponding hazard ratios. The relevant PGS score thus ranged from 0 to 8 points for individual patients with MPM.

Conclusions: The PGS was constructed by taking into consideration the histological subtyping of MPM (epithelioid/biphasic = 0 points; sarcomatoid = 2 points), necrosis (absent = 0 points versus present = 1 point), mitotic count per 1 mm2 (cutoffs as follows: 1-2 = 0 points, 3-5 = 1 point, 6-9 = 2 points, or ≥10 = 4 points), and Ki-67 labeling index based on 2000 cells (<30% = 0 points versus ≥30 = 1 point), all of which are independent factors in both patient sets after adjustment for stage and age at diagnosis. No heterogeneity was seen across the validation centers (p = 0.19). Epithelioid/biphasic MPM patterning and biopsy versus resection did not affect survival, whereas the PGS outperformed mitotic count and Ki-67 LI in both the training (area under the curve receiver operating characteristic = 0.76) and validation sets (area under the curve receiver operating characteristic = 0.73) (p < 0.01). Patient survival progressively deteriorated from a score of 0 (median times of 26.3 and 26.9 months) to a score 1 to 3 (median times of 12.8 and 14.4 months) and a score of 4 to 8 (median times of 3.7 and 7.7 months) in both sets of patients, with the hazard ratio for a 1-point increase in score being 1.46 (95% confidence interval: 1.36-1.56) in the training set and 1.28 (95% confidence interval: 1.22-1.34) in the validation set (after adjustment for age and [when available] tumor stage). The PGS was effective even in subgroup analysis (epithelioid, biphasic, and sarcomatoid tumors).

Discussion: A simple and reproducible multiparametric PGS effectively predicted survival in patients with MPM.

Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Pembrolizumab as Palliative Immunotherapy in Malignant Pleural Mesothelioma. Y. Metaxas, G. Rivalland, L.A. Mauti, et al. 2018;13(11):1784-1791. PubMed · Publisher

Abstract

Introduction: There is no approved second-line treatment for malignant pleural mesothelioma (MPM). On the basis of promising early results, pembrolizumab was used off-label in Switzerland and Australia. We investigated outcomes in association with clinicopathological features and expression of programmed death ligand 1 (PD-L1).

Methods: Registry data in Australia and Switzerland were pooled. Patient characteristics, including age, sex, histological subtype, and previous treatments were captured. Outcomes were assessed locally. PD-L1 expression was categorized as negative (<5%), intermediate (5%-49%), and high (≥50%).

Results: A total of 93 patients (48 from Switzerland and 45 from Australia) were treated; 68 patients (73%) had epithelioid MPM, and 67 (72%) had an Eastern Cooperative Oncology Group performance status of 0 or 1. Pembrolizumab was the second-line treatment in 48 of 93 patients (52%). PD-L1 expression results were available for 66 patients (71%). Most (68%) were negative, 18% were intermediate, and 14% were high for PD-L1 expression. In the full cohort, the overall response rate (ORR) was 18%, the median progression-free survival (mPFS) was 3.1 months, and the median overall survival was 7.2 months. In patients with an Eastern Cooperative Oncology Group performance status of 0 or 1 and only one previous systemic treatment (n = 35), the ORR was 37%, the mPFS was 3.7 months, and the median overall survival was 10.2 months. The nonepitheloid histological subtype showed an improved ORR (24% versus 16% [p = 0.54) and mPFS (5.6 versus 2.8 months [p = 0.02]). Compared with intermediate and negative PD-L1 expression, high PD-L1 expression was associated with an improved ORR (44% versus 42% versus 11% [p = 0.01]) and mPFS (6.2 versus 3.9 versus 2.7 months [p = 0.04]). Toxicity was as expected.

Conclusion: These real-world data demonstrate similar response rates but inferior survival compared with those in early-phase trials. High PD-L1 expression and nonepitheloid histological subtype were associated with greater activity. Anti-PD-L1 immunotherapy is a reasonable second-line therapy in patients with MPM.

Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Programmed Death 1 Blockade With Nivolumab in Patients With Recurrent Malignant Pleural Mesothelioma. D.A. Fennell. 2018;13(10):1436-1437. Editorial · Comment PubMed · Publisher

Summary

This editorial commented on a phase II study by Quispel-Janssen et al., published in the same issue, of the anti-PD-1 drug nivolumab in patients with relapsed malignant pleural mesothelioma. The author noted that no positive randomized trials had been reported in this setting, including one of tremelimumab. He compared the study with the earlier KEYNOTE-028 trial of pembrolizumab in PD-L1-positive patients, which reported a 20% response rate, a 12-month duration of response and a 76% disease control rate. The nivolumab study enrolled patients regardless of PD-L1 status. It reported an overall response rate of 24%, confirmed pseudoprogression in three patients, and responses lasting on average 7 months. More than half of patients were refractory to treatment. Of the 27% of patients with PD-L1 expression above 1%, no correlation with outcome was seen, and fewer than half of responders were PD-L1-positive. A rise in the neutrophil:lymphocyte ratio in the first 6 weeks was associated with poor outcome. The author discussed other possible predictors, including tumor mutation burden, HLA genotype and gut microbiome. He also reviewed ongoing and reported trials, including CONFIRM, PROMISE-meso, NIBIT-MESO-1 (28% response rate, 63% disease control), MAPS2, CheckMate 743 and DREAM. He concluded that the outlook for immunotherapy in mesothelioma remained good. He added that randomized trials were needed to clarify the role of PD-L1 testing.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.
Programmed Death 1 Blockade With Nivolumab in Patients With Recurrent Malignant Pleural Mesothelioma. J. Quispel-Janssen, V. van der Noort, J.F. de Vries, et al. 2018;13(10):1569-1576. PubMed · Publisher

Abstract

Introduction: Malignant pleural mesothelioma (MPM) has limited treatment options and a poor outcome. Programmed death 1/programmed death ligand 1 (PD-L1) checkpoint inhibitors have proven efficacious in several cancer types. Nivolumab is a fully humanized monoclonal antibody against programmed death 1 with a favorable toxicity profile. In MPM, the immune system is considered to play an important role. We therefore tested nivolumab in recurrent MPM.

Methods: In this single-center trial, patients with MPM received nivolumab 3 mg/kg intravenously every 2 weeks. Primary endpoint was the disease control rate at 12 weeks. Pre- and on-treatment biopsy specimens were obtained to analyze biomarkers for response.

Results: Of the 34 patients included, 8 patients (24%) had a partial response at 12 weeks and another 8 had stable disease resulting in a disease control rate at 12 weeks of 47%. One reached a partial response at 18 weeks. In 4 patients with stable disease, the tumor remained stable for more than 6 months. Treatment-related adverse events of any grade occurred in 26 patients (76%), most commonly fatigue (29%) and pruritus (15%). Grades 3 and 4 treatment-related adverse events were reported in 9 patients (26%), with pneumonitis, gastrointestinal disorders, and laboratory disorders mostly seen. One treatment-related death was due to pneumonitis and probably initiated by concurrent amiodarone therapy. PD-L1 was expressed on tumor cells in nine samples (27%), but did not correlate with outcome.

Conclusions: Single-agent nivolumab has meaningful clinical efficacy and a manageable safety profile in pre-treated patients with mesothelioma. PD-L1 expression does not predict for response in this population.

Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Progress in the Management of Advanced Thoracic Malignancies in 2017. R. Ferrara, L. Mezquita, B. Besse. 2018;13(3):301-322. Historical article · Review PubMed · Publisher

Abstract

The treatment paradigm of NSCLC underwent a major revolution during the course of 2017. Immune checkpoint inhibitors (ICIs) brought remarkable improvements in response and overall survival both in unselected pretreated patients and in untreated patients with programmed death ligand 1 expression of 50% or more. Furthermore, compelling preliminary results were reported for new combinations of anti-programmed cell death 1/programmed death ligand 1 agents with chemotherapy or anti-cytotoxic T-lymphocyte associated protein 4 inhibitors. The success of the ICIs appeared to extend to patients with SCLC, mesothelioma, or thymic tumors. Furthermore, in SCLC, encouraging activity was reported for an experimental target therapy (rovalpituzumab teserine) and a new chemotherapeutic agent (lurbinectedin). For oncogene-addicted NSCLC, next-generation tyrosine kinase inhibitors (TKIs) (such as osimertinib or alectinib) have demonstrated increased response rates and progression-free survival compared with first-generation TKIs in patients with both EGFR-mutated and ALK receptor tyrosine kinase gene (ALK)-rearranged NSCLC. However, because of the lack of mature overall survival data and considering the high efficacy of these drugs in patients with NSCLC previously exposed to first- or second-generation TKIs, definitive conclusions concerning the best treatment sequence cannot yet be drawn. In addition, new oncogenes such as mutant BRAF, tyrosine-protein kinase met gene (MET) and erb-b2 receptor tyrosine kinase 2 gene (HER2), and ret proto-oncogene (RET) rearrangements have joined the list of potential targetable drivers. In conclusion, the field of thoracic oncology is on the verge of a breakthrough that will open up many promising new therapeutic options for physicians and patients. The characterization of biomarkers predictive of sensitivity or resistance to immunotherapy and the identification of the optimal therapeutic combinations (for ICIs) and treatment sequence (for oncogene-addicted NSCLC) represent the toughest upcoming challenges in the domain of thoracic oncology.

Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Progress in the Management of Malignant Pleural Mesothelioma in 2017. A.J. McCambridge, A. Napolitano, A.S. Mansfield, et al. 2018;13(5):606-623. Review PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is an uncommon, almost universally fatal, asbestos-induced malignancy. New and effective strategies for diagnosis, prognostication, and treatment are urgently needed. Herein we review the advances in MPM achieved in 2017. Whereas recent epidemiological data demonstrated that the incidence of MPM-related death continued to increase in United States between 2009 and 2015, new insight into the molecular pathogenesis and the immunological tumor microenvironment of MPM, for example, regarding the role of BRCA1 associated protein 1 and the expression programmed death receptor ligand 1, are highlighting new potential therapeutic strategies. Furthermore, there continues to be an ever-expanding number of clinical studies investigating systemic therapies for MPM. These trials are primarily focused on immunotherapy using immune checkpoint inhibitors alone or in combination with other immunotherapies and nonimmunotherapies. In addition, other promising targeted therapies, including pegylated adenosine deiminase (ADI-PEG20), which focuses on argininosuccinate synthase 1-deficient tumors, and tazemetostat, an enhancer of zeste 2 polycomb repressive complex 2 subunit inhibitor of BRCA1 associated protein 1 gene (BAP1)-deficient tumors, are currently being explored.

Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Pseudoprogression Associated with Clinical Deterioration and Worsening Quality of Life in Malignant Pleural Mesothelioma. M.B. Barnet, R.R. Zielinski, A. Warby, et al. 2018;13(1):e1-e2. Case report PubMed · Publisher

Summary

This letter reported two patients with malignant pleural mesothelioma (MPM), described by the authors as an aggressive asbestos-related malignancy, who responded to the immune checkpoint inhibitor pembrolizumab after pseudoprogression. Pseudoprogression is an apparent increase in tumour burden or new lesions caused by T cell infiltrate. Both patients were men with epithelioid MPM. The first, aged 65, had progressive disease after 4 cycles of carboplatin and pemetrexed. After 5 cycles of pembrolizumab, his CT scan showed progressive disease by RECIST criteria, with worsening symptoms and patient-reported outcomes (PRO). Treatment was stopped and he received best supportive care. Thirty-three weeks later his scans showed a near complete response and his PRO improved. He remained untreated 42 weeks after stopping. The second patient, aged 79, began pembrolizumab 53 months after diagnosis, following two lines of chemotherapy. Treatment was stopped after 10 cycles because of radiological progression, clinical deterioration and worsening PRO. Sixteen weeks later his scans showed a significant partial response and his PRO improved beyond baseline. He remained untreated without progression at 41 weeks. The authors stated that, to their knowledge, these were the first reported cases of pseudoprogression in MPM and that the responses could be durable. Because both patients deteriorated clinically during pseudoprogression, they questioned guidance that uses clinical status to judge immunotherapy progression. They called for research on how often pseudoprogression occurs in MPM and on biomarkers of response.

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Revised Modified RECIST Criteria in Malignant Pleural Mesothelioma (Version 1.1): A Step Forward in a Long Race. A.S. Tsao, G.W. Gladish, R.R. Gill. 2018;13(7):871-873. Editorial · Comment PubMed · Publisher

Summary

In this editorial, the authors commented on a paper by Armato and Nowak, published in the same issue, that proposed version 1.1 of the modified RECIST criteria for measuring tumour response in malignant pleural mesothelioma. They noted that the original modified RECIST of 2004, which used six perpendicular measurements of the pleural rind taken from three CT sections, was an improvement over RECIST, but that measurement variability and imprecision remained. They agreed with lowering the minimum measurable pleural disease from 10 mm to 7 mm and the default size in treatment responders from 5 mm to 2 mm. They noted, however, a potential 10% to 15% measurement variability at this size, and that a 2 mm default would be inconsistent with the 5 mm default in RECIST 1.1. They supported the recommendations for consistent measurement practice and for aligning nonpleural and lymph node measurements with RECIST 1.1. They disagreed on four points: the requirement that measurements be taken on the same three sections; the narrow preferred measurement area between the aortic arch and the left atrium, for which they proposed the carina and superior pulmonary veins as landmarks instead; combining both hemithoraces as one organ in bilateral disease, where they recommended treating the contralateral pleura as a metastatic site; and the unclear definition of progressive disease. They concluded that the proposals needed validation in an independent data set and a multicentre consensus before clinical use, and that the future lay in volumetric quantification.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.
Revised Modified Response Evaluation Criteria in Solid Tumors for Assessment of Response in Malignant Pleural Mesothelioma (Version 1.1). S.G. Armato, A.K. Nowak. 2018;13(7):1012-1021. PubMed · Publisher

Abstract

Introduction: Malignant pleural mesothelioma poses unique difficulties in tumor measurement and response assessment; however, robust and reproducible assessment of response is critically important in the conduct, interpretation, and reporting of clinical trials.

Methods: The current de facto standard for the assessment of mesothelioma tumor response, "modified RECIST" (Response Evaluation Criteria in Solid Tumors), was published in 2004 as a research paper. Practical application of the modified RECIST guidelines has suffered from varied interpretations, resulting in inaccuracies and inconsistencies in tumor response assessment across and within mesothelioma clinical trials. The presented "modified RECIST 1.1 for mesothelioma" response assessment guidelines provide a much-needed update that incorporates recommendations from RECIST 1.1 and approaches to other practical issues, including: (1) definition of minimally measurable disease; (2) definition of measurable lesions; (3) acceptable measurement location; (4) non-pleural disease considerations; (5) characterization of non-measurable pleural disease; (6) assessment of pathological lymph nodes; (7) establishing progressive disease; and (8) accommodations for bilateral pleural disease.

Results: These modified RECIST 1.1 guidelines for mesothelioma tumor response collate and apply research published since the development of modified RECIST, align modified RECIST with RECIST 1.1, address those aspects of tumor measurement that were neglected or not well characterized in the modified RECIST paper, and clarify ambiguous or difficult measurement issues that have been highlighted through the subsequent decade of clinical trials research.

Conclusion: Adoption of the modified RECIST 1.1 guidelines for mesothelioma is recommended to harmonize the application of tumor measurement and response assessment across the next generation of clinical trials in this disease.

Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Scientific Advances and New Frontiers in Mesothelioma Therapeutics. L. Mutti, T. Peikert, B.W.S. Robinson, et al. 2018;13(9):1269-1283. Review PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer that arises from the mesothelial surface of the pleural and peritoneal cavities, the pericardium, and rarely, the tunica vaginalis. The incidence of MPM is expected to increase worldwide in the next two decades. However, even with the use of multimodality treatment, MPM remains challenging to treat, with a 5-year survival rate of less than 5%. The International Association for the Study of Lung Cancer has gathered experts in different areas of mesothelioma research and management to summarize the most significant scientific advances and new frontiers related to mesothelioma therapeutics.

Published by Elsevier Inc.
Surgery in Malignant Pleural Mesothelioma. R. Bueno, I. Opitz, IASLC Mesothelioma Taskforce. 2018;13(11):1638-1654. Review PubMed · Publisher

Abstract

Surgical intervention plays an important role in the diagnosis, staging, and treatment of malignant pleural mesothelioma (MPM) and can be applied with curative or palliative intent. The overall aim of surgery should be, as in any oncologic surgery, the macroscopic complete resection (MCR) of the tumor. Most importantly, the majority of patients with the diagnosis of MPM should be appropriately staged and initially evaluated in a multidisciplinary setting, including medical oncology, radiation oncology, and surgery after histologic diagnosis. Surgical staging, including determination of the histologic subtype and lymph node status, as well as clinical staging with positron-emission tomography-computer tomography scan and determination of cardiopulmonary reserve are crucial. Herein, we summarize the role of surgical resection, specifically macroscopic complete resection, performed as extrapleural pneumonectomy or extended pleurectomy/decortication in multimodality treatment settings and advocate for optimal patient selection for one or the other procedure. In addition, the roles of surgery in diagnosis of MPM and in palliative care are discussed.

Copyright © 2018 International Association for the Study of Lung Cancer. All rights reserved.
Treat it or Leave it: Immuno-Oncology in Mesothelioma Observed by the Eyes of Argus. C.J. de Gooijer, P. Baas. 2018;13(11):1619-1622. Editorial · Comment PubMed · Publisher

Summary

This editorial commented on a real-world, retrospective study by Metaxas et al. of pembrolizumab as palliative immunotherapy in malignant pleural mesothelioma (MPM). That study had reported an overall response rate of 18.3%, progression-free survival (PFS) of 3.1 months and overall survival (OS) of 7.2 months in 93 patients treated in first-line or beyond. The authors placed these results alongside earlier immunotherapy trials. Small phase I and II studies of pembrolizumab, nivolumab with or without ipilimumab, and tremelimumab had reported promising results, such as a median PFS of 5.4 months and median OS of 18 months in KEYNOTE-028. However, tremelimumab had failed to show superiority over placebo in the randomized phase IIb DETERMINE trial. The authors noted that the real-world pembrolizumab results were close to the DETERMINE placebo arm (PFS 3.1 versus 2.7 months; OS 7.2 versus 7.3 months). They identified limitations of the Metaxas study: it had no control arm, 29% of patients had a performance score of 2, doses varied, response assessment was not standardized, and there was no central radiological review. They described the evidence on PD-L1 expression as a predictor of outcome as controversial. They concluded that immunotherapy use outside clinical trials should be limited, and that ongoing phase III trials with control arms, CheckMate 743 and CONFIRM, were crucial.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.
Trophoblast Glycoprotein is Associated With a Favorable Outcome for Mesothelioma and a Target for Antibody Drug Conjugates. L.M. Schunselaar, K. Monkhorst, V. van der Noort, et al. 2018;13(10):1577-1587. PubMed · Publisher

Abstract

Introduction: The prognosis for patients with mesothelioma is poor, which prompts the need for the development of better treatment options. Antibody drug conjugates (ADCs) are gaining interest as a therapeutic strategy in mesothelioma. Trophoblast glycoprotein (5T4) is an oncofetal protein overexpressed in mesothelioma with low expression in normal tissue and therefore a good candidate for ADC treatment. Here, we evaluated and manipulated 5T4 as a suitable antigen for ADC targeted therapy in patients with mesothelioma.

Methods: Expression of the 5T4 antigen is evaluated in (primary) mesothelioma cell lines and biopsy specimens, and correlated with clinical outcome. Internalization was assessed in 5T4 expressing cells. The cytotoxicity of three different 5T4-targeting ADCs was tested on (primary) mesothelioma cells.

Results: 5T4 was expressed in 10 of 12 (primary) cell lines. Most biopsy specimens stained positive for the 5T4 antigen, with marked differences in staining intensity and percentage of positive cells. High expression correlated with long progression-free survival. Both free antibody and ADCs targeting 5T4 were internalized and entered lysosomal compartments. Cytotoxicity experiments showed that cell lines with a high expression for 5T4 were sensitive to two of three ADCs. Lack of efficacy for the third ADC could be restored by neutralizing lysosomal compartments with chloroquine.

Conclusions: The 5T4 antigen is expressed in mesothelioma and 5T4-based ADCs are internalized in lysosomes. Two of three ADCs were capable of killing the mesothelioma cells; the third ADC required additional lysosomal neutralization for its effect. 5T4-based ADCs would be a selective strategy for the treatment of mesothelioma.

Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Use of Serum Mesothelin as an Indicator of Tumor Progression in Routine Clinical Practice of Malignant Pleural Mesothelioma Treatment. A. Vigani, M.P. Pistillo, V. Fontana, et al. 2018;13(8):e143-e145. Case report · Letter PubMed · Publisher
A Novel BRCA1-Associated Protein-1 Isoform Affects Response of Mesothelioma Cells to Drugs Impairing BRCA1-Mediated DNA Repair. R. Parrotta, A. Okonska, M. Ronner, et al. 2017;12(8):1309-1319. PubMed · Publisher

Abstract

Introduction: BRCA1 associated protein1 (BAP1) is a tumor suppressor involved in multiple cellular processes such as transcriptional regulation, chromatin modification by deubiquitinating histone 2A, and DNA repair. BAP1 mutations are frequent in malignant pleural mesothelioma (MPM). Our aim was to functionally characterize a newly identified isoform of BAP1 and investigate the effects of its expression on drug sensitivity in MPM.

Methods: Expression of BAP1 isoforms was detected by quantitative polymerase chain reaction in MPM and normal mesothelium cell lines and tumor and nontumor samples. Histone H2A ubiquitination levels were analyzed by Western blot after acidic extraction of core histones. Subcellular localization of BAP1 isoforms was examined by immunofluorescence. MPM cell survival in response to poly(adenosine diphosphate-ribose) polymerase (PARP) and dual phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) inhibitors was analyzed by in vitro assays.

Results: We have identified a novel alternative splice isoform of BAP1 (BAP1Δ) that misses part of the catalytic domain. Cells transfected with BAP1Δ showed reduced deubiquitinating activity compared with full-length BAP1. The expression of BAP1Δ transcript is more abundant in nontumor than in tumor samples. MPM cell lines expressing more than 20% of BAP1Δ are more sensitive to olaparib (a PARP1 inhibitor) cytotoxicity, and this sensitivity is enhanced when olaparib treatment is combined with GDC0980 (a dual PI3K-mTOR inhibitor), which induces downregulation of BRCA1.

Conclusions: These observations suggest that BAP1Δ does regulate DNA damage response and influences drug sensitivity. It might therefore be relevant to investigate whether patients with high expression of BAP1Δ may be responsive to PARP/PI3K-mTOR inhibitors.

Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
BAP1 Is Altered by Copy Number Loss, Mutation, and/or Loss of Protein Expression in More Than 70% of Malignant Peritoneal Mesotheliomas. N. Leblay, F. Leprêtre, N. Le Stang, et al. 2017;12(4):724-733. PubMed · Publisher

Abstract

Introduction: Malignant mesothelioma is a deadly disease that is strongly associated with asbestos exposure. Peritoneal mesotheliomas account for 10% of all the cases. BRCA1 associated protein 1 (BAP1) is a deubiquitinating hydrolase that plays a key role in various cellular processes. Germline and somatic inactivation of BRCA1 associated protein 1 gene (BAP1) is frequent in pleural mesothelioma; however, little is known about its status in peritoneal mesothelioma.

Methods: Taking advantage of the extensive French National Network for the Diagnosis of Malignant Pleural Mesothelioma and Rare Peritoneal Tumors and the French National Network for the Treatment of Rare Peritoneal Surface Malignancies, we collected biological material and clinical and epidemiological data for 46 patients with peritoneal mesothelioma. The status of BAP1 was evaluated at the mutational and protein expression levels and combined with our previous data on copy number alterations assessed in the same samples.

Results: We detected mutations in 32% of the malignant peritoneal mesotheliomas analyzed. In addition, we have previously reported that copy number losses occurred in 42% of the samples included in this series. Overall, 73% of the malignant peritoneal mesotheliomas analyzed carried at least one inactivated BAP1 allele, but only 57% had a complete loss of its protein nuclear expression. Better overall survival was observed for patients with BAP1 mutations (p = 0.04), protein expression loss (p = 0.016), or at least one of these alterations (p = 0.007) independently of tumor histological subtype, age, and sex.

Conclusions: As in pleural mesothelioma, inactivation of BAP1 is frequent in peritoneal mesotheliomas. We found that BAP1 protein nuclear expression is a good prognostic factor and a more reliable marker for the complete loss of BAP1 activity than mutation or copy number loss.

Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Concern: Improving the Accuracy of Mesothelioma Diagnosis in China. Y. Wang. 2017;12(8):e131. Letter · Comment PubMed · Publisher
Epidemiology of Environmental Exposure and Malignant Mesothelioma. B. Liu, M. van Gerwen, S. Bonassi, et al. 2017;12(7):1031-1045. Review PubMed · Publisher

Abstract

Although the association between exposure to asbestos and malignant mesothelioma (particularly malignant pleural mesothelioma) has been well established, the health impact of environmental exposure (EE) to asbestos has been less studied. This review summarizes the most recent studies on the association between malignant mesothelioma and EE with asbestos to identify features associated with EE and quantify the association with malignant mesothelioma. There were 44 studies from 18 countries that met our selection criteria, with a considerable amount of heterogeneity in their study design, measures of exposure, and health outcomes. The male-to-female ratio was close to or less than 1 and generally lower than the ratio reported when both occupational and environmental exposures were considered. Although recent studies have continued to improve our understanding of environmental exposure to asbestos, challenges remain. We have highlighted a few new research directions, such as a need for reliable matrices to identify common and less recognized types of EE, asbestos biomarker studies specifically focusing on EE, and research on populations and geographic areas that have not been previously studied.

Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
FISH Analysis of Crizotinib Target Genes ROS1/ALK/MET in Malignant Mesothelioma. S. Salvi, S. Varesano, S. Boccardo, et al. 2017;12(8):e116-e118. Letter PubMed · Publisher

Summary

In this letter, the authors asked how many patients with malignant mesothelioma might benefit from crizotinib, a drug used in advanced non-small cell lung cancer with ROS1 or ALK gene rearrangement or MET gene amplification. Earlier, they had reported MET amplification in about 2% and high MET polysomy in 6.7% of mesothelioma patients. Here they examined ROS1 and ALK and studied MET in a larger series. They used fluorescence in situ hybridization (FISH) on 106 mesothelioma samples: 60 epithelioid, 34 sarcomatoid and 12 biphasic. Of the patients, 66% were men, and the median age was 64 years. Seventy-nine samples came from two commercial tissue microarrays (US Biomax), 16 from a pathology unit in Genoa and 11 from a histopathology unit in La Spezia, Italy. None of the 106 samples showed ROS1 or ALK rearrangement. Two samples, both epithelioid (1.9%), showed MET amplification. Six samples (5.7%; four epithelioid, one sarcomatoid, one biphasic) showed high MET polysomy. The authors described this as the first FISH analysis of ROS1 in mesothelioma. They noted that ROS1 rearrangement is also rare in lung cancer, so a larger series might find a few positive cases. They concluded that only MET can reasonably be considered a candidate target gene for selecting mesothelioma patients for crizotinib treatment.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.
Improved Outcomes with Modern Lung-Sparing Trimodality Therapy in Patients with Malignant Pleural Mesothelioma. F. Shaikh, M.G. Zauderer, D. von Reibnitz, et al. 2017;12(6):993-1000. PubMed · Publisher · Free full text

Abstract

Introduction: Higher target conformity and better sparing of organs at risk with modern radiotherapy (RT) may result in higher tumor control and less toxicity. In this study, we compare our institutional multimodality therapy experience of adjuvant chemotherapy and hemithoracic intensity-modulated pleural RT (IMPRINT) with previously used adjuvant conventional RT (CONV) in patients with malignant pleural mesothelioma (MPM) treated with lung-sparing pleurectomy/decortication (P/D).

Methods: We analyzed 209 patients who underwent P/D and adjuvant RT (131 who received CONV and 78 who received IMPRINT) for MPM between 1974 and 2015. The primary end point was overall survival (OS). The Kaplan-Meier method and Cox proportional hazards model were used to calculate OS; competing risks analysis was performed for local failure-free survival and progression-free survival. Univariate analysis and multivariate analysis were performed with relevant clinical and treatment factors.

Results: The median age was 64 years, and 80% of the patients were male. Patients receiving IMPRINT had significantly higher rates of the epithelial histological type, advanced pathological stage, and chemotherapy treatment. OS was significantly higher after IMPRINT (median 20.2 versus 12.3 months, p = 0.001). Higher Karnofsky performance score, epithelioid histological type, macroscopically complete resection, and use of chemotherapy/IMPRINT were found to be significant factors for longer OS in multivariate analysis. No significant predictive factors were identified for local failure or progression. Grade 2 or higher esophagitis developed in fewer patients after IMPRINT than after CONV (23% versus 47%).

Conclusions: Trimodality therapy including adjuvant hemithoracic IMPRINT, chemotherapy, and P/D is associated with promising OS rates and decreased toxicity in patients with MPM. Dose constraints should be applied vigilantly to minimize serious adverse events.

Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Improving the Accuracy of Mesothelioma Diagnosis in China. Z. Guo, M. Carbone, X. Zhang, et al. 2017;12(4):714-723. PubMed · Publisher · Free full text

Abstract

Introduction: In the Western world, malignant mesothelioma (MM) is most prevalent in the pleura of older males who have been professionally exposed to asbestos. Information about MM from rapidly industrializing countries such as China is minimal. There is concern that a proportion of MM diagnoses in China may be incorrect because most Chinese physicians do not have experience diagnosing this rare cancer. We recently reported an unusually high incidence of peritoneal MM among eastern Chinese female patients. Here, we review the accuracy of MM diagnoses in China and provide suggestions to improve the accuracy of diagnosis.

Methods: We reviewed 92 pathological diagnosis of MM in 2002-2015 from two reference centers in the province of Zhejiang in eastern China. We performed a large set of immunohistochemistry analyses to increase the reliability of the diagnosis.

Results: We confirmed the MM diagnosis in 12 of 34 of the pleural tumors (35.3%), in 38 of 56 of the peritoneal tumors (67.9%), and in two of two of the MMs of the tunica vaginalis (100%). MMs were characterized by tumor cells showing nuclear Wilms tumor 1 and calretinin staining and by strong membranous staining for cytokeratin CAM5.2. The results of staining for the epithelial markers carcinoembryonic antigen, thyroid transcription factor-1, MOC31, BerEP4, p63, p40, paired box 8, ER and PR were negative. BRCA1 associated protein 1 nuclear staining was lost in percentages similar to what has been reported for samples from Western countries.

Conclusions: Our findings suggest that MM-especially in its pleural localization-is often misdiagnosed in eastern China. Identifying pitfalls and possible solutions in the pathological diagnosis of MM will affect both the standard of care and research in China.

Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Improving the Accuracy of Mesothelioma Diagnosis in China. M. Carbone, Z. Guo, W. Mao. 2017;12(8):e132. Letter · Comment PubMed · Publisher

Summary

In this reply letter, authors of an earlier article on improving the accuracy of mesothelioma diagnosis in China (Guo et al., J Thorac Oncol 2017;12:714–723) responded to a correspondent who had identified a mistake in Table 3 of that article. The table reported BRCA1 associated protein 1 (BAP1) staining in malignant mesotheliomas and in other tumours. The authors acknowledged that an entry should have read 2 of 3, not 3 of 2, and presented a corrected table, in which biphasic mesothelioma is listed as 2 of 3. With the correction, the total number of malignant mesotheliomas showing BAP1 staining was 7 (not 8) out of 22 (32%): 3 of 17 epithelial (18%), 2 of 3 biphasic (67%) and 2 of 2 sarcomatoid (100%). BAP1 staining was seen in all 20 lung cancers (10 adenocarcinomas and 10 squamous cell carcinomas), all 15 carcinosarcomas and all 35 non-mesothelioma tumours. A footnote stated that all tumours showed homogeneous BAP1 nuclear staining in 100% of tumour cells except two lung adenocarcinomas. In these, positivity was seen in about 70% to 80% of tumour cells, and some areas contained nodules of tumour cells that entirely lacked BAP1 staining. The authors stated that the p values for the comparisons remained less than 0.0001.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.
Is Mesothelioma in China Rare or Misdiagnosed?. T. John, P.A. Russell, B. Thapa. 2017;12(4):607-609. Editorial · Comment PubMed · Publisher

Summary

In this editorial, the authors commented on a study by Guo et al., published in the same issue, on the accuracy of mesothelioma diagnosis in China. In China, the reported incidence of malignant mesothelioma (MM) was lower than expected given cumulative and continued asbestos use. The authors suggested this might reflect reduced reporting or limited diagnostic accuracy. They linked accuracy to pathologist experience, access to adequate tissue, and use of an adequate panel of immunohistochemical (IHC) markers, which they summarized in a table. They stressed that biopsies including tissues outside the pleura were essential, because invasion outside the pleura is the most robust histologic indicator of malignancy. In their own retrospective review of pleural MM diagnosed between 1988 and 2014, using surgically obtained large biopsies, they were unable to establish the diagnosis in only five of 376 patients (1.5%). By contrast, Guo et al. confirmed MM in 52 of 92 cases (56%), including 12 of 34 pleural and 38 of 56 peritoneal tumors originally diagnosed as MM. The authors noted that these patients were young, predominantly female and had a limited history of asbestos exposure. They also discussed the limits of BAP1 and CAM5.2 as markers. They concluded that China's continued mining, use and export of chrysotile asbestos heightened the importance of accurate diagnosis and reporting of mesothelioma.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.
Malignant Pleural Mesothelioma Harboring Both G719C and S768I Mutations of EGFR Successfully Treated with Afatinib. N. Agatsuma, Y. Yasuda, H. Ozasa. 2017;12(9):e141-e143. Case report · Letter PubMed · Publisher

Summary

This letter reported the case of a man with malignant pleural mesothelioma (MPM) carrying two uncommon EGFR mutations who was treated with afatinib. The patient was a 55-year-old Japanese man with cough, dyspnea and malignant pleural effusion. He had no significant medical history, no dust exposure, and a one-pack-year smoking history. Chest CT showed left-sided circumferential pleural thickening. FDG PET/CT showed high uptake in the left pleura, multiple lymph nodes, the left adrenal gland and the symphysis pubis. Earlier cytology of the pleural effusion had shown adenocarcinoma, so he was first diagnosed with advanced lung cancer and treated with carboplatin and pemetrexed. Immunohistochemistry on a cell block from the effusion was positive for podoplanin, calretinin and Wilms' tumor-1 and negative for TTF-1, Ber-EP4 and MOC31. PCR testing of EGFR exons 18 to 21 found G719C (exon 18) and S768I (exon 20) mutations. The diagnosis was revised to advanced epithelioid-type MPM with EGFR mutation. First-line and second-line cytotoxic therapies were not effective, and he was then given afatinib 40 mg daily. His pleural effusion was controlled, his lymph node and bone metastases shrank after 43 days, and a partial response by RECIST was achieved. Grade 2 diarrhea was controlled with loperamide. Progression-free survival on afatinib was 65 days, after which he was transferred for best supportive care. The authors stated this was the first reported MPM with both mutations and called for further study of afatinib in EGFR-mutated MPM.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.
National Cancer Database Report on Pneumonectomy Versus Lung-Sparing Surgery for Malignant Pleural Mesothelioma. V. Verma, C.A. Ahern, C.G. Berlind, et al. 2017;12(11):1704-1714. PubMed · Publisher

Abstract

Introduction: Controversy exists regarding the optimal surgical technique for malignant pleural mesothelioma (MPM). We evaluated national practice patterns and outcomes of MPM treated with extrapleural pneumonectomy (EPP) versus lung-sparing extended pleurectomy/decortication (P/D).

Methods: The National Cancer Database was queried for patients with newly diagnosed MPM undergoing EPP or P/D. Multivariable logistic regression ascertained clinical factors independently associated with P/D receipt. Kaplan-Meier analysis was used to evaluate overall survival (OS) between cohorts; multivariable Cox proportional hazards modeling was used to evaluate factors associated with OS. Survival was then evaluated between propensity-matched populations.

Results: Overall, 1307 patients (271 undergoing EPP [21%] and 1036 undergoing P/D [79%]) met the criteria. Patients receiving P/D were older (p = 0.028), whereas those undergoing EPP were more likely to live in a rural area (p = 0.044), live farther from the treating facility (p = 0.039), and receive treatment at an academic center (p = 0.050). There were no differences between cohorts in 30-day readmission or mortality (all p > 0.05). The median OS times in the EPP and P/D groups were 19 versus 16 months, respectively (p = 0.120); no differences were observed after propensity matching (p = 0.540).

Conclusions: In this largest analysis of its kind to date, findings from this contemporary cohort demonstrate that P/D comprised most surgical procedures for MPM. Procedure type was influenced by sociodemographic and geographical factors, without observed differences in survival or postoperative mortality and readmission rates between techniques.

Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
PD-L1 Testing for Immune Checkpoint Inhibitors in Mesothelioma: For Want of Anything Better?. S. Lantuejoul, N. Le Stang, F. Damiola, et al. 2017;12(5):778-781. Editorial · Comment PubMed · Publisher

Summary

In this editorial, the authors commented on a study by Thapa et al., published in the same issue, that evaluated PD-L1 expression by immunohistochemistry, genome-wide copy number alterations and immune infiltrate signature in 329 patients with malignant pleural mesothelioma (MPM). They noted that MPM is highly associated with asbestos exposure and that outcomes with standard chemotherapy remained poor. They summarized early trials of PD-1/PD-L1 inhibitors in MPM, which reported disease control rates of 50% to 72%, although no such drug had yet been approved for MPM. The authors described PD-L1 testing as controversial because some PD-L1-negative patients responded to treatment, and because many different antibody assays, platforms and positivity thresholds had been used in non-small cell lung cancer. They highlighted that PD-L1 expression varies within tumors and over time, and that this problem is greater in MPM because the tumor itself is heterogeneous and biopsy samples are small. On this basis they criticized Thapa et al.'s use of tissue microarrays. They noted that Thapa et al.'s results agreed with earlier studies. In those studies PD-L1 was expressed in up to 41% of MPMs and was strongest in sarcomatoid tumors. Strong expression was linked with poor prognosis and with lymphocyte infiltration. The authors concluded that mutational burden, genomic aberrations and PD-L1 immunohistochemistry were probably not sensitive enough as predictive biomarkers, and that PD-L1 testing needed standardization. They added that expectations for immunotherapy in MPM remained high.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.
Phase I Trial of Cediranib in Combination with Cisplatin and Pemetrexed in Chemonaive Patients with Unresectable Malignant Pleural Mesothelioma (SWOG S0905). A.S. Tsao, J. Moon, I.I. Wistuba, et al. 2017;12(8):1299-1308. PubMed · Publisher · Free full text

Abstract

Introduction: In malignant pleural mesothelioma, targeting angiogenesis with cediranib, a vascular endothelial growth factor receptor and platelet-derived growth factor receptor inhibitor, may have therapeutic potential.

Methods: S0905 phase I combined cediranib (two dose cohorts [30 mg and 20 mg daily]) with cisplatin-pemetrexed for six cycles followed by maintenance cediranib in unresectable chemonaive patients with malignant pleural mesothelioma of any histologic subtype. The primary end point established the maximum tolerated dose in combination with cisplatin-pemetrexed in a dose deescalation scheme.

Results: A total of 20 patients were enrolled (seven to the 30-mg cohort and 13 to the 20-mag cohort). In the cediranib 30-mg cohort, two of the initial six patients reported dose-limiting toxicities and the dose was deemed too toxic to continue. In the next cohort, two patients experienced dose-limiting toxicities, and thus, the maximum tolerated dose of cediranib was established as 20 mg. During the six cycles of cisplatin-pemetrexed-cediranib, 20 mg, there were grade 3 toxicities (neutropenia and gastrointestinal) and grade 4 thrombocytopenia. No patients had any significant episodes of bleeding. According to the Response Evaluation Criteria in Solid Tumors (n = 17 evaluable patients), the median progression-free survival was 12.8 months (95% confidence interval [CI]: 6.9-17.2); according to the Modified Response Evaluation Criteria in Solid Tumors (n = 19 evaluable patients), the median progression-free survival was 8.6 months (95% CI: 6.1-10.9). For all patients, the disease control rate at 6 weeks was 90% and median overall survival time was 16.2 months (95% CI: 10.5-28.7).

Conclusions: Cediranib combined with cisplatin-pemetrexed has a reasonable toxicity profile and preliminary promising efficacy. The phase II S0905 trial will evaluate the efficacy of the triplet regimen compared with the current standard of care, cisplatin-pemetrexed.

Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Pleural IMRT after Lung-Sparing Cytoreduction for Mesothelioma: Mature Enough to Randomize. H.I. Pass. 2017;12(6):919-921. Editorial · Comment PubMed · Publisher
Scientific Advances in Thoracic Oncology 2016. R.A. Soo, E.C.A. Stone, K.M. Cummings, et al. 2017;12(8):1183-1209. Historical article · Review PubMed · Publisher

Abstract

Lung cancer care is rapidly changing with advances in genomic testing, the development of next-generation targeted kinase inhibitors, and the continued broad study of immunotherapy in new settings and potential combinations. The International Association for the Study of Lung Cancer and the Journal of Thoracic Oncology publish this annual update to help readers keep pace with these important developments. Experts in thoracic cancer and care provide focused updates across multiple areas, including prevention and early detection, molecular diagnostics, pathology and staging, surgery, adjuvant therapy, radiotherapy, molecular targeted therapy, and immunotherapy for NSCLC, SCLC, and mesothelioma. Quality and value of care and perspectives on the future of lung cancer research and treatment have also been included in this concise review.

Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
The Immune Microenvironment, Genome-wide Copy Number Aberrations, and Survival in Mesothelioma. B. Thapa, A. Salcedo, X. Lin, et al. 2017;12(5):850-859. PubMed · Publisher

Abstract

Introduction: Results of recent clinical studies of immune checkpoint inhibitors in malignant pleural mesothelioma (MPM) have dampened initial enthusiasm. However, the immune environment and targets of these treatments such as programmed cell death protein 1 and its ligand programmed death ligand 1 (PD-L1) have not been well characterized in MPM. Using a large cohort of patients, we investigated PD-L1 expression, immune infiltrates, and genome-wide copy number status and correlated them to clinicopathological features.

Methods: Tissue microarrays were constructed and stained with PD-L1(clone E1L3N [Cell Signaling Technology, Danvers, MA]), cluster of differentiation 4, cluster of differentiation 8, and forkhead box P3 antibodies. PD-L1 positivity was defined as at least 5% membranous staining regardless of intensity, and high PD-L1 positivity was defined as at least 50%. Genomic DNA from a representative subset of 113 patients was used for genome-wide copy number analysis. The percent genome alteration was computed as a proxy for genomic instability, and statistical analyses were used to relate copy number aberrations to other variables.

Results: Among 329 patients evaluated, PD-L1 positivity was detected in 130 of 311 (41.7%), but high PD-L1 positivity was seen in only 30 of 311 (9.6%). PD-L1 positivity correlated with nonepithelioid histological subtype and increased infiltration with cluster of differentiation 4-positive, cluster of differentiation 8-positive, and forkhead box P3-positive lymphocytes. High PD-L1-positive expression correlated with worse prognosis (hazard ratio = 2.37, 95% confidence interval: 1.57-3.56, p < 0.001) in univariate analysis but not in multivariate analysis. Higher percent genome alteration was associated with epithelioid histological subtype and poorer survival (hazard ratio = 1.59, 95% confidence interval: 1.01-2.5, p = 0.04) but not PD-L1 expression.

Conclusions: PD-L1 expression was associated with nonepithelioid MPM, poor clinical outcome, and increased immunological infiltrates. Increased genomic instability did not correlate with PD-L1 expression but was associated with poorer survival.

Copyright © 2017 International Association for the Study of Lung Cancer. All rights reserved.
Trametinib plus 4-Methylumbelliferone Exhibits Antitumor Effects by ERK Blockade and CD44 Downregulation and Affects PD-1 and PD-L1 in Malignant Pleural Mesothelioma. H. Cho, S. Matsumoto, Y. Fujita, et al. 2017;12(3):477-490. PubMed · Publisher

Abstract

Introduction: Malignant pleural mesothelioma (MPM) is a highly aggressive malignancy in which the mitogen-activated protein kinase pathway plays a critical role in the regulation of tumorigenesis. Hyaluronic acid (HA) is a major component of the extracellular matrix, and elevated HA levels with a concurrent increase in malignant properties are associated with MPM.

Methods: We evaluated the effects of trametinib, a mitogen-activated protein kinase (MEK) inhibitor, and 4-methylumbelliferone (4-MU), an HA synthesis inhibitor, alone and in combination on MPM cells in vitro and in vivo. We studied the effects of trametinib, 4-MU, and their combination on MPM cells by using cell viability assays, Western blot analysis, and a mouse xenograft model.

Results: Trametinib and 4-MU exhibited antiproliferative activity in MPM cells. Trametinib blocked MEK-dependent extracellular signal-regulated kinase (ERK) phosphorylation and decreased CD44 expression in a concentration-dependent manner. Trametinib inhibited the expression of Fra-1 (the activator protein 1 [AP1] component), inhibited ERK phosphorylation, and decreased CD44 expression. 4-MU inhibited ERK phosphorylation but not CD44 expression. In a mouse xenograft model, trametinib and 4-MU alone suppressed tumor growth compared with a control. The combination had a greater inhibitory effect than either monotherapy. Immunohistochemical analysis showed that trametinib treatment alone significantly reduced expression of programmed cell death 1 ligand 1. Furthermore, the combination of trametinib and 4-MU resulted in higher expression of programmed cell death 1 and programmed cell death 1 ligand 1 than did the 4-MU treatment alone.

Conclusions: Our results suggest that trametinib and 4-MU are promising therapeutic agents in MPM and that further study of the combination is warranted.

Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Tumor Suppressor microRNAs Contribute to the Regulation of PD-L1 Expression in Malignant Pleural Mesothelioma. S.C. Kao, Y.Y. Cheng, M. Williams, et al. 2017;12(9):1421-1433. PubMed · Publisher

Abstract

Introduction: The upregulation of programmed death ligand 1 (PD-L1) is found in many cancers and contributes to evasion of the host's immune defense. In malignant pleural mesothelioma (MPM), PD-L1 expression is associated with the nonepithelioid histological subtype and poor prognosis, but the pathways involved in control of PD-L1 expression in MPM are poorly understood. To address one possible means of PD-L1 regulation we investigated the relationship between dysregulated microRNA levels and PD-L1 expression.

Methods: PD-L1 expression was analyzed by immunohistochemistry in tissue microarrays prepared from samples from patients undergoing an operation (pleurectomy with or without decortication). MicroRNA expression was analyzed by reverse-transcriptase quantitative polymerase chain reaction. Regulation of PD-L1 expression in cell lines was assessed after transfection with microRNA mimics and small interfering RNAs. Interaction between microRNAs and PD-L1 was analyzed by using argonaute-2 immunoprecipitation and a luciferase reporter assay.

Results: In a series of 72 patients with MPM, 18 (25%) had positive PD-L1 staining, and this was more common in patients with the nonepithelioid subtype (p = 0.01). PD-L1 expression was associated with poor survival (median overall survival 4.0 versus 9.2 months with positive versus negative PD-L1 expression [p < 0.001]), and in multivariate analyses, PD-L1 expression remained a significant adverse prognostic indicator (hazard ratio = 2.2, 95% confidence interval: 1.2-4.1, p < 0.01). In the same patient series, PD-L1 expression was also associated with downregulation of microRNAs previously shown to have tumor suppressor activity in MPM. The median microRNA expression levels of miR-15b, miR-16, miR-193a-3p, miR-195, and miR-200c were significantly lower in the PD-L1-positive samples. Transfecting MPM cell lines with mimics corresponding to miR-15a and miR-16, both of which are predicted to target PD-L1, led to downregulation of PD-L1 mRNA and protein. In addition, miR-193a-3p, with an alternative G-U-containing target site, also caused PD-L1 downregulation.

Conclusions: Together, these data suggest that tumor suppressor microRNAs contribute to the regulation of PD-L1 expression in MPM.

Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
A Novel Clinical Prediction Model for Prognosis in Malignant Pleural Mesothelioma Using Decision Tree Analysis. F.J. Brims, T.M. Meniawy, I. Duffus, et al. 2016;11(4):573-82. PubMed · Publisher

Abstract

Introduction: Malignant pleural mesothelioma (MPM) is a rare cancer with a heterogeneous prognosis. Prognostic models are not widely utilized clinically. Classification and regression tree (CART) analysis examines the interaction of multiple variables with a given outcome.

Methods: Between 2005 and 2014, all cases with pathologically confirmed MPM had routinely available histological, clinical, and laboratory characteristics recorded. Classification and regression tree analysis was performed using 29 variables with 18-month survival as the dependent variable. Risk groups were refined according to survival and clinical characteristics. The model was then tested on an external international cohort.

Results: A total of 482 cases were included in the derivation cohort; the median survival was 12.6 months, and the median age was 69 years. The model defined four risk groups with clear survival differences (p < 0.0001). The strongest predictive variable was the presence of weight loss. The group with the best survival at 18 months (86.7% alive, median survival 34.0 months, termed risk group 1) had no weight loss, a hemoglobin level greater than 153 g/L, and a serum albumin level greater than 43 g/L. The group with the worst survival (0% alive, median survival 7.5 months, termed risk group 4d) had weight loss, a performance score of 0 or 1, and sarcomatoid histological characteristics. The C-statistic for the model was 0.761, and the sensitivity was 94.5%. Validation on 174 external cases confirmed the model's ability to discriminate between risk groups in an alternative data set with fair performance (C-statistic 0.68).

Conclusions: We have developed and validated a simple, clinically relevant model to reliably discriminate patients at high and lower risk of death using routinely available variables from the time of diagnosis in unselected populations of patients with MPM.

Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
A Phase II Study of PF-03446962 in Patients with Advanced Malignant Pleural Mesothelioma. CCTG Trial IND.207. P. Wheatley-Price, Q. Chu, M. Bonomi, et al. 2016;11(11):2018-2021. PubMed · Publisher

Abstract

There is no approved second-line systemic therapy option for malignant pleural mesothelioma (MPM), but targeting angiogenesis is an area of investigation. PF-03446962 is a fully human antibody against activin receptor-like kinase 1, which is commonly expressed in tumor vasculature. We performed a multicenter, open label, single-arm, two-stage phase II study of PF-03446962 in patients with MPM and progressive disease after platinum-based chemotherapy. In total, 17 patients were enrolled, but no partial or complete responses were observed. The trial did not meet the prespecified response criterion for moving to the second stage. There were only three grade 3 (G3) or higher nonhematological toxicities observed (G3 hypertension [n=2] and G3 fatigue [n=1]) and just one episode of G3 lymphopenia. In conclusion, PF-03446962, despite being generally well tolerated, failed to demonstrate efficacy in the treatment of advanced MPM as a single agent. There are no plans for further investigation of this agent in MPM.

Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
A Randomized Phase II Study Adding Axitinib to Pemetrexed-Cisplatin in Patients with Malignant Pleural Mesothelioma: A Single-Center Trial Combining Clinical and Translational Outcomes. W.A. Buikhuisen, M. Scharpfenecker, A.W. Griffioen, et al. 2016;11(5):758-768. Randomized trial PubMed · Publisher

Abstract

Introduction: Mesothelioma often presents with a high vessel count and increased vascular growth factors levels. Interference with angiogenesis may therefore improve outcome. This study reports on clinical and translational parameters in patients treated with the small molecule tyrosine kinase inhibitor axitinib and chemotherapy.

Methods: Chemonaive patients with mesothelioma were eligible. Patients received pemetrexed (500 mg/m(2) every 3 weeks) and cisplatin (75 mg/m(2) every 3 weeks) and were randomized to receive axitinib daily (two 5-mg tablets on days 2-19) or observation. Before treatment and after three cycles of chemotherapy, a thoracoscopy was performed to evaluate vascular changes.

Results: Twenty-five patients were randomized after a successful lead-in with six patients who received axitinib. Median follow-up was 45 months. In all but one patient, it was feasible to perform a second thoracoscopy. However, there was more grade 3 or 4 neutropenia leading to pneumonia in the axitinib group. The rates of partial response and stable disease in the axitinib arm were 36% and 43% compared with 18% and 73% in the chemotherapy-only arm. Median progression-free survival and overall survival (5.8 and 18.9 months versus 8.3 and 18.5 months) were not different between the two groups. Axitinib reduced vessel number and vessel immaturation. Yet, the mRNA levels of a number of vascular growth factors, their receptors, serum VEGF levels, and activation of tissue vascular endothelial growth factor receptor 2 were increased. Gene expression of platelet-derived growth factor receptor beta, fms-related tyrosine kinase 1, and fms-related tyrosine kinase 4 even correlated with outcome.

Conclusions: Axitinib was well tolerated in combination with cisplatin and pemetrexed. Despite the lack of a clinical benefit, axitinib reduced angiogenesis. Whether changes in differentially expressed growth factors in tissue and serum may serve as a biomarker needs further investigation.

Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
BRCA1-Associated Protein 1 (BAP1) Immunohistochemical Expression as a Diagnostic Tool in Malignant Pleural Mesothelioma Classification: A Large Retrospective Study. L. Righi, E. Duregon, S. Vatrano, et al. 2016;11(11):2006-2017. PubMed · Publisher

Abstract

Introduction: Malignant pleural mesothelioma (MPM) is a highly aggressive disease with limited therapeutic options. Histological subtype remains among the most reliable prognostic factors, because the epithelioid subtype associated with the best prognosis and the sarcomatoid subtype with the worst. The biphasic subtype has an intermediate prognosis, but its definitive histological diagnosis may be challenging owing to the difficulty of assessing the neoplastic nature of the stromal component. Recent data identified BRCA1-associated protein 1 gene (BAP1) as one of the most frequently mutated genes in MPM. Immunohistochemical testing for BRCA1-associated protein 1 (BAP1) has been proposed to be predictive for the detection of BAP1 mutation in neoplastic cells. The aim of the present study was to define the diagnostic usefulness of immunohistochemical determination of BAP1 in MPM, with clinicopathological correlation.

Methods: A series of 143 MPMs were investigated for BAP1 protein expression in correlation with clinical and pathological data, including with a newly proposed nuclear grade. A pilot series of 20 selected cases were also investigated for BAP1 mutational status.

Results: Negative nuclear staining for BAP1 occurred in 62% of MPMs (including 27% with a cytoplasmic pattern) and was significantly associated with the presence of BAP1 mutation, epithelioid subtype, and a better prognosis. In a subgroup of cases, the pattern of expression of BAP1 in stromal cells supported their distinction as reactive versus neoplastic, thus helping achieve the correct classification of biphasic histological subtype.

Conclusions: We showed that BAP1 protein determination is a diagnostic tool to correctly distinguish biphasic MPM from epithelial subtypes with an atypical/activated reactive stroma and an independent prognostic parameter in MPM.

Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Consensus Report of the 2015 Weinman International Conference on Mesothelioma. M. Carbone, S. Kanodia, A. Chao, et al. 2016;11(8):1246-1262. Consensus statement PubMed · Publisher · Free full text

Abstract

On November 9 and 10, 2015, the International Conference on Mesothelioma in Populations Exposed to Naturally Occurring Asbestiform Fibers was held at the University of Hawaii Cancer Center in Honolulu, Hawaii. The meeting was cosponsored by the International Association for the Study of Lung Cancer, and the agenda was designed with significant input from staff at the U.S. National Cancer Institute and National Institute of Environmental Health Sciences. A multidisciplinary group of participants presented updates reflecting a range of disciplinary perspectives, including mineralogy, geology, epidemiology, toxicology, biochemistry, molecular biology, genetics, public health, and clinical oncology. The group identified knowledge gaps that are barriers to preventing and treating malignant mesothelioma (MM) and the required next steps to address barriers. This manuscript reports the group's efforts and focus on strategies to limit risk to the population and reduce the incidence of MM. Four main topics were explored: genetic risk, environmental exposure, biomarkers, and clinical interventions. Genetics plays a critical role in MM when the disease occurs in carriers of germline BRCA1 associated protein 1 mutations. Moreover, it appears likely that, in addition to BRCA1 associated protein 1, other yet unknown genetic variants may also influence the individual risk for development of MM, especially after exposure to asbestos and related mineral fibers. MM is an almost entirely preventable malignancy as it is most often caused by exposure to commercial asbestos or mineral fibers with asbestos-like health effects, such as erionite. In the past in North America and in Europe, the most prominent source of exposure was related to occupation. Present regulations have reduced occupational exposure in these countries; however, some people continue to be exposed to previously installed asbestos in older construction and other settings. Moreover, an increasing number of people are being exposed in rural areas that contain noncommercial asbestos, erionite, and other mineral fibers in soil or rock (termed naturally occurring asbestos [NOA]) and are being developed. Public health authorities, scientists, residents, and other affected groups must work together in the areas where exposure to asbestos, including NOA, has been documented in the environment to mitigate or reduce this exposure. Although a blood biomarker validated to be effective for use in screening and identifying MM at an early stage in asbestos/NOA-exposed populations is not currently available, novel biomarkers presented at the meeting, such as high mobility group box 1 and fibulin-3, are promising. There was general agreement that current treatment for MM, which is based on surgery and standard chemotherapy, has a modest effect on the overall survival (OS), which remains dismal. Additionally, although much needed novel therapeutic approaches for MM are being developed and explored in clinical trials, there is a critical need to invest in prevention research, in which there is a great opportunity to reduce the incidence and mortality from MM.

Copyright © 2016 International Association for the Study of Lung Cancer. All rights reserved.
Contemporary Analysis of Prognostic Factors in Patients with Unresectable Malignant Pleural Mesothelioma. A. Billé, L.M. Krug, K.M. Woo, et al. 2016;11(2):249-55. PubMed · Publisher · Free full text

Abstract

Introduction: Previous prognostic scoring systems for malignant pleural mesothelioma (MPM) included patients managed surgically and predated the use of pemetrexed. We analyzed prognostic factors in a contemporary cohort of patients with unresectable MPM who received pemetrexed-based chemotherapy.

Methods: This single-institution analysis included patients with MPM who were managed nonsurgically from 2000 to 2013. Variables correlated with overall survival (OS) included sex, performance status (PS), asbestos exposure, tumor laterality, histology, clinical stage, initial positron emission tomography maximum standardized uptake value, hemoglobin level, platelet count, lymphocyte count, white cell and neutrophil counts, treatment type, and clinical benefit from treatment. OS was analyzed by the Kaplan-Meier method, and significance (p < 0.05) of prognostic factors was analyzed by the log-rank test and Cox regression.

Results: A total of 191 patients met the study criteria: median age 71 years (range 46-90), 147 men (77%), 128 epithelioid tumors (67%), and 157 cases of stage III or IV MPM (82%). Median OS for all patients was 13.4 months. According to a univariate analysis, histology (p < 0.001), platelet count (< or = 450,000 versus >450,000, p < 0.001), initial PS (0-1 versus > or = 2), maximum standardized uptake value (< or = 8.1 versus >8.1, p = 0.037), and lymphocyte counts (p = 0.019) were associated with OS. According to a multivariable analysis, only histology, platelet count, and PS were independent prognostic factors. Epithelioid histology, PS, and elevated lymphocyte count at diagnosis were significantly associated with clinical benefit from first-line chemotherapy.

Conclusions: Our results confirm the significance of elements of the Cancer and Leukemia Group B and European Organisation for Research and Treatment of Cancer prognostic scoring systems, identify factors associated with clinical benefit from chemotherapy, and emphasize the impact of histology and clinical benefit of chemotherapy on outcomes.

Copyright © 2015 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Diffuse Pleural Myeloid Sarcoma Mimicking Malignant Mesothelioma. A. Dong, C. Bai, C. Zuo. 2016;11(4):603-5. Case report PubMed · Publisher

Summary

This "Image of the Month" report described a 23-year-old man referred to Changhai Hospital, Shanghai, China, with a 2-month history of cough and chest discomfort. Contrast-enhanced chest computed tomography (CT) showed an ill-circumscribed mediastinal tumor encasing the vessels and diffuse thickening of the right pleura with effusion. Fluorine 18-labeled fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT showed increased FDG uptake by the mediastinal tumor and the thickened right pleura, with large pericardial and right pleural effusions. Right pleural malignant mesothelioma with mediastinal involvement was suspected. CT-guided biopsy of the mediastinal tumor showed tumor cells positive for vimentin, leukosialin, myeloperoxidase and leukocyte common antigen, consistent with myeloid sarcoma. The authors explained that myeloid sarcoma is an uncommon localized tumor formed by primitive myeloid cells outside the bone marrow. It may precede, follow or occur without systemic acute myeloid leukemia. In adults it most often involves the skin, central nervous system, bone and lymph nodes. They noted that FDG PET/CT is useful for detection, staging and assessing treatment response, and that diffuse pleural and mediastinal involvement was unusual for this tumor. They concluded that, although rare, myeloid sarcoma should be considered in the differential diagnosis of diffuse pleural thickening with abnormal FDG uptake, along with malignant mesothelioma and tuberculosis.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.
EGFR Status in Mesothelioma: Possible Implications for the Efficacy of Anti-EGFR and Anti-MET Therapies. S. Salvi, S. Varesano, S. Boccardo, et al. 2016;11(6):e78-80. Letter PubMed · Publisher

Summary

In this letter, the authors reported epidermal growth factor receptor (EGFR) gene copy number in malignant mesothelioma (MM) and discussed what it might mean for targeted therapy with tyrosine kinase inhibitors (TKIs). They used fluorescence in situ hybridization (FISH) on the same paraffin-embedded MM tissue samples from 60 patients that they had studied in an earlier letter on MET gene status. The study was approved by the Liguria Region Ethics Committee in Italy, and all patients gave written informed consent. EGFR protein expression was assessed by immunohistochemistry. Using the University of Colorado Cancer Center scoring system, the authors found no EGFR amplification. Four of 60 MMs (6.7%), all epithelioid, showed high EGFR polysomy, with four to 10 EGFR signals in approximately 60% to 80% of tumor cells. All EGFR-positive MM cells also overexpressed membrane and cytoplasmic EGFR protein. Both EGFR and MET lie on chromosome 7. All four cases were the same cases the authors had previously reported as showing high MET polysomy. Citing other studies of resistance to single-agent TKIs, the authors suggested that simultaneous high EGFR and MET polysomy might reduce the efficacy of anti-EGFR or anti-MET monotherapy. They proposed that combined inhibition of EGFR and MET might be a better choice for MM with high chromosome 7 polysomy. They concluded that chromosome 7 copy number gain might be a predictive marker for combined targeted therapy, but that this needs evaluation in controlled trials.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.
Functional Analysis of the Adrenomedullin Pathway in Malignant Pleural Mesothelioma. L. Greillier, A. Tounsi, C. Berenguer-Daizé, et al. 2016;11(1):94-107. PubMed · Publisher

Abstract

Introduction: Malignant pleural mesothelioma (MPM) grows aggressively within the thoracic cavity and has a very low cure rate, thus highlighting the need for identification of new therapeutic targets. Adrenomedullin (AM) is a multifunctional peptide that is highly expressed in several tumors and plays an important role in angiogenesis and tumor growth after binding to its receptors, calcitonin receptor-like receptor/receptor activity-modifying protein 2 (CLR/RAMP2) and calcitonin receptor-like receptor/receptor activity-modifying protein 3 (CLR/RAMP3).

Methods: Real time quantitative reverse transcriptase polymerase chain reaction (RT-PCR) was used to assess the steady-state levels of AM, CLR, RAMP2 and RAMP3 messenger RNA (mRNA) transcripts in normal pleural tissue (n=5) and MPM (n=24). The expression of these candidates at protein level was revealed by immunohistochemistry. We also characterized the expression and regulation by hypoxia of AM system in MPM cell lines and MeT-5A cells. In vitro and in vivo studies were performed to determine the functional role of AM system in MPM.

Results: In this study, real-time quantitative reverse transcriptase polymerase chain reaction showed twofold to 10-fold higher levels of AM messenger RNA in MPM tissue than in normal pleural tissue. The MPM cell lines H2452, H2052, and human mesothelioma cell line MSTO-211H showed a significant increase in expression of AM messenger RNA under hypoxic conditions. Our results also show that AM stimulates cell proliferation in vitro through the Raf1 proto-oncogene, serine/threonine kinase (CRAF)/ Mitogen-activated protein kinase kinase 1 (MEK)/Extracellular regulated MAPKinase (ERK) pathway. Furthermore, the proliferation, migration, and invasion of MPM cells were decreased after treatment with anti-AM (αAM) and anti-AM receptor antibodies, thus indicating that MPM cells are regulated by AM. The action of AM was specific and mediated by CLR/RAMP2 and CLR/RAMP3 receptors. In vivo, αAM and AM22-52 antagonist therapies blocked angiogenesis and induced apoptosis in MSTO-211H xenografts, thereby resulting in tumor regression. Histologic examination of tumors treated with AM22-52 and αAM antibody showed evidence of disruption of tumor vasculature with depletion of vascular endothelial cells and a significant decrease in lymphatic endothelial cells.

Conclusions: Our findings highlight the importance of the AM pathway in growth of MPM and in neovascularization by supplying and amplifying signals that are essential for pathologic neoangiogenesis and lymphangiogenesis.

Copyright © 2015 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Genetic Basis of Mesothelioma--More Than Asbestos Exposure. D. Lee. 2016;11(2):e27-8. Letter · Comment PubMed · Publisher
Malignant Mesothelioma Effusions Are Infiltrated by CD3+ T Cells Highly Expressing PD-L1 and the PD-L1+ Tumor Cells within These Effusions Are Susceptible to ADCC by the Anti-PD-L1 Antibody Avelumab. S. Khanna, A. Thomas, D. Abate-Daga, et al. 2016;11(11):1993-2005. PubMed · Publisher · Free full text

Abstract

Introduction: The functional aspects of programmed death 1 (PD-1) and PD ligand 1 (PD-L1) immune checkpoints in malignant mesothelioma have not been studied.

Methods: Tumor samples from 65 patients with mesothelioma were evaluated for PD-L1 expression by immunohistochemistry, and its prognostic significance was examined. Malignant effusions from patients with pleural and peritoneal mesothelioma were evaluated for PD-1-positive and PD-L1-positive infiltrating lymphocytes and their role in inducing PD-L1 expression in tumor cells. Antibody-dependent cellular cytotoxicity (ADCC) of avelumab, a fully humanized immunoglobulin G1 anti PD-L1 antibody against primary mesothelioma cell lines, was evaluated in presence of autologous and allogeneic natural killer cells.

Results: Of 65 pleural and peritoneal mesothelioma tumors examined, 41 (63%) were PD-L1-positive, which was associated with slightly inferior overall survival compared to patients with PD-L1-negative tumors (median 23.0 versus 33.3 months, p = 0.35). The frequency of PD-L1 expression was similar in patients with pleural and peritoneal mesothelioma, with 62% and 64% of samples testing positive, respectively. In nine mesothelioma effusion samples evaluated, the fraction of cells expressing PD-L1 ranged from 12% to 83%. In seven patients with paired malignant effusion and peripheral blood mononuclear cell (PBMC) samples, PD-L1 expression was significantly higher on CD3-positive T cells present in malignant effusions as compared with PBMCs (p = 0.016). In addition, the numbers of CD14-positive PD-1-positive cells were increased in malignant effusions compared with PBMCs (p = 0.031). The lymphocytes present in malignant effusions recognized autologous tumor cells and induced interferon-γ-mediated PD-L1 expression on the tumor cell surface. Of the three primary mesothelioma cell lines tested, two were susceptible to avelumab-mediated ADCC in the presence of autologous natural killer cells.

Conclusions: Most pleural as well as peritoneal mesotheliomas express PD-L1. Malignant effusions in this disease are characterized by the presence of tumor cells and CD3-positive T cells that highly express PD-L1. In addition, mesothelioma tumor cells are susceptible to ADCC by the anti-PD-L1 antibody avelumab.

Published by Elsevier Inc.
MET Gene Status in Malignant Mesothelioma Using Fluorescent In Situ Hybridization. S. Varesano, S. Salvi, S. Boccardo, et al. 2016;11(2):e28-30. Letter · Comment PubMed · Publisher

Summary

The authors followed up their earlier report of a patient with malignant mesothelioma (MM) whose tumor showed MET gene amplification with MET receptor expression, and examined how often MET copy number changes occur in MM. Tumor tissue from 60 patients was analyzed (66.7% male; median age 60.0 years, range 5–85 years). There were 36 epithelioid, 12 sarcomatoid, 8 biphasic, 2 desmoplastic and 2 papillary cases. Thirty cases came from a commercial tissue microarray, 12 from IRCCS A.O.U. San Martino–IST in Genova, Italy, and 18 from ASL5 in La Spezia, Italy. MET and chromosome 7 centromere (CEP7) copy numbers were measured by fluorescence in situ hybridization (FISH) and scored with criteria proposed for non-small cell lung cancer. MET protein was assessed by immunohistochemistry. Five cases (8.3%), all epithelioid, were FISH-positive. One had MET amplification (MET/CEP7 ratio 4.0) with moderate MET protein expression. Four showed high MET polysomy with low protein staining. The other 55 cases (91.7%) were disomic for MET. The authors concluded that MET amplification was rare in MM (1.7% of cases) and that polysomy was more frequent (6.7%). They suggested these findings reinforce new treatment possibilities, but stated that whether patients with MM could benefit from MET-targeted therapies remains to be established in clinical trials.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.
Modulating Immunosuppression in the Intrapleural Space of Malignant Pleural Mesothelioma and Predictive Biomarkers to Guide Treatment Decisions. R.M. Wong. 2016;11(10):1602-3. Editorial PubMed · Publisher
Moving Immune Checkpoint Blockade in Thoracic Tumors beyond NSCLC. F. Facchinetti, A. Marabelle, G. Rossi, et al. 2016;11(11):1819-1836. Review PubMed · Publisher

Abstract

SCLC and malignant pleural mesothelioma (MPM) are historically characterized by a disappointing lack of significant therapeutic breakthroughs for novel agents, and both malignancies represent true unmet medical needs. Given the promising results of anti-cytotoxic T-lymphocyte associated protein-4 and anti-programmed cell death-1/programmed death ligand-1 antibodies in the treatment of advanced NSCLCs, these immune checkpoint inhibitors are now also under investigation in SCLC and MPM, as well as in thymic epithelial tumors (TETs). Here, we review the biological and clinical rationale for immune checkpoint inhibition in SCLC, MPM, and TETs and present preliminary clinical results with available antibodies. Immunotherapeutic perspectives for these malignancies in terms of novel agents currently under evaluation or anticipated in the near future are also discussed. Current immune checkpoint blockers targeting cytotoxic T-lymphocyte associated protein-4 and the programmed cell death-1/programmed death ligand-1 axis, administered alone or in combination and as multimodality treatment, are likely to be a valuable addition to the therapeutic array for managing SCLC and MPM; studies in TETs, which are currently in their infancy, are merited. Close attention to potential toxicities will be important to the success of such strategies in these settings.

Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
North American Multicenter Volumetric CT Study for Clinical Staging of Malignant Pleural Mesothelioma: Feasibility and Logistics of Setting Up a Quantitative Imaging Study. R.R. Gill, D.P. Naidich, A. Mitchell, et al. 2016;11(8):1335-1344. PubMed · Publisher · Free full text

Abstract

Background: Clinical tumor (T), node, and metastasis staging is based on a qualitative assessment of features defining T descriptors and has been found to be suboptimal for predicting the prognosis of patients with malignant pleural mesothelioma (MPM). Previous work suggests that volumetric computed tomography (VolCT) is prognostic and, if found practical and reproducible, could improve clinical MPM classification.

Methods: Six North American institutions electronically submitted clinical, pathologic, and imaging data on patients with stages I to IV MPM to an established multicenter database and biostatistical center. Two reference radiologists blinded to clinical data independently reviewed the scans; calculated clinical T, node, and metastasis stage by standard criteria; performed semiautomated tumor volume calculations using commercially available software; and submitted the findings to the biostatistical center. Study end points included the feasibility of a multi-institutional VolCT network, concordance of independent VolCT assessments, and association of VolCT with pathological T classification.

Results: Of 164 submitted cases, 129 were evaluated by both reference radiologists. Discordant clinical staging of most cases confirmed the inadequacy of current criteria. The overall correlation between VolCT estimates was good (Spearman correlation 0.822), but some were significantly discordant. Root cause analysis of the most discordant estimates identified four common sources of variability. Despite these limitations, median tumor volume estimates were similar within subgroups of cases representing each pathological T descriptor and increased monotonically for each reference radiologist with increasing pathological T status.

Conclusions: The good correlation between VolCT estimates obtained for most cases reviewed by two independent radiologists and qualitative association of VolCT with pathological T status combine to encourage further study. The identified sources of user error will inform design of a follow-up prospective trial to more formally assess interobserver variability of VolCT and its potential contribution to clinical MPM staging.

Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Plasma Biomarker Enrichment of Clinical Prognostic Indices in Malignant Pleural Mesothelioma. H.I. Pass, C. Goparaju, O. Espin-Garcia, et al. 2016;11(6):900-9. PubMed · Publisher · Free full text

Abstract

Objectives: Prognostic models for malignant pleural mesothelioma (MPM) are needed to prevent potentially futile outcomes. We combined MPM plasma biomarkers with validated clinical prognostic indices to determine whether stratification of risk for death in 194 patients with MPM improved.

Methods: Individuals were recruited from three different centers: a discovery cohort (83 patients with MPM) created by combining patients from two U.S. centers and a separate, independent cohort from Canada (111 patients with MPM). Univariable and multivariable analyses were performed on the initial discovery and independent cohorts separately. In the multivariable analyses, prognostic factors were adjusted for the European Organisation for Research and Treatment of Cancer (EORTC) prognostic index (PI) of mesothelioma. The prognostic significance of adding plasma biomarker data to the PI was determined by using the likelihood ratio test, comparing models with and without the addition of biomarker to the clinical PI. The predictive ability of the biomarker was then assessed formally using Harrell's C-index by applying the fitted model variables of the discovery cohort to the second, independent cohort, including and not including the biomarker with the PI.

Results: Higher levels of osteopontin and mesothelin were individually associated with worse prognosis after adjusting for the PI. In the independent cohort, incorporating either plasma osteopontin or mesothelin into the baseline predictive PI model substantively and statistically significantly improved Harrell's C-statistic. In the final prognostic model, log-osteopontin, EORTC clinical prognostic index, and hemoglobin remained as independently significant predictors and the entire prognostic model improved the optimism-corrected Harrell's C-index significantly, from 0.718 (0.67-0.77) to 0.801 (0.77-0.84).

Conclusions: These data suggest a possible role for preoperative plasma biomarkers to improve the prognostic capability of the EORTC PI of MPM.

Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Pleural Effusion of Patients with Malignant Mesothelioma Induces Macrophage-Mediated T Cell Suppression. L.A. Lievense, R. Cornelissen, K. Bezemer, et al. 2016;11(10):1755-64. PubMed · Publisher

Abstract

Introduction: Clinical studies have demonstrated beneficial effects of immunotherapy in malignant pleural mesothelioma. The pleural cavity seems an attractive compartment to administer these types of therapies; however, local immunosuppressive mechanisms could hamper their efficacy. Macrophages are abundantly present within the mesothelioma microenvironment. This study investigates the influence of the macrophage phenotype, macrophages' capacity to inhibit local immune responses, and the decisive role of pleural effusion (PE) in this regard.

Methods: We cultured macrophages in the presence of PEs and investigated their phenotype. Macrophages and T cells were cocultured in the presence of PEs and tumor cell line supernatants. The levels of 11 cytokines and the prostanoid prostaglandin E2 were measured in PEs and supernatants. The presence and phenotype of macrophages and T cell subsets was measured in the PE of patients with mesothelioma.

Results: PE induced a tumor-promoting M2 phenotype in macrophages, which was confirmed by the suppressive activity of macrophages on T cell proliferation during coculture. Prostanoid prostaglandin E2 was identified as a potential inducer of the suppressive capacity of macrophages in PE. Macrophages isolated from PEs displayed an M2 phenotype and were negatively correlated with T cells in vivo.

Conclusions: The current study demonstrates that macrophages in PE can play a pivotal role in directly hampering the antitumor T cell immune response. This emphasizes the potential of macrophages as a therapeutic target in mesothelioma and indicates that the presence and phenotype of macrophages in PE should be taken into consideration in the application of (intrapleural) immunotherapies.

Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Pleural Effusions from Patients with Mesothelioma Induce Recruitment of Monocytes and Their Differentiation into M2 Macrophages. A.L. Chéné, S. d'Almeida, T. Blondy, et al. 2016;11(10):1765-73. PubMed · Publisher

Abstract

Introduction: Mesothelioma is a rare and aggressive cancer related to asbestos exposure. We recently showed that pleural effusions (PEs) from patients with mesothelioma contain high levels of the C-C motif chemokine ligand 2 (CCL2) inflammatory chemokine. In the present work, we studied the effect of CCL2 contained in mesothelioma samples, particularly on monocyte recruitment. Then, we studied the fate of these monocytes in malignant pleural mesothelioma (MPM) PEs and their impact on tumor cells' properties.

Methods: The implication of CCL2 in monocyte recruitment was evaluated using transmigration assays and a CCL2 blocking antibody. The phenotype of macrophages was determined by flow cytometry and enzyme-linked immunosorbent assay. Immunohistochemical analysis was used to support the results. Cocultures of macrophages with mesothelioma cells were performed to study cancer cell proliferation and resistance to treatment.

Results: We showed that CCL2 is a major factor of monocyte recruitment induced by MPM samples. Macrophages obtained in MPM samples were M2 macrophages (high CD14, high CD163, and interleukin-10 secretion after activation). The colony-stimulating factor 1 receptor/macrophage colony-stimulating factor (M-CSF) pathway is implicated in M2 polarization, and high levels of M-CSF were measured in MPM samples compared with benign PE (4.17 ± 2.75 ng/mL and 1.94 ± 1.47 ng/mL, respectively). Immunohistochemical analysis confirmed the presence of M2 macrophages in pleural and peritoneal mesothelioma. Finally, we showed that M2 macrophages increased mesothelioma cell proliferation and resistance to treatment.

Conclusions: These results demonstrate the implication of CCL2 in MPM pathogenesis and designate M-CSF as a new potential biomarker of MPM. This study also identifies CCL2 and colony-stimulating factor 1 receptor/M-CSF as interesting new targets to modulate pro-tumorigenic properties of the tumor microenvironment.

Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
The 2015 World Health Organization Classification of Tumors of the Pleura: Advances since the 2004 Classification. F. Galateau-Salle, A. Churg, V. Roggli, et al. 2016;11(2):142-54. Review PubMed · Publisher

Abstract

A new World Health Organization (WHO) Classification of Tumors of the Pleura has recently been published. While the histologic classification of pleural malignant mesothelioma remains the same in the 2015 WHO classification as it was in the 2004 classification, multiple new observations have been recorded. First, more detailed study has been performed of histologic subtyping of epithelioid mesothelioma. In particular, it has been recognized that the pleomorphic subtype is associated with a poor prognosis, similar to that of sarcomatoid malignant mesothelioma. Second, there is improved understanding of the role of immunohistochemistry in distinguishing mesothelioma from carcinomas of various sites. Third, the criteria for distinguishing malignant mesothelioma from reactive mesothelial proliferations has been further refined. Fourth, additional studies of sarcomatoid mesothelioma have defined the frequency and spectrum of various histologic and immunohistochemical features, including heterologous elements. Finally, pleural well-differentiated papillary mesotheliomas are better defined and cases with invasive foci are recognized. In addition, several promising observations in mesothelioma pathology and genetics have been made in the past decade. These are now the subject of further investigation to determine if they can be validated in ways that will significantly impact clinical practice. These include a preliminary study of grading, suggesting that nuclear atypia and mitotic count are independent prognostic markers. The discovery of inactivating mutations in the BRCA1-associated protein 1 gene in sporadic and hereditary mesothelioma has opened up a variety of novel molecular, clinical, and diagnostic investigations. One possible diagnostic application includes the setting of separating mesothelioma from reactive mesothelial proliferations, where it may play a role in conjunction with p16 FISH. Another useful discovery was that the NAB2-STAT6 fusion is characteristic of solitary fibrous tumors. This led to development of a STAT6 antibody that is a reliable immunohistochemical marker for solitary fibrous tumors. Genetic studies also led to the finding that WWTR1-CAMTA1 fusions are useful diagnostic markers for epithelioid hemangioendotheliomas, which can present as pleural-based masses. Finally, desmoid type fibromatosis, a locally aggressive tumor that can present in the pleura, has been shown to frequently have CTNNB1 gene mutations and express β-catenin by immunohistochemistry.

Copyright © 2015 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
The Genetic Landscape of Malignant Pleural Mesothelioma: Results from Massively Parallel Sequencing. M. Hylebos, G. Van Camp, J.P. van Meerbeeck, et al. 2016;11(10):1615-26. Review PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) is a rare yet aggressive tumor that is causally associated with-mostly professional-asbestos exposure. Given the long latency between exposure and disease, and because asbestos is still being used, MPM will remain a global health issue for decades to come. Notwithstanding the increasing incidence of MPM and the fact that patients with MPM face a poor prognosis, currently available treatment options are limited. To enable the development of novel targeted therapies, identification of the genetic alterations underlying MPM will be crucial. The first studies reporting on the genomic background of MPM identified recurrent somatic mutations in a number of tumor suppressor genes (i.e., cyclin-dependent kinase inhibitor 2A gene [CDKN2A], neurofibromin 2 (merlin) gene [NF2], and BRCA1 associated protein 1 gene [BAP1]). More recently, massively parallel sequencing strategies have been used and have provided a more genome-wide view on the genetic landscape of MPM. This review summarizes their results, describing alterations that cluster mainly in four pathways: the tumor protein p53/DNA repair, cell cycle, mitogen-activated protein kinase, and phosphoinisitide 3-kinase (PI3K)/AKT pathways. As these pathways are important during tumor development, they provide interesting candidates for targeting with novel drugs.

Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
The IASLC Mesothelioma Staging Project: Improving Staging of a Rare Disease Through International Participation. H. Pass, D. Giroux, C. Kennedy, et al. 2016;11(12):2082-2088. Review PubMed · Publisher

Abstract

For nearly 40 years, there was no generally accepted staging system for malignant pleural mesothelioma. In 1994, members of the International Mesothelioma Interest Group, in collaboration with the International Association for the Study of Lung Cancer, proposed a TNM staging system based on analyses of outcomes in retrospective surgical series and small clinical trials. Subsequently accepted by the American Joint Commission on Cancer and the Union for International Cancer Control for the sixth editions of their staging manuals, this system has since been the international staging standard. However, it has significant limitations, particularly with respect to clinical staging and to the categories for lymph node staging. Here we provide an overview of the development of the International Association for the Study of Lung Cancer malignant pleural mesothelioma staging database, which was designed to address these limitations through the development of a large international data set. Analyses of this database, described in papers linked to this overview, are being used to inform revisions in the eighth editions of the American Joint Commission on Cancer and Union for International Cancer Control staging systems.

Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
The IASLC Mesothelioma Staging Project: Proposals for Revisions of the N Descriptors in the Forthcoming Eighth Edition of the TNM Classification for Pleural Mesothelioma. D. Rice, K. Chansky, A. Nowak, et al. 2016;11(12):2100-2111. PubMed · Publisher

Abstract

Introduction: Nodal categories for malignant pleural mesothelioma are derived from the lung cancer staging system and have not been adequately validated. The International Association for the Study of Lung Cancer developed a multinational database to generate evidence-based recommendations to inform the eighth edition of the TNM classification of malignant pleural mesothelioma.

Methods: Data from 29 centers were entered prospectively (n = 1566) or by transfer of retrospective data (n = 1953). Survival according to the seventh edition N categories was evaluated using Kaplan-Meier survival curves and Cox proportional hazards regression analysis. Survival was measured from the date of diagnosis.

Results: There were 2432 analyzable cases: 1603 had clinical (c) staging, 1614 had pathologic (p) staging, and 785 had both. For clinically staged tumors there was no separation in Kaplan-Meier curves between cN0, cN1 or cN2 (cN1 versus cN0 hazard ratio [HR] = 1.06, p = 0.77 and cN2 versus cN1 HR = 1.04, p = 0.85). For pathologically staged tumors, patients with pN1 or pN2 tumors had worse survival than those with pN0 tumors (HR = 1.51, p < 0.0001) but no survival difference was noted between those with pN1 and pN2 tumors (HR = 0.99, p = 0.99). Patients with both pN1 and pN2 nodal involvement had poorer survival than those with pN2 tumors only (HR = 1.60, p = 0.007) or pN0 tumors (HR = 1.62, p < 0.0001).

Conclusions: A recommendation to collapse both clinical and pN1 and pN2 categories into a single N category comprising ipsilateral, intrathoracic nodal metastases (N1) will be made for the eighth edition staging system. Nodes previously categorized as N3 will be reclassified as N2.

Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
The IASLC Mesothelioma Staging Project: Proposals for Revisions of the T Descriptors in the Forthcoming Eighth Edition of the TNM Classification for Pleural Mesothelioma. A.K. Nowak, K. Chansky, D.C. Rice, et al. 2016;11(12):2089-2099. PubMed · Publisher

Abstract

Introduction: The current T component for malignant pleural mesothelioma (MPM) has been predominantly informed by surgical data sets and consensus. The International Association for the Study of Lung Cancer undertook revision of the seventh edition of the staging system for MPM with the goal of developing recommendations for the eighth edition.

Methods: Data elements including detailed T descriptors were developed by consensus. Tumor thickness at three pleural levels was also recorded. An electronic data capture system was established to facilitate data submission.

Results: A total of 3519 cases were submitted to the database. Of those eligible for T-component analysis, 509 cases had only clinical staging, 836 cases had only surgical staging, and 642 cases had both available. Survival was examined for T categories according to the current seventh edition staging system. There was clear separation between all clinically staged categories except T1a versus T1b (hazard ratio = 0.99, p = 0.95) and T3 versus T4 (hazard ratio = 1.22, p = 0.09), although the numbers of T4 cases were small. Pathological staging failed to demonstrate a survival difference between adjacent categories with the exception of T3 versus T4. Performance improved with collapse of T1a and T1b into a single T1 category; no current descriptors were shifted or eliminated. Tumor thickness and nodular or rindlike morphology were significantly associated with survival.

Conclusions: A recommendation to collapse both clinical and pathological T1a and T1b into a T1 classification will be made for the eighth edition staging system. Simple measurement of pleural thickness has prognostic significance and should be examined further with a view to incorporation into future staging.

Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
The IASLC Mesothelioma Staging Project: Proposals for the M Descriptors and for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Mesothelioma. V.W. Rusch, K. Chansky, H.L. Kindler, et al. 2016;11(12):2112-2119. PubMed · Publisher

Abstract

Introduction: The M component and TNM stage groupings for malignant pleural mesothelioma (MPM) have been empirical. The International Association for the Study of Lung Cancer developed a multinational database to propose evidence-based revisions for the eighth edition of the TNM classification of MPM.

Methods: Data from 29 centers were submitted either electronically or by transfer of existing institutional databases. The M component as it currently stands was validated by confirming sufficient discrimination (by Kaplan-Meier analysis) with respect to overall survival (OS) between the clinical M0 (cM0) and cM1 categories. Candidate stage groups were developed by using a recursive partitioning and amalgamation algorithm applied to all cM0 cases.

Results: Of 3519 submitted cases, 2414 were analyzable and 84 were cM1 cases. Median OS for cM1 cases was 9.7 months versus 13.4 months (p = 0.0013) for the locally advanced (T4 or N3) cM0 cases, supporting inclusion of only cM1 in the stage IV group. Exploratory analyses suggest a possible difference in OS for single- versus multiple-site cM1 cases. A recursive partitioning and amalgamation-generated survival tree on the OS outcomes restricted to cM0 cases with the newly proposed (eighth edition) T and N components indicates that optimal stage groupings for the eighth edition will be as follows: stage IA (T1N0), stage IB (T2-3N0), stage II (T1-2N1), stage IIIA (T3N1), stage IIIB (T1-3N2 or any T4), and stage IV (any M1).

Conclusions: This first evidence-based revision of the TNM classification for MPM leads to substantial changes in the T and N components and the stage groupings.

Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
A New Prognostic Score Supporting Treatment Allocation for Multimodality Therapy for Malignant Pleural Mesothelioma: A Review of 12 Years' Experience. I. Opitz, M. Friess, P. Kestenholz, et al. 2015;10(11):1634-41. Review PubMed · Publisher

Abstract

Introduction: Treatment of malignant pleural mesothelioma (MPM) remains a clinical challenge. The aim of this study was to identify selection factors for allocation of MPM patients to multimodal therapy based on survival data from 12 years of experience.

Methods: Eligible patients had MPM of all histological subtypes with clinical stage T1-3 N0-2 M0. Induction chemotherapy consisted of cisplatin/gemcitabine (cis/gem) or cisplatin/pemetrexed (cis/pem), followed by extrapleural pneumonectomy (EPP). Multivariate analysis was performed to assess independent prognosticators for overall survival (OS). A Multimodality Prognostic Score was developed based on clinical variables available before surgery.

Results: From May 1999 to August 2011, 186 MPM patients were intended to be treated with induction chemotherapy followed by EPP. Hematologic toxicity was significantly less frequent after cis/pem compared to cis/gem, but there was no difference in response or OS between the regimens. One hundred and twenty-eight patients underwent EPP with a 30-day mortality of 4.7%. Fifty-two percent of the patients received adjuvant radiotherapy. The median OS of patients undergoing EPP was significantly longer with 22 months (95% confidence interval: 20-24) when compared to 11 months (9-12) for patients treated without EPP. A prognostic score was defined considering tumor volume, histology, C-reactive protein level, and response to chemotherapy that identified patient groups not benefitting from multimodality treatment which was confirmed in an independent cohort.

Conclusion: Patients receiving induction chemotherapy followed by EPP for MPM of all histological subtypes and irrespective of nodal status showed a median survival of 22 months. A prognostic score is proposed to help patient allocation for surgery after validation in an independent cohort.
Amplification of MET in a Patient with Malignant Pleural Mesothelioma. S. Varesano, S. Salvi, S. Boccardo, et al. 2015;10(10):e103-4. Case report · Letter PubMed · Publisher
High Incidence of Somatic BAP1 alterations in sporadic malignant mesothelioma. M. Nasu, M. Emi, S. Pastorino, et al. 2015;10(4):565-76. PubMed · Publisher · Free full text

Abstract

Background: Breast cancer 1-associated protein 1 (BAP1) is a nuclear deubiquitinase that regulates gene expression, transcription, DNA repair, and more. Several findings underscore the apparent driver role of BAP1 in malignant mesothelioma (MM). However, the reported frequency of somatic BAP1 mutations in MM varies considerably, a discrepancy that appeared related to either methodological or ethnical differences across various studies.

Methods: To address this discrepancy, we carried out comprehensive genomic and immunohistochemical (IHC) analyses to detect somatic BAP1 gene alterations in 22 frozen MM biopsies from U.S. MM patients.

Results: By combining Sanger sequencing, multiplex ligation-dependent probe amplification, copy number analysis, and cDNA sequencing, we found alteration of BAP1 in 14 of 22 biopsies (63.6%). No changes in methylation were observed. IHC revealed normal nuclear BAP1 staining in the eight MM containing wild-type BAP1, whereas no nuclear staining was detected in the 14 MM biopsies containing tumor cells with mutated BAP1. Thus, IHC results were in agreement with those obtained by genomic analyses. We then extended IHC analysis to an independent cohort of 70 MM biopsies, of which there was insufficient material to perform molecular studies. IHC revealed loss of BAP1 nuclear staining in 47 of these 70 MM biopsies (67.1%).

Conclusions: Our findings conclusively establish BAP1 as the most commonly mutated gene in MM, regardless of ethnic background or other clinical characteristics. Our data point to IHC as the most accessible and reliable technique to detect BAP1 status in MM biopsies.
Hippo pathway gene mutations in malignant mesothelioma: revealed by RNA and targeted exon sequencing. A. Miyanaga, M. Masuda, K. Tsuta, et al. 2015;10(5):844-851. PubMed · Publisher

Abstract

Introduction: Malignant mesothelioma (MM) is an aggressive neoplasm causatively associated with exposure to asbestos. MM is rarely responsive to conventional cytotoxic drugs, and the outcome remains dismal. It is, therefore, necessary to identify the signaling pathways that drive MM and to develop new therapeutics specifically targeting the molecules involved.

Methods: We performed comprehensive RNA sequencing of 12 MM cell lines and four clinical samples using so-called next-generation sequencers.

Results: We found 15 novel fusion transcripts including one derived from chromosomal translocation between the large tumor suppressor 1 (LATS1) and presenilin-1 (PSEN1) genes. LATS1 is one of the central players of the emerging Hippo signaling pathway. The LATS1-PSEN1 fusion gene product lacked the ability to phosphorylate yes-associated protein and to suppress the growth of a MM cell line. The wild-type LATS1 allele was undetectable in this cell line, indicating two-hit genetic inactivation of its tumor suppressor function. Using pathway-targeted exon sequencing, we further identified a total of 11 somatic mutations in four Hippo pathway genes (neurofibromatosis type 2 [NF2], LATS2, RASSF1, and SAV1) in 35% (8 of 23) of clinical samples. Nuclear staining of yes-associated protein was detected in 55% (24 of 44) of the clinical samples. Expression and/or phosphorylation of the Hippo signaling proteins, RASSF1, Merlin (NF2), LATS1, and LATS2, was frequently absent.

Conclusions: The frequent alterations of Hippo pathway molecules found in this study indicate the therapeutic feasibility of targeting this pathway in patients with MM.
In Response. A. Billè, L. Porcu. 2015;10(9):e93-e94. Letter · Comment PubMed · Publisher
Is Radiotherapy Useful for Treating Pain in Mesothelioma?: A Phase II Trial. N. MacLeod, A. Chalmers, N. O'Rourke, et al. 2015;10(6):944-50. PubMed · Publisher

Abstract

Introduction: Radiotherapy is often used to treat pain in malignant pleural mesothelioma (MPM), although there is limited evidence to support this. The aim of this trial was to assess the role of radiotherapy for the treatment of pain in MPM.

Methods: A multicentre, single arm phase II trial was conducted. Eligible patients fulfilled the following criteria: pathological or radiological diagnosis of MPM; pain secondary to MPM; radiotherapy indicated for pain control; and more than 18 years of age. Patients had assessments of pain and other symptoms at baseline and then received 20 Gy in five daily fractions. Key follow-up points were 5 and 12 weeks posttreatment. The primary end point measure was assessment of pain at the site of radiotherapy at 5 weeks. Secondary end points included effects on quality of life, breathlessness, fatigue, mood, toxicity, and the radiological response.

Results: Forty patients were recruited from three UK oncology centers. Fourteen patients had a clinically meaningful improvement in their pain 5 weeks post radiotherapy (intention to treat), with five patients having a complete improvement. On the basis of a complete case analysis of the 30 patients assessable at week 5, 47% (confidence intervals, 28.3-65.7) of patients alive at week 5 had an improvement in their pain. There was no improvement in other key symptoms or quality of life.

Conclusions: Radiotherapy for pain control in MPM is an effective treatment in a proportion of patients. Future studies examining differing radiotherapy regimens with a view to improving response rates are warranted.
No Increased Risk for Mesothelioma in Relation to Natural-Occurring Asbestos in Southern Nevada. P.S. Pinheiro, H. Jin. 2015;10(7):e62-3. Letter · Comment PubMed · Publisher · Free full text
Recent insights emerging from malignant mesothelioma genome sequencing. M. Carbone, G. Gaudino, H. Yang. 2015;10(3):409-11. Editorial · Comment PubMed · Publisher · Free full text

Summary

This editorial discussed two studies that sequenced the genomes of malignant mesothelioma (MM). Lo Iacono et al. used targeted next-generation sequencing of a commercial cancer-gene library on 123 formalin-fixed, paraffin-embedded biopsies from 123 patients, with separate testing of BAP1 and NF2. Guo et al. performed whole exome sequencing on 22 frozen biopsies with matched blood samples, together with copy number analysis. All patients in the first study and 41% in the second had received chemotherapy, which the authors noted may have contributed to some mutations. Both studies found fewer mutations than in other cancers. Guo et al. found 490 mutated genes, 447 (97%) of them mutated in only one biopsy, with an average of 23 mutations per biopsy. The genes most often mutated in both studies were BAP1, NF2 and CDKN2A. Somatic BAP1 mutations were found in 41% and 58% of MMs, and NF2 mutations in about 50%. The authors also described their own integrated genomic approach, which found BAP1 mutation or inactivation in 14 of 22 (63.6%) biopsies. No single method captured all cases, but immunohistochemistry for nuclear BAP1 appeared to. The authors concluded that shared driver mutations were rare and that tumour heterogeneity complicates targeted therapy, but that BAP1 is a frequent and potentially useful therapeutic target.

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Reply to "No Increased Risk for Mesothelioma in Relation to Natural-Occurring Asbestos in Southern Nevada". F. Baumann, B.J. Buck, R.V. Metcalf, et al. 2015;10(7):e64-5. Letter · Comment PubMed · Publisher · Free full text
Surgery and Survival of Patients with Diagnosis of Malignant Pleural Mesothelioma. C. Carbonelli, C. Rapicetta, A. Cesario. 2015;10(9):e92-e93. Letter · Comment PubMed · Publisher
SWOG S0722: phase II study of mTOR inhibitor everolimus (RAD001) in advanced malignant pleural mesothelioma (MPM). S.H. Ou, J. Moon, L.L. Garland, et al. 2015;10(2):387-91. PubMed · Publisher · Free full text

Abstract

Introduction: The PI3K/Akt/mammalian target of rapamycin pathway is activated in a majority of malignant pleural mesotheliomas (MPM). We evaluated the activity of everolimus, an oral mammalian target of rapamycin inhibitor, in patients with unresectable MPM.

Methods: MPM patients who had received at least one but no more than two prior chemotherapy regimens, which must have been platinum-based, were treated with 10 mg of everolimus daily. The primary endpoint was 4-month progression-free survival (PFS) by RECIST 1.1.

Results: A total of 59 evaluable patients were included in the analysis. The median duration of treatment was 2 cycles (56 days). Overall response rate was 2% [95% confidence interval (CI): 0-12%] by RECIST 1.1 and 0% (0-10%) by modified RECIST for MPM. The 4-month PFS rate was 29% (95% CI: 17-41%) by RECIST 1.1, and 27% (95% CI: 16-39%) by modified RECIST. The median PFS was 2.8 months (95% CI: 1.8-3.4) by RECIST 1.1. The median overall survival was 6.3 months (95% CI: 4.0-8.0). There was no difference in PFS among patients who received one or two prior chemotherapy regimens (p = 0.74). There was no difference in overall survival between patients with epithelioid histology versus other types (p = 0.47). The most common toxicities were fatigue (59%), hypertriglyceridemia (44%), anemia (42%), oral mucositis (34%), nausea (32%), and anorexia (32%). The most common grade 3 to 4 toxicities were fatigue (10.2%), anemia (6.8%), and lung infection (6.8%).

Conclusion: Everolimus has limited clinical activity in advanced MPM patients. Additional studies of single-agent everolimus in advanced MPM are not warranted.
Targeted next-generation sequencing of cancer genes in advanced stage malignant pleural mesothelioma: a retrospective study. M. Lo Iacono, V. Monica, L. Righi, et al. 2015;10(3):492-9. PubMed · Publisher

Abstract

Introduction: Malignant pleural mesothelioma (MPM) is a rare malignant disease, and the understanding of molecular pathogenesis has lagged behind other malignancies.

Methods: A series of 123 formalin-fixed, paraffin-embedded tissue samples with clinical annotations were retrospectively tested with a commercial library kit (Ion AmpliSeq Cancer Hotspot Panel v.2, Life Technologies, Grand Island, NY) to investigate 50 genes plus other two, BRCA1-associated protein-1 (BAP-1) and neurofibromatosis-2 (NF2), frequently altered in MPM. DNA was obtained from tissues after manual microdissection and enriched for at least 50% cancer cells. Variations affecting protein stability or previously correlated to cancer, more frequently identified (≥ 25 patients with at least 10% of allelic frequency), were subsequently evaluated by Sanger sequencing. Immunohistochemistry staining for BAP1 and NF2 proteins was also performed.

Results: The commonest genetic variations were clustered in two main pathways: the p53/DNA repair (TP53, SMACB1, and BAP1) and phosphatidylinositol 3-kinase-AKT pathways (PDGFRA, KIT, KDR, HRAS, PIK3CA, STK11, and NF2). PIK3CA:c.1173A>G mutation, STK11:rs2075606 (T>C), or TP53:rs1042522 (Pro/Pro) was significantly associated with time to progressive disease (TTPD; all p values < 0.01). Furthermore, the accumulation of genetic alterations correlated with shorter TTPD and reduced overall survival (TTPD p value = 0.02, overall survival p value = 0.04). BAP1 genetic variations identified were mainly located in exons 13 and 17, and BAP1 nonsynonymous variations were significantly correlated with BAP1 protein nuclear localization.

Conclusion: Next-generation sequencing was applied to a relatively large retrospective series of MPM using formalin-fixed, paraffin-embedded archival material. Our results indicate a complex mutational landscape with a higher number of genetic variations in the p53/DNA repair and phosphatidylinositol 3-kinase pathways, some of them with prognostic value.
The Presence of Asbestos in the Natural Environment is Likely Related to Mesothelioma in Young Individuals and Women from Southern Nevada. F. Baumann, B.J. Buck, R.V. Metcalf, et al. 2015;10(5):731-737. PubMed · Publisher · Free full text

Abstract

Background: Inhalation of asbestos and other mineral fibers is known causes of malignant mesothelioma (MM) and lung cancers. In a setting of occupational exposure to asbestos, MM occurs four to eight times more frequently in men than in women, at the median age of 74 years, whereas an environmental exposure to asbestos causes the same number of MMs in men and women, at younger ages.

Methods: We studied the geology of Nevada to identify mineral fibers in the environment. We compared MM mortality in different Nevada counties, per sex and age group, for the 1999 to 2010 period.

Results: We identified the presence of carcinogenic minerals in Nevada, including actinolite asbestos, erionite, winchite, magnesioriebeckite, and richterite. We discovered that, compared with the United States and other Nevada counties, Clark and Nye counties, in southern Nevada, had a significantly higher proportion of MM that occurred in young individuals (<55 years) and in women.

Conclusions: The elevated percentage of women and individuals younger than 55 years old, combined with a sex ratio of 1:1 in this age group and the presence of naturally occurring asbestos, suggests that environmental exposure to mineral fibers in southern Nevada may be contributing to some of these mesotheliomas. Further research to assess environmental exposures should allow the development of strategies to minimize exposure, as the development of rural areas continues in Nevada, and to prevent MM and other asbestos-related diseases.
A common polymorphism within MSLN affects miR-611 binding site and soluble mesothelin levels in healthy people. S. Garritano, C. De Santi, R. Silvestri, et al. 2014;9(11):1662-8. PubMed · Publisher

Abstract

Introduction: Soluble mesothelin related peptide (SMRP) was proposed as a promising diagnostic marker for malignant pleural mesothelioma (MPM). In a previous study, we found that rs1057147 within the 3' untranslated region of MSLN gene was associated with SMRP levels. Thus, we aimed to (1) confirm the previous association on a large series of volunteers and (2) test the hypothesis that the SNP could affect microRNA binding sites.

Methods: The association analysis was verified in 759 subjects. Then, in silico predictions highlighted miR-611 and miR-887 as candidate miRNAs binding to the polymorphic site. Thus, chimeric constructs bearing the alternative alleles (G > A) were assayed alone or in cotransfection with the miRNA mimics, with dual luciferase reporter assay in non-MPM Met-5A cells. The miRNAs were also assayed by western blot analysis for their ability to down-regulate endogenous mesothelin in the MPM Mero-14 cell line.

Results: We confirmed that, among non-MPM volunteers, GG homozygotes have the lowest SMRP levels. When the genotype is taken into account, the specificity of SMRP as biomarker improves from 79.7% to 85.3%. Dual-luciferase assays showed a significantly lower reporter activity when the vector harbored the G allele as compared to A allele. miR-887 mimic caused a reduced reporter activity of vectors harboring A or G alleles, while miR-611 was effective only on the vector harboring the G allele. Transfection of these miRNAs into Mero-14 cells significantly reduced endogenous MSLN protein.

Conclusion: SMRP performance as diagnostic biomarker improved by considering the genotype rs1057147. This polymorphism most likely affects a binding site for miR-611.
A feasibility study evaluating Surgery for Mesothelioma After Radiation Therapy: the "SMART" approach for resectable malignant pleural mesothelioma. B.C. Cho, R. Feld, N. Leighl, et al. 2014;9(3):397-402. PubMed · Publisher

Abstract

Introduction: We developed an innovative approach for malignant pleural mesothelioma (MPM) with a short accelerated course of high-dose hemithoracic intensity-modulated radiation therapy (IMRT) followed by extrapleural pneumonectomy (EPP). This phase I/II study assessed the feasibility of Surgery for Mesothelioma After Radiation Therapy (SMART).

Methods: All resectable clinical T1-3N0M0 histologically proven, previously untreated MPMs were eligible. Patients received 25 Gy in five daily fractions during 1 week to the entire ipsilateral hemithorax with concomitant 5 Gy boost to areas at risk followed by EPP within 1 week of completing neoadjuvant IMRT. Adjuvant chemotherapy was offered to ypN2 patients on final pathologic findings. The primary end point was treatment-related mortality and secondary end points were overall survival, disease-free survival, treatment-related morbidity, and patterns of failure.

Results: Targeted accrual of 25 patients was completed between November 2008 and October 2012. All patients completed SMART. IMRT was well tolerated with no grade 3+ toxicities. EPP was performed 6 ± 2 days after completing IMRT without any perioperative mortality. Thirteen patients developed grade 3+ surgical complications. One patient (4%) died from treatment-related toxicity (empyema) during follow-up. All but one patient had stage III or IV disease on final pathologic findings. Five of 13 ypN2 patients received adjuvant chemotherapy. After a median follow-up of 23 months (range, 6-51), the cumulative 3-year survival reached 84% in epithelial subtypes compared with 13% in biphasic subtypes (p = 0.0002).

Conclusions: SMART is feasible in resectable MPM patients. This innovative protocol presents encouraging results and supports future studies looking at long-term outcome in patients with epithelial subtypes.
B7-H1 expression in malignant pleural mesothelioma is associated with sarcomatoid histology and poor prognosis. A.S. Mansfield, A.C. Roden, T. Peikert, et al. 2014;9(7):1036-1040. PubMed · Publisher · Free full text

Abstract

Introduction: B7 homolog 1 (B7-H1; aka programmed cell death 1 ligand 1) is a negative costimulatory molecule that is associated with poor prognosis in many tumor types. Given the poor prognosis and the limited treatments available for mesothelioma, we decided to examine B7-H1 expression and its association with survival in patients with mesothelioma.

Methods: Expression of B7-H1 was determined in 106 patients using a mouse monoclonal antihuman B7-H1 (clone 5H1-A3) antibody with immunohistochemistry. Positive expression was defined as ≥5% positively stained cells. Clinicopathologic features and survival were compared between B7-H1-positive and B7-H1-negative groups.

Results: Malignant mesotheliomas of 42 patients (40%) expressed B7-H1. Patients with B7-H1-postive tumors were less likely to be offered or undergo therapeutic surgery (p = 0.03). All sarcomatoid mesotheliomas except one desmoplastic subtype expressed B7-H1. Survival was significantly decreased for patients whose tumors expressed B7-H1 (5 months median, 2-9.5 months interquartile range) compared with those whose tumors did not (14.5 months, 9.25-19 months; p < 0.0001). In a multivariate model, B7-H1 expression and sarcomatoid mesothelioma remained significantly associated with worse survival (risk ratio 1.71, 95% confidence interval 1.03-2.78 [p = 0.04] and risk ratio 2.18, 1.08-4.23 [p = 0.03], respectively).

Conclusions: B7-H1 is expressed in a substantial proportion of malignant pleural mesotheliomas and is associated with poor survival. Almost all malignant pleural mesotheliomas with sarcomatoid differentiation expressed B7-H1. The expression of B7-H1 may have important therapeutic implications for the management of malignant pleural mesothelioma.
Does surgery improve survival of patients with malignant pleural mesothelioma?: a multicenter retrospective analysis of 1365 consecutive patients. P. Bovolato, C. Casadio, A. Billè, et al. 2014;9(3):390-6. PubMed · Publisher

Abstract

Background: Surgery with pleurectomy/decortication (P/D) or extrapleural pneumonectomy (EPP) can be an option for selected patients with resectable malignant pleural mesothelioma (MPM). The aim of this study was to investigate the impact of surgical treatment on the outcome of patients with MPM.

Methods: We retrospectively reviewed data from 1365 consecutive patients with histologically proven MPM, treated from 1982 to 2012 in six Institutions. Patients received chemotherapy alone (n = 172), best supportive care (n = 690), or surgical treatment (n = 503), by either P/D (n = 202) or EPP (n = 301) with or without chemotherapy.

Results: After a median follow-up of 6.7 years (range, 1.1-14.8), 230 patients (16.8%) were alive; median survival for patients who received palliative treatment or chemotherapy alone, P/D, and EPP were 11.7 (95% CI, 10.5-12.5), 20.5 (95% CI, 18.2-23.1), and 18.8 (95% CI, 17.2-20.9) months, respectively. The 30-day mortality was 2.6% after P/D and 4.1% after EPP (p = 0.401). According to multivariate analysis (n = 1227), age less than 70, epithelial histology, and chemotherapy were independent favorable prognostic factors. In the subset of 313 patients (25.5%) with all favorable prognostic factors, median survival was 18.6 months after medical therapy alone, 24.6 months after P/D, and 20.9 months after EPP (p = 0.596).

Conclusions: Our data suggest that patients with good prognostic factors had a similar survival whether they received medical therapy only, P/D, or EPP. The modest benefit observed after surgery during medical treatment requires further investigation, and a large multicenter, randomized trial, testing P/D after induction chemotherapy versus chemotherapy alone in MPM patients with good prognostic factors, is needed.
Epidermal growth factor receptor mutations in 510 Finnish non--small-cell lung cancer patients. S. Mäki-Nevala, M. Rönty, M. Morel, et al. 2014;9(6):886-91. PubMed · Publisher

Abstract

Introduction: Among the driver gene mutations in non-small-cell lung cancer, mutations in epidermal growth factor receptor (EGFR) are the most important because of their predictive role in selecting patients eligible for targeted therapy. Our aim was to study EGFR mutations in a Finnish non-small-cell lung cancer cohort of 528 patients.

Methods: Mutation testing was conducted on DNA extracted from paraffin-embedded, formalin-fixed tumor material using the following real-time polymerase chain reaction-based kits: Therascreen EGFR PCR Kit and cobas EGFR Mutation Test.

Results: EGFR mutation frequency was 11.4% and all positive cases were adenocarcinomas, of which a majority had an acinar predominant pattern. Mutations were seen significantly more often in females and never-smokers than in males and smokers. The most frequent mutations were L858R in exon 21 and deletions in exon 19. Overall survival of the patients, not treated with EGFR inhibitor, did not differ between EGFR mutation-positive and EGFR mutation-negative patients.

Conclusion: EGFR mutation profile in this Finnish non-small-cell lung cancer cohort resembles in many respect with that of other Western European cohorts, even though the overall frequency of mutations is slightly higher. We show the occurrence of EGFR mutations in patients with occupational asbestos exposure and also in those diagnosed with chronic obstructive pulmonary disease who have not been often investigated before.
Frequent coamplification and cooperation between C-MYC and PVT1 oncogenes promote malignant pleural mesothelioma. E. Riquelme, M.B. Suraokar, J. Rodriguez, et al. 2014;9(7):998-1007. PubMed · Publisher · Free full text

Abstract

Introduction: Malignant pleural mesothelioma (MPM) is a deadly disease with poor prognosis and few treatment options. We characterized and elucidated the roles of C-MYC and PVT1 involved in the pathogenesis of MPM.

Methods: We used small interfering RNA (siRNA)-mediated knockdown in MPM cell lines to determine the effect of C-MYC and PVT1 abrogation on MPM cells undergoing apoptosis, proliferation, and cisplatin sensitivity. We also characterized the expression of microRNAs spanning the PVT1 region in MPM cell lines. Copy number analysis was measured by quantitative polymerase chain reaction and fluorescence in situ hybridization.

Results: Copy number analysis revealed copy number gains (CNGs) in chromosomal region 8q24 in six of 12 MPM cell lines. MicroRNA analysis showed high miR-1204 expression in MSTO-211H cell lines with four copies or more of PVT1. Knockdown by siRNA showed increased PARP-C levels in MSTO-211H transfected with siPVT1 but not in cells transfected with siC-MYC. C-MYC and PVT1 knockdown reduced cell proliferation and increased sensitivity to cisplatin. Analysis of the expression of apoptosis-related genes in the MSTO-211H cell line suggested that C-MYC maintains a balance between proapoptotic and antiapoptotic gene expression, whereas PVT1 and, to a lesser extent, miR-1204 up-regulate proapoptotic genes and down-regulate antiapoptotic genes. Fluorescence in situ hybridization analysis of MPM tumor specimens showed a high frequency of both CNGs (11 of 75) and trisomy (three copies; 11 of 75) for the C-MYC locus.

Conclusion: Our results suggest that C-MYC and PVT1 CNG promotes a malignant phenotype of MPM, with C-MYC CNG stimulating cell proliferation and PVT1 both stimulating proliferation and inhibiting apoptosis.
Gingival metastasis as first sign of multiorgan dissemination of epithelioid malignant mesothelioma. A. Billè, M. Platania, G. Pelosi, et al. 2014;9(8):1226-9. Case report PubMed · Publisher

Abstract

Introduction: Metastatic malignant mesothelioma to the oral cavity is extremely rare. They are more common in the jaw bones than the soft tissue. Occurrence of the malignant disease typically carries an average survival rate of 9-12 months

Methods: : Thirteen patients underwent neoadjuvant chemotherapy and radical pleurectomy decortication, followed by radiotherapy from August 2012 to September 2013. Patients were followed up with computed tomography of the chest and the abdomen every 3 months. All patients were followed up until February 2014.

Results: In January 2014, 11 patients were still alive with a median survival of 11 months, eight patients developed a recurrence and two patients died at 8 and 9 months after surgery. After 1 year from macroscopic radical pleurectomy decortication, a 68-year-old man suffered from gingival mass turned out to be a metastatic deposit of biphasic malignant mesothelioma as first sign of multiorgan recurrence. The patient underwent chemotherapy and local radiotherapy in the oral cavity.

Conclusions: This case points out the relevance of biopsy to all new growing lesions, even in uncommon anatomical sites, whenever a history of mesothelioma is on record.
Observer variability in mesothelioma tumor thickness measurements: defining minimally measurable lesions. S.G. Armato, A.K. Nowak, R.J. Francis, et al. 2014;9(8):1187-94. PubMed · Publisher

Abstract

Introduction: Single time-point unidimensional tumor thickness measurements define measurable disease for clinical trial inclusion and also constitute a field in the International Association for the Study of Lung Cancer prospective mesothelioma staging database. The modified Response Evaluation Criteria in Solid Tumors (RECIST) guidelines for mesothelioma did not alter the 10-mm minimum tumor measurement recommendation. However, as computed tomography technology has advanced, we sought to examine whether interobserver agreement was acceptable at smaller tumor thickness in mesothelioma.

Methods: The primary observer selected 170 discrete measurement sites from 105 thoracic computed tomography scans from 50 consenting patients with pleural mesothelioma. Sites represented a range of tumor thickness, lesion morphology, and location. The outer (parietal) tumor margin was marked at each site and presented to five additional observers, who then selected the visceral margin of the tumor to create a line segment that captured tumor thickness. Relative differences among the observer measurements were estimated using a random-effects analysis of variance model to identify the smallest tumor thickness at which linear measurements could be made reliably.

Results: Systematic bias was observed, with some observers consistently measuring larger or smaller thicknesses than the thickness measured by others. The mean range across all 170 sites was 15.1% of the mean per-site measurement (SD = 9.1%; median range, 13.1%). Measurements acquired at sites with mean tumor thickness less than 7.5 mm demonstrated interobserver variability with a 75th percentile included 20% of the tumor thickness. The 95% confidence interval for relative interobserver measurement differences obtained for mean measurement lengths in the range 5 to 7.5 mm does not exceed the RECIST thresholds.

Conclusions: This study has implications for the definition of minimally measurable tumor adopted by clinical trial and staging protocols. Although the statistical findings suggest that a reduction in "minimally measurable disease" from 10 mm to 5 or 7.5 mm might be warranted, clinical factors may ultimately dictate the most appropriate definition.
PI3K/mTOR signaling in mesothelioma patients treated with induction chemotherapy followed by extrapleural pneumonectomy. B.K. Bitanihirwe, M. Meerang, M. Friess, et al. 2014;9(2):239-47. PubMed · Publisher

Abstract

Introduction: The prognostic significance of activity biomarkers within the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway was assessed in two independent cohorts of malignant pleural mesothelioma (MPM) patients uniformly treated with a multimodal approach. We specifically assessed expression signatures in a unique set of pre- and postchemotherapy tumor samples.

Methods: Biomarker expression was assessed in samples of two independent cohorts of 107 (cohort 1) and 46 (cohort 2) MPM cases uniformly treated with platinum-based induction chemotherapy followed by extrapleural pneumonectomy from two different institutions, assembled on tissue microarrays. Expression levels of phosphatase and tensin homologue (PTEN), phospho-mTOR, and p-S6 in addition to marker of proliferation (Ki-67) and apoptosis (cleaved caspase-3) were evaluated by immunohistochemistry and correlated with overall survival (OAS) and progression-free survival (PFS). To assess PTEN genomic status, fluorescence in situ hybridization was performed.

Results: Survival analysis showed that high p-S6 and Ki-67 expression in samples of treatment naïve patients of cohort 1 was associated with shorter PFS (p = 0.02 and p = 0.04, respectively). High Ki-67 expression after chemotherapy remained associated with shorter PFS (p = 0.03) and OAS (p = 0.02). Paired comparison of marker expression in samples before and after induction chemotherapy of cohort 1 revealed that decreased cytoplasmic PTEN and increased phospho-mTOR expression was associated with a worse OAS (p = 0.04 and p = 0.03, respectively).

Conclusions: These novel data reveal a prognostic significance of expression changes of PI3K/mTOR pathway components during induction chemotherapy if confirmed in other patient cohorts and support the growing evidence to target the PI3K/mTOR pathway in the treatment of MPM.
Supplementary prognostic variables for pleural mesothelioma: a report from the IASLC staging committee. H.I. Pass, D. Giroux, C. Kennedy, et al. 2014;9(6):856-64. PubMed · Publisher · Free full text

Abstract

Introduction: The staging system for malignant pleural mesothelioma is controversial. To revise this system, the International Association for the Study of Lung Cancer Staging Committee developed an international database. This report analyzes prognostic variables in a surgical population, which are supplementary to previously published CORE variables (stage, histology, sex, age, and type of procedure).

Methods: Supplementary prognostic variables were studied in three scenarios: (1) all data available, that is, patient pathologically staged and other CORE variables available (2) only clinical staging available along with CORE variables, and (3) only age, sex, histology, and laboratory parameters are known. Survival was analyzed by Kaplan-Meier, prognostic factors by log rank and stepwise Cox regression modeling after elimination of nonsignificant variables. p value less than 0.05 was significant.

Results: A total of 2141 patients with best tumor, node, metastasis (TNM) stages (pathologic with/without clinical staging) had nonmissing age, sex, histology, and type of surgical procedure. Three prognostic models were defined. Scenario A (all parameters): best pathologic stage, histology, sex, age, type of surgery, adjuvant treatment, white blood cell count (WBC) (≥15.5 or not), and platelets (≥400 k or not) (n = 550). Scenario B (no surgical staging): clinical stage, histology, sex, age, type of surgery, adjuvant treatment, WBC, hemoglobin (<14.6 or not), and platelets (n = 627). Scenario C (limited data): histology, sex, age, WBC, hemoglobin, and platelets (n = 906).

Conclusion: Refinement of these models could define not only the appropriate patient preoperatively for best outcomes after cytoreductive surgery but also stratify surgically treated patients after clinical and pathologic staging who do or do not receive adjuvant therapy.
Synergistic antitumor activity of recombinant human Apo2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in combination with carboplatin and pemetrexed in malignant pleural mesothelioma. G. Pasello, L. Urso, M. Silic-Benussi, et al. 2014;9(7):1008-1017. PubMed · Publisher

Abstract

Introduction: Malignant pleural mesothelioma (MPM) is an aggressive, currently incurable tumor with increasing incidence in industrialized countries. Tumor necrosis factor-related, apoptosis-inducing ligand (TRAIL) is a member of the TNF family, which induces cancer cell death through extrinsic apoptotic pathway, while sparing normal cells. The aim of this study was to investigate the antitumor activity of recombinant human Apo2L/TRAIL (dulanermin) in combination with chemotherapy in MPM in vitro and in vivo.

Methods: In the present studies, we employed a panel of MPM cell lines to test the antitumor activity of recombinant human Apo2L/TRAIL (T) in combination with carboplatin and pemetrexed (CP) in vitro and SCID mice.

Results: Results demonstrated a significant increase of apoptosis in cell lines treated with CPT compared with those receiving CP or T as single agents. This synergistic effect was dependent on the ability of CP to increase the expression of the TRAIL receptors DR4 and DR5 in a p53 manner. The CPT combination was also effective in blocking the growth of MPM cell lines in a SCID mice preclinical model.

Conclusions: CPT increases MPM cell death in vitro and in vivo compared with CP. In vitro results suggest that chemotherapy sensitizes MPM to TRAIL-dependent apoptosis through p53 activation and subsequent upregulation of DRs.
The challenge of malignant pleural mesothelioma: new directions. V.W. Rusch, A. Rimner, L.M. Krug. 2014;9(3):271-2. Editorial · Comment PubMed · Publisher

Summary

This editorial, by authors from Memorial Sloan-Kettering Cancer Center, commented on two articles about the management of malignant pleural mesothelioma (MPM) published in the same journal issue. The first, by Bovolato et al., retrospectively analyzed outcomes in 1365 MPM patients treated at six Italian institutions over a 30-year period. The editorialists noted that it corroborated data from the IASLC International Staging and Prognostic Factors Committee, including the gap between clinical and pathological staging, the significance of tumor histology and patient age, and apparently better outcomes with combined modality therapy. They listed its strengths as the large number of patients, long follow-up and apparently uniform surgical approaches. They listed its limitations as variable adjuvant therapy, the long study duration and likely patient-selection biases. They also noted that outcomes could not be clearly distinguished between extrapleural pneumonectomy (EPP) and pleurectomy/decortication. The second article, by Cho et al. in Toronto, reported a phase II trial of immediate preoperative hemithoracic intensity-modulated radiation therapy followed by EPP. In highly selected patients this approach was associated with a 3-year overall survival of 84%. It did not seem to improve local control over postoperative radiation, and it was applicable to 18% of patients. The authors called for larger, preferably multicenter trials and formal guidelines for adjuvant chemotherapy. They concluded that future MPM trials need stricter inclusion criteria and strictly defined treatment in strictly defined patient cohorts.

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"One marker does not fit all": additional translational and validation studies are needed to identify faithful predictors of pemetrexed activity in mesothelioma. E. Giovannetti, G.J. Peters, P.A. Zucali. 2013;8(8):e79-80. Letter · Comment PubMed · Publisher
A case of pleural epithelioid sarcoma of proximal type presenting as malignant pleural mesothelioma. G.A. Madsen, T.R. Rasmussen, S. Bærentzen. 2013;8(10):e89-90. Case report PubMed · Publisher

Summary

The authors reported a case of pleural epithelioid sarcoma of proximal type that presented as malignant pleural mesothelioma (MPM), seen at Aarhus University Hospital, Denmark. A 45-year-old man presented with one month of progressing dyspnea and right shoulder pain. He was a truck driver and a smoker of about 15 pack-years, with no history of asbestos exposure. A chest radiograph showed a large right pleural effusion, and 3300 ml of bloody fluid was drained; cytology showed no malignant cells. Computed tomography showed several irregular pleural plaques resembling MPM. Positron emission tomography–computed tomography showed increased 18F-fluorodeoxyglucose uptake in the right pleura and in mediastinal and retroperitoneal lymph nodes. Pleural biopsies taken at thoracoscopy showed tumor cells with rhabdoid characteristics. The tumor stained strongly for vimentin, pancytokeratin KL-1 and CK8, was positive for CD34, and showed loss of INI-1. It was negative for specific mesothelial markers, including calretinin, HBME1, nuclear WT-1 and D2-40. The findings were judged consistent with epithelioid sarcoma of proximal type rather than mesothelioma. The patient deteriorated rapidly and died in a hospice about two months later. A PubMed search found no other cases of primary pleural epithelioid sarcoma. The authors concluded that such tumors may in the past have been diagnosed as MPM. They stated that correct diagnosis matters because MPM and sarcomas are treated differently.

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An unusual cause of Dysphagia in a 76-year-old heavy smoker. A. Derweduwen, P. Nafteux, E. Verbeken, et al. 2013;8(10):1339-40. Case report PubMed · Publisher
An unusual presentation of malignant pleural mesothelioma. M.M. Lacle, M.F. van Oosterhout. 2013;8(7):e63-4. Case report PubMed · Publisher

Summary

This case report described an unusual presentation of malignant pleural mesothelioma in a 65-year-old man. He was admitted with several months of progressive shortness of breath on exertion and cough. He had a history of hypertension and smoking, no previous cancers, and had never been exposed to asbestos. High-resolution computed tomography showed diffuse nodular opacities in both lungs, ground-glass opacities in the upper left lobe, septal thickening, increased peripheral vascular markings and pleural effusion, but no pleural thickening. These findings were first interpreted as small airways disease with an added component of congestive heart failure. He did not improve after diuretics and stopping smoking, so a lung biopsy was taken by video-assisted thoracoscopic surgery. His condition worsened after the biopsy and he died. No autopsy was performed. Microscopy showed widespread infiltration of the lung tissue and pleura by epithelioid cells, with prominent involvement of the lung lymphatics. The cells were positive for pan-keratin, calretinin, D2-40 and cytokeratin 5/6, and negative for carcinoembryonic antigen, MOC-31, TTF-1 and CD31. This confirmed epithelioid malignant mesothelioma. Epithelioid hemangioendothelioma had initially been considered. The authors stated that, to their knowledge, no epithelioid mesothelioma with this growth pattern had been reported before. They concluded that recognizing unusual growth patterns is important to avoid misdiagnosis, which could adversely affect treatment and prognosis.

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Clinical characteristics of patients with malignant pleural mesothelioma harboring somatic BAP1 mutations. M.G. Zauderer, M. Bott, R. McMillan, et al. 2013;8(11):1430-3. PubMed · Publisher · Free full text

Abstract

Introduction: Genomic studies of malignant pleural mesothelioma (MPM) have recently identified frequent mutations in the BRCA-associated protein 1(BAP1) gene. In uveal melanoma and clear cell renal cell carcinoma, BAP1 mutations are associated with poor outcomes but their clinical significance in MPM is unknown. We therefore undertook this study to define the characteristics of patients whose MPM tumors harbor somatic BAP1 mutation and to examine the relationship between BAP1 mutation and survival.

Methods: We reviewed the charts of 121 patients with MPM tumors diagnosed between 1991 and 2009 tested for BAP1 mutation, and extracted the following information: age at diagnosis, sex, histology, stage, smoking status, asbestos exposure, family or personal history of malignancy, and treatment including surgery, chemotherapy, and radiation as well as survival status.

Results: Twenty-four of the 121 tumors (20%) harbored somatic BAP1 mutations. The percentage of current or former smokers among cases with BAP1 mutations was significantly higher than in BAP1 wild-type cases, (75% versus 42%; p = 0.006). However, the types of nucleotide substitutions in BAP1 did not suggest that this association was because of a causative role of smoking in BAP1 mutations. No other clinical feature was significantly different among those with and without BAP1 mutations in their MPM. There was also no difference in survival according to somatic BAP1 mutation status.

Conclusion: There is no apparent distinct clinical phenotype for MPM with somatic BAP1 mutation. The significance of the more frequent history of smoking among patients with BAP1-mutated MPM warrants further study.
Combination of mesothelin and CEA significantly improves the differentiation between malignant pleural mesothelioma, benign asbestos disease, and lung cancer. T. Muley, H. Dienemann, F.J. Herth, et al. 2013;8(7):947-51. PubMed · Publisher

Abstract

Introduction: Soluble mesothelin-related peptides (SMRP) have been reported as potential markers for the diagnosis of malignant pleural mesothelioma (MPM). We wondered, whether a combination with a carcinoembryonic antigen (CEA) test might improve the relatively low diagnostic yield of the SMRP test.

Methods: In a retrospective study, SMRP (mesothelin) and CEA serum concentrations were measured, using commercially available kits, in 93 previously untreated MPM patients, 75 patients with benign asbestos disease, and 139 patients suffering from lung cancer (LC).

Results: The differentiation between MPM, LC, and benign asbestos disease could be improved by applying the ratio mesothelin/CEA. Whereas CEA expression was found to be low in MPM, most LC patients had elevated CEA serum levels. The area under curve (AUC) of the receiver operator characteristics curve for mesothelin alone was found to be only 0.708. For mesothelin/CEA the AUC of the receiver operator characteristics curve increased to 0.978. The sensitivity was 93% (69%) at 95% (100%) specificity for the differentiation between MPM and LC. Comparison of MPM and benign asbestos disease showed that the AUC was 0.887 and the sensitivity 56% (47%) at 95% (100%) specificity. In contrast, the AUC for the mesothelin test alone was only 0.715, and for the CEA test alone it was 0.16. An average increment in sensitivity of 38% (range, 16%-63%) could be achieved by the quotient mesothelin/CEA compared with the sensitivity of mesothelin alone.

Conclusion: The diagnostic yield of the mesothelin test can be considerably improved when combined with a CEA test with regard to the differential diagnosis between MPM and LC and between MPM and benign asbestos disease.
Differential expression of extracellular matrix constituents and cell adhesion molecules between malignant pleural mesothelioma and mesothelial hyperplasia. G. Alì, N. Borrelli, G. Riccardo, et al. 2013;8(11):1389-95. PubMed · Publisher

Abstract

Introduction: Malignant pleural mesothelioma (MPM) is a highly aggressive neoplasm associated with asbestos exposure. Currently, the molecular mechanisms that induce MPM development are still unknown. The purpose of this study was to identify new molecular biomarkers for mesothelial carcinogenesis.

Methods: We analyzed a panel of 84 genes involved in extracellular matrix remodeling and cell adhesion by polymerase chain reaction (PCR) array in 15 samples of epithelioid mesothelioma and 10 samples of reactive mesothelial hyperplasia (MH; 3 of 25 samples were inadequate for mRNA analysis). To validate the differentially expressed genes identified by PCR array, we analyzed 27 more samples by immunohistochemistry, in addition to the 25 samples already studied.

Results: Twenty-five genes were differentially expressed in MPM and MH by PCR array. Of these we studied matrix metalloproteinase 7 (MMP7), MMP14, CD44, and integrin, alpha3 expression by immunohistochemistry in 26 epithelioid MPM and 26 MH samples from the entire series of 52 cases. We observed higher MMP14 and integrin, alpha3 expression in MPM samples compared with MH samples (p = 0.000002 and p = 0.000002, respectively). Conversely, CD44 expression was low in most (57.7%) mesothelioma samples but only in 11.5% of the MH samples (p = 0.0013). As regards MMP7, we did not observe differential expression between MH and MPM samples.

Conclusions: We have extensively studied genes involved in cell adhesion and extracellular matrix remodeling in MPM and MH samples, gaining new insight into the pathophysiology of mesothelioma. Moreover, our data suggest that these factors could be potential biomarkers for MPM.
Lung volume measurements as a surrogate marker for patient response in malignant pleural mesothelioma. Z.E. Labby, S.G. Armato, J.J. Dignam, et al. 2013;8(4):478-86. PubMed · Publisher · Free full text

Abstract

Introduction: The purpose of this study was to investigate the continuous changes in three distinct response assessment methods during treatment as a marker of response for patients with mesothelioma. Linear tumor thickness measurements, disease volume measurements, and lung volume measurements (a physiological correlate of disease volumes) were investigated in this study.

Methods: Serial computed tomography scans were obtained during the course of clinically standard chemotherapy for 61 patients. For each of the 216 computed tomography scans, the aerated lung volumes were segmented using a fully automated method, and the pleural disease volume was segmented using a semiautomated method. Modified Response Evaluation Criteria in Solid Tumors linear-thickness measurements were acquired clinically. Diseased (ipsilateral) lung volumes were normalized by the respective contralateral lung volumes to account for the differences in inspiration between scans for each patient. Relative changes in each metric from baseline were tracked over the course of follow-up imaging. Survival modeling was performed using Cox proportional hazards models with time-varying covariates.

Results: Median survival from pretreatment baseline imaging was 12.7 months. A negative correlation was observed between measurements of lung volume and disease volume, and a positive correlation was observed between linear-thickness measurements and disease volume. As continuous numerical parameters, all three response assessment methods were significant imaging biomarkers of patient prognosis in independent survival models.

Conclusions: Analysis of trajectories of linear-thickness measurements, disease volume measurements, and lung volume measurements during chemotherapy for patients with mesothelioma indicates that increasing linear thickness, increasing disease volume, and decreasing lung volume are all significantly and independently associated with poor patient prognosis.
MARS: a sense of perspective and an inconvenient truth. T. Treasure, M. Utley, K. O'Byrne. 2013;8(5):e48-9. Letter · Comment PubMed · Publisher

Summary

In this letter to the editor, the authors responded to comments by Kindler and by Rusch et al., published in the November issue of the Journal of Thoracic Oncology, about the Mesothelioma and Radical Surgery (MARS) trial of extrapleural pneumonectomy (EPP) for malignant pleural mesothelioma. They stated that MARS, which reported 50 randomized patients, was funded by Cancer Research UK as a feasibility study. A full trial with 80% power to detect a survival advantage from EPP had been estimated to need 670 patients. They argued that 50 patients were enough to raise serious concern that EPP might shorten life and reduce its quality. On operative mortality, they reported EPP mortality in MARS of 2 of 19 (10.5%; exact 95% confidence limits 1.3%-33.1%). They said this lay within the 0% to 11.8% range of 30-day mortality in a systematic review of 34 studies including 2320 patients. Median survival in the EPP arm was 14.4 months from randomization, which they said was in line with EPP cohorts published from 2007 to 2009 (10 to 14 months). Patients randomized to no surgery had a median survival of 19.5 months. On feasibility, MARS registered 112 patients in 2005-2008, and 57 consented to randomization. The authors concluded that effort should go into obtaining high-quality evidence, for example on lung-sparing surgery and quality of life.

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MARS: a sense of perspective and an inconvenient truth. V.W. Rusch, H.L. Kindler. 2013;8(5):e49-50. Letter · Comment PubMed · Publisher

Summary

In this letter, Rusch and Kindler replied to a letter from Drs. Treasure, Utley and O'Byrne. Those authors had written to correct what they considered misperceptions about the Mesothelioma and Radical Surgery (MARS) trial, which compared extrapleural pneumonectomy (EPP) with no EPP in patients with malignant pleural mesothelioma (MPM). Rusch and Kindler stated that significant concerns about the trial's methodology had already been reported by an international group of mesothelioma investigators and did not need to be repeated. They described a major concern: a trial originally designed to accrue 50 patients with MPM, to test whether randomizing between EPP and no surgery was feasible, had been reported as a definitive phase III trial showing no survival benefit for EPP. They called this a fundamental violation of the principles of clinical trial analysis and reporting. They stated that the article in the November issue of the Journal of Thoracic Oncology and its accompanying editorial had focused on the International Association for the Study of Lung Cancer Staging Committee's effort to develop an international database. That database was intended to lead to evidence-based revisions of the UICC and AJCC staging system for MPM. They concluded that discussions of the role of EPP in managing MPM, or of the MARS trial, were tangential to the primary focus of that effort.

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Overexpression of EPH receptor B2 in malignant mesothelioma correlates with oncogenic behavior. C. Goparaju, J.S. Donington, T. Hsu, et al. 2013;8(9):1203-11. PubMed · Publisher

Abstract

Introduction: Malignant pleural mesothelioma (MM) is an aggressive asbestos-associated malignancy with limited therapeutic options. This study describes the overexpression of Ephrin B2 receptor (EPHB2) in MM cell lines and tumors, and the effect of its manipulation on proliferative and invasive qualities of the disease.

Methods: Using expression arrays, we investigated EPHB2 in MM tumors compared with normal mesothelium. EPHB2 and downstream target expression were evaluated using reverse-transcriptase polymerase chain reaction and immunoblotting methods. The biological significance of EPHB2 in MM was evaluated using in vitro functional assays with and without targeting by EPHB2-short hairpin RNA or blocking peptide in two mesothelioma cell lines, HP-1 and H2595.

Results: EPHB2 is overexpressed in all MM cell lines, but not in benign mesothelial cells, and is significantly elevated in MM tumor tissue compared with matched normal peritoneum. Targeted knockdown of EPHB2 in HP-1 and H2595 cell lines reduced its expression and that of EPHB2 downstream targets such as matrix metalloproteinase (MMP-2) and vascular endothelial growth factor, whereas caspase 2 and caspase 8 had increased expression. Inhibition of EPHB2 resulted in a significant decrease in scratch closure (1.25-fold-1.8-fold), proliferation (1.5-fold), and invasion (1.7-fold-1.8-fold) compared with the controls. Most notably, however, EPHB2 silencing resulted in a significant increase in apoptotic proteins and activity.

Conclusion: EPHB2 seems to play an important role in MM pathogenesis and these findings indicate that EPHB2 could serve as a potential novel therapeutic target for treatment of the disease.
Patterns of failure, toxicity, and survival after extrapleural pneumonectomy and hemithoracic intensity-modulated radiation therapy for malignant pleural mesothelioma. D.R. Gomez, D.S. Hong, P.K. Allen, et al. 2013;8(2):238-45. PubMed · Publisher · Free full text

Abstract

Introduction: We investigated safety, efficacy, and recurrence after postoperative hemithoracic intensity-modulated radiation therapy (IMRT) in patients with malignant pleural mesothelioma treated with extrapleural pneumonectomy (EPP), during the past decade at a single institution.

Methods: In 2001-2011, 136 consecutive patients with malignant pleural mesothelioma underwent EPP with planned adjuvant IMRT. Eighty-six patients (64%) underwent hemithoracic IMRT; the rest were not eligible because of postoperative complications, disease progression, or poor performance status. We assessed toxicity, survival, and patterns of failure in these 86 patients. Toxicity was scored with the Common Terminology Criteria for Adverse Events version 4.0; survival outcomes were estimated with the Kaplan-Meier method; and locoregional patterns of failure were classified as in-field, marginal, or out-of-field. Risk factors related to survival were identified by univariate and multivariate Cox regression analysis.

Results: Median overall survival time for all 86 patients receiving IMRT was 14.7 months. Toxicity rates of grade of 3 or more were: skin 17%, lung 12%, heart 2.3%, and gastrointestinal toxicity 16%. Five patients experienced grade 5 pulmonary toxicity. Rates of locoregional recurrence-free survival, distant metastasis-free survival, and overall survival (OS) were 88%, 55%, and 55% at 1 year and 71%, 40%, and 32% at 2 years. On multivariate analysis, pretreatment forced expiratory volume in 1 second, nonepithelioid histology, and nodal status were associated with distant metastasis-free survival and OS.

Conclusion: IMRT after EPP is associated with low rates of locoregional recurrence, though some patients experience life-threatening lung toxicity. Tumor histology and nodal status can be helpful in identifying patients for this aggressive treatment.
Phase 2 study of sorafenib in malignant mesothelioma previously treated with platinum-containing chemotherapy. S. Papa, S. Popat, R. Shah, et al. 2013;8(6):783-7. PubMed · Publisher

Abstract

Introduction: The incidence of mesothelioma is rising. First-line cisplatin and pemetrexed confers a survival benefit, with a median progression-free survival (PFS) of 5.7 months. Sorafenib inhibits tyrosine kinases, including receptors for vascular endothelial growth factor, which are implicated in mesothelioma pathogenesis by preclinical and clinical data.

Methods: Sorafenib, at 400 mg twice daily, was assessed in a single-arm multicenter phase 2 study, using Simon's two-stage design. Eligible patients had received platinum combination chemotherapy earlier. The primary endpoint was PFS at 6 months, with secondary endpoints, including response rate and metabolic response, assessed using fluorodeoxyglucose positron emission tomography. Published reference values for PFS in mesothelioma provide a benchmark for the null hypothesis of 28% progression-free at 6 months, and for moderate or significant clinical activity of 35% or 43% progression-free at 6 months, respectively.

Results: Fifty-three patients (72%) were treated. Most had epithelioid histology. Ninety-three percent of patients had a performance status 0 or 1. Treatment was well tolerated with few grade 3 or 4 toxicities. Median PFS was 5.1 months, with 36% of patients being progression-free at 6 months. Nine percent of patients remained on study beyond 1 year. Changes in fluorodeoxyglucose positron emission tomography parameters did not predict clinical outcome.

Conclusions: Sorafenib is well tolerated in patients with mesothelioma after completion of platinum-containing chemotherapy. PFS of sorafenib compares favorably with that reported for other targeted agents, and suggests moderate activity in this disease.
Recurrence of malignant pleural mesothelioma at the resection borders--local or distant recurrence?. S. Bölükbas, M. Eberlein, J. Schirren. 2013;8(7):e65. Letter · Comment PubMed · Publisher
Recurrence of malignant pleural mesothelioma at the resection borders--local or distant recurrence?. D. Gomez, A. Tsao, D. Rice. 2013;8(7):e65-6. Letter · Comment PubMed · Publisher
Reduced folate carrier and folylpolyglutamate synthetase, but not thymidylate synthase predict survival in pemetrexed-treated patients suffering from malignant pleural mesothelioma. F. Mairinger, C. Vollbrecht, I. Halbwedl, et al. 2013;8(5):644-53. PubMed · Publisher

Abstract

Background: Malignant mesothelioma is a highly aggressive tumor arising from mesothelial-lined surfaces, most often in the pleura cavities. Antifolates belong to the most effective cytotoxic drugs for malignant pleural mesothelioma (MPM) treatment. Pemetrexed is an antifolate inhibiting different folate pathway genes (thymidylate synthase [TS], dihydrofolate reductase, glycinamide ribonucleotide formyltransferase [GARFT], and aminoimidazole carboxamide ribonucleotide formyltransferase, [AICARFT]). Increased activity of pemetrexed occurs by folylpolyglutamate synthetase (FPGS), intracellular transport by reduced folate carrier (RFC). The aim of the study was to explore potential correlations between TS, GARFT, AICARFT, RFC, and FPGS levels in MPM and associations with clinical benefit from pemetrexed treatment.

Methods: Samples from 63 patients were tested using immunohistochemistry (IHC) and quantitative polymerase chain reaction(qPCR) for expression levels of TS, GARFT, AICARFT, RFC, and FPGS. Clinical data were evaluated to determine associations between efficacy of pemetrexed and enzyme expression levels. Evaluation of expression levels was done through TaqMan-based qPCR, and IHC was evaluated semiquantitatively by using the H-score.

Results: qPCR analysis showed no difference in expression pattern of GARFT and AICARFT. IHC analysis revealed a heterogeneous staining pattern for all the enzymes. No significant association was found between TS expression and survival or objective response of the tumors after pemetrexed treatment. FPGS (p = 0.0111) and RFC (p = 0.0088) mRNA expression levels were strongly associated with overall survival in these patients.

Conclusions: Our results reveal that in pemetrexed-treated MPMs TS expression levels have no influence on patient outcome. Furthermore, GARFT and AICARFT were homogeneously expressed in the patient samples. Folate uptake mechanisms by RFC and activation by FPGS were associated with clinical benefit from pemetrexed treatment.
Sarcomatoid mesothelioma with osteoid differentiation. M. Evison, P.A. Crosbie, M. Howe, et al. 2013;8(9):1222-3. Case report PubMed · Publisher

Summary

The authors reported the case of a 75-year-old man at the University Hospital of South Manchester, United Kingdom. He presented with 3 months of progressive breathlessness and right-sided chest pain. Initial investigations showed a right pleural effusion with extensive pleural calcification and irregular pleural thickening. His serum alkaline phosphatase was markedly elevated at 11,209 (reference range 30–130). An isotope bone scan showed marked tracer uptake in the right hemithorax. Pleural biopsies taken at video-assisted thoracoscopic surgery showed a malignant neoplasm of plump to spindle cells with focal areas of osteoid formation. The malignant cells were positive for calretinin and cytokeratin 5/6. After clinical, radiological and histological review at thoracic oncology and sarcoma multidisciplinary team meetings, sarcomatoid mesothelioma with osteoid differentiation was diagnosed. The patient was given palliative chemotherapy with cisplatin and pemetrexed. After three cycles his condition deteriorated and repeat imaging confirmed significant disease progression. Chemotherapy was stopped, and he died 4 weeks later. The authors noted that this subtype is well described in the literature, with reported survival ranging from an average of 5.7 months in a series of 10 patients to case reports of 36 to 69 months. They stated that this was the first case to show significant elevation of serum alkaline phosphatase, diffuse rather than focal pleural calcification on follow-up computed tomography, and abnormal tracer uptake on bone scan. They concluded that radiological features of malignant pleural disease together with pleural calcification should raise suspicion of this rare subtype of mesothelioma. The report did not mention asbestos exposure.

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Surgery in mesothelioma--where do we go after MARS?. B.I. Hiddinga, J.P. van Meerbeeck. 2013;8(5):525-9. Review PubMed · Publisher

Abstract

The role of surgery in the management of malignant pleural mesothelioma remains controversial. Surgical resection consists of different procedures for diagnostic or therapeutic reasons. The latter includes either an extrapleural pleuropneumonectomy (EPP) or lung-sparing operations like debulking of the parietal and visceral pleura by pleurectomy/decortication (P/D) or extended pleurectomy/decortication, in which further debulking of the diaphragm or pericardium is included. Because of the modest outcome of surgery as single-modality therapy, combinations of chemotherapy, surgery, and radiation therapy were initiated as a new treatment strategy to improve prognosis. The observations that patients treated with P/D had an equal to better outcome than those treated with EPP, and that EPP with perioperative chemotherapy was better than EPP alone, raises the issue whether performing a P/D with perioperative chemotherapy would result in a further improvement of outcome with a lower operative mortality than with EPP and perioperative chemotherapy. This is the rationale for the next European Organisation for Research and Treatment of Cancer trial exploring the feasibility of P/D with perioperative chemotherapy.
The issue of studies evaluating biomarkers which predict outcome after pemetrexed-based chemotherapy in malignant pleural mesothelioma. F. Mairinger, C. Vollbrecht, T. Mairinger, et al. 2013;8(8):e80-2. Letter · Comment PubMed · Publisher

Summary

This letter was the authors' reply to a letter by Giovannetti, Peters and Zucali criticizing the authors' earlier study of folate pathway markers as predictors of survival after pemetrexed-based chemotherapy in malignant pleural mesothelioma (MPM). The authors noted that Zucali and colleagues' own study of 99 MPM patients treated with carboplatin and pemetrexed had examined only thymidylate synthase (TS) and ERCC1, and that earlier studies had reported either a correlation between TS and pemetrexed response or none. They stated that some previous studies had immunohistochemical sections evaluated by inexperienced researchers rather than pathologists. They agreed that the whole thymidylate pathway must be investigated and that a multi-institutional prospective trial was probably needed. On FPGS, they wrote that no validated antibodies against splice variants were available for formalin-fixed paraffin-embedded tissue, so they chose polyclonal antibodies expected to detect several isoforms, and their mRNA assay covered both known physiological isoforms. They described their validation: immunohistochemistry on whole-tissue sections and tissue microarrays with negative and positive controls, and quantitative PCR following MIQE guidelines with two reference genes, controls, small amplicons and exon-spanning assays. They agreed that drug metabolites and uptake mechanisms should be studied. They argued that repeat biopsies for research were uncommon and would not be approved, and said they had used at least three tissue cores per tumor to address heterogeneity.

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Thymidylate synthase and folyl-polyglutamate synthase are not clinically useful markers of response to pemetrexed in patients with malignant pleural mesothelioma. D.E. Lustgarten, C. Deshpande, C. Aggarwal, et al. 2013;8(4):469-77. PubMed · Publisher · Free full text

Abstract

Purpose: Thymidylate synthase (TS) is a potential predictor of outcome after pemetrexed (Pem) in patients with malignant pleural mesothelioma (MPM), and assays measuring TS levels are commercially marketed. The goal of this study was to further evaluate the value of TS and to study another potential biomarker of response, the enzyme, folyl-polyglutamate synthase (FPGS), which activates Pem intracellularly.

Methods: Levels of TS and FPGS were semi-quantitatively determined immunohistochemically using H-scores on tissue samples from 85 MPM patients receiving Pem as primary therapy. H-score was correlated with radiographic disease control rate (DCR), time to progression (TTP) and overall survival (OS). In addition, expression levels of TS and FPGS in MPM cell lines were determined using immunoblotting and correlated with their sensitivity to Pem-induced cell death.

Results: H-scores from patients with disease control versus progressive disease showed extensive overlap. There were no significant correlations of DCR, TTP, or OS to either TS levels (p = 0.73, 0.93, and 0.59, respectively), FPGS levels (p = 0.95, 0.77, and 0.43, respectively) or the ratio of FPGS/TS using the median scores of each test as cutoffs. There was no correlation between TS or FPGS expression and chemosensitivity of mesothelioma cells to Pem in vitro.

Conclusions: Although previous retrospective data suggest that TS and FPGS expression might be potential markers of Pem efficacy in MPM, our data indicate these markers lack sufficient predictive value in individual patients and should not be used to guide therapeutic decisions in the absence of prospective studies.
Tomotherapy after pleurectomy or decortication or biopsy for malignant pleural mesothelioma. M. Trovo, E. Minatel. 2013;8(5):e50-1. Letter · Comment PubMed · Publisher
Tomotherapy after pleurectomy or decortication or biopsy for malignant pleural mesothelioma. S. Bölükbas, J. Schirren, M. Eberlein. 2013;8(5):e50. Letter · Comment PubMed · Publisher
ZIC1 is silenced and has tumor suppressor function in malignant pleural mesothelioma. Y.Y. Cheng, M.B. Kirschner, N.C. Cheng, et al. 2013;8(10):1317-28. PubMed · Publisher

Abstract

Introduction: Epigenetic inactivation of tumor suppressor genes is involved in the development of malignant pleural mesothelioma (MPM). ZIC1, a potential tumor suppressor gene involved in regulating cell growth and apoptosis, was investigated in MPM cell lines and tumors.

Methods: ZIC1 expression and promoter methylation were evaluated in MPM cell lines and tumor samples by quantitative polymerase chain reaction (PCR), Combined Bisulfite Restriction Analysis, and methylation-specific PCR. ZIC1 was reexpressed in cell lines and functional effects were assessed. miRNA expression was quantified by microarray and reverse transcription quantitative PCR. ZIC1 knockdown and miRNA inhibitors were used to study the relationship between ZIC1 and miRNA expression and confirmed by chromatin immunoprecipitation PCR.

Results: ZIC1 expression was low in MPM cells, and was correlated with ZIC1 promoter methylation and reversed upon decitabine treatment. ZIC1 reexpression inhibited proliferation and invasion in MPM cells whereas knockdown enhanced the growth of MeT-5A. In MPM tumor samples ZIC1 expression was either low or undetectable, with promoter methylation observed in 16 of 24 cases. The overexpression of miR-23a and miR-27a was reduced by ZIC1 reexpression, with inhibitors of miR-23a or miR-27a reducing colony formation. miR-23a overexpression was also associated with shorter survival of MPM patients.

Conclusion: ZIC1 is down-regulated in MPM through promoter methylation and acts as a tumor suppressor through down-regulation of its direct targets miR-23a and miR-27a.
A phase II study of intermittent sunitinib malate as second-line therapy in progressive malignant pleural mesothelioma. A.K. Nowak, M.J. Millward, J. Creaney, et al. 2012;7(9):1449-56. PubMed · Publisher

Abstract

Introduction: There is no accepted second-line therapy for patients with advanced malignant pleural mesothelioma (MPM), whose disease has progressed after first-line chemotherapy. The multitargeted tyrosine kinase inhibitor sunitinib malate targets several pathways overexpressed in mesothelioma. This phase II study assessed objective response to sunitinib and correlative biomarkers in patients with progressive pretreated MPM.

Methods: Eligible patients had confirmed MPM, radiological progression after chemotherapy, Eastern Cooperative Oncology Group performance status 0 to 1, and measurable disease. Patients received oral sunitinib 50 mg daily for 28 of every 42 days. The primary endpoint was objective radiological response. Patients without prior pleurodesis had fluorodeoxyglucose positron emission tomographic response assessed by total glycolytic volume criteria. Correlative biomarkers included serum mesothelin, vascular endothelial growth factor (VEGF)-A, VEGF-C, interleukin-8, sVEGFR-2, sVEGFR-3, and s-kit.

Results: Fifty-three patients received sunitinib between July 2006 and December 2009; 51 were assessable for response. Patients received a median of two cycles (range, 1-12); 40% required dose reduction. Fatigue was the most prominent toxicity. Six patients (12%) had a confirmed radiological partial response, 34 (65%) had stable disease, and 11 (22%) had progressive disease as best response. Six of 20 patients had a decrease in fluorodeoxyglucose positron emission tomographic total glycolytic volume of 15% or more. Median overall survival was 6.1 months, and median time to progression was 3.5 months. Correlative biomarkers did not predict treatment response.

Conclusions: Sunitinib has activity in a subset of patients with pretreated MPM. Consideration should be given to different treatment schedules and examination of other biomarkers for further study of sunitinib in MPM.
Activated leukocyte cell-adhesion molecule (ALCAM) promotes malignant phenotypes of malignant mesothelioma. F. Ishiguro, H. Murakami, T. Mizuno, et al. 2012;7(5):890-9. PubMed · Publisher

Abstract

Introduction: Cell-adhesion molecules play important roles involving the malignant phenotypes of human cancer cells. However, detailed characteristics of aberrant expression status of cell-adhesion molecules in malignant mesothelioma (MM) cells and their possible biological roles for MM malignancy remain poorly understood.

Methods: DNA microarray analysis was employed to identify aberrantly expressing genes using 20 MM cell lines. Activated leukocyte cell-adhesion molecule (ALCAM) expression in MM cell lines was analyzed with quantitative reverse transcription-polymerase chain reaction and Western blot analyses in 47 primary MM specimens with immunohistochemistry. ALCAM knockdown in MM cell lines was performed with lentivirus-mediated short hairpin RNA (shRNA) transduction. Purified soluble ALCAM (sALCAM) protein was used for in vitro experiments, whereas MM cell lines infected with the sALCAM-expressing lentivirus were tested for tumorigenicity in vivo.

Results: ALCAM, a member of the immunoglobulin superfamily, was detected as one of the most highly upregulated genes among 103 cell-adhesion molecules with microarray analysis. Elevated expression levels of ALCAM messenger RNA and protein were detected in all 20 cell lines. Positive staining of ALCAM was detected in 26 of 47 MM specimens (55%) with immunohistochemistry. ALCAM knockdown with shRNA suppressed cell migration and invasion of MM cell lines. Purified sALCAM protein impaired the migration and invasion of MM cells in vitro, and the infection of sALCAM-expressing virus into MM cells significantly prolonged survival periods of MM-transplanted nude mice in vivo.

Conclusion: Our study suggests that overexpression of ALCAM contributes to tumor progression in MM and that ALCAM might be a potential therapeutic target of MM.
Cause-specific mortality in relation to chrysotile-asbestos exposure in a Chinese cohort. S. Lin, X. Wang, I.T. Yu, et al. 2012;7(7):1109-14. PubMed · Publisher

Abstract

Introduction: The carcinogenic potency of chrysotile asbestos remains a contentious topic, and more data are needed to address this issue. We examine cause-specific mortality, especially lung cancer, and its association with chrysotile-asbestos exposure in a Chinese cohort.

Methods: A cohort of 577 workers from a chrysotile-textile plant was followed prospectively from 1972 to 2008. Occupational history, exposure information, and smoking data were obtained from company records and personal interviews; vital status and causes of death were ascertained from death registries and hospitals. Workers were classified into three exposure levels on the basis of exposure assessments of different workshops. Standardized Mortality Ratios (SMRs) were calculated in terms of exposure levels and other indices.

Results: Among 259 identified deaths, 53 died from lung cancer, with an SMR of 4.08 (95% confidence interval 3.12, 5.33), and 96 from all cancers with an SMR of 2.09 (1.71, 2.55). In addition, two deaths from mesothelioma were observed. Increased mortality from respiratory diseases was also observed (SMR 3.38, 95% confidence interval 2.72, 4.21). Asbestos-exposure levels, exposure years, and birth cohorts showed a clear trend of risk for lung cancer and respiratory diseases.

Conclusion: The current analysis indicated that exposure to chrysotile asbestos was closely associated with excess mortality from lung cancer and respiratory diseases.
CCL2, galectin-3, and SMRP combination improves the diagnosis of mesothelioma in pleural effusions. C. Blanquart, F. Gueugnon, J.M. Nguyen, et al. 2012;7(5):883-9. PubMed · Publisher

Abstract

Introduction: Malignant pleural mesothelioma (MPM) is a highly aggressive tumor with poor prognosis. One major challenge for this disease is the development of new, early, and highly reliable diagnostic markers. The aim of this study was to compare the diagnostic value of the chemokine chemokine (C-C motif) ligand 2 (CCL2), galectin-3, and the secretory leukocyte peptidase inhibitor (SLPI) with soluble mesothelin-related peptides (SMRP), and to evaluate the diagnostic performance of marker combinations.

Methods: The levels of the different markers were measured by enzyme-linked immunosorbent assay in pleural fluids from patients with MPM (n = 61), adenocarcinomas (ADCA, n = 25), or with benign pleural effusions (BPE, n = 15).

Results: SMRP, SLPI, and CCL2 concentrations were significantly higher in pleural effusions from mesothelioma patients. Conversely, galectin-3 levels seemed to be elevated in patients with pulmonary ADCA. Receiver operating characteristic curve analysis revealed that SMRP (area under the curve [AUC] = 0.9059), CCL2 (AUC = 0.7912), galectin-3 (AUC = 0.7584), and SLPI (AUC = 0.7219) were potentially interesting biomarkers for the differentiation of MPM patients from those with BPE or ADCA. Of interest, we showed that the combination of SMRP/CCL2/galectin-3 greatly improved MPM diagnosis (AUC = 0.9680), when compared with SMRP alone.

Conclusion: The combination of SMRP/CCL2/galectin-3 seems to represent a promising panel of biomarkers for the reliable diagnosis of MPM in pleural fluids.
Cigarette smoking associated with lung adenocarcinoma in situ in a large case-control study (SFBALCS). P.M. Bracci, J. Sison, H. Hansen, et al. 2012;7(9):1352-60. PubMed · Publisher · Free full text

Abstract

Introduction: Adenocarcinoma in situ (AIS), formerly bronchioloalveolar carcinoma, is an uncommon subtype of lung adenocarcinoma and accounts for approximately 3% to 4% of lung cancers. Compared with other lung cancer histologies, AIS patients are less likely to be smokers, yet associations with other lung cancer risk factors and differences by sex have not been determined.

Methods: A total of 338 AIS patients and frequency-matched controls from the parent study (cases = 6039, controls = 2073) were included in these analyses. Odds ratios and 95% confidence intervals as estimates of the relative risk were obtained from multivariable unconditional logistic regression analyses.

Results: Risk of AIS was associated with ever smoking (OR = 2.7, 95% confidence intervals: 2.1, 3.6), increased 20% to 30% for each 10-year increase in pack-years of smoking and decreased with increased years since quitting (p for trend <0.0001). There was no evidence that risk differed by sex but there was some suggestion that risk may differ by exposure to asbestos and by second-hand tobacco smoke exposure in whites.

Conclusion: There is an association between AIS and smoking, which is smaller in magnitude than the association between other subtypes of non-small-cell lung cancer and smoking. Our findings suggesting that effects may differ by exposure to asbestos and second-hand tobacco smoke should be interpreted conservatively and warrant validation and further evaluation in larger studies of AIS.
DNA repair polymorphisms and treatment outcomes of patients with malignant mesothelioma treated with gemcitabine-platinum combination chemotherapy. N. Erčulj, V. Kovač, J. Hmeljak, et al. 2012;7(10):1609-17. PubMed · Publisher

Abstract

Introduction: Genetic polymorphisms that affect DNA repair capacity can modulate the efficacy and toxicity of cytotoxic agents. Therefore, the aim of our study was to evaluate the influence of genetic variability in DNA repair genes on treatment outcome in patients with malignant mesothelioma (MM) treated with gemcitabine-platinum combination chemotherapy.

Methods: In total, 109 patients with MM were genotyped for 10 polymorphisms in XRCC1, NBN, RAD51, and XRCC3 genes. The influence of selected polymorphisms on tumor response and occurrence of treatment-related toxicity was determined by logistic regression analysis, whereas their influence on survival was estimated by Cox proportional hazards model.

Results: There were no associations between the investigated polymorphisms and tumor response, but we observed a significant association between XRCC1 399Gln allele and reduced overall survival (hazards ratio = 1.70; 95% confidence interval [CI] 1.06-2.73; p = 0.028). Interaction between XRCC1 399Gln allele and C-reactive protein levels revealed that carriers of at least one XRCC1 399Gln allele with C-reactive protein levels above median had significantly shorter overall survival time compared with other patients (12.9 months versus 25.3 months, log-rank p < 0.001). We also observed an association between XRCC1 399Gln and lower frequency of leukopenia (odds ratio [OR] = 0.25; 95% CI 0.09-0.67; p = 0.006), neutropenia (OR = 0.24; 95% CI 0.09-0.68; p = 0.007), and thrombocytopenia (OR = 0.27; 95% CI 0.09-0.84; p = 0.024). In addition, NBN 3474A>C, XRCC3 -316A>G, and Thr241Met polymorphisms showed significant associations with treatment-related toxicity.

Conclusions: Our results support the hypothesis that DNA repair gene polymorphisms, particularly XRCC1 Arg399Gln, may modify the response to gemcitabine-platinum combination chemotherapy and, for the first time, show this effect in patients with MM.
E1B-55 kDa-defective adenoviruses activate p53 in mesothelioma and enhance cytotoxicity of anticancer agents. M. Yamanaka, Y. Tada, K. Kawamura, et al. 2012;7(12):1850-1857. PubMed · Publisher

Abstract

Introduction: Genetic characterization of malignant mesothelioma shows a homozygous deletion of the INK4A/ARF locus, which results in inactivation of the p53 pathways.

Methods: We examined possible antitumor effects of adenoviruses with a deletion of the E1B-55kD gene (Ad-delE1B55) on mesothelioma and investigated combinatory actions with the first-line chemotherapeutic agents.

Results: Ad-delE1B55 produced cytotoxicity on mesothelioma cells, which was associated with p53 phosphorylation, pRb dephosphorylation, and cleavage of caspases. Ad-delE1B55-infected cells displayed hyperploidy at the cell-cycle analysis and showed enlarged nuclear configurations. Combination of Ad-delE1B55 plus cisplatin or pemetrexed produced antitumor effects in vitro. Furthermore, Ad-delE1B55 and cisplatin showed combinatory effects in an orthotopic animal model.

Conclusions: Cell death caused by Ad-delE1B55 is attributable to cell-cycle arrest at M-phase checkpoint followed by activated apoptotic pathways, and combination of the first-line chemotherapeutic agents and the oncolytic adenovirus is a potential therapeutic for mesothelioma.
Folylpoly-glutamate synthetase expression is associated with tumor response and outcome from pemetrexed-based chemotherapy in malignant pleural mesothelioma. D.C. Christoph, B.R. Asuncion, C. Mascaux, et al. 2012;7(9):1440-8. PubMed · Publisher · Free full text

Abstract

Background: Pemetrexed-based chemotherapy represents the standard of care in first-line 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). After cellular uptake pemetrexed is converted into more effective polyglutamated forms by folylpoly-γ-glutamate synthetase (FPGS). We hypothesized that FPGS and TS protein expressions are associated with clinical outcome after pemetrexed-based chemotherapy.

Methods: Pretreatment tumor samples from 84 patients with histologically confirmed MPM, who received pemetrexed combined with platinum (79 of 84) or single-agent pemetrexed (5 of 84) as first-line treatment, were retrospectively analyzed. FPGS and TS protein expressions were semiquantitatively assessed by using the Hybrid (H)-scoring system (range, 0-300). H-scores were correlated with radiological response according to modified Response Evaluation Criteria in Solid Tumors, 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 (partial response versus stable disease + progressive disease; pKW = 0.003), and improved disease-control rate (partial response + stable disease versus progressive disease; pKW = 0.0208), but not with OS. In addition, high TS protein expression was associated with progressive disease under pemetrexed-based therapy (p = 0.0383), and shorter OS (pCOX = 0.0071), but no association with PFS was observed.

Conclusion: FPGS and TS expressions were associated with clinical response and outcome to pemetrexed-based first-line chemotherapy in MPM. Prospective evaluation of FPGS and TS expressions and their prognostic/predictive power in MPM patients is warranted.
High SUVmax on FDG-PET indicates pleomorphic subtype in epithelioid malignant pleural mesothelioma: supportive evidence to reclassify pleomorphic as nonepithelioid histology. K. Kadota, S.S. Kachala, J. Nitadori, et al. 2012;7(7):1192-7. PubMed · Publisher · Free full text

Abstract

Background: We have recently proposed to reclassify the pleomorphic subtype of epithelioid malignant pleural mesothelioma (MPM) as nonepithelioid (biphasic/sarcomatoid) histology because of its similarly poor prognosis. We sought to investigate whether preoperative maximum standardized uptake value (SUVmax) on F-fluorodeoxyglucose (FDG) positron emission tomography (PET) correlates with histologic subtype in MPM.

Methods: Clinical data were collected for 78 patients with MPM who underwent preoperative FDG-PET. We retrospectively classified the epithelioid tumors into five subtypes: trabecular, tubulopapillary, micropapillary, solid, and pleomorphic. Tumors were categorized by SUVmax into two groups: low (<10.0) and high (≥10.0).

Results: The median overall survival of epithelioid tumors with high SUVmax (n = 12) was significantly shorter (7.1 months) than that of epithelioid tumors with low SUVmax (n = 54, 18.9 months, p < 0.001) and comparable to nonepithelioid tumors (n = 12, 7.2 months). Epithelioid tumors with pleomorphic subtype (n = 9) had marginally higher SUVmax (mean ± SD: 10.6 ± 5.9) than epithelioid nonpleomorphic subtype (n = 57, 6.5 ± 3.2, p = 0.050), and were comparable to that of nonepithelioid tumors (n = 12, 9.1 ± 4.8). Among the epithelioid tumors with high SUVmax (n = 12), 50% (n = 6) showed pleomorphic subtype. In contrast, among epithelioid tumors with low SUVmax (n = 54), 6% (n = 3) showed epithelioid pleomorphic subtypes (p = 0.001). A positive correlation between mitotic count and SUVmax was observed (r = 0.30, p = 0.010).

Conclusions: Pleomorphic subtype of epithelioid MPM showed higher SUVmax than the epithelioid nonpleomorphic subtype and was similar to nonepithelioid histology. Preoperative SUVmax on FDG-PET in epithelioid MPM can indicate patients with pleomorphic subtype with poor prognosis, supporting their reclassification as nonepithelioid.
Incidence and survival of malignant pleural mesothelioma in norway: a population-based study of 1686 cases. Å. Helland, S. Solberg, O.T. Brustugun. 2012;7(12):1858-1861. PubMed · Publisher

Abstract

Background: Asbestos-related malignant pleural mesothelioma is one of the most lethal tumor types. The advent of antimetabolite treatment as pemetrexed, introduced in the early 2000s, may have increased survival on a population basis. In this study, we have analyzed population-based incidence and survival data over the last 40 years.

Methods: Complete national data on 1686 patients from the Cancer Registry of Norway sampled from 1970 to 2009 are presented, with incidence rates in 5-year periods. Relative survival for 1 year and 3 years and median survival in 5-year intervals were calculated.

Results: The incidence of malignant pleural mesothelioma has been significantly and steadily increasing from 1970 until 2009, with 50 patients diagnosed in the period 1970-1974 and 377 diagnosed in 2005-2009. The incidence was highest among men in all time periods. A slight decline was observed in the last period. The 1-year survival rate increased from 20.7% to 44.0% during the period 1970-2009, whereas the 3-year survival rate remained below 10%. Median survival increased from 4.0 months in the first period to 9.3 months in the last period.

Conclusions: The incidence of malignant pleural mesothelioma follows the curve of asbestos exposure with a 20- to 40-year lag. There has been a significant increase in survival, most likely because of earlier diagnosis and improvements in cytostatic treatment.
Increased circulating miR-625-3p: a potential biomarker for patients with malignant pleural mesothelioma. M.B. Kirschner, Y.Y. Cheng, B. Badrian, et al. 2012;7(7):1184-91. PubMed · Publisher

Abstract

Introduction: We investigated the ability of cell-free microRNAs (miRNAs) in plasma and serum to serve as a biomarker for malignant mesothelioma (MM).

Methods: Using miRNA microarrays, we profiled plasma samples from MM patients and healthy controls. miRNAs with significantly different abundance between cases and controls were validated in a larger series of MM patients and in an independent series of MM patients using quantitative real-time polymerase chain reaction. Levels of candidate miRNAs were also quantified in MM tumor samples.

Results: We compared cell-free miRNA profiles in plasma from MM patients with healthy controls. Reviewing 90 miRNAs previously reported to be associated with MM, we found that the levels of two miRNAs, miR-29c* and miR-92a, were elevated in plasma samples from MM patients. In addition, we identified 15 novel miRNAs present at significantly higher levels in the plasma of MM patients. Further analysis of candidate miRNAs by real time-quantitative polymerase chain reaction confirmed that one of them, miR-625-3p, was present in significantly higher concentration in plasma/serum from MM patients and was able to discriminate between cases and controls, in both the original and the independent series of patients. MiR-625-3p was also found to be up-regulated in tumor specimens from a group of 18 MM patients, who underwent extrapleural pneumonectomy.

Conclusion: Our data confirm the potential of miR-29c* and miR-92a as candidate tumor markers and reveal that miR-625-3p is a promising novel diagnostic marker for MM.
Inflammation-based prognostic indices in malignant pleural mesothelioma. D.J. Pinato, F.A. Mauri, R. Ramakrishnan, et al. 2012;7(3):587-94. PubMed · Publisher

Abstract

Introduction: Chronic inflammation plays a key role in the pathogenesis of malignant pleural mesothelioma (MPM) as a result of asbestos exposure. Biomarkers of systemic inflammation have been shown to predict the natural history of MPM; however, this observation lacks independent validation. Our aim was to compare the prognostic performance of three inflammation-based biomarkers in predicting overall survival (OS) in MPM.

Methods: In patients with histologically proven MPM, the inflammation-based prognostic scores modified Glasgow Prognostic Score (mGPS), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio were studied and compared with the European Organization for the Research and Treatment of Cancer Prognostic Score (EPS) and other known potential prognostic factors such as gender, histologic subtype, Eastern Cooperative Oncology Group performance status, and baseline blood parameters.

Results: A total of 171 MPM patients presenting to Imperial College NHS Trust were studied. In univariate analyses, the following parameters were predictors of OS: female gender (p = 0.03), epithelioid histology (p = 0.03), normal C-reactive protein (p = 0.03), baseline white blood cell count <8.3 × 10/liter (p = 0.04), EPS (p = 0.003), mGPS (p < 0.001), NLR (p = 0.006), and platelet-to-lymphocyte ratio (p = 0.03). Multivariate survival analysis confirmed the mGPS (hazard ratio = 2.6; p < 0.001) and NLR (hazard ratio = 2.0; p = 0.008), but not the EPS, as independent predictors of OS. Tissue expression of Ki-67 (p < 0.001) and vascular endothelial growth factor (p < 0.001) was higher in a subgroup of patients with high-risk inflammatory scores.

Conclusions: The mGPS and NLR are externally validated prognostic indices in patients with MPM and correlate with sustained neoangiogenesis and increased proliferative index.
Initial analysis of the international association for the study of lung cancer mesothelioma database. V.W. Rusch, D. Giroux, C. Kennedy, et al. 2012;7(11):1631-9. PubMed · Publisher

Abstract

Background: The current staging system for malignant pleural mesothelioma (MPM) is controversial. To plan revisions of this system, the International Association for the Study of Lung Cancer Staging Committee developed an international database. Initial analyses focus on patients managed surgically.

Methods: Participation was solicited from centers known to have MPM registries. Common data elements were analyzed by the International Association for the Study of Lung Cancer Staging Committee Statistical Center. Survival was analyzed by the Kaplan-Meier method, prognostic factors by log rank and Cox regression model. p Value less than 0.05 was significant.

Results: Data included 3101 patients (15 centers, 4 continents).

Demographics: median age 63 years, 79% men, 62.3% epithelioid tumor. Best tumor, node, metastasis (bTNM) stages were: I (11%), II, (21%), III (48%), and IV (20%). Curative-intent surgery was performed in 1494 patients (64.5%). Median survivals by clinical TNM and pathological TNM were similar: stage I, 21 months; stage II, 19 months; stage III, 16 months; and stage IV, 12 months. Median survival by histology: epithelioid 19 months, biphasic 13 months, and sarcomatoid 8 months. By multivariable analyses, significant differences in overall survival were seen for: T4 versus T3 and T3 versus T2 but not T2 versus T1; N0 versus N1 and N2 but not N1 versus N2; stages III and IV versus I but not II versus I; epithelioid histology versus other; age of female versus age of male; and palliative versus curative-intent surgery.

Conclusions: This is the largest international database examining outcomes in surgically managed MPM patients. Survival differences reported from smaller databases are confirmed but suggest the need to revise tumor and node staging.
Is it time to consider pleurectomy and decortication as the only surgical treatment for malignant pleural mesothelioma?. M.J. Weyant. 2012;7(4):629-30. Editorial PubMed · Publisher

Summary

In this editorial, the author discussed the choice between radical extrapleural pneumonectomy (EPP) and pleurectomy and decortication (P/D) as surgical treatments for malignant pleural mesothelioma (MPM). He wrote in response to a study by Lang-Lazdunski et al. He noted that EPP had been considered the gold standard operation, but that its operative mortality had been reported as high as 18% in some series. He summarized a series of 663 patients reported by Flores et al. That series suggested P/D might be superior in stage-I disease with R0 resection, and that EPP might benefit patients with more extensive disease. He also summarized the MARS trial, which randomized 50 patients and whose authors suggested EPP should be abandoned in trimodal therapy; that trial was criticized for its high surgical mortality and small sample size. The Lang-Lazdunski study involved a single surgeon at a single institution over 7 years. It reported surgical mortality of 4.5% for EPP and nil for P/D, and the authors stated that P/D patients had significantly improved survival in all parameters evaluated. The editorial argued that the study did not analyze why patients were steered toward P/D rather than EPP. It also argued that stage-for-stage survival conclusions were unfounded given the small subgroup sizes. The author concluded that the findings supported considering P/D in all MPM treatment trials, but that it was too early to abandon EPP altogether, as some patient subsets may benefit.

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Low ERCC1 expression in malignant pleural mesotheliomas treated with cisplatin and vinorelbine predicts prolonged progression-free survival. Z.G. Zimling, J.B. Sørensen, T.A. Gerds, et al. 2012;7(1):249-56. PubMed · Publisher

Abstract

Introduction: The relationship between excision repair cross-complementation group 1 (ERCC1) expression and outcome, in patients with malignant pleural mesothelioma (MPM), treated with cisplatin/vinorelbine combination-therapy, was retrospectively evaluated in a patient population from a previously published phase II clinical trial.

Methods: The study population consisted of 54 inoperable patients with MPM enrolled between 2003 and 2006. ERCC1 expression was evaluated by immunohistochemistry (IHC) on the formalin-fixed paraffin-embedded diagnostic biopsies. The immunoreaction was quantified using an H-score (staining intensity multiplied by a proportion score based on the percentage of stained tumor cells). The cutoff point was chosen as the median H-score in a cohort of non-neoplastic pleural samples from patients with benign thoracic diseases. The tumor samples were separated according to this cutoff point into ERCC1-negative (H-score ≤ median) and ERCC1-positive (H-score > median) cases.

Results: Fifty patients had tumor tissue available for IHC. There were 20 ERCC1-positive and 30 ERCC1-negative tumors. There was a significant correlation between negative ERCC1 status and long progression-free survival (PFS). Median PFS was 10.9 months in the ERCC1-negative group, opposed to 6.7 months in the ERCC1-positive group (p = 0.053). Multivariate Cox regression showed ERCC1 to be the only variable significantly associated with PFS, and ERCC1-positive patients had a significantly shorter time to progression compared with ERCC1-negative patients (hazard ratios, 2.24; 95% confidence interval, 1.16-4.34; p = 0.0163). We found no association between ERCC1 status and overall survival.

Conclusion: Our retrospective study in MPM patients treated with cisplatin/vinorelbine suggests that low ERCC1 expression, evaluated by IHC, may predict longer PFS, a result that warrants further validation.
Malignant pleural mesothelioma localized in the thoracic wall. D. Morimoto, N. Fujimoto, H. Nishi, et al. 2012;7(10):e21-2. Case report PubMed · Publisher
Mesothelioma. A.S. Tsao. 2012;7(16 Suppl 5):S399-400. Review PubMed · Publisher
Optimization of response classification criteria for patients with malignant pleural mesothelioma. Z.E. Labby, S.G. Armato, H.L. Kindler, et al. 2012;7(11):1728-34. PubMed · Publisher · Free full text

Abstract

Introduction: Response-assessment metrics play an important role in clinical trials and routine patient management. For patients with malignant pleural mesothelioma (MPM), the standard for response assessment is image-based measurements of tumor thickness made according to the modified RECIST (Response Evaluation Criteria in Solid Tumors) protocol. To classify tumor response, changes in tumor thickness are compared with the standard RECIST -30% and +20% cutoffs for partial response (PR) and progressive disease (PD), respectively, which are not specific to MPM. The purpose of this work is to optimize the correlation between tumor response and patient survival by assessing the validity of existing response criteria in MPM and proposing alternative criteria.

Methods: Computed tomography measurements of tumor thickness were acquired at baseline and throughout treatment for 78 patients undergoing standard-of-care chemotherapy. Overall survival was correlated with best response and first follow-up response using Harrell's C statistic. The response criteria for PD and PR were each varied in 1% increments to obtain optimized classification criteria. The performance was cross-validated using a leave-one-out approach.

Results: Median survival was 14.9 months. The performance of the standard RECIST criteria in correlating response with survival was C=0.778, whereas the optimized performance of C=0.855 was obtained with criteria of -64% for PR and +50% for PD. After cross-validation, this performance was slightly reduced to C=0.829.

Conclusions: Optimized tumor-response classification criteria were obtained for patients with MPM. These criteria improve the correlation between image-based response and patient survival.
Phase II clinical trial of first or second-line treatment with bortezomib in patients with malignant pleural mesothelioma. D.A. Fennell, C. McDowell, S. Busacca, et al. 2012;7(9):1466-70. PubMed · Publisher

Abstract

Based on promising preclinical efficacy of bortezomib in mesothelioma, a single-arm phase II trial (Ireland Cooperative Oncology Research Group 05-10 study), with Simon's two-stage design, was undertaken to assess efficacy of bortezomib monotherapy in the first-line (poor performance status) and second-line settings. The Bcl-2 homology domain 3-only protein Noxa has been implicated as a key inducer of apoptosis by bortezomib. Thus, in a biomarker research substudy, we hypothesized that deficiency in Noxa expression might correlate with resistance. In the second-line setting, 23 patients were enrolled. Partial response was confirmed in one patient (4.8%) who received four cycles of bortezomib. One patient had stable disease; however, progression occurred in the majority of patients within the first two cycles. Median progression-free survival and overall survival were 2.1 and 5.8 months, respectively. In the first-line setting, ten patients were accrued, and there was no evidence of objective response. In the tumor analysis, expression of Noxa was seen in all biopsies. Bortezomib monotherapy exhibits insufficient activity to warrant further investigation in unselected patients with mesothelioma.
Phase II study of dasatinib in patients with previously treated malignant mesothelioma (cancer and leukemia group B 30601): a brief report. A.Z. Dudek, H. Pang, R.A. Kratzke, et al. 2012;7(4):755-9. PubMed · Publisher · Free full text

Abstract

Introduction: We conducted a phase II trial of dasatinib in malignant mesothelioma (MM) patients to evaluate its toxicity and efficacy as a second-line treatment.

Methods: Patients with unresectable MM and no symptomatic effusions were given dasatinib 70 mg twice daily as part of a 28-day cycle. We also measured plasma vascular endothelial growth factor and platelet-derived growth factor b and colony stimulating factor 1 (CSF-1) and mesothelin-related protein at baseline and during therapy.

Results: Forty-six patients were enrolled in this study. Fifty percent of the first 12 patients enrolled experienced ≥grade 3 treatment-related adverse events, and therefore, the starting dose was reduced to 50 mg twice daily. Grade 3 and 4 toxicities included fatigue (11%) and pleural effusion (9%). The overall disease control rate was 32.6%, and progression-free survival at 24 weeks was 23% (95% confidence interval: 13.5-40.0%). Survival was markedly longer in patients with lower pretreatment CSF-1 levels and in patients whose CSF-1 levels decreased from baseline during therapy.

Discussion: Single-agent dasatinib has no activity in MM and is associated with pulmonary toxicities that prohibit its use in an unselected MM population.
Plasma cell membrane localization of c-MET predicts longer survival in patients with malignant mesothelioma: a series of 157 cases from the MESOPATH Group. G. Levallet, M. Vaisse-Lesteven, N. Le Stang, et al. 2012;7(3):599-606. PubMed · Publisher

Abstract

Introduction: By regulating cell functions such as growth, survival, motility/migration, and invasion, the c-mesenchymal-epithelial transition (c-MET) receptor tyrosine kinase/hepatocyte growth factor (HGF) axis accounts for a critical pathway in malignant pleural mesothelioma.

Methods: Overall survival correlations of c-MET and phospho-c-MET immunostainings were investigated in 157 malignant pleural mesothelioma patients for whom paraffin-embedded specimens were referred to our center for pathological diagnosis certification (MESOPATH French National group). Subcellular localization of the activated c-MET receptor after HGF stimulation was assessed in nontumorogenic cell lines.

Results: Positive c-MET expression was found in 119 samples (75.8%), more frequently in the epithelioid subtype (p < 0.0001). Among those 119 positive c-MET specimens, 77 (64.7%) were also positive for phospho-c-MET. Both c-MET and phospho-c-MET scoring were independent of patient gender or age. Phospho-c-MET scoring or localization did not associate with survival. Conversely, patients with a c-MET immunohistochemical staining intensity higher than 1, but exclusively confined to plasma membrane, had a median overall survival of 25 months versus 13 months for all other patients. Only exclusive plasma membrane staining remained significantly associated with a worse prognosis in multivariate analysis (hazard ratio = 2.9, 95% confidence interval 1.0-8.2, p = 0.043). Using the HBEC3 immortalized epithelial cell lines treated with HGF, we showed the physiological relevance of phospho-c-MET nuclear translocation.

Conclusions: Our results lighten that, disregarding the intracellular c-MET receptor traffic, only c-MET plasma membrane localization could be a relevant prognosis biomarker in malignant pleural mesothelioma. Whether patients with c-MET plasma membrane immunostaining could beneficiate from c-MET-targeted therapies remains to be established in prospective trials.
Pleural fluid cytological yield and visceral pleural invasion in patients with epithelioid malignant pleural mesothelioma. V. Pinelli, S. Laroumagne, L. Sakr, et al. 2012;7(3):595-8. PubMed · Publisher

Abstract

Introduction: Malignant pleural mesothelioma (MPM) is an aggressive malignancy arising from mesothelial cells lining the pleura. Most commonly, it presents as a unilateral pleural effusion. MPM usually develops on the parietal pleural surface and later spreads to the visceral pleura. Visceral pleural involvement entails a more advanced disease stage and is therefore an important prognostic factor. Pleural fluid (PF) cytology is often the first diagnostic test, but the sensitivity in the literature varies from 4 to 77%. However, no data are available for the diagnostic yield of cytological PF analysis with regard to the visceral pleural involvement. The aim of this study is to assess whether PF cytological yield is related to the extent and pattern of visceral pleural invasion, as assessed by thoracoscopy.

Methods: Medical records of all patients who underwent thoracoscopy for suspicion of malignant pleural effusion from two hospitals were reviewed. Patients were selected if they initially underwent a diagnostic thoracentesis before thoracoscopy, if visceral pleural appearance during thoracoscopy was clearly documented, and MPM confirmed on pleural tissue biopsy.

Results: Seventy-five patients were selected. Forty-five patients had a positive PF cytology on thoracentesis, while 30 had a negative PF cytology. Thoracoscopy showed parietal pleural invasion in all subjects. Interestingly, 82% of patients with positive PF cytology on thoracentesis had visceral pleural involvement, whereas only 30% of those with negative PF cytology had visceral pleural invasion. The pattern of visceral pleural invasion consisted of pleural masses, nodules, or pleural thickening. A multivariate regression identified visceral pleural invasion (p < 0.001) as the only independent factor predicting the positivity of cytology on pleural effusion.

Conclusion: In epithelioid MPM, PF cytological yield was significantly higher in patients with visceral pleural invasion assessed by thoracoscopy. Positive PF cytology is associated with a more advanced disease.
Pleurectomy/decortication is superior to extrapleural pneumonectomy in the multimodality management of patients with malignant pleural mesothelioma. L. Lang-Lazdunski, A. Bille, R. Lal, et al. 2012;7(4):737-43. PubMed · Publisher

Abstract

Introduction: To compare the outcomes of two different multimodality regimens involving neoadjuvant chemotherapy, extrapleural pneumonectomy (EPP) and adjuvant radiotherapy versus pleurectomy/decortication (P/D), hyperthermic pleural lavage with povidone-iodine, and adjuvant chemotherapy in patients with malignant pleural mesothelioma.

Methods: Nonrandomized prospective study of patients treated by multimodality therapy and operated on between January 2004 and June 2011. Second-line treatments were administered when appropriate. Survival and prognostic factors were analyzed by the Kaplan Meier method, log rank test, and Cox regression analysis.

Results: Twenty-five consecutive patients received neoadjuvant chemotherapy, 22 underwent EPP, and 17 received adjuvant radiotherapy. Over the same period, 54 consecutive patients underwent P/D and hyperthermic pleural lavage and received prophylactic radiotherapy and adjuvant chemotherapy. The 30-day mortality rate was 4.5%in the EPP group and nil in the P/D group. Fifteen patients (68%) in the EPP group and 15 (27.7%) in the P/D group experienced complications. There were no differences between the EPP and P/D groups for age, sex, histology, pathologic stage, and nodal status. Trimodality therapy was completed by 68%of the patients in the EPP group and 100%in the P/D group. Survival was significantly better in the P/D group: median survival was 23 months versus 12.8 months, 2-year survival was 49%versus 18.2 %, and 5-year survival was 30.1%versus 9%, respectively (p = 0.004). At multivariate analysis, epithelioid histology, P/D, and completeness of resection were independent prognostic factors.

Conclusions: In our experience, P/D, hyperthermic pleural lavage with povidone-iodine, and adjuvant chemotherapy were superior to neoadjuvant chemotherapy, EPP, and adjuvant radiotherapy.
Prospective study on functional results after lung-sparing radical pleurectomy in the management of malignant pleural mesothelioma. S. Bölükbas, M. Eberlein, J. Schirren. 2012;7(5):900-5. PubMed · Publisher

Abstract

Introduction: Malignant pleural mesothelioma (MPM) can reduce lung function by entrapping lung parenchyma via a rind of tumor with or without concurrent effusion. Radical pleurectomy (RP) allows expansion of the trapped lung. The purpose of this study was to investigate changes in pulmonary function and lung perfusion in patients undergoing RP.

Methods: In a prospective, nonrandomized study, all patients with histologically proven MPM were evaluated from January to December 2010 for trimodality therapy including RP as surgical procedure. Pulmonary-function tests and perfusion scans were obtained before and 2 months after RP. Primary end points were pulmonary function (forced vital capacity [FVC], forced expiratory volume in 1 second [FEV1]) and ipsilateral lung perfusion.

Results: Sixteen out of 25 consecutive patients (age 68.8±8.9 years) were enrolled in the study. Macroscopic complete resection could be achieved in 13 patients (81.3%). Diaphragm resection was necessary in 5 patients. Significant postsurgical improvement of pulmonary function at 2 months was observed for FVC and FEV1 (both absolute and percentage of predicted values) and ipsilateral perfusion (p < 0.001). Avoidance of diaphragm resection was associated with greater increase in FVC (+34.6±17.0% versus +13.5±5.4%; p = 0.002) and FEV1 (+29.2±18.1% versus +12.1±6.4%; p = 0.015), respectively.

Conclusions: Lung-sparing RP leads to significant improvement of pulmonary function and perfusion after a recovery time of 2 months. Functional results are better after preservation of the diaphragm. Preservation of physiological reserve via lung-sparing RP might allow patients with MPM to be eligible for further therapeutic options in the long term.
Robust data: the essential foundation of a revised staging system for pleural mesothelioma. H.L. Kindler. 2012;7(11):1623-4. Editorial PubMed · Publisher

Summary

In this editorial, the author commented on the initial retrospective analysis of the International Association for the Study of Lung Cancer (IASLC) mesothelioma database, published in the same journal issue. She noted that earlier staging systems for pleural mesothelioma were mostly built on small single-institution data sets that were not externally validated. The 1995 International Mesothelioma Interest Group/IASLC system, adopted by the UICC and the American Joint Commission on Cancer, was a consensus document based on several small retrospective surgical databases and was hard to apply reproducibly in clinically staged patients. The new analysis covered 3101 patients from 15 centers in four continents. The author highlighted several of its findings. Up to 80% of patients clinically thought to have stage I or II disease were upstaged at surgery. Outcomes for T1 and T2 disease did not differ significantly. Lymph node involvement was prognostic, but N1 versus N2 status was not. Median survival was 19 months for epithelial and 8 months for sarcomatoid histology. It was 20 versus 11 months for multimodality treatment versus surgery alone, and 18 versus 12 months for curative-intent versus palliative surgery. In stage I patients it was 40 months after extrapleural pneumonectomy versus 23 months after pleurectomy/decortication. She cautioned about selection bias in retrospective series and described the ongoing prospective staging project. She concluded that the analysis was a great beginning.

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Smoking, occupational risk factors, and bronchial tumor location: a possible impact for lung cancer computed tomography scan screening. M. Gonzalez, J.M. Vignaud, C. Clement-Duchene, et al. 2012;7(1):128-36. PubMed · Publisher

Abstract

Introduction: The aim of this study was to describe associations between lung tumor location and smoking as well as selected occupational exposures. In the context of lung cancer screening by computed tomography scan, tumor location may have an interest. Computed tomography scan is known to better detect more peripheral tumors.

Methods: Lung cancer cases diagnosed in two French University hospitals between 1997 and 2009 were included. Tumors visible on white-light bronchoscopy were defined as central. Occupational exposures were assessed by the same expert. Data were analyzed by case-case comparisons using unconditional logistic regressions.

Results: A total of 1701 cases were included, comprising mainly men (86.3%), current smokers (52.8%), or former smokers (42.8%). Main histological subtypes of cancer were adenocarcinomas (33.8%) and squamous cell carcinomas (32.6%). The tumor location was found to be central in 61% of cases, and never smokers and women had more often peripheral tumors. Exposure to asbestos was significantly associated with central location with dose-response relationship (odds ratio [OR] for peripheral tumors = 0.45, 95% confidence interval [CI] 0.29-0.70) for the highest level of exposure. Exposure to silica dust was significantly associated with peripheral tumor (OR for peripheral tumors = 3.28, 95%CI 1.50-7.17) for the highest level of exposure. Exposure to welding fumes was associated with central location (OR for peripheral tumors = 0.51, 95% CI 0.26-0.96) for the first level of exposure).

Conclusions: Smoking characteristics and occupational exposures have to be considered to define more accurately high-risk populations suitable for lung cancer screening or early detection programs.
Sustained expression of steroid receptor coactivator SRC-2/TIF-2 is associated with better prognosis in malignant pleural mesothelioma. C.J. Jennings, A. O'Grady, R. Cummins, et al. 2012;7(1):243-8. PubMed · Publisher

Abstract

Introduction: Estrogen receptor beta (ERβ) overexpression by malignant pleural mesothelioma (MPM) tumor cells correlates with enhanced patient survival. ER-regulated transcription is mediated by the p160 family of steroid receptor coactivators (SRCs), and SRC isoform overexpression is associated with worse prognosis in many steroid-related malignancies. The aim of this study was to establish whether SRC isoform expression varied between individual MPM tumors with positive or negative prognostic significance.

Methods: Immunohistochemical analysis of tumor biopsies from 89 subjects with confirmed histological diagnosis of MPM and biopsies from 3 normal control subjects was performed to detect the expression of SRC-1, SRC-2 (TIF-2), SRC-3 (AIB-1), and ERβ. Allred scores for expression of ERβ and each of the SRCs were determined, and Kaplan-Meier survival curves were calculated to correlate biomarker expression, gender, and histology type with postdiagnosis survival.

Results: ERβ and all the SRCs were expressed at high levels in normal pleural mesothelium, and expression of each biomarker was reduced or lost in a subset of the MPM subjects; however, postdiagnosis survival only significantly correlated with TIF-2 expression. Low or intermediate expression of TIF-2 correlated with reduced median postdiagnosis survival (9 months) compared with those subjects whose tumors highly expressed TIF-2 (20 months) (p = 0.036, log-rank test).

Conclusions: Maintained high expression of TIF-2 in tumor cells is a positive prognostic indicator for postdiagnosis survival in patients with confirmed MPM. This is the first clinical study to correlate high TIF-2 expression with improved patient prognosis in any malignancy.
Tomotherapy after pleurectomy/decortication or biopsy for malignant pleural mesothelioma allows the delivery of high dose of radiation in patients with intact lung. E. Minatel, M. Trovo, J. Polesel, et al. 2012;7(12):1862-1866. PubMed · Publisher

Abstract

Introduction: This study aimed to assess the safety of high doses of radiation delivered with tomotherapy to the intact lung after radical pleurectomy/decortication or biopsy for malignant pleural mesothelioma (MPM).

Methods: Twenty-eight patients were enrolled in this prospective study and underwent adjuvant or definitive tomotherapy after radical pleurectomy/decortication (n = 20) or pleural biopsy (n = 8) for MPM. The dose prescribed to the planning target volume, defined as the entire hemithorax, including chest-wall incisions and drain sites and excluding the intact lung, was 50 Gy delivered in 25 fractions. All patients underwent fluorodeoxyglucose-positron emission tomography for staging after surgery. Any fluorodeoxyglucose-avid areas or regions of particular concern for residual disease were given a simultaneous boost of radiotherapy to 60 Gy. Specific lung dosimetric parameters were reported. Toxicity was graded using the modified Common Toxicity Criteria version 3.0.

Results: The median follow-up was of 19 months (range, 6-29 months). Five patients (17.8%) experienced severe respiratory symptoms corresponding to grade 2 pneumonitis in three cases, and grade 3 pneumonitis in two cases. No fatal respiratory toxicity was reported. Controlateral lung V5 was strongly correlated with the risk of pneumonitis. Patients who developed grade 2 and 3 pneumonitis had a higher controlateral lung V5 (mean V5=32%) than those without pneumonitis (mean V5=17%) (p=0.002). Other two grade 3 toxicities were registered: one severe pain to the chest wall, and one severe thrombocytopenia.

Conclusions: Tomotherapy allows the safe delivery of high dose of radiation to the hemithorax of MPM patients with intact lung.
Zoledronic acid produces antitumor effects on mesothelioma through apoptosis and S-phase arrest in p53-independent and Ras prenylation-independent manners. S. Okamoto, K. Kawamura, Q. Li, et al. 2012;7(5):873-82. PubMed · Publisher

Abstract

Introduction: We examined whether zoledronic acid (ZOL), the third generation of bisphosphonates, produced cytotoxic effects on human mesothelioma cells in vitro and in vivo, and investigated a possible involvement of p53, Ras, and extracellular signal-regulated kinase1/2 (ERK1/2) pathways.

Methods: Cytotoxicity and cell cycles were assessed with a colorimetric assay and flow cytometry, respectively. Expression levels of apoptosis-linked proteins and prenylation of small guanine-nucleotide-binding regulatory proteins were tested with p53-small interfering RNA, an ERK kinase1/2-inhibitor, and prenyl alcohols. The antitumor activity was examined in an orthotopic animal model.

Results: ZOL treatments suppressed growth of mesothelioma cells bearing the wild-type p53 gene through apoptosis induction accompanied by activation of caspases, or S-phase arrest by up-regulated cyclin A and B1. ZOL induced p53 phosphorylation and subsequent activation of the downstream pathways. Down-regulated p53 expression with the small interfering RNA, however, showed that both apoptosis and S-phase arrest were irrelevant to the p53 activation. Geranylgeranyl but not farnesyl pyrophosphate inhibited ZOL-induced apoptosis and S-phase arrest, and the geranylgeraniol supplement decreased ZOL-mediated Rap1A but not Ras unprenylation. Inhibition of ERK1/2 pathways suppressed ZOL-induced apoptosis but not S-phase arrest. We further demonstrated that ZOL, administrated intrapleurally, inhibited the tumor growth in the pleural cavity.

Conclusions: These data indicate that ZOL induces apoptosis or S-phase arrest, both of which are independent of p53 activation and Ras unprenylation, and suggest that ZOL is a possible therapeutic agent to mesothelioma partly through non-Ras- and ERK1/2-mediated pathways.
A practical guide of the Southwest Oncology Group to measure malignant pleural mesothelioma tumors by RECIST and modified RECIST criteria. A.S. Tsao, L. Garland, M. Redman, et al. 2011;6(3):598-601. PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is difficult to measure radiographically due to the nonradial and variable pattern of growth and response to therapy. Inaccurate and inconsistent tumor measurements often compromise results from clinical trials that are dependent on identifying response rate and progression-free survival. In this article, we sought to provide a practical guide through the Southwest Oncology Group on how to measure MPM by the updated RECIST version 1.1 and by modified RECIST. We hope that these steps will provide a simple means by which computed tomography measurements can be consistently performed, minimizing intra- and interobserver variability. With this consistency, we may be able to better estimate the prognosis and response to therapy. With greater utilization, we will be able to better understand the biology of MPM.
A practical guide to measure "all" malignant pleural mesothelioma tumors by modified RECIST criteria?. K. Nackaerts, J. Vansteenkiste, P. Nafteux. 2011;6(12):2143-4; author reply 2144-5. Letter · Comment PubMed · Publisher
Accuracy of diagnostic biopsy for the histological subtype of malignant pleural mesothelioma. S.C. Kao, T.D. Yan, K. Lee, et al. 2011;6(3):602-5. PubMed · Publisher

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.
Aromatase inhibitor exemestane has antiproliferative effects on human mesothelioma cells. D. Stoppoloni, L. Salvatori, A. Biroccio, et al. 2011;6(3):583-91. PubMed · Publisher

Abstract

Purpose: The aim of this study was to investigate the expression and biological activity of aromatase (CYP19A1) in malignant mesothelioma (MM).

Experimental Design: We found CYP19A1 in five human MM cell lines using reverse transcription polymerase chain reaction and Western immunoblots and in a group of samples from patients with MM by immunohistochemistry. Aromatization activity was determined in MM cells by enzyme-linked immunosorbent assay as a measure of estradiol (E2) product, in basal condition and after addition of cytokine, prostaglandin-E2, and epidermal growth factor to MM cells. Treatment of MM cells with exemestane, a CYP19A1 inhibitor, was assessed by cell proliferation kit, cell cycle analysis, and Western blot for caspase, poly(ADP-ribose)polymerase, Bcl-xL, and v-akt murin thymoma viral oncogene homolog (Akt).

Results: Biological activity of CYP19A1, already present in basal condition, was increased in MPP89 and Ist-Mes1 cells after treatment with cytokine, in all MM cells on prostaglandin-E2 treatment, and in MPP89, Ist-Mes2, and Ist-Mes1 after addition of epidermal growth factor. Treatment of MM cells with exemestane led to significant reduction of tumor cell growth, perturbation of cell cycle, caspase activation, poly(ADP-ribose)polymerase cleavage, and down-regulation of phosphorylation of Akt and Bcl-xL. In tumor tissues, we found a cytoplasmic localization of CYP19A1. By univariate analysis, overall survival resulted to be strongly influenced by high CYP19A1 expression (p = 0.001).

Conclusion: These findings show that CYP19A1 is present in MM and that cell growth can be down-regulated by exemestane. As Akt pathway and Bcl-xL are implicated in conferring resistance to conventional chemotherapy, exemestane could open new treatment strategies to be associated with standard therapy for patients afflicted with MM.
Brief report: a phase II study of sunitinib in malignant pleural mesothelioma. the NCIC Clinical Trials Group. S.A. Laurie, A. Gupta, Q. Chu, et al. 2011;6(11):1950-4. PubMed · Publisher

Abstract

Introduction: Malignant pleural mesothelioma (MPM) is an aggressive malignancy that most often presents at an advanced, incurable stage. After the failure of standard first-line cisplatin/antifolate chemotherapy, there is no accepted treatment. The vascular endothelial growth factor pathway may be a relevant therapeutic target in MPM.

Methods: This open-labeled phase II trial evaluated single-agent sunitinib, an inhibitor of multiple receptor tyrosine kinases including the vascular endothelial growth factor receptors, given at 50 mg daily orally for 4 weeks followed by a 2-week rest, in patients with advanced MPM. Two cohorts were studied: cohort 1, in which patients had previously received cisplatin-based chemotherapy, and cohort 2, consisting of previously untreated patients. A two-stage design was used for both cohorts; the primary outcome was objective response rate as determined by the RECIST criteria modified for MPM. Secondary outcomes included rates and duration of disease control, progression-free survival and overall survival, and safety and tolerability.

Results: A total of 35 eligible patients were enrolled (17 to cohort 1 and 18 to cohort 2). Neither cohort met the criteria for continuing to the second stage of accrual; only one objective response, confirmed by independent review, was observed in a previously untreated patient. Median progression-free and overall survivals were 2.8 and 8.3 months in cohort 1, and 2.7 and 6.7 months in cohort 2, respectively. Observed toxicity was within that expected for sunitinib.

Conclusions: Sunitinib, similar to other angiogenesis inhibitors, has limited activity in MPM. Future trials of angiogenesis inhibitors given as single agents in unselected patients with MPM are not warranted.
Clinical significance of serum vascular endothelial growth factor in malignant pleural mesothelioma. N. Fujimoto, K. Gemba, T. Kishimoto. 2011;6(5):971-2. Comment · Letter PubMed · Publisher
Coactivation of receptor tyrosine kinases in malignant mesothelioma as a rationale for combination targeted therapy. M. Brevet, S. Shimizu, M.J. Bott, et al. 2011;6(5):864-74. PubMed · Publisher

Abstract

Introduction: To identify new therapeutic approaches in malignant mesothelioma (MM), we examined the expression and activation of receptor tyrosine kinases (RTKs) and the effects of specific RTK inhibitors and the mammalian target of rapamycin (mTOR) inhibitor rapamycin; the latter being of special interest in MM given the recent linkage between NF2 loss and mTOR activation.

Methods: We performed a screen for mutated or activated RTKs in 14 MM cell lines and 70 primary tumors. Expression of phosphorylated RTKs was analyzed by Western blotting and a membrane-based antibody array in normal growth conditions and after treatment by specific inhibitors. MET and epidermal growth factor receptor (EGFR) mutations were screened by sequencing. MET, hepatocyte growth factor, insulin-like growth factor 1 receptor, and EGFR expression were studied by Western blotting, immunohistochemistry, enzyme-linked immunosorbent assay, and by Affymetrix expression microarrays.

Results: Profiling of the phosphorylation status of 42 RTKs showed prominent coactivation of MET and EGFR in 8 of 14 (57%) MM cell lines. MET, EGFR, and insulin-like growth factor 1 receptor were the main RTKs activated after mTOR inhibition and contributed to AKT feedback activation. Knockdown of MET by RNA interference inhibited not only the phosphorylation of MET but also that of EGFR. Conversely, stimulation with hepatocyte growth factor increased both phospho-MET and phospho-EGFR. The combination of PHA-665752 and the EGFR inhibitor, erlotinib, suppressed cell growth more than either agent alone in three of six cell lines tested. Finally, combinations of rapamycin and different RTK inhibitors were more active than either drug alone in 12 of 13 cell lines.

Conclusion: Combination targeting of kinase signaling pathways is more effective than single agents in most MM.
Combined serum mesothelin and plasma osteopontin measurements in malignant pleural mesothelioma. A. Cristaudo, A. Bonotti, S. Simonini, et al. 2011;6(9):1587-93. PubMed · Publisher

Abstract

Introduction: Malignant pleural mesothelioma (MPM) is a lethal tumor related to asbestos exposure. At present, the only instruments for screening and diagnosis are based on radiological tests, posing evident economic and radio-protectionist problems. Some authors are evaluating biological indicators, such as plasma osteopontin (pOPN) and serum soluble mesothelin-related peptides (SMRP). This study aimed to evaluate whether a combination of these two markers could increase sensitivity and specificity in diagnosis of epithelioid MPM.

Methods: We enrolled 93 healthy subjects, 111 individuals with benign respiratory disease (BRD), and 31 patients with MPM, histologically and/or cytologically confirmed. SMRP and pOPN levels were determined using commercially available enzyme-linked immunosorbent assay kits. Though a logistic regression analysis, SMRP and pOPN were combined and translated into a new index, called "combined risk index."

Results: Differences in both SMRP and pOPN mean values between epithelial MPM patients and healthy subjects or BRD patients were statistically significant (p < 0.0001), whereas there was no difference in SMRP and pOPN mean values between healthy subjects and BRD patients. The performance in MPM diagnosis resulted improved by the combination of the two markers. The results of our study should be confirmed by a larger scale and, possibly, a multicenter study, which could better take into consideration the influence of some possible confounding factors such as glomerular filtration rate and other blood parameters.

Conclusions: We combined SMRP and pOPN dosages to increase diagnostic accuracy. This study showed for the first time that combined SMRP and pOPN measurements can increase both sensitivity and specificity in terms of combined risk index.
Computed tomography-guided interstitial high-dose-rate brachytherapy in the local treatment of primary and secondary intrathoracic malignancies. N. Tselis, K. Ferentinos, C. Kolotas, et al. 2011;6(3):545-52. PubMed · Publisher

Abstract

Introduction: Image-guided interstitial (IRT) brachytherapy (BRT) is an effective treatment option as part of a multimodal approach to the treatment of isolated lung tumors. In this study, we report our results of computed tomography-guided IRT high-dose-rate (HDR) BRT in the local treatment of inoperable primary and secondary intrathoracic malignancies.

Methods: Between 1997 and 2007, 55 patients underwent a total of 68 interventional procedures for a total of 60 lung lesions. The median tumor volume was 160 cm³ (range, 24-583 cm³). Thirty-seven patients were men and 18 were women, with a median age of 64 years (range, 31-93 years). The IRT-HDR-BRT delivered a median dose of 25.0 Gy (range, 10.0-32.0 Gy) in twice-daily fractions of 4.0 to 15.0 Gy in 27 patients and 10.0 Gy (range, 7.0-32.0 Gy) in once-daily fractions of 4.0 to 20.0 Gy in 28 patients.

Results: The median follow-up was 14 months (range, 1-49 months). The overall survival rate was 63% at 1 year, 26% at 2 years, and 7% at 3 years. The local control rate for metastatic tumors was 93%, 82%, and 82% and for primary intrathoracic cancers 86%, 79%, and 73% at 1, 2, and 3 years, respectively. Pneumothoraces occurred in 11.7% of interventional procedures, necessitating postprocedural drainage in one (1.8%) patient.

Conclusions: In patients with inoperable intrathoracic malignancies, computed tomography-guided IRT-HDR-BRT is a safe and effective alternative to other locally ablative techniques.
Intensity-modulated radiotherapy after extrapleural pneumonectomy in the combined-modality treatment of malignant pleural mesothelioma. A. Chi, Z. Liao, N.P. Nguyen, et al. 2011;6(6):1132-41. Systematic review PubMed · Publisher

Abstract

Introduction: Local therapy is becoming increasingly important as a part of the definitive treatment for malignant pleural mesothelioma after extrapleural pneumonectomy (EPP) because of the emergence of trimodality therapy consisted of chemotherapy, EPP, and adjuvant radiotherapy. Herein, we explore the current evidence and indications for adjuvant intensity-modulated radiotherapy (IMRT), as well as how to further improve this technique and adapt new technology in the delivering adjuvant radiotherapy in the setting of trimodality therapy.

Methods: A systematic review of relevant studies identified through PubMed, ISI Web of Knowledge (Web of Science), the Cochrane Library, and the National Guideline Clearinghouse search engines was performed.

Results: Local control remains poor despite the inclusion of conventional adjuvant radiation therapy in trimodality therapy. This can be improved by the delivery of adjuvant IMRT. However, IMRT can be associated with severe pulmonary toxicity if the radiation dose to the remaining lung is not kept to a very low level. This is especially true when patients are receiving chemotherapy. New advances in technology can allow for lower doses to the contralateral lung, decreased treatment delivery time, and improved target dose coverage.

Conclusion: Excellent local control can be achieved through adjuvant IMRT after EPP for malignant pleural mesothelioma. Severe pulmonary toxicity may be avoided by setting stringent dose constraints for the contralateral lung. This can be aided by the advances in technology. Post-treatment surveillance may be reliably conducted by periodical [18F]-fluorodeoxyglucose-positron emission tomography imaging.
Low calretinin expression and high neutrophil-to-lymphocyte ratio are poor prognostic factors in patients with malignant mesothelioma undergoing extrapleural pneumonectomy. S.C. Kao, S. Klebe, D.W. Henderson, et al. 2011;6(11):1923-9. PubMed · Publisher

Abstract

Introduction: Survival after extrapleural pneumonectomy (EPP) is variable in patients with malignant pleural mesothelioma (MPM), and there are no validated prognostic factors that could be used preoperatively. We investigated the calretinin and D2-40 expression and the neutrophil-to-lymphocyte ratio (NLR), an index of systemic inflammation as potential preoperative prognostic factors.

Methods: Consecutive patients who underwent EPP were included in this retrospective study. Potential prognostic factors such as age, gender, histological subtype, baseline laboratory parameters including NLR, and immunohistochemical staining for calretinin and D2-40 were evaluated. Overall survival (OS) from the date of surgery was determined by the Kaplan-Meier method. The prognostic value of the variables was examined using Cox regression, and significant factors (p < 0.05) were entered into a multivariate model to determine their independent effect.

Results: A total of 85 patients were included: median age 58 years; 80% men; 77% epithelial and 23% biphasic MPM. The median OS was 19.7 months. The following variables were predictive of longer OS: female gender (p = 0.02), epithelial subtype (p = 0.04), low NLR (p < 0.01), and high calretinin score (p < 0.001). In a multivariate analysis, only NLR ≥3 (hazard ratio 1.79; 95% confidence interval: 1.04-3.07; p = 0.04) and calretinin score ≤33 versus more than 67% (hazard ratio 4.72; 95% confidence interval: 1.97-11.32; p < 0.01) remained independent predictors. The addition of calretinin score increased the explained variation by 10.1%.

Conclusions: Both low calretinin expression and high NLR were independently associated with poor prognosis in patients with MPM undergoing EPP, and the calretinin score seemed to improve the accuracy of the prognostic model.
Mesothelioma and small cell lung cancer. A.S. Tsao, J. Heymach. 2011;6(11 Suppl 4):S1825-6. PubMed · Publisher
MicroRNAs dysregulation in human malignant pleural mesothelioma. V. Balatti, S. Maniero, M. Ferracin, et al. 2011;6(5):844-51. PubMed · Publisher

Abstract

Background: Malignant pleural mesothelioma (MPM) is a rare but aggressive asbestos-related cancer that develops by mesothelial cell transformation. At present, there are no effective therapies for MPM. Great efforts have been made in finding specific markers/mechanisms for MPM onset, including studies into microRNAs (miRNAs). Recent studies have shown the differential expression of mature miRNAs in several human cancers, suggesting their potential role as oncogenes or tumor suppressor genes.

Methods: In this study, we investigated miRNAs profile in five human normal pleural mesothelial short-term cell cultures (HMCs) and five MPMs, with microarray approach. These results were confirmed by real-time quantitative reverse-transcriptase polymerase chain reaction and Western blotting.

Results: A comparative analysis of miRNA expression in MPM and HMCs was carried out. Microarray profiling showed different miRNA expression between MPM and HMCs. Specifically, members of the oncomiRNA miR 17-92 cluster and its paralogs, namely miR 17-5p, 18a, 19b, 20a, 20b, 25, 92, 106a, 106b, were markedly upregulated. Besides, in our investigation, additional miRNAs, such as miR-7, miR-182, miR-214, and miR-497 were found to be dysregulated in MPM.

Conclusions: These data are in agreement with results that have previously been reported on dysregulated miRNAs for other solid human tumors. Moreover, in our investigation, additional miRNAs were found to be dysregulated in MPM. Interestingly, gene products that regulate the cell cycle are targets and predicted targets for these miRNAs. Our data suggest that specific miRNAs could be key players in MPM development/progression. In addition, some of these miRNAs may represent MPM markers and potential targets for new therapeutic approaches.
Miliary mesothelioma: a new clinical and radiological presentation in mesothelioma patients with prolonged survival after trimodality therapy. L. Purek, S. Laroumagne, H. Dutau, et al. 2011;6(10):1753-6. Case report PubMed · Publisher

Abstract

Malignant pleural mesothelioma is usually a fatal disease and is considered a locally aggressive tumor. Consequently, distant metastases are very rare and a diffuse involvement of the lung is seldom reported. However, due to more efficient chemotherapy protocols and aggressive management strategies including induction chemotherapy followed by extrapleural pneumonectomy and adjuvant high-dose hemithoracic radiation therapy, so called trimodality therapy, survival is prolonged in selected patients. Therefore, new presentations of the disease are appearing with new diagnostic and therapeutic challenges. Herein, we report two cases of treated mesothelioma patients who developed a miliary mesothelioma in the remaining lung 36 and 41 months after undergoing multimodal therapy. Diagnostic assessment and therapeutic strategy are discussed taking into account the different evolutions of each patient.
miR-1254 and miR-574-5p: serum-based microRNA biomarkers for early-stage non-small cell lung cancer. K.M. Foss, C. Sima, D. Ugolini, et al. 2011;6(3):482-8. PubMed · Publisher

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.
Phase II study of cediranib in patients with malignant pleural mesothelioma: SWOG S0509. L.L. Garland, K. Chansky, A.J. Wozniak, et al. 2011;6(11):1938-45. PubMed · Publisher · Free full text

Abstract

Introduction: Malignant pleural mesothelioma (MPM) tumors express vascular epithelial growth factor (VEGF) and VEGF receptors. We conducted a phase II study of the oral pan-VEGF receptor tyrosine kinase inhibitor, cediranib, in patients with MPM after platinum-based systemic chemotherapy.

Methods: Patients with MPM previously treated with a platinum-containing chemotherapy regimen and a performance status 0 to 2 were eligible for enrollment. Cediranib 45 mg/d was administered until progression or unacceptable toxicity. The primary end point was response rate. Tumor measurements were made by RECIST criteria, with a subset analysis conducted using modified RECIST. A two-stage design with an early stopping rule based on response rate was used.

Results: Fifty-four patients were enrolled. Of 47 evaluable patients, 4 patients (9%) had objective responses, 16 patients (34%) had stable disease, 20 patients (43%) had disease progression, 2 patients (4%) had symptomatic deterioration, and 1 patient (2%) had early death. The most common toxicities were fatigue (64%), diarrhea (64%), and hypertension (70%); 91% of patients required a dose reduction. Median overall survival was 9.5 months, 1-year survival was 36%, and median progression-free survival was 2.6 months.

Conclusion: Cediranib monotherapy has modest single-agent activity in MPM after platinum-based therapy. However, some patient tumors were highly sensitive to cediranib. This study provides a rationale for further testing of cediranib plus chemotherapy in MPM and highlights the need to identify a predictive biomarker for cediranib.
Pleomorphic epithelioid diffuse malignant pleural mesothelioma: a clinicopathological review and conceptual proposal to reclassify as biphasic or sarcomatoid mesothelioma. K. Kadota, K. Suzuki, C.S. Sima, et al. 2011;6(5):896-904. PubMed · Publisher

Abstract

Introduction: In patients with epithelioid diffuse malignant pleural mesothelioma (DMPM), clinical stage is the current primary prognostic factor. We sought to investigate whether histologic subtyping can prognostically stratify patients with epithelioid DMPM.

Methods: Hematoxylin and eosin-stained slides of 232 patients with epithelioid DMPM (14 stage I, 54 stage II, 130 stage III, and 34 stage IV) from a single institution were reviewed. We classified the tumors into five subtypes, according to the predominant histological pattern: trabecular, tubulopapillary, micropapillary, solid, and pleomorphic (≥10% of tumor).

Results: Median overall survival (OS) of all patients with epithelioid DMPM was 16.2 months. Patients with pleomorphic subtype (n = 34) had the worst median OS (8.1 months), followed by solid (n = 89, 13.7 months), micropapillary (n = 20, 15.8 months), tubulopapillary (n = 51, 17.9 months), and trabecular (n = 38, 24.9 months). The pleomorphic subtype was associated with lymphatic and vascular invasion (p < 0.001). The micropapillary subtype was associated with lymphatic invasion (p < 0.001). In univariate analyses, pleomorphic subtype was significantly associated with poor OS (p = 0.003). The pleomorphic subtype showed no significant difference on OS compared with biphasic and sarcomatoid DMPM. In a multivariate analysis, the pleomorphic subtype was an independent predictor of poor OS (p = 0.031). In patients who underwent R1 resection, pleomorphic subtype had the shortest median time to recurrence (13.7 months).

Conclusion: Our finding that the pleomorphic subtype is a predictor of aggressive behavior in epithelioid DMPM with no survival difference from biphasic or sarcomatoid DMPM suggests that it may be best regarded as a sarcomatoid pattern rather than a subtype of epithelioid DMPM.
Pleurectomy/decortication, hyperthermic pleural lavage with povidone-iodine followed by adjuvant chemotherapy in patients with malignant pleural mesothelioma. L. Lang-Lazdunski, A. Bille, E. Belcher, et al. 2011;6(10):1746-52. PubMed · Publisher

Abstract

Introduction: Malignant pleural mesothelioma is a fatal neoplasm related to asbestos exposure. We investigated the effects of pleurectomy/decortication (P/D), hyperthermic pleural lavage with povidone-iodine and adjuvant chemotherapy in patients with malignant pleural mesothelioma.

Patients And Methods: Observational prospective study of patients referred for multimodality therapy and operated on at our institution between October 2004 and May 2010. Thirty-six selected patients underwent P/D and hyperthermic pleural lavage, prophylactic radiotherapy, and adjuvant chemotherapy. All patients were reviewed at 4 weeks and then 6 monthly in the outpatient clinic, with positron-emission tomography-computed tomography. Second-line treatments were administered when appropriate.

Results: Thirty-day mortality was nil. Nine patients experienced postoperative complications: persistent air leak (n = 5, 13.9%), chylothorax requiring surgical intervention (n = 4, 11%), and adult respiratory distress syndrome (n = 1, 3.9%). Fourteen of 36 patients were alive at last follow-up (median follow-up: 33 months, range: 12-63 months). Ten patients were alive with no evidence of disease recurrence, four patients were alive with disease recurrence, and 22 patients had died of disease progression. Overall median survival (Kaplan-Meier) was 24 months (95% confidence interval: 18.5-29.4 months). One-year survival was 91.7%, and 2-year survival was 61%. Patients undergoing complete macroscopical resection (R0-R1) had a significantly better survival than those undergoing an incomplete macroscopical resection (R2) (median overall survival: 32 months versus 18.9 months, p = 0.012).

Conclusion: In our experience, P/D combined with hyperthermic pleural lavage with povidone-iodine and adjuvant chemotherapy is a well-tolerated multimodality treatment associated with low morbidity and mortality. This multimodality treatment compares favorably with classical trimodality regimens involving chemotherapy, extrapleural pneumonectomy, and adjuvant radiotherapy, in our experience. Study limitations include small sample size, nonrandomization, and patient selection bias.
Recommendations for uniform definitions of surgical techniques for malignant pleural mesothelioma: a consensus report of the international association for the study of lung cancer international staging committee and the international mesothelioma interest group. D. Rice, V. Rusch, H. Pass, et al. 2011;6(8):1304-12. Consensus statement PubMed · Publisher

Abstract

Introduction: Extrapleural pneumonectomy has been well defined; however, surgeons vary regarding the surgical extent and goals of "pleurectomy/decortication" (P/D). We explored mesothelioma surgeons' concepts of P/D with the aim of unifying surgical nomenclature.

Methods: A web-based survey was administered to surgeons who operated on malignant pleural mesothelioma (MPM) for diagnosis, staging, palliation, or cytoreduction. One hundred thirty surgeons from 59 medical centers were included. Surgeons who did not perform surgery for MPM within the last year were excluded.

Results: There were 62 (48%) respondents from 39 medical centers in 14 countries. The mean number of patients with MPM seen annually at each medical center was 46, and the mean annual number of cytoreductive procedures performed per surgeon was 8. Most (88%) agreed that the goal of cytoreductive surgery should be macroscopic complete resection of tumor. P/D was defined as resection of parietal and visceral pleura with the aim of achieving macroscopic complete resection by 72% of respondents. If the diaphragm or pericardium required resection, 64% preferred the term "radical P/D," whereas "P/D" (40%) or "total pleurectomy" (39%) was preferred if these structures were not removed. Most surgeons believed that extrapleural pneumonectomy (90%) or "radical P/D" (68%) could provide adequate cytoreduction, whereas only 23% thought that P/D could.

Conclusions: There was significant variation regarding surgical nomenclature for procedures for MPM. The International Staging Committee of the International Association for the Study of Lung Cancer and the International Mesothelioma Interest Group recommend that P/D should aim to remove all macroscopic tumor involving the parietal and visceral pleura and should be termed "extended" P/D when the diaphragm or pericardium is resected.
Serial measurements of mesothelioma serum biomarkers in asbestos-exposed individuals: a prospective longitudinal cohort study. K. Hollevoet, J. Van Cleemput, J. Thimpont, et al. 2011;6(5):889-95. PubMed · Publisher

Abstract

Introduction: Soluble mesothelin (SM) and megakaryocyte potentiating factor (MPF) are serum biomarkers of mesothelioma. This study aims to examine the longitudinal behavior of SM and MPF in controls to gain insight in the optimal use of these biomarkers in screening.

Methods: Asbestos-exposed individuals, with no malignant disease at inclusion, were surveilled for 2 years with annual measurements of SM and MPF. Fixed thresholds were set at 2.10 nmol/L for SM and 13.10 ng/ml for MPF. Longitudinal biomarker analysis, using a random intercept model, estimated the association with age and glomerular filtration rate (GFR), and the intraclass correlation. The latter represents the proportion of total biomarker variance accounted for by the between-individual variance.

Results: A total of 215 participants were included, of whom 179 and 137 provided a second sample and third sample, respectively. Two participants with normal SM and MPF levels presented afterward with mesothelioma and lung cancer, respectively. Participants with elevated biomarker levels were typically older and had a lower GFR. During follow-up, biomarker levels significantly increased. Longitudinal analysis indicated that this was in part due to aging, while changes in GFR had a less pronounced effect on serial biomarker measurements. SM and MPF had a high intraclass correlation of 0.81 and 0.78, respectively, which implies that a single biomarker measurement and fixed threshold are suboptimal in screening.

Conclusions: The longitudinal behavior of SM and MPF in controls indicates that a biomarker-based screening approach can benefit from the incorporation of serial measurements and individual-specific screening rules, adjusted for age and GFR. Large-scale validation remains nevertheless mandatory to elucidate whether such an approach can improve the early detection of mesothelioma.
Soluble mesothelin, megakaryocyte potentiating factor, and osteopontin as markers of patient response and outcome in mesothelioma. K. Hollevoet, K. Nackaerts, R. Gosselin, et al. 2011;6(11):1930-7. PubMed · Publisher

Abstract

Introduction: Soluble mesothelin (SM), megakaryocyte potentiating factor (MPF), and osteopontin (OPN) are blood biomarkers of mesothelioma. This study evaluates their use as markers of response to therapy and outcome.

Methods: Sixty-two patients with malignant pleural mesothelioma were included in an observational multicenter study. Blood samples and matched computed tomography scans were collected at diagnosis and, when possible, during and after therapy. For each patient, the best overall radiological response was compared with the changes in serum SM, MPF, and plasma OPN levels across corresponding time points.

Results: In five patients, blood sampling was done shortly before and after extrapleural pneumonectomy. SM and MPF levels markedly decreased after surgery, whereas OPN levels showed a median increase. Fifty-seven patients were surveilled during (and after) chemotherapy, of whom 27 (47%) had stable disease, 14 (25%) partial response, and 16 (28%) progressive disease. In patients with stable disease, SM and MPF levels did not change significantly across the corresponding time points, whereas OPN levels significantly decreased. In those with partial response, SM and MPF levels significantly decreased, whereas OPN levels showed no significant change. In patients with progressive disease, all three biomarker levels significantly increased. Patient responses correlated with a 15% change in all three biomarkers, although SM and MPF appeared more accurate than OPN. Low baseline OPN levels were independently associated with favorable progression-free survival and overall survival. Neither SM nor MPF showed prognostic value.

Conclusions: SM and MPF levels were more closely associated with disease course than OPN and might prove useful in monitoring patient response in mesothelioma. Baseline OPN levels were an independent negative predictor of survival. These promising results require further validation.
Summary of presentations from the 46th Annual Meeting of the American Society of Clinical Oncology (2010) focus on tumor biology and biomarkers related to lung cancer. J. Subramanian, L. Corrales, D. Soulieres, et al. 2011;6(2):399-403. PubMed · Publisher

Abstract

Globally, lung cancer remains the most common cause of cancer-related death. In recent years, it has become clear that development of rational molecular targeted therapies is critical to improve the outcomes of patients with lung cancer. A better understanding of the tumor biology is crucial to achieve this goal. Several new findings in the field of tumor biology were presented at the 46th Annual Meeting of the American Society of Clinical Oncology. Novel genetic mutations were identified in pleural mesothelioma using array-based technologies. Several studies on the development and testing of new molecular diagnostic tests to detect epidermal growth factor receptor tyrosine kinase mutations and EML4-ALK (Echinoderm Microtubule-associated Protein like 4 Anaplastic Lymphoma Receptor Tyrosine Kinase) fusion gene were presented as well.
Techniques of surgery and radiotherapy for multimodal treatment of pleural mesothelioma. P. Bonnette. 2011;6(12):2146. Letter PubMed · Publisher
Temsirolimus inhibits malignant pleural mesothelioma growth in vitro and in vivo: synergism with chemotherapy. M.A. Hoda, A. Mohamed, B. Ghanim, et al. 2011;6(5):852-63. PubMed · Publisher

Abstract

Introduction: Human malignant pleural mesothelioma (MPM) is an asbestos-related malignancy characterized by frequent resistance to chemotherapy and radiotherapy. Here, we investigated the feasibility of mammalian target of rapamycin (mTOR) inhibition by temsirolimus as an antimesothelioma strategy.

Methods: Phosphorylation of mTOR (p-mTOR) was assessed by immunohistochemistry in MPM surgical specimens (n = 70). Activation of mTOR and impact of mTOR inhibition by temsirolimus was determined in MPM cell lines in vitro (n = 6) and in vivo as xenografts in severe combined immunodeficiency mice (n = 2) either as single agent or in combination with cisplatin.

Results: Strong immunoreactivity for p-mTOR was predominantly detected in epitheloid and biphasic but not sarcomatoid MPM specimens while adjacent normal tissues remained widely unstained. Accordingly, all mesothelioma cell lines harbored activated mTOR, which was further confirmed by hyperphosphorylation of the downstream targets pS6K, S6, and 4EBP1. Temsirolimus potently blocked mTOR-mediated signals and exerted a cytostatic effect on mesothelioma cell lines in vitro cultured both as adherent monolayers and as nonadherent spheroids. Mesothelioma cells with intrinsic or acquired cisplatin resistance exhibited hypersensitivity against temsirolimus. Accordingly, cisplatin and temsirolimus exerted synergistic inhibition of the mTOR downstream signals and enhanced growth inhibition and/or apoptosis induction in mesothelioma cell lines. Finally, temsirolimus was highly active against MPM xenograft models in severe combined immunodeficiency mice both as a single agent and in combination with cisplatin.

Conclusion: The mTOR inhibitor temsirolimus is active against mesothelioma in vitro and in vivo and synergizes with chemotherapy. These data suggest mTOR inhibition as a promising novel therapeutic strategy against MPM.
The use of pleural fluid sCD44v6/std ratio for distinguishing mesothelioma from other pleural malignancies. J.M. Porcel, A. Esquerda, F. Rodriguez-Panadero, et al. 2011;6(1):190-4. PubMed · Publisher

Abstract

Objective: Differentiating metastatic adenocarcinoma from malignant pleural mesothelioma is often a challenging task. Spliced forms of CD44, such as exon v6 (CD44v6), have been implicated in tumor metastasis. We examined the diagnostic performance of soluble (s) CD44v6 and CD44 standard (sCD44std) as biomarkers for nonmesothelioma pleural malignancies in a retrospective series.

Methods: The pleural fluid from 161 patients with pleural effusion (33 mesotheliomas, 104 nonmesothelioma malignancies, and 24 benign conditions) was analyzed for sCD44v6 and sCD44std levels using an enzyme-linked immunosorbent assay kit. The ability of sCD44v6 and sCD44std levels and the sCD44v6/std ratio for distinguishing mesothelioma from nonmesothelioma malignancy were examined.

Results: Median pleural fluid concentrations of sCD44v6 but not sCD44std were significantly higher in patients with nonmesothelioma malignancy (101.5 ng/mL) than in those with mesothelioma (38 ng/mL, p < 0.0001). Fluids from metastatic squamous cell carcinomas exhibited particularly high sCD44v6 levels (388 ng/mL). A cutoff value of 100 ng/mL had the highest accuracy for distinguishing mesothelioma from nonmesothelioma malignancy (sensitivity 53% and specificity 88%) or metastatic adenocarcinoma (sensitivity 60% and specificity 88%). An sCD44v6/std ratio of more than 0.34 discriminated between adenocarcinoma and mesothelioma with a sensitivity of 60%, a specificity of 93%, a likelihood ratio positive of 9.97, and an area under the curve of 0.87 (95% confidence interval: 0.80-0.94).

Conclusions: The pleural fluid sCD44v6/std ratio may be a new diagnostic marker in the differential diagnosis between primary mesothelioma and other pleural malignancies. Values greater than 0.34 predict nonmesothelioma malignancy and may be a help in determining whether an invasive thoracoscopy is necessary.
A pathological complete response in malignant pleural mesothelioma after combination chemotherapy with Carboplatin and pemetrexed. S.C. Kao, B. McCaughan, A. Muljono, et al. 2010;5(3):405-6. Case report PubMed · Publisher
A phase II study of sorafenib in malignant mesothelioma: results of Cancer and Leukemia Group B 30307. S. Dubey, P.A. Jänne, L. Krug, et al. 2010;5(10):1655-61. PubMed · Publisher · Free full text

Abstract

Hypothesis: Malignant mesotheliomas (MMs) express vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor, and cKIT. Sorafenib is a potent inhibitor of the ras/raf/MEK pathway and also targets VEGFR and cKIT. We evaluated the activity of sorafenib in patients with unresectable mesothelioma.

Methods: MM patients who had received 0 to 1 prior chemotherapy regimens were treated with sorafenib 400 mg orally twice daily continuously. The primary end point was objective response. ERK1/2 phosphorylation in archival tissues was correlated with response and survival.

Results: A total of 51 patients were enrolled, 50 were evaluable and included in the analysis. Three patients had a partial response (6% [95% confidence interval = 1.3-16.6%]), and 27 (54% [95% confidence interval = 39.3-68.2%]) had stable disease. Median progression-free survival and median overall survival (OS) were 3.6 and 9.7 months, respectively. Median survival was superior in epithelioid histology versus other types (10.7 versus 3.7 months, p = 0.0179). The difference in median OS between pretreated and chemonaive patients was not statistically significant (13.2 versus 5 months, p = 0.3117). Low/negative baseline tumor phospho-ERK1/2 levels were associated with improved OS (13.9 versus 5.2 months, p = 0.0066).

Conclusion: Sorafenib has limited activity in advanced MM patients, similar to that seen with other VEGFR tyrosine kinase inhibitors. Additional studies of sorafenib in MM are not warranted.
A systematic review of extrapleural pneumonectomy for malignant pleural mesothelioma. C.Q. Cao, T.D. Yan, P.G. Bannon, et al. 2010;5(10):1692-703. Systematic review PubMed · Publisher

Abstract

Introduction: The primary objective of the present systematic review was to evaluate the safety and efficacy of extrapleural pneumonectomy (EPP) for patients with malignant pleural mesothelioma.

Methods: A systematic review of relevant studies identified through five online search databases was performed. Two reviewers independently appraised each study.

Results: Thirty-four of 58 relevant studies from 26 institutions containing the most updated data were evaluated for survival and perioperative outcomes after EPP. The median overall survival varied from 9.4 to 27.5 months, and 1-, 2-, and 5-year survival rates ranged from 36 to 83%, 5 to 59%, and 0 to 24%, respectively. Overall perioperative mortality rates ranged from 0 to 11.8%, and the perioperative morbidity rates ranged from 22 to 82%. Quality of life assessments from three studies reported improvements in nearly all domains at 3 months postoperatively. Patients who underwent trimodality therapy involving EPP and adjuvant chemoradiotherapy had a median overall survival of 13 to 23.9 months.

Discussions: The current evidence suggests that selected patients with malignant pleural mesothelioma may benefit from EPP, especially when combined with neoadjuvant or adjuvant chemotherapy and adjuvant radiotherapy.
Assessment of therapy responses and prediction of survival in malignant pleural mesothelioma through computer-aided volumetric measurement on computed tomography scans. F. Liu, B. Zhao, L.M. Krug, et al. 2010;5(6):879-84. PubMed · Publisher

Abstract

Purpose: The purposes of this study were (1) to calculate the tumor volume in patients with malignant pleural mesothelioma using computed tomography (CT) scan images and a computer-aided measurement technique and (2) to investigate whether the baseline volume, or volume change after chemotherapy, predicts patient survival.

Methods: We compiled the clinical characteristics and outcome from 30 patients enrolled in two clinical trials at our cancer center in which the patients were treated with induction chemotherapy followed by surgery and radiation. CT scans of 30 patients were obtained at baseline and after two cycles of chemotherapy. Tumor volumes were calculated using a semiautomated computer algorithm. Overall survival was measured using a landmark time at 3 months post-treatment start date such that all patients had already received two cycles of chemotherapy and a follow-up scan. Association of volume changes with overall survival were determined by a Cox Proportional Hazards Model or log-rank test. The relationship between both pre and postoperative clinical stage and baseline tumor volume was analyzed using the rank sum test.

Results: The median baseline tumor volume was 473 cm(3) (range, 61 cm(3)-2108 cm(3)). Patients with high preoperative stages (III and IV) had larger baseline tumor volume than those with low preoperative stages (I and II) (p = 0.05). Patients with baseline volumes smaller than 619 cm(3) tended to survive longer than those with baseline volumes larger than or equal to 619 cm(3) (p = 0.07). Percentage change of tumor volume from baseline to first follow-up CT after two cycles of chemotherapy was significantly associated with overall survival (hazard ratio: 1.94 [95% confidence interval, 1.05-3.60], p = 0.04). Whereas the relative change in modified RECIST measurements was not significantly associated with overall survival (hazard ratio: 1.06 [95% confidence interval, 0.96-1.16], p = 0.25). By classifying changes of tumor volumes between two scans into two groups, i.e., "increase" and "decrease," a significant difference in survival was found between those who increased and decreased after two cycles of chemotherapy (p = 0.03).

Conclusions: Changes in tumor volume after two cycles of chemotherapy predicted overall survival in patients with malignant pleural mesothelioma. Tumor volume at baseline was shown to be associated with preoperative clinical stage and survival. Computer-aided volumetric measurements may enable more reliable therapeutic response assessment and could provide additional prognostic information.
Characteristics of thoracic malignancies that occur after solid-organ transplantation. C. Génébès, L. Brouchet, N. Kamar, et al. 2010;5(11):1789-95. PubMed · Publisher

Abstract

Background: Chronic immunosuppression after solid-organ transplantation is associated with increased risk of developing malignancies. The purpose of this study was to determine the clinical characteristics and the outcome of thoracic malignancies in patients who have undergone solid-organ transplantation.

Methods: Among a cohort of 2831 patients who received a transplant at our institution and were followed between 1984 and 2009, 24 patients (0.85%) developed thoracic malignancies. Risk factors for lung cancer, as well as demographic, cancer, and transplantation characteristics, were analyzed. Survival data were also collected.

Results: Twenty-four patients were included (21 men, median age 61.7 years). Twenty-two patients were smokers. The most frequent histologic types were squamous cell carcinoma (n = 11, 46%) and adenocarcinoma (n = 9, 37%). The median time period between transplantation and diagnosis of lung cancer was 6.6 years. Ten lung malignancies occurred after kidney transplantation (0.5%), eight after liver transplantation (1.3%), and six after heart transplantation (2.8%). Seven patients underwent surgery, three had radiotherapy, four had chemotherapy, and six had multimodal treatment. The median survival time was 1.5 years, ranging from 6 months for stage IV to 3.7 years for stage I.

Conclusion: Solid-organ transplantation is associated with a high risk of lung cancer and may have an important synergetic part with other risk factors for lung cancer (tobacco). However, survival rates from lung cancer in our study population are similar to those of nontransplanted patients. In addition, surgery can result in favorable survival results.
Chemotherapy induced pathologic complete response in malignant pleural mesothelioma: a review and case report. C. Bech, J.B. Sørensen. 2010;5(5):735-40. Case report · Review PubMed · Publisher

Abstract

Introduction: Malignant pleural mesothelioma is a rare aggressive disease with a poor prognosis and usually modest responses to chemotherapy. Complete responses (CRs) to chemotherapy are rare. Evaluation is usually based on radiology, and CR is therefore clinical CR (cCR) and whether this indicates absence of viable tumor cells is unknown. We have observed two cases of CR which at subsequent surgery were histologically verified, thus being pathologic CRs (pCRs). pCR after chemotherapy is thus possible but rare, and we here present the cases from our institution together with a review on the literature available on the subject.

Methods: A literature search using relevant keywords was performed in PubMed and MedLine.

Results: A larger number of reports on cCR but only five reports on pCR were identified. All published cases of pCR, 16 patients in five trials, are presented and discussed, and larger trials reporting cCR are mentioned. pCR did not in all cases correspond to cCR. The cases having pCR identified all had the epithelial or unknown subtype, and all had early-stage disease before treatment.

Conclusion: pCR is possible but rare, and a pCR does not always require a cCR. So far reported cases of pCR have all had the epithelial or unknown subtype and pretreatment stages have been low. The cases in our institution also had epithelial subtype but had stage III disease ,and it thus seems possible to obtain a pCR despite a larger tumor burden.
Clinical significance of serum vascular endothelial growth factor in malignant pleural mesothelioma. A. Yasumitsu, C. Tabata, R. Tabata, et al. 2010;5(4):479-83. PubMed · Publisher

Abstract

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.
Fatal pemetrexed-induced lung injury in patients with advanced mesothelioma: a report of two cases. K. Nagata, R. Kaji, K. Tomii. 2010;5(10):1714-5. Case report · Letter PubMed · Publisher

Summary

In this letter, the authors described two patients with advanced malignant pleural mesothelioma who developed fatal lung injury after receiving pemetrexed. They noted that only one earlier report of pemetrexed-induced lung injury had been published, and that case was mild and easily treated with corticosteroids. The patients were treated at Kobe City Medical Center General Hospital, Japan. The first, a 71-year-old man with sarcomatous mesothelioma, received cisplatin (60 mg/m2) and pemetrexed (500 mg/m2). He became breathless 4 weeks later. Chest CT showed diffuse ground-glass opacities in the right lung, and his KL-6 level was 2700 U/ml. The second, a 77-year-old man with biphasic mesothelioma, received carboplatin and pemetrexed (500 mg/m2). He developed progressive exertional breathlessness after 3 weeks, with ground-glass opacities in the left lower lobe and a KL-6 level of 1236 U/ml, which rose to 2417 U/ml before death. In both patients, extensive workup found no infectious, tumor-related, embolic or cardiac cause. Both received methylprednisolone 500 mg/d but worsened and died, 7 and 5 weeks after starting chemotherapy. Neither had taken any other new drug, and platinum agents rarely cause acute lung injury, so the authors concluded that pemetrexed was responsible. They noted that many risk factors reported for gefitinib-induced lung injury were present in both patients. They advised clinicians to be aware of this possible severe pulmonary complication.

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Frequency of use and predictors of cancer-directed surgery in the management of malignant pleural mesothelioma in a community-based (Surveillance, Epidemiology, and End Results [SEER]) population. R.M. Flores, E. Riedel, J.S. Donington, et al. 2010;5(10):1649-54. PubMed · Publisher

Abstract

Introduction: Surgical intervention rates for mesothelioma patients treated at specialized tertiary hospitals are well more than 42%. Mesothelioma surgical strategies in the community are less well defined. This study evaluates the frequency of use and predictors of cancer-directed surgical intervention in a nontertiary-based population and the predictors for surgical intervention.

Methods: The Surveillance, Epidemiology, and End Results database was searched from 1990 to 2004. Variables analyzed included age, sex, race, year of diagnosis, region, vital status, stage, surgery, and reasons for no surgery. The association of patient variables on receipt of cancer-directed surgery was evaluated using χ(2) tests and logistic regression. The incidence of mesothelioma was also evaluated over this period of time.

Results: Pathologically proven malignant pleural mesothelioma was identified in 1166 women and 4771 men. The rate of cancer-directed surgery was 22% (n = 1317). Significant predictors of receiving cancer-directed surgery included race, age, and stage (all p < 0.0001). A landmark analysis on the effect of cancer-directed surgery on survival after adjusting for patient and disease characteristics demonstrated a hazard ratio of 0.68 (p < 0.0001). The incidence rate of malignant pleural mesothelioma has remained constant.

Conclusions: The rate of surgical intervention in the community is lower compared with tertiary referral centers. Age, stage, and race predict the likelihood of receiving cancer-directed surgery. A lower rate of cancer-directed surgery and worse overall outcome were observed in black patients. As part of quality assurance, referral of patients to centers with multidisciplinary programs that include thoracic surgical expertise should be considered.
Histone deacetylase inhibitors in malignant pleural mesothelioma: preclinical rationale and clinical trials. P.K. Paik, L.M. Krug. 2010;5(2):275-9. Review PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer of the mesothelium with only a limited range of treatment options that are largely ineffective in improving survival. Recent efforts have turned toward the analysis of specific, dysregulated biologic pathways for insight into new treatment targets. Epigenetic regulation of tumor suppressor genes through chromatin condensation and decondensation has emerged as an important mechanism that leads to tumorogenesis. A family of histone acetyltransferases and deacetylases regulates this balance, with the latter facilitating chromatin condensation, thus preventing gene transcription, resulting in the loss of heterozygosity of tumor suppressors. Inhibition of this process, coupled with a similar inhibition of nonhistone protein deacetylation, ultimately leads to the promotion of apoptosis, cell cycle arrest, and inhibition of angiogenesis. An increasing amount of preclinical data highlighting the effectiveness of histone deacetylase inhibition in MPM cell lines and mouse xenograft models has led to a number of early phase clinical trials in patients with MPM. The results of these efforts have led to a multicenter, randomized, placebo-controlled phase III study of the histone deacetylase inhibitor vorinostat in patients with advanced MPM, offering hope for a new and effective therapy in patients with this disease.
Malignant pleural mesothelioma: a population-based study of survival. M.T. Milano, H. Zhang. 2010;5(11):1841-8. PubMed · Publisher

Abstract

Introduction: This study characterizes the overall survival (OS) and variables affecting OS in patients with malignant pleural mesothelioma.

Methods: A total of 9701 patients with malignant pleural mesothelioma, diagnosed from 1973 to 2006, were retrospectively analyzed using the population-based surveillance, epidemiology, and end results database.

Results: The 6-month, 1-year, and 5-year OS were 55, 33, and 5%, respectively. Significantly adverse prognostic factors from univariate analyses included older age, male gender, higher tumor grade, nonepithelioid histology, higher stage, no cancer-directed surgery, and no radiotherapy. Race was not significant. Patients undergoing cancer-directed surgery and radiotherapy, when grouped by stage, histology, or grade, had the best median survival (versus radiotherapy or surgery alone or no surgery/radiotherapy). From Cox proportional hazards analyses, grade (range, 1-4) was associated with a hazard ratio (HR) of >1.5 (p < 0.0001), and not undergoing cancer-directed surgery was associated with a HR of >1.4 (p < 0.0001). Male gender and older age were also significantly adverse factors. Tumor histology (HR = 1.5) and nonlocalized stage (HR = 1.3) were significant in a Cox model omitting tumor grade. With grade and histology included in the Cox model, the HRs of histology and stage were of smaller magnitude and not significant.

Conclusions: From a population-based registry analysis of patients with malignant pleural mesothelioma, tumor grade and cancer-directed surgery seem to have the greatest impact on OS. Although being amenable to surgery likely reflects more indolent disease and/or better performance status and cardiopulmonary function, the significantly favorable impact of surgery, accounting for tumor grade, histology, and stage, may reflect a therapeutic benefit.
Primary malignant pericardial mesothelioma mimicking pericardial metastasis from adenocarcinoma. M. Horie, S. Noguchi, W. Tanaka, et al. 2010;5(12):2012-4. Case report PubMed · Publisher
Prognostic factors for survival after surgical palliation of malignant pleural effusion. J.E. Pilling, M.E. Dusmet, G. Ladas, et al. 2010;5(10):1544-50. PubMed · Publisher

Abstract

Introduction: To investigate prognostic factors for patient survival after surgical palliation of malignant pleural effusion (MPE).

Method: We reviewed 278 consecutive nonoverseas patients (108 men, median age: 60 years [range 26-89]) undergoing 310 surgical procedures for palliation of MPE over a 72-month period. There were 195 thoracoscopic talc pleurodesis, 39 pleuroperitoneal shunts, 38 pleurodesis by an intercostal drain, 29 pleural biopsies alone, and nine long-term drains. Referring physicians provided survival data. The significance of prognostic factors was examined with the log-rank test (Kaplan-Meier), those significant entered a Cox logistic multivariate regression analysis.

Results: Follow-up was complete until death (following 264 procedures) and for a median 648 days (range 173-2135) for surviving patients. Overall median postoperative survival was 211 days (95% confidence interval: 169-253). Survival was not significantly different for tumor type or method of palliation. In univarate analysis, preoperative leucocytosis, hypoxemia, raised alanine transaminase, body mass index below 18 and hypoalbuminemia were associated with a significantly reduced postoperative survival. In multivariate analysis, leucocytosis (p < 0.0001), hypoxemia (p = 0.014), and hypoalbuminemia (p < 0.0001) maintained significance.

Conclusions: The survival reported demonstrates the necessity of an active approach to palliation of MPE. The identification of prognostic factors will assist the choice of palliative technique. In addition, an appreciation of the influence of selection on survival after surgical palliation of malignant pleural mesothelioma, especially that of unforeseen prognostic factors, is useful when evaluating the results of aggressive treatment such as chemoradiotherapy and radical surgery for these diseases.
Role of integrated 18-fluorodeoxyglucose position emission tomography-computed tomography in patients surveillance after multimodality therapy of malignant pleural mesothelioma. C. Tan, S. Barrington, S. Rankin, et al. 2010;5(3):385-8. PubMed · Publisher

Abstract

Introduction: To investigate the role of 18-fluorodeoxyglucose positron emission tomography-computed tomography (18-FDG-PET-CT) in the surveillance of patients after multimodality treatment of malignant pleural mesothelioma.

Methods: Retrospective study of patients who had chemotherapy, radical surgery, extrapleural pneumonectomy or pleurectomy/decortication, and radiotherapy for mesothelioma in our unit. PET-CT was performed after multimodality therapy to evaluate response to treatment or when disease recurrence was suspected. 18-FDG-PET scans were acquired from skull base to upper thigh with low-dose CT scans for attenuation correction and image fusion.

Results: Forty-four patients had extrapleural pneumonectomy (21) or pleurectomy/decortication (23) between January 2004 and July 2008. Twenty-five patients had PET-CT performed after multimodality therapy. This was performed in 11 patients in whom disease recurrence was suspected at a median of 9 (range, 6-16) months after treatment. PET-CT correctly diagnosed recurrent disease in eight patients and missed microscopic recurrence in one. Surveillance PET-CT was performed in 14 asymptomatic patients at a median of 11 (range, 7-13) months after treatment. It showed unsuspected recurrences in four patients. The standard uptake value max of recurrent mesothelioma was 8.9 +/- 4.0 (4-18.4). PET-CT had a sensitivity of 94%, a specificity of 100%, and the positive and negative predictive values of 100 and 88%, respectively.

Conclusions: 18-FDG-PET-CT is useful in diagnosing disease recurrence after multimodality therapy for malignant pleural mesothelioma. We propose a prospective study to fully assess its value in this group of patients.
Sensitivity of urinary mesothelin in patients with malignant mesothelioma. J. Creaney, A.W. Musk, B.W. Robinson. 2010;5(9):1461-6. PubMed · Publisher

Abstract

Introduction: Malignant mesothelioma (MM) is an aggressive, uniformly fatal tumor usually caused by exposure to asbestos. Soluble mesothelin has been intensively investigated in the serum as a biomarker for this disease. As urine is less complex and less invasive to collect than serum and may be a more acceptable specimen for large-scale screening studies of asbestos-exposed individuals, we determined whether the sensitivity and specificity for MM could be improved by measuring soluble mesothelin in the urine.

Methods: Soluble mesothelin concentrations were determined using the MESOMARK assay in concurrent serum and urine samples from 70 patients with pleural MM, 111 patients with asbestos-related lung or pleural disease, and 45 patients with benign nonasbestos-related lung and pleural disease. Only patients with serum creatinine levels within the normal range were included in the study. Sensitivities were determined and receiver operator characteristic curves were generated to compare the diagnostic accuracy of mesothelin in the serum and urine.

Results: At a specificity of 95% relative to individuals with benign lung or pleural disease, serum mesothelin had a sensitivity of 66% and area under the curve of 0.882, whereas urinary mesothelin corrected for urine creatinine concentration had a sensitivity of 53% and area under the curve of 0.787.

Conclusions: The sensitivity of urinary mesothelin does not warrant the use of urine as a biomarker specimen for MM diagnosis.
The mesothelioma and radical surgery feasibility study. P. Goldstraw. 2010;5(2):287. Comment · Letter PubMed · Publisher
What should a support program for people with lung cancer look like? Differing attitudes of patients and support group facilitators. B. Devitt, A. Hatton, C. Baravelli, et al. 2010;5(8):1227-32. PubMed · Publisher

Abstract

Introduction: Patients with lung cancer have higher levels of unmet need for psychosocial support than those with other cancers. However, uptake of existing support programs by patients with lung cancer is low. We explored this issue by seeking the views of patients and support group facilitators.

Methods: Surveys of a convenience sample of 100 patients with lung cancer and all support group facilitators registered with Cancer Council Victoria (n = 145) were performed. Respondents were asked about preferred content, location, running, and potential barriers to attendance of a lung cancer support program.

Results: The response rate from facilitators was 51%. Fifty-three percent of patients reported willingness to attend a support program, although only 12% had previously attended a group. Patients showed a preference for any program to be held at a hospital (p = 0.01), whereas facilitators preferred a community setting (p < 0.001). Patients preferred facilitation by a health professional, rather than a volunteer p < 0.001), whereas facilitators preferred a volunteer. Patients preferred sessions primarily focused on cancer information provision rather than emotional support, whereas facilitators rated emotional support as highly as cancer information. Overall, patients perceived fewer barriers to attendance than facilitators. Both agreed that a group environment, discussing their cancer, parking, and travel were barriers to attendance.

Conclusions: Disparities in the views of patients and facilitators about the preferred location, type of facilitator, and content of a support program may in part explain the poor uptake of existing support programs by patients with lung cancer and should be considered in the design of future programs.

2000s

Chronic obstructive lung diseases and risk of non-small cell lung cancer in women. A.G. Schwartz, M.L. Cote, A.S. Wenzlaff, et al. 2009;4(3):291-9. PubMed · Publisher · Free full text

Abstract

Introduction: The link between lung cancer and chronic obstructive lung diseases (COPD) has not been well studied in women even though lung cancer and COPD account for significant and growing morbidity and mortality among women.

Methods: We evaluated the relationship between COPD and non-small cell lung cancer in a population-based case-control study of women and constructed a time course of chronic lung diseases in relation to onset of lung cancer. Five hundred sixty-two women aged 18 to 74, diagnosed with non-small cell lung cancer and 564 population-based controls matched on race and age participated. Multivariable unconditional logistic regression models were used to estimate risk associated with a history of COPD, chronic bronchitis, or emphysema.

Results: Lung cancer risk increased significantly for white women with a history of COPD (odds ratios [OR] = 1.85; 95% confidence intervals [CI]: 1.21-2.81), but this was not seen in African American women. Risk associated with a history of chronic bronchitis was strongest when diagnosed at age 25 or earlier (OR = 2.35, 95% CI: 1.17-4.72); emphysema diagnosed within 9 years of lung cancer was also associated with substantial risk (OR = 6.36, 95% CI: 2.36-17.13). Race, pack-years of smoking, exposure to environmental tobacco smoke as an adult, childhood asthma, and exposure to asbestos were associated with a history of COPD among lung cancer cases.

Conclusions: In women, COPD is associated with risk of lung cancer differentially by race. Untangling whether COPD is in the causal pathway or simply shares risk factors will require future studies to focus on specific COPD features, while exploring underlying genetic susceptibility to these diseases.
Clinical value of fluorodeoxyglucose-positron emission tomography/computed tomography in differentiation of malignant mesothelioma from asbestos-related benign pleural disease: an observational pilot study. H. Yildirim, M. Metintas, E. Entok, et al. 2009;4(12):1480-4. PubMed · Publisher

Abstract

Background: Several studies have already addressed the potential role of an increased fluorine 18 fluorodeoxyglucose (18F FDG) uptake in identification of pleural malignancy. In this pilot study, we investigate the role of 18F-FDG positron emission tomography/computed tomography (PET/CT) for differentiating asbestos-related benign pleural disease from malignant mesothelioma.

Materials And Methods: The study population comprised 31 consecutive patients (17 malignant mesotheliomas, nine benign asbestos pleurisies, and five diffuse pleural fibrosis) with a mean age of 61 years between January 2006 and December 2008. Thoracoscopy or image-guided pleural needle biopsy were systematically performed to reveal pathologic diagnosis and/or clinical follow-up for at least 3 years for presence or absence of malignant pleural effusion. ROCs analyses for standardized uptake value (SUV) adjusted to body weight were calculated between benign and malignant pleural diseases.

Results: 18F-FDG PET/CT imaging correctly detected the presence of malignancies in 15 of 17 patients with malignant mesothelioma for sensitivity, specificity, and overall accuracy of 88.2%, 92.9%, and 90.3%, respectively. 18F-FDG PET/CT imaging correctly identified 13 of 14 cases of benign pleural disease. The mean SUV values were 6.5 +/- 3.4 for malignant mesothelioma cases and 0.8 +/- 0.6 for benign pleural diseases (p < 0.001). When we compared the two groups of pleural disease, a cut-off value of 2.2 for SUV gave the best accuracy with 94.1%, 100%, 100%, and 93.3% for sensitivity, specificity, positive predictive value, and negative predictive value, respectively.

Conclusion: Preliminary results of this trial provide evidence that 18F-FDG PET/CT imaging is a highly accurate and reliable noninvasive test to decide for further investigation of differentiating malignant mesothelioma from benign pleural disease.
Localized malignant pleural mesothelioma: report of two cases. S. Tanzi, M. Tiseo, E. Internullo, et al. 2009;4(8):1038-40. Case report PubMed · Publisher

Abstract

Localized malignant pleural mesothelioma is very rare tumor disease. There are sporadic reports in the literature showing that this entity has a different biologic behavior compared with diffuse pleural mesothelioma. We report two cases of radically resected localized pleural malignant mesothelioma, with a previous history of asbestos exposure. Both cases showed a microscopic and immunohistochemical findings of malignant mesothelioma, biphasic and sarcomatoid lympho-histiocitoid variant type, respectively, without evidence of diffuse pleural spread. The first is very peculiar case of bilateral localized malignant pleural mesothelioma with complete response to chemotherapy and localized late recurrence, radically resected and treated with adjuvant radiotherapy. The second case revealed as a solitary localized mass, underwent a complete en bloc resection and adjuvant radiotherapy. Both cases demonstrate that the localized malignant mesothelioma should be distinguished from diffuse form and that complete resection is associated with good prognosis.
Phase II study of belinostat (PXD101), a histone deacetylase inhibitor, for second line therapy of advanced malignant pleural mesothelioma. S.S. Ramalingam, C.P. Belani, C. Ruel, et al. 2009;4(1):97-101. PubMed · Publisher · Free full text

Abstract

Background: Belinostat (PXD 101) is a novel inhibitor of class I and II histone deacetylases. This class of compounds has demonstrated anticancer activity in malignant mesothelioma. We conducted a phase II study of belinostat in patients with relapsed malignant pleural mesothelioma.

Methods: Patients with advanced mesothelioma, progression with one prior chemotherapy regimen and Eastern Cooperative Oncology Group performance status 0-2 were eligible. Belinostat was administered at 1000 mg/m intravenously over 30 minutes on days 1-5 of every 3 week cycle. The primary end point was response rate. The Simon two-stage design was used. Disease assessments were performed every two cycles.

Results: Thirteen patients were enrolled. Baseline characteristics were: median age of 73 years; Eastern Cooperative Oncology Group performance status 0 (n = 4), 1 (8) and 2 (1). A median of two cycles of therapy were administered. Disease stabilization was seen in two patients. No objective responses were noted and the study did not meet criteria to proceed to the second stage of accrual. Median survival was 5 months with a median progression-free survival of 1 month. Salient toxicities included nausea, emesis, fatigue, and constipation. One patient died as a consequence of cardiac arrhythmia which was deemed 'possibly' related to therapy.

Conclusions: Belinostat is not active as monotherapy against recurrent malignant pleural mesothelioma. Evaluation of combination strategies or alternate dosing schedules may be necessary for further development of this novel agent in mesothelioma.
Screening for malignant pleural mesothelioma and lung cancer in individuals with a history of asbestos exposure. H.C. Roberts, D.A. Patsios, N.S. Paul, et al. 2009;4(5):620-8. PubMed · Publisher

Abstract

Purpose: We established a screening program for prior asbestos workers using low-dose computed tomography (LDCT).

Methods: Between March 2005 and October 2007 we performed LDCT (50-60 mA, 120 kV, 1.25 mm) in 516 asbestos-exposed individuals. Parenchymal nodules were followed according to lung cancer screening recommendations, morphology and location of pleural plaques was noted in detail.

Results: We included 507 men and 9 women (median 60.0 years), 395 (76.6%) were smokers. Annual repeat has been performed in 356 participants. We found plaques in 357 subjects (69.2%), commonly calcified (79.6%), flat (86.6%), and symmetric (86.8%), and mostly involving the costal (96.4%) and diaphragmatic (81.8%) pleura. Uncommon plaques were lobulated (13.2%), right-dominant asymmetric (4.5%), or with effusions (0.1%).We found pulmonary nodules in 371 subjects (71.9%), 91 (17.6%) had at least one nodule > or =5 mm; 10 growing nodules were found on annual repeat LDCT. In 41 individuals, plaques were regarded as atypical; three had new pleural/peritoneal abnormalities on annual repeat LDCT. An interim limited computed tomography of the observed abnormality prompted 10 diagnostic biopsies, resulting in a diagnosis of six lung cancers, two pleural mesothelioma and two peritoneal mesothelioma; overall rate of screen-detected malignancies is 2.1%. There were four interval cancers, diagnosed after baseline (n = 1) or after the annual repeat (n = 3): two pleural and one peritoneal mesothelioma, and one mixed squamous/small cell carcinoma.

Conclusion: Screening prior asbestos workers detects advanced malignant pleural mesothelioma and early as well as late stage lung cancer. We expect to learn more about the appearance of "early mesothelioma" with continued screening.
Spontaneous pneumothorax and lung carcinoma: should one consider synchronous malignant pleural mesothelioma?. T.A. Flood, H.S. Sekhon, J.M. Seely, et al. 2009;4(6):770-2. Case report PubMed · Publisher

Abstract

We describe the clinical and pathologic findings of a 68-year-old smoker with previous asbestos exposure who presented with spontaneous hydropneumothorax and was diagnosed with synchronous undifferentiated lung carcinoma and incidental malignant pleural mesothelioma. The synchronous occurrence of these two neoplasms is an extremely rare event with fewer than 20 reported cases in the English literature. The accurate diagnosis of synchronous tumors can be extremely challenging and the identification of a concomitant mesothelioma in our case was not made until an extensive immunohistochemical analysis was done on the resection specimen. Spontaneous pneumothorax occurs much more commonly in patients with malignant mesothelioma than with primary lung carcinomas. Consequently, although synchronous pleural mesotheliomas and lung carcinomas are infrequent, this diagnosis should be considered when a patient with a lung mass and a history of asbestos exposure presents with spontaneous pneumothorax and pleural thickening on imaging. Identification of synchronous tumors is of critical importance for determining the patient's stage and management and can have significant medicolegal implications should the patient seek compensation.
Survey and biological insights of pemetrexed-related therapeutic improvement in mesothelioma: The Nancy Centre of Biological Resources' Mesothelioma Cohort. F. Vlastos, G. Hillas, P. Vidal, et al. 2009;4(10):1259-63. PubMed · Publisher

Abstract

Introduction: We report a survey of mesothelioma survival rates with insights into the survival benefit because of pemetrexed. We also studied a potential link between specific single nucleotide polymorphisms of transcobalamin II (TCII) gene and susceptibility to both asbestos and pemetrexed.

Methods: Clinical and occupational data from 287 consecutive mesothelioma patients were collected from the north-east region of France (1989-2007). Blood or paired tumoral and normal samples were collected from the last 210 French patients to study the TCII single nucleotide polymorphisms at the codon 259 (quantitative polymerase chain reaction). Results were compared with those obtained from a group of 263 French control healthy subjects and to a group of 91 German mesothelioma patients. Patients' characteristics and genotypes results were statistically analyzed for significant correlations.

Results: The mean overall patient's survival was 18.19 +/- 21.07 months. Pemetrexed increased the patients' survival by 50% (21.81 versus 16.99 months). The TCII allele Proline (Pro) was overrepresented into the mesothelioma cohort when compared with the controls (35 versus 19.77%). This also concerned German patients. The alleles Pro and Proline Arginine (ProArg) were more frequent among patients exposed to asbestos (p = 0.005, p < 0.001, respectively). The allele ProArg was associated with the longest survival while under pemetrexed (p = 0.007). No difference was found in the genotypes of patients untreated with pemetrexed.

Conclusions: Pemetrexed treatment is related to a survival increase in mesothelioma patients. The allele Pro seems overrepresented in mesothelioma patients. Those having the allele ProArg present a better outcome under pemetrexed.
An electrocautery pleural biopsy for the diagnosis of desmoplastic malignant mesothelioma during semirigid thoracoscopy. S. Sasada, K. Kawahara, T. Iwasaki, et al. 2008;3(7):803-4. Case report · Letter PubMed · Publisher
Comparison of osteopontin, megakaryocyte potentiating factor, and mesothelin proteins as markers in the serum of patients with malignant mesothelioma. J. Creaney, D. Yeoman, Y. Demelker, et al. 2008;3(8):851-7. PubMed · Publisher

Abstract

Introduction: There is increasing interest in identifying a blood-based marker for the asbestos-related tumor, malignant mesothelioma. Three potential markers for mesothelioma are mesothelin, megakaryocyte potentiating factor (MPF) and osteopontin. The purpose of the current study was to directly compare these biomarkers in the same sample population, determining their sensitivity and specificity in establishing a diagnosis, and to determine if diagnostic accuracy for mesothelioma is improved by combining the data from all three markers.

Methods: Serum levels of mesothelin, MPF and osteopontin were determined by commercially available assays in 66 samples from patients with pleural malignant mesothelioma, 20 healthy individuals, 21 patients with asbestos-related lung or pleural disease, 30 patients presenting with benign pleural effusions and 30 patients with other malignancies.

Results: Serum levels of the three markers were elevated in mesothelioma patients. At a level of specificity of 95% relative to healthy controls and patients with benign asbestos related disease, the sensitivity for mesothelioma was 34% for MPF, 47% for osteopontin and 73% for mesothelin. Osteopontin and MPF were unable to differentiate patients with mesothelioma from patients with other malignancies or those presenting with transudative pleural effusions. Combining the data from the three biomarkers using a logistic regression model did not improve sensitivity for detecting mesothelioma above that of the mesothelin marker alone.

Conclusion: Serum mesothelin remains the most specific marker for the diagnosis of mesothelioma.
Good vibrations and the power of positron thinking: positron emission tomography and endoscopic ultrasound in staging of mesothelioma-two case reports. C.P. Carden, J.S. Myerson, S. Popat, et al. 2008;3(5):539-41. Case report PubMed · Publisher
Inhibition of Hsp90 leads to cell cycle arrest and apoptosis in human malignant pleural mesothelioma. J. Okamoto, I. Mikami, Y. Tominaga, et al. 2008;3(10):1089-95. PubMed · Publisher · Free full text

Abstract

Introduction: Heat shock protein 90 (Hsp90) is an abundant molecular chaperone that mediates the maturation and stability of a variety of proteins associated with the promotion of cell growth and survival. Inhibition of Hsp90 function leads to proteasomal degradation of its mis-folded client proteins. Recently, Hsp90 has emerged as being of prime importance to the growth and survival of cancer cells and its inhibitors have already been used in phase I and II clinical trials.

Methods: We investigated how 17-allylamino-17-demethoxygeldanamycin (17-AAG), a small molecule inhibitor of Hsp90, is implicated in human malignant pleural mesothelioma (MM).

Results: We found that 17-AAG led to significant G1 or G2/M cell cycle arrest, inhibition of cell proliferation, and decrease of AKT, AKT1, and survivin expression in all human malignant pleural mesothelioma cell lines examined. We also observed significant apoptosis induction in all MM cell lines treated with 17-AAG. Furthermore, 17-AAG induced apoptosis in freshly cultured primary MM cells and caused signaling changes identical to those in 17-AAG treated MM cell lines.

Conclusion: These results suggest that Hsp90 is strongly associated with the growth and survival of MM and that inhibition of Hsp90 may have therapeutic potential in the treatment of MM.
Lung asbestos content in lungs resected for primary lung cancer. C.M. Wright, R.V. Bowman, M.E. Tan, et al. 2008;3(6):569-76. PubMed · Publisher

Abstract

Introduction: The majority of Australia's burden of lung cancer occurs in current or former tobacco smokers. To determine the possible contribution of asbestos exposure in Australians presenting with primary lung cancer, we measured lung asbestos content in cases resected consecutively at a single cardio-thoracic hospital.

Methods: Asbestos bodies were quantified by lung tissue digestion, filtration, and light microscopy, and were correlated with exposure questionnaires and clinicopathological features.

Results: We demonstrate high intrarater reproducibility and interrater reliability using these methods. In 463 patients with resected primary lung cancers, asbestos content ranged from 0 to 749 asbestos bodies per gram wet weight (AB/gww). Forty-eight percent of patients had no asbestos bodies identified. One-third had less than or equal to 20 AB/gww (a level previously found to be consistent with urban dwelling). Nineteen percent had lung content in excess of this level. Only 20 cases had AB >100/gww, approximately equivalent to the Helsinki threshold for attribution of lung cancer to asbestos. Median asbestos body counts were higher in patients who reported previous asbestos exposure than in those who reported no exposure. A subgroup of cases gave detailed exposure histories that did not predict presence or absence of asbestos bodies in men or women. In cases with cumulative tobacco exposure less than 20 pack-years, asbestos body counts exceeding 20 AB/gww were overrepresented.

Conclusions: We found that the majority of patients with primary lung cancer at a single Australian center have detectable asbestos in resected lung tissue, but fiber burdens are generally low. The contributory role of this low-level asbestos exposure in causing lung cancer remains uncertain.
Recent advances in the treatment of malignant pleural mesothelioma. S.S. Ramalingam, C.P. Belani. 2008;3(9):1056-64. Review PubMed · Publisher

Abstract

Malignant pleural mesothelioma clinically manifests after decades of initial exposure to etiologic agents, such as asbestos, and presents with nonspecific symptoms such as dyspnea, pain, or weight loss. In patients with limited, resectable disease, surgical therapy with extrapleural pneumonectomy or pleurectomy is recommended, although, it is unclear which approach is superior. Radiation has a limited role and is used primarily for palliation. The palliative efficacy of traditional chemotherapeutic agents and combination regimens is modest at best. The combination of cisplatin and pemetrexed, a novel multitargeted antifolate agent, is the approved "standard of care" for patients with unresectable malignant pleural mesothelioma. A number of molecularly targeted agents are currently under evaluation for mesothelioma such as the Histone deacetylase (HDAC) inhibitors that have demonstrated promising anticancer activity. Vorinostat, a small molecule inhibitor of HDAC, which targets select members of class I and II HDACs, has shown early evidence of activity and is currently being evaluated in a randomized study for patients who progress with standard therapy for advanced mesothelioma. It is hoped that the HDAC inhibitors and other novel targeted agents will pave the way for improved outcomes for patients with this disease.
Treatment of malignant pleural mesothelioma with carboplatin, liposomized doxorubicin, and gemcitabine: a phase II study. G. Hillerdal, J.B. Sorensen, S. Sundström, et al. 2008;3(11):1325-31. PubMed · Publisher

Abstract

Background: Malignant pleural mesothelioma has a poor prognosis and there is limited effect of treatment. The Nordic Mesothelioma groups decided in the year 2000 to investigate a combination of liposomized doxorubicin, carboplatin, and gemcitabine for this disease in a phase II study.

Methods: From January 2001, to December 2003, 173 evaluable patients with biopsy-verified malignant mesothelioma were included. Two patients were lost to follow-up, but all the others were followed for at least 4 years or until death.

Results: Toxicity was fairly low. There were 56 responses (32.4%), of which 2 were complete; the median time to progression was 8.6 months, and the median overall survival was 13 months. Some patients had their responses 4 to 6 months after last treatment. For 116 patients with epitheloid subtype, median survival was 17 months. A subgroup of these patients with good performance status, early stage, and age 70 years or less, showed a median survival of 22 months.

Conclusion: The treatment yields good results with a high number of responses and long survival, and a low toxicity. The long survival of the epitheloid subgroup with good prognostic factors is as good as or even better than some studies on "radical" surgery or multimodal treatment, underlining the need of randomized studies to evaluate such treatment options.
Trimodality treatment of malignant pleural mesothelioma. H.F. Batirel, M. Metintas, H.B. Caglar, et al. 2008;3(5):499-504. PubMed · Publisher

Abstract

Introduction: Multimodality treatment has achieved significant success in local control and treatment of early-stage malignant pleural mesothelioma patients. However, its favorable effect on survival is questionable.

Methods: We have instituted a trimodality treatment protocol consisting of extrapleural pneumonectomy, adjuvant high-dose (54 Gy) hemithoracic irradiation, and platin-based chemotherapy in a multi-institutional setting. Preoperative pulmonary function tests, echocardiogram, chest computed tomography, and magnetic resonance imaging scans were performed in all patients. Twenty patients have been treated with this protocol during 2003-2007. Seventeen had a history of environmental asbestos/erionite exposure. Clinical stages were T1-3N0-2.

Results: Median age was 56 (41-70, 8 female). There was one postoperative mortality (% 5) due to ARDS. Morbidity occurred in 11 patients (% 55). Histology was epithelial in 17, mixed in 2, and sarcomatoid in 1. Sixteen patients underwent extrapleural pneumonectomy. Microscopic margin positivity was present in 14 patients with macroscopic complete resection. Twelve patients completed all three treatments. Median follow-up was 16 months (1-43). Overall median survival was 17 months (24% at 2 years). Eight patients had extrapleural lymph node involvement (internal mammary [n = 3], subcarinal [n = 2], pulmonary ligament [n = 1], diaphragmatic [n = 1], subaortic [n = 1]). There was better survival in patients without lymph node metastasis (24 versus 13 months median survival, p = 0.052). Currently, 7 patients are alive, 6 without recurrence, and 2 patients at 40 and 45 months.

Conclusions: Trimodality treatment in malignant pleural mesothelioma seems to prolong survival in patients without lymph node metastasis. Novel techniques are needed for preoperative assessment of extrapleural lymph nodes.
Constrictive pericarditis after left extrapleural pneumonectomy and radiotherapy for malignant mesothelioma. E.J. Hickey, A.A. Khan, J.B. Chambers, et al. 2007;2(7):673-5. Case report PubMed · Publisher

Abstract

We report the devastating complication of constrictive pericarditis after multimodality therapy including left extrapleural pneumonectomy for malignant pleural mesothelioma. The patient presented with progressive dyspnea, ascites, and peripheral edema 6 months after receiving adjuvant radiotherapy. A diagnosis of constrictive pericarditis was made late in the clinical course after exhaustive investigation to exclude primary disease recurrence. Pericardial decortication was subsequently undertaken 12 months after the initial surgery, but the patient died of multi-organ failure. Our experience, combined with a review of the available literature, leads us to advise a low level of suspicion and early operation to relieve cardiac constriction. Furthermore, these complications emphasize the importance of trials such as the Mesothelioma and Radical Surgery (MARS) study.
Prognostic factors in the treatment of malignant pleural mesothelioma at a large tertiary referral center. R.M. Flores, M. Zakowski, E. Venkatraman, et al. 2007;2(10):957-65. PubMed · Publisher

Abstract

Introduction: Most studies describing the natural history and prognostic factors for malignant pleural mesothelioma antedate accurate pathologic diagnosis, staging by computed tomography, and a universal staging system. We conducted a large single-institution analysis to identify prognostic factors and assess the association of resection with outcome in a contemporary patient population.

Methods: Patients with biopsy-proven malignant pleural mesothelioma at our institution were identified and clinical data were obtained from an institutional database. Survival and prognostic factors were analyzed by the Kaplan-Meier method, log-rank test, and Cox proportional hazards analysis. A p value <0.05 was considered statistically significant.

Results: From 1990 to 2005, 945 patients were identified: 755 men, 190 women; median age, 66 years (range, 26-93). Extrapleural pneumonectomy was performed in 208 (22%), pleurectomy/decortication in 176 (19%). Operative mortality was 4% (16/384). Multimodality therapy including surgery was associated with a median survival of 20.1 months. Significant predictors of overall survival included histology, gender, smoking, asbestos exposure, laterality, surgical resection by extrapleural pneumonectomy or pleurectomy/decortication, American Joint Committee on Cancer stage, and symptoms. A Cox model demonstrated a hazard ratio of 1.4 without surgical resection when controlling for histology, stage, gender, asbestos exposure, smoking history, symptoms, and laterality (p = 0.003).

Conclusions: In addition to tumor histology and pathologic stage, predictors of survival include gender, asbestos exposure, smoking, symptoms, laterality, and clinical stage. Surgical resection in a multimodality setting was associated with improved survival.
Rapid growth of malignant pleural mesothelioma. K. Kaira, K. Dobashi, N. Yanagitani, et al. 2007;2(10):966-7. Case report PubMed · Publisher

Summary

This 'Image of the Month' report described a man with malignant pleural mesothelioma that grew very rapidly. The patient, a 67-year-old male smoker with no known asbestos exposure, was treated at Gunma University in Japan in 2006. He came in with a 4-day history of shortness of breath on exertion. Chest radiography showed a massive right-sided pleural effusion. A chest tube drained 3000 ml of serosanguineous fluid. Cytology of the pleural fluid was reported as adenocarcinoma. Serial chest CT scans on August 16, 21 and 24 showed the right pleural thickening progressing from partial to circumferential. His condition deteriorated because of uncontrollable pleural effusion, and he died on August 28, 2006. At autopsy, the tumour formed circumferential pleural thickening more than 1 cm thick, typical of diffuse malignant mesothelioma. Immunohistochemistry was positive for WT-1, weakly positive for calretinin, and negative for carcinoembryonic antigen, TTF-1 and Ber-EP4, confirming malignant pleural mesothelioma. There was no distant metastasis or left-sided involvement, and the left pleural effusion contained no malignant cells. The time from onset of symptoms to death was 2 weeks, so the definite diagnosis could not be made before the postmortem examination. The authors said the factors behind such rapid growth are unknown. They concluded that awareness that mesothelioma may progress so quickly may help in diagnosis.

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