BMC Cancer

About the journal

Publisher: BioMed Central
Published: 2001 to the present, England
Language: English
ISSN: 1471-2407 (electronic)
Its record in the NLM Catalog

2020s

Clinical, diagnostic and prognostic relevance of GATA3 in malignant pleural mesothelioma: a retrospective cohort study. A. Avilés-Salas, D.D. Dupont, A. Aranda-Gutierrez, et al. 2026;26(1). PubMed · Publisher · Free full text

Abstract

BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive malignancy with a poor prognosis and limited treatment options. Recently, GATA3 has emerged as a useful adjunct immunohistochemical marker, especially for non-epithelioid subtypes. Although the diagnostic and prognostic roles of GATA3 have been described in other malignancies, its frequency and clinical relevance in MPM remains unclear. METHODS: We conducted a retrospective, single-center cohort study of 91 patients with histologically confirmed MPM and suitable tumor tissue for GATA3 immunohistochemistry. Staining intensity was scored semi-quantitatively (mild, moderate, or strong). Clinical, pathological, and treatment data were collected. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier methods and Cox regression models. RESULTS: GATA3 expression was observed in 64 of 91 cases (70.3%). No differences in PFS or OS were observed according to GATA3 positivity. GATA3 positivity demonstrated the ability to discrimine MPM and LUAD, with area under the curve (AUC) values of 0.83 for overall MPM, 0.81 for epithelioid MPM, and 0.93 for non-epithelioid MPM. The diagnostic performance was further improved by Combining GATA3 with WT1, yielding AUC values of 0.94 for MPM, 0.93 for epithelioid MPM, and 1.00 for non-epithelioid MPM. High GATA3 staining intensity was associated with shorter median PFS (6.14 vs. 10.94 months; p = 0.023) and OS (7.89 vs. 33.35 months; p = 0.004) compared with cases showing low or moderate intensity. High GATA3 staining intensity remained an independent adverse prognostic factor for OS (HR 6.59; 95% CI 1.55–28.05; p = 0.011) in a multivariate analysis adjusted for asbestos exposure, ECOG PS, clinical stage, PD-L1 positivity, and histological type. CONCLUSION: GATA3 is frequently expressed in MPM and demonstrates good diagnostic performance differentiating MPM from LUAD. Furthermore, high GATA3 staining intensity was independently associated with a poorer prognosis. These findings support GATA3 diagnostic utility and suggest a potential prognostic role in MPM that warrants validation in larger, prospective cohorts.
Distinct epidemiologic patterns of mesothelioma: evidence from a 16-year provincial cohort in China. S. Yin, T. Hu, X. Li, et al. 2026;26(1). PubMed · Publisher · Free full text

Abstract

Background: Epidemiologic data on mesothelioma in China remain limited, particularly with respect to long-term, province-level characterization of demographic features and survival outcomes.

Methods: We conducted a 16-year retrospective cohort study of mesothelioma patients diagnosed at a major provincial tertiary referral center in China between 2009 and 2025. Among 128 identified cases, 93 met strict pathological criteria and were included for analysis. We evaluated sex distribution, anatomic site, age at diagnosis, and survival outcomes, and compared these features with representative cohorts from the United States, Europe, and Japan.

Results: Our 16-year provincial cohort showed a nearly equal male-to-female ratio that markedly distinct from the male predominance reported in Western populations. Peritoneal mesothelioma accounted for 33.3% of cases, a proportion higher than that typically reported in global cohorts. The higher proportion of female patients was observed across both pleural and peritoneal mesothelioma. The median age at diagnosis was significantly younger than that observed in the United States. The median progression-free survival (PFS) and overall survival (OS) were 10 months and 16 months, with a notable survival advantage for females with peritoneal mesothelioma. Notably, only 7.5% of patients had documented asbestos exposure, indicating additional environmental and/or genetic contributors maybe relevant in this setting.

Conclusions: This long-term provincial cohort delineates mesothelioma epidemiology at the province level in China, marked by a near-equal sex distribution with substantial female representation across disease subtypes, a high proportion of peritoneal cases, younger age at diagnosis and a low prevalence of documented asbestos exposure. These findings show clear region-specific evidence, underscoring potential geographic heterogeneity in mesothelioma epidemiology.

© 2026. The Author(s).
Gemcitabine as maintenance treatment of diffuse pleural mesothelioma: randomized phase II study. M.E. Sobeih, M. Helal, M. Yahia, et al. 2026;26(1). Randomized trial PubMed · Publisher · Free full text

Abstract

BACKGROUND: Diffuse Pleural Mesothelioma (DPM) is an aggressive cancer with limited treatment options and a poor prognosis. Maintenance therapy has emerged as a potential strategy to delay disease progression following first-line chemotherapy. This study evaluates the efficacy and safety of gemcitabine maintenance therapy compared to best supportive care (BSC) in patients with unresectable DPM. METHODS: This single-center, randomized, phase II, open-label trial included 64 patients with unresectable DPM who achieved a complete/partial response or stable disease after first-line platinum-based chemotherapy. They were randomized 1:1 to receive gemcitabine maintenance therapy (GEM group, n = 32) or BSC (BSC group, n = 32). Progression-free survival (PFS) was the primary endpoint, while overall survival (OS) and toxicity were secondary endpoints. RESULTS: Gemcitabine maintenance therapy significantly improved PFS (median: 6.2 months vs. 2.8 months; HR: 4.33, 95% CI: 2.48–7.56, p < 0.001). However, no significant difference in OS was observed between the GEM and BSC groups (p = 0.155). Performance status (PS) at randomization and histological type were significant prognostic factors for survival. The GEM group experienced higher rates of hematological toxicities, while the BSC group reported more dyspnea, fatigue, and chest pain. No grade 3 or 4 toxicities were observed. CONCLUSION: Gemcitabine maintenance therapy effectively delays disease progression in patients with unresectable DPM, with a manageable toxicity profile. However, its impact on OS is limited. Performance status and histological type remain critical factors in predicting treatment outcomes. TRIAL REGISTRATION: ClinicalTrials.gov (ID NCT07411144, Date 1322026).
Cephalomannine as in vitro and in vivo anticancer agent in mesothelioma cells: mechanisms of action. F. Morani, I. Dell'Anno, A. Daga, et al. 2025;25(1):1625. PubMed · Publisher · Free full text

Abstract

BACKGROUND: In our previous drug screening, cephalomannine, fludarabine, and crenolanib were among the most active compounds against permanent cell lines of Pleural Mesothelioma (PM). METHODS: Here, firstly we assessed the efficacy of these compounds on PM-xenograft NOD-SCID mice and evaluated the overall survival (OS) as major endpoint. Then, we evaluated in vitro the underlying mechanisms involving CPM (at 0.1 µM) as anticancer agent on REN (derived from PM) and MeT-5A, a mesothelial cell line often used as a non-malignant model of mesothelial cells. We measured the oxygen consumption rate (OCR), the intracellular reactive oxygen species (ROS) production and the protein level of BAX and Bcl2, as proxy for apoptosis. Moreover, we measured IL-18 levels, as marker of the inflammasome pathway activation. RESULTS: While no effects were found for fludarabine (40, 100, or 200 mg/kg body weight) and crenolanib (15 mg/kg body weight), for cephalomannine (CPM, 2 mg/kg body weight) we observed a prolonged median OS in the treated group (75 days) vs vehicle control group (55 days; P = 0.0021). We found an increase in ROS production and a reduction in OCR in the REN cell line, compared to MeT-5A. We also noticed an activation of apoptosis, but not of inflammation. CONCLUSIONS: These results confirm the effectiveness of CPM on PM, suggesting novel targets and pathways for investigation.
Comprehensive pan-cancer analysis of CHRDL1 and experimental validation of its role in lung adenocarcinoma. G. Ou, T. Gao, S. Hu, et al. 2025;25(1):783. PubMed · Publisher · Free full text

Abstract

Chordin-like 1 (CHRDL1) is a secreted antagonist of bone morphogenetic proteins, and has been implicated in various biological processes and cancer prognosis. This study offered a detailed examination of CHRDL1 expression across 33 diverse cancer types, leveraging data from The Cancer Genome Atlas (TCGA) and supplementary public datasets. We demonstrated that, for the majority of cancer types, CHRDL1 expression was reduced in tumor tissues compared to normal adjacent tissues. Notably, lower CHRDL1 expression led to negative prognosis in malignancies such as lung adenocarcinoma (LUAD), melanoma (SKCM), and mesothelioma (MESO). Furthermore, CHRDL1 expression was positively correlated with the infiltration of CD4⁺ T cells, CD8⁺ T cells, B cells, neutrophils, macrophages, and dendritic cells in most tumors. Higher CHRDL1 expression correlated with more favorable immune profiles and a reduction in tumor stemness. To assess the effect of CHRDL1 overexpression on LUAD progression, we conducted CCK-8, wound healing, and invasion assays in vitro, along with subcutaneous tumor formation experiments in nude mice. The results showed that the proliferation, migration, and invasion abilities of A549 and H1299 cells with high CHRDL1 expression were reduced, and the growth of A549 cells was also significantly inhibited in nude mice. These findings underscored CHRDL1's potential as a prognostic biomarker and its influence on tumor immunology and cellular dynamics.

© 2025. The Author(s).
Exploring RNA cargo in extracellular vesicles for pleural mesothelioma detection. A. Kraft, M.B. Kirschner, V. Orlowski, et al. 2025;25(1):212. PubMed · Publisher · Free full text

Abstract

Background: Pleural Mesothelioma (PM) is a highly aggressive cancer, for which effective early detection remains a challenge due to limited screening options and low sensitivity of biomarkers discovered so far. While extracellular vesicles (EVs) have emerged as promising candidates for blood-based biomarkers, their role in PM has not been studied yet. In this study, we characterized the transcriptomic profile of EVs secreted by PM primary cells and explored their potential as a biomarker source for PM detection.

Methods: We collected cell culture supernatant from early-passage PM cell cultures derived from the pleural effusion of 4 PM patients. EVs were isolated from the supernatant using Qiagen exoEasy Maxi kit. RNA isolation from EVs was done using the mirVana PARIS kit. Finally, single-end RNA sequencing was done with Illumina Novaseq 6000.

Results: We identified a range of RNA species expressed in EVs secreted by PM cells, including protein-coding RNA (80%), long non-coding RNA (13%), pseudogenes (4.5%), and short non-coding RNA (1.6%). We detected a subset of genes associated with the previously identified epithelioid (32 genes) and sarcomatoid molecular components (36 genes) in PM-EVs. To investigate whether these markers could serve as biomarkers for PM detection in blood, we compared the RNA content of PM-EVs with the cargo of EVs isolated from the plasma of healthy donors (publicly available data). Majority of upregulated genes in PM-EVs were protein-coding and long non-coding RNAs. Interestingly, 25 of them were the sarcomatoid and epithelioid marker genes. Finally, functional analysis revealed that the PM-EV RNA cargo was associated with Epithelial-Mesenchymal transition, glycolysis, and hypoxia.

Conclusions: This is the first study to characterize the transcriptomic profile of EVs secreted by PM primary cell cultures, demonstrating their potential as biomarker source for early detection. Further investigation of the functional role of PM-EVs will provide new insights into disease biology and therapeutic avenues.

© 2025. The Author(s).
Health inequality and the global burden of mesothelioma: insights from the global burden of disease study 2021. L. Lv, W. Gao, D. Fan, et al. 2025;25(1):1179. PubMed · Publisher · Free full text

Abstract

BACKGROUND: This study aims to systematically analyze the disease burden and epidemiological trends of mesothelioma at the global, regional, and national levels from 1990 to 2021, based on the Global Burden of Disease (GBD) 2021 database, and to explore its relationship with health inequality. METHOD: DALYs were calculated by integrating Years of Life Lost due to premature mortality (YLL) and Years Lost due to disability (YLD) to comprehensively assess the disease burden. Additionally, the study analyzes cross-country health inequalities using the Slope Index of Inequality (SII) and the Concentration Index (CI). RESULTS: Over the past 32 years, global mesothelioma prevalence, incidence, DALYs, and death cases have increased significantly. In 2021, prevalence and incidence rates were highest in the high SDI regions, while the fastest growth occurred in the middle SDI regions. At the national level, Qatar, Bahrain, and Kuwait experienced the largest increases. The 75–79 age group had the highest prevalence and death cases globally. The analysis of health inequity indicates that countries with higher SDI levels are facing a more severe disease burden. CONCLUSION: From 1990 to 2021, the disease burden of mesothelioma exhibited a sustained upward trend. The widening gap in DALYs rates between countries with the highest and lowest SDI levels highlights the growing health inequality. Therefore, there is an urgent need for effective public health policies aimed at reducing occupational exposure, alleviating disease burden, and narrowing health disparities between countries.
Is ADC a rising star in solid tumor? An umbrella review of systematic reviews and meta-analyses. H. Wei, Y. Zhang, Y. Lu, et al. 2025;25(1):380. Systematic review PubMed · Publisher · Free full text

Abstract

Background: Antibody-drug conjugates (ADCs) combine the specificity of monoclonal antibodies with the potency of highly cytotoxic drugs and are known as panaceas, completely changing the treatment paradigm for solid tumors. Compared with other anti-cancer drugs, do they have better efficacy and lower toxicity risks? It is necessary to summarize and analyze the published clinical research data in this area to provide additional evidence-based evidence for clinical practice.

Objective: To comprehensively assess and overview the efficacy and safety of antibody-drug conjugates for the treatment of solid tumors.

Design: An umbrella review of systematic reviews and meta-analyses.

Methods: Systematic search of eight electronic databases and one registration platform including Embase, PubMed, Cochrane Database of Systematic Reviews (CDSR), Web of Science (WoS), China National Knowledge Infrastructure (CNKI), Chinese BioMedical Literature Database (CBM), Wan Fang Data, China Science and Technology Journal Database (VIP) and international prospective register of systematic reviews (PROSPERO) on Aug 1, 2024, to identify relevant systematic reviews or meta-analyses. Three authors completed research screening and data extraction independently. AMSTAR 2 was used to evaluate the methodological quality of the included studies and the Grading of Recommendations Assessment, Development and Evaluation Working Group (GRADE) was performed to evaluate the quality of the evidence. We examined progression-free survival (PFS), overall survival (OS), objective response rate (ORR) as efficacy endpoints, and the incidence of adverse events (AEs) as safety profiles.

Results: A total of 16 eligible publications, including 32 clinical studies, were included in the umbrella review. The methodological quality of the included study was poor, with 2 articles of moderate-quality (12.5%), 5 articles of low quality (31.25%), and 9 articles of critically low quality (56.25%). Only one third of the evidence was of high quality. Within the included studies, breast cancer accounted for four-fifths, 2 studies were gastric cancer, and 1 study was a solid tumor. The overall results showed that ADCs significantly increased PFS and OS in patients with solid tumors, and the risk of toxicity was within an acceptable range. ado-Trastuzumab emtansine (T-DM1) and Trastuzumab deruxtecan (T-Dxd) treatment of human epidermal growth factor receptor 2(HER2) low/positive advanced metastatic breast cancer significantly prolonged PFS and OS, but the ORR showed a significant advantage. Compared with the chemotherapy group, T-Dxd significantly prolonged OS and PFS in gastric cancer patients, while T-DM1 did not. In other cancer types (ovarian cancer, renal cell carcinoma, and malignant pleural mesothelioma), ADCs tended to extend overall survival or progression-free survival compared with controls, but the difference was not statistically significant.

Conclusions: Based on the available evidence, in breast cancer, ADCs were proved to with significant improvements in prolonging survival time and demonstrates a tolerable safety profile. Meanwhile, ADCs were proved to have enormous potential for the treatment of solid tumors. However, well-designed, multi-center RCTs need to further identify its potential in various solid tumors.

Systematic Review Registration: PROSPERO CRD 42,024,564,517.

© 2025. The Author(s).
Prognostic importance of the neutrophil-to-lymphocyte ratio in malignant peritoneal mesothelioma patients receiving cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Z. Xinjing, G. Lei, L. Xinbao, et al. 2025;25(1):270. PubMed · Publisher · Free full text

Abstract

Background: Malignant peritoneal mesothelioma (MPM) is a rare but aggressive cancer. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) was the preferred choice for selected patients. The purpose of this study was to thoroughly examine the impact of the combined treatment and the prognostic variables, particularly the neutrophil-to-lymphocyte ratio (NLR).

Methods: Characteristics of MPM patients who underwent CRS combined HIPEC treatment, followed by adjuvant chemotherapy were retrospectively collected. The univariable analysis was performed to identify the decisive influential factor. Using Kaplan-Meier analysis, the cumulative probability of survival was determined. Using Univariate Cox analysis, the prognostic factors-particularly NLR-and its correlation with survival were assessed. In the multivariate Cox proportional hazards model, predictive factors that demonstrated significance in univariate analysis were used. The degree of connection between predictors and survival was evaluated through the use of hazard ratios (HRs) and 95% confidence intervals (95% CIs).

Results: A total of 64 patients were enrolled in this study. The 1, 3, 5 years survival rates were 70.3%, 65.6%, 59.4%, respectively. According to multivariate Cox analysis, patients' survival was found to be substantially associated with post-operative NLR (HR 0.180, 0.067-0.531), Ki-67 (HR 0.184, 0.024-0.817), post-operative neutrophil count (HR 0.228, 0.075-0.696), and bidirectional pathological type (HR, 0.375, 0.146-0.964).

Conclusions: NLR is associated with the patients' prognosis after CRS combined HIPEC treatment.

© 2025. The Author(s).
Proteomics of malignant pleural mesothelioma under hypoxic and normoxic conditions in a large animal (porcine) tumor model. W. Min, D. He, X. Liu, et al. 2025;26(1):52. PubMed · Publisher · Free full text

Abstract

BACKGROUND: Malignant Pleural Mesothelioma (MPM) is a rare but highly aggressive malignant tumor, whose occurrence is closely associated with asbestos exposure. Clinical treatment options are limited and the prognosis is poor. The tumor microenvironment, especially hypoxia, plays a key regulatory role in the occurrence and development of MPM, yet its specific molecular mechanism remains unclear. To explore the effects of different oxygen metabolic states on the protein expression profiles and functional characteristics of MPM, this study first cultured MPM cells under normoxic and hypoxic conditions and conducted proteomic analysis. Furthermore, it explored MPM animal models simulating normoxic and hypoxic conditions, aiming to provide an experimental platform closer to the physiological state for MPM mechanism research and targeted intervention. METHODS: In in vitro studies, MSTO-211 H cells were cultured under 1% O₂ concentration (experimental group) and 21% O₂ concentration (control group) for 48 h, passaged for 3 generations, with 3 biological replicates in each group. TMT quantitative proteomics was used to screen differential proteins, and GO and KEGG analyses were performed to explore related signaling pathways. In animal experiments, the hypoxic group and normoxic group were injected with benzo(a)pyrene solution via a closed thoracic device, while the blank control group was injected with normal saline. Clinical symptoms and multiple biological indicators of the animals were monitored, and tumor characteristics were described based on CT, histopathological and immunohistochemical results. RESULTS: In in vitro studies, a total of 42 differential proteins were identified between the hypoxic group and the normoxic group. GO and KEGG analyses revealed that the two groups shared differences in three signaling pathways: protein digestion and absorption, neuroactive ligand-receptor interaction, and Staphylococcus aureus infection. In in vivo studies, MPM occurred in both the hypoxic group (Tibetan pigs) and the normoxic group (Landrace pigs) after intrathoracic injection of benzo(a)pyrene, while the normoxic group was accompanied by benign pleural hyperplasia. Only inflammatory cell infiltration was observed in the normal saline control group. The tumor tissue was composed of well-differentiated epithelioid cells and fibrovascular stroma. IHC detection showed that the tumor cells expressed specific proteins consistent with MPM, and the tumor microenvironment contained abundant CD31-positive small vascular endothelial cells. During the follow-up period of 224–238 days, the experimental pigs remained in good health. CONCLUSION: Based on the study of differentially expressed proteins in malignant pleural mesothelioma under hypoxic and normoxic conditions, the successfully constructed large-scale porcine tumor model can pre-verify the effect of drugs on tumors in different oxygen environments during new drug development, improving screening efficiency and success rate. It can also accurately simulate clinical scenarios, providing experimental support for the efficacy evaluation and scheme optimization of intervention strategies such as chemotherapy, radiotherapy, and immune targeting, thereby effectively promoting the development of clinical treatment for malignant pleural mesothelioma.
The global burden of cancers attributable to occupational factors, 1990-2021. B. Zou, P. Wu, J. Chen, et al. 2025;25(1):503. PubMed · Publisher · Free full text

Abstract

This study assessed the global cancer burden due to occupational carcinogens (OCs) using data from Global Burden of Disease (GBD) 2021. Mortality and disability-adjusted life years (DALYs) were employed to assess the evolving trend of cancer attributable to occupational risk. The analysis was conducted by age, year, geographical location, and socio-demographic index (SDI). Subsequently, the estimated annual percentage change (EAPC) values were calculated. Globally, asbestos exposure showed the most severe impact on age-standardized death rate (ASDR) and age-standardized DALY rate but decreased significantly. Conversely, diesel engine exhaust exposure increased, with EAPCs of 0.80 for deaths. Trichloroethylene exposure, although low in absolute terms, exhibited the fastest growth with an EAPC of 1.21 in age-standardized DALY rate. Notably, diesel engine exhaust exposure in South Asia and polycyclic aromatic hydrocarbons (PAHs) in Southeast Asia, East Asia, and Oceania increased significantly in age-standardized DALY rate. Regions with low to middle SDI, such as South Asia and sub-Saharan Africa, showed the highest increases in OC-related cancer burdens in age-standardized DALY rate. Lesotho, Kenya, and Egypt exhibited the fastest growth, with EAPCs in age-standardized DALY rate of 3.45, 2.13, and 2.95, respectively. High-income regions like the Netherlands, the United Kingdom, and Italy had the most severe OC-related cancer of ASDR burdens in 2021. OC exposure remains a major contributor to the global cancer burden, especially from asbestos and silica. Exposure to diesel engine exhaust was associated with increased risk of cancers, particularly in low -to -middle SDI regions such as South Asia and sub-Saharan Africa.

© 2025. The Author(s).
Trends in the disease burden of early-onset cancers in China from 1990 to 2021: a systematic analysis of the 2021 Global Burden of Disease study. J. Zhu, T. Li, J. Chen, et al. 2025;25(1):1168. PubMed · Publisher · Free full text

Abstract

Background: In recent years, the incidence of early-onset cancers among individuals under 50 years of age has been on the rise. We aimed to analyze the disease burden and temporal trends of early-onset cancers in China, providing a basis for policymakers to develop appropriate strategies.

Methods: We utilized data from the 2021 Global Burden of Disease (GBD) study to describe the changes in early-onset cancers in China from 1990 to 2021, including incidence, mortality and disability-adjusted life years (DALYs). The age-standardized average annual percentage change (AAPC) was estimated using the Joinpoint regression program.

Results: From 1990 to 2021, the incidence rate of all early-onset cancers in China increased by 150.72 per 100,000, while the mortality and DALY rates decreased by 4.30 per 100,000 and 279.34 per 100,000, respectively. In 2021, early-onset breast cancer had the highest incidence rate (17.14 per 100,000), and trachea/bronchus/lung cancer had the highest mortality rate (6.15 per 100,000) and DALY rate (292.48 per 100,000). The standardized DALY rate of all early-onset cancers decreased (AAPC = -1.49%, 95% CI: -1.51% to -1.46%), while multiple myeloma, neuroblastoma and other peripheral nervous cell tumors, malignant neoplasm of bone and articular cartilage, kidney cancer, and mesothelioma showed significant increases with AAPC of 4.14% (4.01-4.28%), 3.83% (3.77-3.88%), 1.20% (1.16-1.25%), 0.65% (0.58-0.73%), and 0.33% (0.29-0.37%), respectively. Tobacco consumption (23.01%) was the primary contributor to the disease burden of early-onset cancers in males, whereas unsafe sexual behavior (10.53%) was the primary contributor in females.

Conclusion: The mortality and DALY rate of early-onset cancers in China decreased, while the incidence rate increased. Trachea/bronchus/lung cancer is one of the most severe early-onset cancers, and effective measures need to be taken against the main risk factors.

© 2025. The Author(s).
ESCO2's oncogenic role in human tumors: a pan-cancer analysis and experimental validation. Y. Huang, D. Chen, Y. Bai, et al. 2024;24(1):452. PubMed · Publisher · Free full text

Abstract

Purpose: Establishment of sister chromatid cohesion N-acetyltransferase 2 (ESCO2) is involved in the mitotic S-phase adhesins acetylation and is responsible for bridging two sister chromatids. However, present ESCO2 cancer research is limited to a few cancers. No systematic pan-cancer analysis has been conducted to investigate its role in diagnosis, prognosis, and effector function.

Methods: We thoroughly examined the ESCO2 carcinogenesis in pan-cancer by combining public databases such as The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression Project (GTEx), UALCAN and Tumor Immune Single-cell Hub (TISCH). The analysis includes differential expression analysis, survival analysis, cellular effector function, gene mutation, single cell analysis, and tumor immune cell infiltration. Furthermore, we confirmed ESCO2's impacts on clear cell renal cell carcinoma (ccRCC) cells' proliferative and invasive capacities in vitro.

Results: In our study, 30 of 33 cancer types exhibited considerably greater levels of ESCO2 expression in tumor tissue using TCGA and GTEx databases, whereas acute myeloid leukemia (LAML) exhibited significantly lower levels. Kaplan-Meier survival analyses in adrenocortical carcinoma (ACC), kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), brain lower grade glioma (LGG), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), mesothelioma (MESO), and pancreatic adenocarcinoma (PAAD) demonstrated that tumor patients with high ESCO2 expression have short survival periods. However, in thymoma (THYM), colon adenocarcinoma (COAD) and rectum adenocarcinoma (READ), ESCO2 was a favorable prognostic factor. Moreover, ESCO2 expression positively correlates with tumor stage and tumor size in several cancers, including LIHC, KIRC, KIRP and LUAD. Function analysis revealed that ESCO2 participates in mitosis, cell cycle, DNA damage repair, and other processes. CDK1 was identified as a downstream gene regulated by ESCO2. Furthermore, ESCO2 might also be implicated in immune cell infiltration. Finally, ESCO2'S knockdown significantly inhibited the A498 and T24 cells' proliferation, invasion, and migration.

Conclusions: In conclusion, ESCO2 is a possible pan-cancer biomarker and oncogene that can reliably predict the prognosis of cancer patients. ESCO2 was also implicated in the cell cycle and proliferation regulation. In a nutshell, ESCO2 is a therapeutically viable and dependable target.

© 2024. The Author(s).
Monitoring immunE DysregulAtion foLLowing Immune checkpOint-inhibitioN (MEDALLION): protocol for an observational cancer immunotherapy cohort study. A. Gault, L. Hogarth, K.C. Williams, et al. 2024;24(1):733. PubMed · Publisher · Free full text

Abstract

Background: Checkpoint inhibitors (CPIs) are widely used in cancer treatment, with transformative impacts on survival. They nonetheless carry a significant risk of toxicity in the form of immune-related adverse events (IrAEs), which may be sustained and life-altering. IrAEs may require high-dose and/or prolonged steroid use and represent a significant healthcare burden. They mimic immune-mediated inflammatory diseases (IMIDs) but understanding of their pathogenesis is limited. The MEDALLION project aims to determine targetable mechanisms of immune dysregulation in IrAE development, employing an immune monitoring approach to determine changes in circulating and tissue resident cells of CPI recipients who do/do not develop them and assessing the contribution of the microbiome in parallel.

Methods: MEDALLION is a non-randomised longitudinal cohort study aiming to recruit 66 cancer patient recipients of anti-PD1/PD-L1, anti-CTLA-4 or combination therapy. Eligible participants include those with malignant melanoma in the adjuvant or metastatic setting, mesothelioma and non-small cell lung carcinoma (NSCLC) treated in the metastatic setting. Comprehensive clinical evaluation is carried out alongside blood, skin swab and stool sampling at the time of CPI initiation (baseline) and during subsequent routine hospital visits on 6 occasions over a 10-month follow-up period. It is conservatively anticipated that one third of enrolled patients will experience a "significant IrAE" (SirAE), defined according to pre-determined criteria specific to the affected tissue/organ system. Those developing such toxicity may optionally undergo a biopsy of affected tissue where appropriate, otherwise being managed according to standard of care. Peripheral blood mononuclear cells will be analysed using multi-parameter flow cytometry to investigate immune subsets, their activation status and cytokine profiles. Stool samples and skin swabs will undergo DNA extraction for 16 S ribosomal RNA (rRNA) sequencing and internal transcribed spacer (ITS) gene sequencing to determine bacterial and fungal microbiome diversity, respectively, including species associated with toxicity. Stored tissue biopsies will be available for in situ and single-cell transcriptomic evaluation. Analysis will focus on the identification of biological predictors and precursors of SirAEs.

Discussion: The pathogenesis of IrAEs will be assessed through the MEDALLION cohort, with the potential to develop tools for their prediction and/or strategies for targeted prevention or treatment.

Trial Registration: The study was registered on 18/09/2023 in the ISRCTN registry (43,419,676).

© 2024. The Author(s).
Revisiting the association between pretreatment thrombocytosis and cancer survival outcomes: an umbrella review of meta-analyses. C. Shu, X. Wang, C. Li, et al. 2024;24(1):1246. Systematic review PubMed · Publisher · Free full text

Abstract

Background: Although associations have been reported linking pretreatment thrombocytosis to cancer survival outcomes, the validity and strength of existing observational evidence have been contested. This study aimed to conduct an umbrella review to comprehensively appraise the strength, validity and credibility of these reported associations.

Methods: We searched Medline, Embase and Cochrane Database of Systematic Reviews from inception to 8 April 2023 to retrieve meta-analyses of observational studies. Meta-analyses were re-performed using a random-effect model and the strength of evidence was graded as convincing, highly suggestive, suggestive and weak according to seven pre-defined quantitative criteria reflecting statistical significance, amount of data, heterogeneity, and evidence of bias. The quality of review was appraised using the AMSTAR2 checklist. The umbrella review was reported adhering to the PRISMA guideline and was registered on PROSPERO (CRD42023455391).

Results: A total of 21 unique meta-analyses investigating ten cancer subtypes were included. All meta-analyses reported inferior survival outcome in cancer patients with pretreatment thrombocytosis, and 18 of them (85.7%) yielded statistically significant results (P < 0.05). Consistent effects were observed across meta-analyses that adopted different cut-off values (i.e. platelet count > 300 or 400 × 109 /L) to define thrombocytosis. Although evidence appraisal did not identify convincing evidence (Class I), the associations of thrombocytosis with inferior overall survival of lung, gastric, colorectal cancer and malignant mesothelioma were classified as highly suggestive evidence (Class II). According to AMSTAR2 ratings, no meta-analysis was identified with high or moderate quality.

Conclusions: Our findings consolidated the association between pretreatment thrombocytosis and poor survival outcomes in various cancers. Nonetheless, the absence of convincing associations indicates a need for further large-scale, high-quality evidence to confirm whether platelets can serve as a prognostic predictor or a therapeutic target.

© 2024. The Author(s).
Safety and efficacy of PD-1/PD-L1 immune checkpoint inhibitors in patients with pre-treated advanced stage malignant mesothelioma: a systematic review and meta-analysis. A. Zafar, A.A. Rashid, A. Moeed, et al. 2024;24(1):1353. Systematic review · Meta-analysis PubMed · Publisher · Free full text

Abstract

Background: Malignant mesothelioma is an aggressive cancer with poor prognosis. Programmed cell death protein-1 (PD-1) and its ligand 1 (PD-L1) immune checkpoint inhibitors (ICIs) have recently presented as a viable option in some first line but primarily as a second-line treatment of advanced-stage malignant mesothelioma (asMM). Therefore, this systematic review and meta-analysis aims to assess the safety and efficacy of PD-1/L-1 ICIs in advanced-stage malignant mesothelioma.

Methods: PubMed, Scopus, and Cochrane databases were searched for all studies assessing the safety and efficacy of anti PD-1/PD-L1 agents. Primary outcomes were objective response rate (ORR) and disease control rate (DCR). Secondary outcomes were median progression free (mPFS) and overall survival (mOS). Safety outcomes were treatment- (TRAEs) and immune-related adverse events (IRAEs). A random-effects meta-analysis was performed to pool medians and to derive event rates.

Results: A total of 15 studies were included with total of 1064 asMM patients. ORR and DCR were 16% and 57%, respectively. A pooled mPFS was 4.53 (CI: 3.40-5.65) and mOS was 10.51 (CI: 9.03-12.00). Overall TRAEs had an event rate of 0.69 (0.50-0.83) whereas IRAEs had an event rate of 0.28 (0.15-0.46). There were no significant differences between pembrolizumab, nivolumab primarily, and avelumab subgroups for all the outcomes. Additionally, meta-regression found no covariate to be a significant factor in ORR and DCR.

Conclusion: In this meta-analysis we found that anti-PD1/PD-L1 treatment could be useful in pretreated asMM as they had at least comparable or greater mPFS, mOS, ORR, and DCR than other second-line agents currently being used.

Registration Number: This systematic review was registered at PROSPERO prior to the literature search, CRD42023442350.

© 2024. The Author(s).
Tretinoin improves the anti-cancer response to cyclophosphamide, in a model-selective manner. C.M. Tilsed, M.L.O. Morales, R.M. Zemek, et al. 2024;24(1):203. PubMed · Publisher · Free full text

Abstract

Background: Chemotherapy is included in treatment regimens for many solid cancers, but when administered as a single agent it is rarely curative. The addition of immune checkpoint therapy to standard chemotherapy regimens has improved response rates and increased survival in some cancers. However, most patients do not respond to treatment and immune checkpoint therapy can cause severe side effects. Therefore, there is a need for alternative immunomodulatory drugs that enhance chemotherapy.

Methods: We used gene expression data from cyclophosphamide (CY) responders and non-responders to identify existing clinically approved drugs that could phenocopy a chemosensitive tumor microenvironment (TME), and tested combination treatments in multiple murine cancer models.

Results: The vitamin A derivative tretinoin was the top predicted upstream regulator of response to CY. Tretinoin pre-treatment induced an inflammatory, interferon-associated TME, with increased infiltration of CD8 + T cells, sensitizing the tumor to subsequent chemotherapy. However, while combination treatment significantly improved survival and cure rate in a CD4+ and CD8+ T cell dependent manner in AB1-HA murine mesothelioma, this effect was model-selective, and could not be replicated using other cell lines.

Conclusions: Despite the promising data in one model, the inability to validate the efficacy of combination treatment in multiple cancer models deprioritizes tretinoin/cyclophosphamide combination therapy for clinical translation.

© 2024. The Author(s).
Correlation of toxicities and efficacies of pemetrexed with clinical factors and single-nucleotide polymorphisms: a prospective observational study. Y. Takeda, G. Naka, Y. Katsuya, et al. 2023;23(1):800. PubMed · Publisher · Free full text

Abstract

Background: Pemetrexed is an efficacious multi-targeted antifolate with acceptable toxicity for non-squamous non-small cell lung cancer (non-Sq NSCLC) and malignant pleural mesothelioma. Vitamin B12 and folic acid as premedication can reduce the frequency of severe toxicities of pemetrexed chemotherapy. However, adverse effects are frequent in clinical settings. In this study, we aimed to identify the clinical factors and single-nucleotide polymorphisms (SNPs) associated with the toxicity and efficacy of pemetrexed chemotherapy.

Methods: This observational study was conducted from October 2012 to December 2019; we evaluated the toxicities and efficacies of pemetrexed chemotherapy using multivariate logistic or Cox regression analysis. In total, 106 patients received pemetrexed chemotherapy. SNPs were analyzed for four patients with malignant pleural mesothelioma and 67 with non-Sq NSCLC.

Results: The median progression-free survival (PFS) and overall survival of 63 patients with non-Sq NSCLC, excluding four in the adjuvant setting, were 6.8 and 33.3 months, respectively. Per propensity-score-adjusted multivariate Cox analyses, favorable factors for PFS were folic acid level ≥ 9.3 ng/mL before premedication, platinum combination, bevacizumab combination, vitamin B12 level < 1136 pg/mL before chemotherapy, A/A + A/G of BHMT (742 G > A), and A/A + A/C of DHFR (680 C > A). Favorable prognostic factors included good performance status, low smoking index, body mass index ≥ 20.66 kg/m2, folic acid level ≥ 5.55 ng/mL before premedication, higher retinol-binding protein before chemotherapy, and A/G of MTRR (66 A > G). Among the 71 patients who were analyzed for SNPs, the frequencies of hematologic toxicities and non-hematologic toxicities in Grades 3-4 were 38% and 36.6%, respectively. Per propensity-score-adjusted multivariate logistic analyses, risk factors for Grades 3-4 hematologic toxicities were vitamin B12 level < 486 pg/mL before premedication, leucocyte count < 6120 /µL before chemotherapy, folic acid level < 15.8 ng/mL before chemotherapy, status with a reduced dose of chemotherapy, and C/T + T/T of MTHFR (677 C > T). Risk factors for Grades 2-4 non-hematologic toxicities were homocysteine levels ≥ 11.8 nmol/mL before premedication, transthyretin level < 21.5 mg/dL before chemotherapy, C/C + T/T of MTHFR (677 C > T), and A/A + G/G of SLC19A1 [IVS2 (4935) G > A].

Conclusion: The information on metabolites and SNPs of the folate and methionine cycle will help predict the toxicities and efficacies of pemetrexed.

Trial Registration: This trial was retrospectively registered with the University hospital Medical Information Network (UMIN000009366) on November 20, 2012.

© 2023. BioMed Central Ltd., part of Springer Nature.
Integrated pancancer analysis reveals the oncogene characteristics and prognostic value of DIP2B in breast cancer. C. Song, F. Shang, W. Tu, et al. 2023;23(1):296. PubMed · Publisher · Free full text

Abstract

Background: Disco-interaction protein 2 homologue B (DIP2B) plays an important role in DNA methylation. There have been many reports on DIP2B in various diseases, but neither the diagnostic value nor the prognostic value of DIP2B across cancer types has been deeply explored.

Methods: The expression levels of DIP2B in 33 cancer types were analysed based on data sets from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) database. The relationships of DIP2B expression with immune cell infiltration and immune-related gene expression were studied via the CIBERSORT, ESTIMATE and TISIDB tools. Gene set variation analysis (GSVA) was performed to identify pathways related to DIP2B. DIP2B knockdown by siRNA was performed in breast cancer cell lines to investigate the effect on proliferation, apoptosis and migration. The relationships of DIP2B expression with clinicopathological features and prognosis were analysed based on immunohistochemistry.

Results: DIP2B was highly expressed in 26 of 33 cancer types and was significantly associated with poor overall survival (OS) in breast invasive carcinoma (BRCA), mesothelioma and chromophobe renal cell carcinoma (each P < 0.05). DIP2B showed a negative correlation with the immune score, the infiltration levels of key immune killer cells (CD8 + T cells, activated NK cells and plasma cells), and the expression of major histocompatibility complex-related genes and chemokine-related genes in BRCA. Subtype analysis showed that DIP2B expression was associated with poor OS in Her-2 + BRCA patients (P < 0.05). DIP2B showed a negative correlation with immune killer cell infiltration and immune regulatory genes in BRCA subtypes. In BRCA, the GSVA results revealed that genes correlating positively with DIP2B were enriched in cancer-related pathways (PI3K-AKT) and cell-cycle-related pathways (MITOTIC_SPINDLE, G2M_CHECKPOINT and E2F_TARGETS), while genes correlating negatively with DIP2B were enriched in DNA_REPAIR. Knockdown of the DIP2B gene induced a reduction in proliferation and migration and an increase in apoptosis in breast cancer cell lines. DIP2B expression was associated with lymph node metastasis and poor histological grade in BRCA according to immunohistochemistry (each P < 0.05). DIP2B expression predicted reduced disease-free survival and OS in BRCA patients (each P < 0.05), especially those with the Her-2 + subtype (P = 0.023 and P = 0.069).

Conclusions: DIP2B may be a prognostic biomarker for BRCA, especially for the Her-2 + subtype. DIP2B is associated with a "cold" tumour immune microenvironment in BRCA and might serve as a future target for immunotherapy.

© 2023. The Author(s).
LAG3 is an independent prognostic biomarker and potential target for immune checkpoint inhibitors in malignant pleural mesothelioma: a retrospective study. K. Arimura, K. Hiroshima, Y. Nagashima, et al. 2023;23(1):1206. PubMed · Publisher · Free full text

Abstract

Background: Lymphocyte-activation gene 3 (LAG3) is an immune checkpoint receptor; novel LAG3 immune checkpoint inhibitors (ICIs) exhibit therapeutic activity in melanoma. The role of LAG3and ICIs of LAG3 are unknown in malignant pleural mesothelioma (MPM). This study aimed to uncover the prognostic landscape of LAG3 in multiple cancers and investigate the potential of using LAG3 as an ICIs target in patients with MPM.

Methods: We used The Cancer Genome Atlas (TCGA) cohort for assessing mRNA expression and our cohort for immunohistochemical expression. TCGA cohort were analyzed using the Wilcoxon rank-sum test to compare mRNA expression between normal and tumor tissues in multiple cancers. We used 86 MPM cases from TCGA and 38 MPM cases from our cohort to analyze the expression of LAG3 in tumor-infiltrating lymphocytes. The mean LAG3 mRNA expression was set as the cut-off and samples were classified as positive/negative for immunohistochemical expression. Overall survival (OS) of patients with MPM was determined using the Kaplan-Meier method based on LAG3 mRNA and immunohistochemical expression. OS analysis was performed using the multivariate Cox proportional hazards model. The correlation of LAG3 expression and mRNA expression of tumor immune infiltration cells (TIICs) gene markers were estimated using Spearman correlation. To identify factors affecting the correlation of LAG3 mRNA expression, a multivariate linear regression model was performed.

Results: LAG3 mRNA was associated with prognosis in multiple cancers. Elevated LAG3 mRNA expression was correlated with a better prognosis in MPM. LAG3 expression was detected immunohistochemically in the membrane of infiltrating lymphocytes in MPM. LAG3 immunohistochemical expression was correlated with a better prognosis in MPM. The multivariate Cox proportional hazards model revealed that elevated LAG3 immunohistochemical expression indicated a better prognosis. In addition, LAG3 mRNA expression was correlated with the expression of various gene markers of TIICs, the most relevant to programmed cell death 1 (PD-1) with the multivariate linear regression model in MPM.

Conclusions: LAG3 expression was correlated with prognosis in multiple cancers, particularly MPM; LAG3 is an independent prognostic biomarker of MPM. LAG3 regulates cancer immunity and is a potential target for ICIs therapy. PD-1 and LAG3 inhibitors may contribute to a better prognosis in MPM.

Trial Registration: This study was registered with UMIN000049240 (registration day: August 19, 2022) and approved by the Institutional Review Board (approval date: August 22, 2022; approval number: 2022-0048) at Tokyo Women's Medical University.

© 2023. The Author(s).
Matrigel-based organoid culture of malignant mesothelioma reproduces cisplatin sensitivity through CTR1. F. Ito, K. Kato, I. Yanatori, et al. 2023;23(1):487. PubMed · Publisher · Free full text

Abstract

Organoids are a three-dimensional (3D) culture system that simulate actual organs. Therefore, tumor organoids are expected to predict precise response to chemotherapy in patients. However, to date, few studies have studied the drug responses in organoids of malignant mesothelioma (MM). The poor prognosis of MM emphasizes the importance of establishing a protocol for generating MM-organoid for research and clinical use. Here, we established murine MM organoids from p53+/- or wild-type C57BL/6 strain by intraperitoneal injection either with crocidolite or carbon nanotube. Established MM-organoids proliferated in Matrigel as spheroids. Subcutaneous injection assays revealed that the MM-organoids mimicked actual tissue architecture and maintained the original histological features of the primary MM. RNA sequencing and pathway analyses revealed that the significant expressional differences between the 2D- and 3D-culture systems were observed in receptor tyrosine kinases, including IGF1R and EGFR, glycosylation and cholesterol/steroid metabolism. MM-organoids exhibited a more sensitive response to cisplatin through stable plasma membrane localization of a major cisplatin transporter, copper transporter 1/Slc31A1 (Ctr1) in comparison to 2D-cultures, presumably through glycosylation and lipidation. The Matrigel culture system facilitated the localization of CTR1 on the plasma membrane, which simulated the original MMs and the subcutaneous xenografts. These results suggest that the newly developed protocol for MM-organoids is useful to study strategies to overcome chemotherapy resistance to cisplatin.

© 2023. The Author(s).
Peripheral PD-1 and Tim-3 percentages are associated with primary sites and pathological types of peritoneal neoplasms. H. Hu, J. Zhao, J. Yuan, et al. 2023;23(1):287. PubMed · Publisher · Free full text

Abstract

Purpose: Programmed death-1 (PD-1) and T cell immunoglobulin and mucin-domain-containing molecule 3(Tim-3) may be used as the biomarkers for the therapy in patients with peritoneal neoplasms. In the current study, the differential percentages of peripheral PD-1 and Tim-3 are explored to investigate whether to associate with primary sites and pathological types of patients with peritoneal neoplasms or not. We also investigated the frequencies of PD-1 and Tim-3 on circulating Lymphocytes, CD3 + T cells, CD3 + CD4 + T cells and CD3 + CD8 + T cells if would correlate with the progression-free survival of peritoneal neoplasms patients.

Methods: 115 patients with peritoneal neoplasms were recruited, subjected to multicolor flow cytometric analyses of the percentages of PD-1 and Tim-3 receptors of circulating Lymphocytes, CD3 + T cells, CD3 + CD4 + T cells and CD3 + CD8 + T cells. The peritoneal neoplasms patients were divided into primary group and secondary group depending on whether the tumor had primary focus and limited to peritoneal tumor or not. Then all the patients were regrouped by the pathological types of neoplasms (adenocarcinoma, mesothelioma, and pseudomyxoma). The secondary peritoneal neoplasms group was divided into the different primary site groups (colon, gastric, gynecology). This study also enrolled 38 cases of normal volunteers. The above markers were explored by flow cytometer, to find the differential levels in peritoneal neoplasms patients compared with normal group in peripheral blood.

Results: Higher levels of CD4 + T lymphocytes, CD8 + T lymphocytes, CD45 + PD-1 + lymphocytes, CD3 + PD-1 + T cells, CD3 + CD4 + PD-1 + T cells, CD3 + CD8 + PD-1 + T cells and CD45 + Tim-3 + lymphocytes were found in peritoneal neoplasms group than normal control (the p value was respectively 0.004, 0.047, 0.046, 0.044, 0.014, 0.038 and 0.017). Compared with primary peritoneal neoplasms group, the percentages of CD45 + PD-1 + lymphocytes, CD3 + PD-1 + T cells, and CD3 + CD4 + PD-1 + T cells were increased in the secondary peritoneal neoplasms group (the p value was respectively 0.010, 0.044, and 0.040), while PD-1 did not correlate with the primary sites in secondary group (P > 0.05). Tim-3 had no statistical differences in primary peritoneal neoplasms group compared with secondary group (p > 0.05), but CD45 + Tim-3+% lymphocytes, CD3 + Tim-3+%T cells, and CD3 + CD4 + Tim-3 + T cells were associated with different secondary sites of peritoneal neoplasms (p < 0.05). In the different pathological type groups, the percentages of CD45 + PD-1 + lymphocytes, CD3 + PD-1 + T cells presented the higher levels in adenocarcinoma group compared with mesothelioma group (p = 0.048, p = 0.045). The frequencies of CD45 + PD-1 + lymphocytes and CD3 + PD-1 + T cells in peripheral blood were associated with progression-free survival (PFS).

Conclusions: Our work uncovers peripheral PD-1 and Tim-3 percentages are associated with primary sites and pathological types of peritoneal neoplasms. Those findings might provide important assessment to predict peritoneal neoplasms patients' immunotherapy responses.

© 2023. The Author(s).
Predicting survival for patients with mesothelioma: development of the PLACE prognostic model. Y. Zhang, N. Li, R. Li, et al. 2023;23(1):698. PubMed · Publisher · Free full text

Abstract

Introduction: The overall survival of patients with mesothelioma is poor and heterogeneous. At present, the prediction model for Chinese patients needs to be improved. We sought to investigate predictors of survival in malignant pleural mesothelioma and develop prognostic prediction models.

Methods: This Two-center retrospective cohort study recruited patients with pathologically diagnosed mesothelioma at Beijing Chao-Yang Hospital and Beijing Tong-Ren Hospital. We developed a new prognostic prediction model based on COX multivariable analysis using data from patients who were recruited from June 1, 2010 to July 1, 2021 in Beijing Chao-Yang Hospital (n = 95, development cohort) and validated this model using data from patients recruited from July 18, 2014 to May 9, 2022 in Beijing Tong-Ren Hospital (n = 23, validation cohort). Receiver operating characteristic analysis was used to estimate model accuracy.

Results: The parameters in this new model included PLT > 289.5(10^9/L) (1 point), Lymphocyte > 1.785(10^9/L) (-1point), Age > 73 years old (1 point), Calcium > 2.145(mmol/L) (-1point), Eastern Cooperative Oncology Group performance status (ECOG PS) > 2 (2 points). When the sum of scores < 0, it is recognized as a low-risk group; when the score is 0 ~ 3, it is recognized as a high-risk group. The survival rate of patients in the high-risk group was significantly lower than that in the low-risk group (hazard ratio [HR], 3.878; 95% confidence interval [CI], 2.226-6.755; P < 0.001). The validation group had similar results (HR,3.574; 95%CI,1.064-12.001; P = 0.039). Furthermore, the areas under the curve 6 months after diagnosis in the two cohorts were 0.900 (95% CI: 0.839-0.962) and 0.761 (95% CI: 0.568-0.954) for development and validation cohorts, respectively.

Conclusion: We developed a simple, clinically relevant prognostic prediction model for PLACE by evaluating five variables routinely tested at the time of diagnosis. The predictive model can differentiate patients of Chinese ethnicity into different risk groups and further guide prognosis.

© 2023. The Author(s).
Prognostic role of CD74, CD10 and Ki-67 immunohistochemical expression in patients with diffuse malignant peritoneal mesothelioma: a retrospective study. Y. Liang, C. Li, Y. Liu, et al. 2023;23(1):406. PubMed · Publisher · Free full text

Abstract

Background: Diagnosis and treatment of diffuse malignant peritoneal mesothelioma (DMPM) are still challenging. The aim of the present study was to explore the correlation between CD74, CD10, Ki-67 and clinicopathological parameters, and identify independent prognostic factors of DMPM.

Methods: Seventy patients with pathologically proven DMPM were retrospectively reviewed. The expression of CD74, CD10 and Ki-67 in peritoneal tissues was detected by immunohistochemical analysis using standard avidin biotin complex (ABC) immunostaining technique. Kaplan-Meier survival analysis and multivariate Cox regression analyses were performed to assess prognostic factors. The nomogram based on the Cox hazards regression model was established. C-index and calibration curve were performed to evaluate the accuracy of nomogram models.

Results: The median age of DMPM was 62.34 years, and the male-to-female ratio was 1: 1.80. CD74 expression was identified in 52 (74.29%) of 70 specimens, CD10 in 34 (48.57%) specimens, and higher Ki-67 in 33(47.14%) specimens. CD74 was negatively associated with asbestos exposure(r = -0.278), Ki-67(r = -0.251) and TNM stage(r = -0.313). All patients were effectively followed up in the survival analysis. Univariate analysis revealed that PCI, TNM stage, treatment, Ki-67, CD74 and ECOG PS were associated with DMPM prognosis. CD74 (HR = 0.65, 95%Cl:0.46-0.91, P = 0.014), Ki-67(HR = 2.09, 95%Cl:1.18-3.73, P = 0.012),TNM stage (HR = 1.89, 95%Cl:1.16-3.09, P = 0.011), ECOG PS(HR = 2.12, 95%Cl:1.06-4.25, P = 0.034), systemic chemotherapy (HR = 0.41, 95%Cl:0.21-0.82, P = 0.011) and intraperitoneal chemotherapy (HR = 0.34, 95%Cl:0.16-0.71, P = 0.004) were independent predictors by multivariate Cox analysis. The C‑index of the nomogram for predicting overall survival (OS) was 0.81. The OS calibration curve showed good agreement between nomogram-predicted and observed survival.

Conclusions: CD74, Ki-67, TNM stage, ECOG PS and treatment were independent factors affecting prognosis of DMPM. Reasonable chemotherapy treatment might improve the prognosis of patients. The proposed nomogram was a visual tool to effectively predict the OS of DMPM patients.

© 2023. The Author(s).
BMP and activin membrane-bound inhibitor regulate connective tissue growth factor controlling mesothelioma cell proliferation. N.T.D. Hoang, G. Hassan, T. Suehiro, et al. 2022;22(1):984. PubMed · Publisher · Free full text

Abstract

Background: Malignant mesothelioma (MM) is an aggressive mesothelial cell cancer type linked mainly to asbestos inhalation. MM characterizes by rapid progression and resistance to standard therapeutic modalities such as surgery, chemotherapy, and radiotherapy. Our previous studies have suggested that tumor cell-derived connective tissue growth factor (CTGF) regulates the proliferation of MM cells as well as the tumor growth in mouse xenograft models.

Methods: In this study, we knock downed the bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) and CTGF in MM cells and investigated the relationship between both and their impact on the cell cycle and cell proliferation.

Results: The knockdown of CTGF or BAMBI reduced MM cell proliferation. In contrast to CTGF knockdown which decreased BAMBI, knockdown of BAMBI increased CTGF levels. Knockdown of either BAMBI or CTGF reduced expression of the cell cycle regulators; cyclin D3, cyclin-dependent kinase (CDK)2, and CDK4. Further, in silico analysis revealed that higher BAMBI expression was associated with shorter overall survival rates among MM patients.

Conclusions: Our findings suggest that BAMBI is regulated by CTGF promoting mesothelioma growth by driving cell cycle progression. Therefore, the crosstalk between BAMBI and CTGF may be an effective therapeutic target for MM treatment.

© 2022. The Author(s).
Dynamic contrast-enhanced MRI in malignant pleural mesothelioma: prediction of outcome based on DCE-MRI measurements in patients undergoing cytotoxic chemotherapy. M. Vivoda Tomšič, P. Korošec, V. Kovač, et al. 2022;22(1):191. PubMed · Publisher · Free full text

Abstract

Background: The malignant pleural mesothelioma (MPM) response rate to chemotherapy is low. The identification of imaging biomarkers that could help guide the most effective therapy approach for individual patients is highly desirable. Our aim was to investigate the dynamic contrast-enhanced (DCE) MR parameters as predictors for progression-free (PFS) and overall survival (OS) in patients with MPM treated with cisplatin-based chemotherapy.

Methods: Thirty-two consecutive patients with MPM were enrolled in this prospective study. Pretreatment and intratreatment DCE-MRI were scheduled in each patient. The DCE parameters were analyzed using the extended Tofts (ET) and the adiabatic approximation tissue homogeneity (AATH) model. Comparison analysis, logistic regression and ROC analysis were used to identify the predictors for the patient's outcome.

Results: Patients with higher pretreatment ET and AATH-calculated Ktrans and ve values had longer OS (P≤.006). Patients with a more prominent reduction in ET-calculated Ktrans and kep values during the early phase of chemotherapy had longer PFS (P =.008). No parameter was identified to predict PFS. Pre-treatment ET-calculated Ktrans was found to be an independent predictive marker for longer OS (P=.02) demonstrating the most favourable discrimination performance compared to other DCE parameters with an estimated sensitivity of 89% and specificity of 78% (AUC 0.9, 95% CI 0.74-0.98, cut off > 0.08 min-1).

Conclusions: In the present study, higher pre-treatment ET-calculated Ktrans values were associated with longer OS. The results suggest that DCE-MRI might provide additional information for identifying MPM patients that may respond to chemotherapy.

© 2022. The Author(s).
Malignant pleural mesothelioma: treatment patterns and humanistic burden of disease in Europe. A. Moore, B. Bennett, G. Taylor-Stokes, et al. 2022;22(1):693. PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is an aggressive and rare tumour with poor prognosis. Most patients are diagnosed with advanced disease and there is a paucity of data on the humanistic burden of MPM in terms of impact on health-related quality of life (HRQoL) and activity. This study examined real-world treatment patterns and humanistic disease burden of MPM in Europe.

Methods: Physicians abstracted demographic/clinical characteristics and treatment data from MPM-patient medical records; MPM patients self-completed a questionnaire including symptoms, 3-level-EQ-5D questionnaire and Visual Analogue Scale (VAS), Lung Cancer Symptom Scale for Mesothelioma (LCSS-Meso), and Work Productivity and Activity Impairment (WPAI) questionnaire.

Results: Physicians (n = 171) abstracted data of 1390 patients; 767/1390 patients self-completed questionnaires. Patients were elderly with advanced, unresectable MPM. Treatment patterns followed guidelines with most (81%) patients receiving platinum+antifolate chemotherapy at first line (1 L). Maintenance treatment use was high (51.1%) despite no recommended maintenance therapies. Symptom burden was high and health states and HRQoL were poor at 1; declining further with progression. Overall mean (SD): LCSS-Average Symptom Burden Index score was 48.8 (19.3; n = 758); EQ-5D Utility Index score was 0.510 (0.349; n = 763); EQ-5D VAS score was 54.2 (20.3;n = 766); LCSS-3-Item Global Index score was 143.2 (64.5; n = 762); LCSS-normal activities score was 51.9 (24.6;n = 765); WPAI-activity impairment was 56.0% (23.2%; n = 737).

Conclusion: The humanistic burden of MPM is high, despite treatments being prescribed as per available guidance. Treatments that delay progression and provide palliation of symptoms are most likely to improve/maintain HRQoL.

© 2022. The Author(s).
Prognosis of resected non-small cell lung cancer with pleural plaques on intrathoracic findings. A. Kagimoto, T. Mimura, A. Kamigaichi, et al. 2022;22(1):469. PubMed · Publisher · Free full text

Abstract

Background: The prognosis of patients with lung cancer who demonstrate pleural plaques intraoperatively, which may be associated with exposure to asbestos, is unclear. Here, we compared the clinicopathological characteristics and prognosis of these patients to those of patients without pleural plaques.

Methods: We included patients who underwent curative-intent resection for non-small cell lung cancer. We retrospectively investigated the relationship of intrathoracic findings of pleural plaques with clinicopathological features and prognosis.

Results: Pleural plaques were found in 121/701 patients (17.3%) during surgery. The incidence of squamous cell carcinoma (P < 0.001) and the pathological stage (P = 0.021) were higher in patients with pleural plaques. Overall survival was significantly worse in patients with pleural plaques (5-year rate; 64.5% vs. 79.3%; P < 0.001), and the same finding was noted in clinical stage I patients (5-year rate; 64.8% vs. 83.4%; P < 0.001). In multivariable analysis, the presence of pleural plaques was a significant predictor of overall survival in patients with clinical stage I (hazard ratio, 1.643; P = 0.036). In the analysis among patients with emphysema more severe than Goddard score 5 points or interstitial pneumonia, overall survival was significantly worse in those with pleural plaques than in those without pleural plaques (5-year rate; 66.3% vs. 49.5%; P < 0.001).

Conclusions: Patients with non-small cell lung cancer who underwent resection and demonstrated pleural plaques intraoperatively had a significantly worse prognosis. It is important to recognize the presence of pleural plaques intraoperatively, and our findings will be useful in determining the treatment and follow-up strategy for such patients with lung cancer and pleural plaques on intrathoracic examination.

© 2022. The Author(s).
Systemic treatment in patients with malignant pleural mesothelioma - real life experience. B. Ziółkowska, B. Cybulska-Stopa, D. Papantoniou, et al. 2022;22(1):432. PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is a rare, aggressive malignancy of the pleural cavity linked to asbestos exposure. The combination of pemetrexed and platinum is a standard first-line therapy for malignant pleural mesothelioma. Despite some progress, almost all MPM patients experience progression after first-line therapy. The second-line treatment is still being under discussion and there are very limited data available on the second-line and subsequent treatments.

Methods: The retrospective analysis included 57 patients (16 females and 41 males) from two Polish oncological institutions treated for advanced mesothelioma between 2013 and 2019. We analysed the efficacy of first-line and second-line therapy: progression-free survival (PFS), overall survival (OS), overall response rate (ORR).

Results: In the first-line treatment, 55 patients received pemetrexed-based chemotherapy (PBC) and two cisplatin in monotherapy. Patients' characteristics at baseline: median age was 64.2 years, ECOG PS ≤ 1 (86.2%), epithelial histology (85.7%). Median PFS and OS were 7.6 months and 14 months, respectively. Patients with ECOG PS ≤ 1 vs > 1 had a longer median OS (14.8 months vs 9.7 months, p = 0.057). One-year OS and PFS were 60.9% and 32.0%, respectively. Disease control rate (DCR) was 82.5%. Response to first-line therapy: PFS ≥ 6 months and PFS ≥ 12 months had a significant impact on median OS. Twelve patients received second-line therapy (seven PBC and five other cytotoxic single agents: navelbine, gemcitabine, or adriamycin/vincristine/methotrexate triplet). Median PFS and OS were 3.7 months and 7.2 months, respectively. DCR was 83%. One-year OS and PFS were 37% and 16.7%, respectively. In the group receiving PBC, OS was prolonged by 4.5 months compared to the non-PBC group (6.0 months vs 10.5 months, p = 0.47).

Conclusion: Patients who benefited from first-line therapy and had prolonged PFS at first-line and achieve PFS longer than 6 months at first-line should be offered second-line treatment. Consideration of retreatment with the same cytotoxic agent could to be a viable option when no other treatment are available.

© 2022. The Author(s).
YAP1 is essential for malignant mesothelioma tumor maintenance. L. Calvet, O. Dos-Santos, E. Spanakis, et al. 2022;22(1):639. PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma, a tumor arising from the membrane covering the lungs and the inner side of the ribs, is a cancer in which genetic alterations of genes encoding proteins that act on or are part of the Hippo-YAP1 signaling pathway are frequent. Dysfunctional Hippo signaling may result in aberrant activation of the transcriptional coactivator protein YAP1, which binds to and activates transcription factors of the TEAD family. Recent studies have associated elevated YAP1 protein activity with a poor prognosis of malignant mesothelioma and its resistance to current therapies, but its role in tumor maintenance is unclear. In this study, we investigate the dependence of malignant mesothelioma on YAP1 signaling to maintain fully established tumors in vivo. We show that downregulation of YAP1 in a dysfunctional Hippo genetic background results in the inhibition of YAP1/TEAD-dependent gene expression, the induction of apoptosis, and the inhibition of tumor cell growth in vitro. The conditional downregulation of YAP1 in established tumor xenografts leads to the inhibition of YAP1-dependent gene transcription and eventually tumor regression. This effect is only seen in the YAP1-activated MSTO-211H mesothelioma xenograft model, but not in the Hippo-independent HCT116 colon cancer xenograft model. Our data demonstrate that, in the context of a Hippo pathway mutated background, YAP1 activity alone is enough to maintain the growth of established tumors in vivo, thus validating the concept of inhibiting the activated YAP1-TEAD complex for the treatment of malignant pleural mesothelioma patients.

© 2022. The Author(s).
A novel PDX modeling strategy and its application in metabolomics study for malignant pleural mesothelioma. Z. Chen, C. Yang, Z. Guo, et al. 2021;21(1):1235. PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is a rare and aggressive carcinoma located in pleural cavity. Due to lack of effective diagnostic biomarkers and therapeutic targets in MPM, the prognosis is extremely poor. Because of difficulties in sample extraction, and the high rate of misdiagnosis, MPM is rarely studied. Therefore, novel modeling methodology is crucially needed to facilitate MPM research.

Methods: A novel patient-derived xenograft (PDX) modeling strategy was designed, which included preliminary screening of patients with pleural thickening using computerized tomography (CT) scan, further reviewing history of disease and imaging by a senior sonographer as well as histopathological analysis by a senior pathologist, and PDX model construction using ultrasound-guided pleural biopsy from MPM patients. Gas chromatography-mass spectrometry-based metabolomics was further utilized for investigating circulating metabolic features of the PDX models. Univariate and multivariate analysis, and pathway analysis were performed to explore the differential metabolites, enriched metabolism pathways and potential metabolic targets.

Results: After screening using our strategy, 5 out of 116 patients were confirmed to be MPM, and their specimens were used for modeling. Two PDX models were established successfully. Metabolomics analysis revealed significant metabolic shifts in PDX models, such as dysregulations in amino acid metabolism, TCA cycle and glycolysis, and nucleotide metabolism.

Conclusions: To sum up, we suggested a novel modeling strategy that may facilitate specimen availability for MM research, and by applying metabolomics in this model, several metabolic features were identified, whereas future studies with large sample size are needed.

© 2021. The Author(s).
Conspicuity of malignant pleural mesothelioma in contrast enhanced MDCT - arterial phase or late phase?. L. Luerken, P.L. Thurn, F. Zeman, et al. 2021;21(1):1144. PubMed · Publisher · Free full text

Abstract

Background: To determine if late phase is superior to arterial phase intraindividually regarding conspicuity of MPM in contrast enhanced chest MDCT.

Methods: 28 patients with MPM were included in this retrospective study. For all patients, chest CT in standard arterial phase (scan delay ca. 35 s) and abdominal CT in portal venous phase (scan delay ca. 70 s) was performed. First, subjective analysis of tumor conspicuity was done independently by two radiologists. Second, objective analysis was done by measuring Hounsfield units (HU) in tumor lesions and in the surrounding tissue in identical locations in both phases. Differences of absolute HUs in tumor lesions between phases and differences of contrast (HU in lesion - HU in surrounding tissue) between phases were determined. HU measurements were compared using paired t-test for related samples. Potential confounding effects by different technical and epidemiological parameters between phases were evaluated performing a multiple regression analysis.

Results: Subjective analysis: In all 28 patients and for both readers conspicuity of MPM was better on late phase compared to arterial phase. Objective analysis: MPM showed a significantly higher absolute HU in late phase (75.4 vs 56.7 HU, p < 0.001). Contrast to surrounding tissue was also significantly higher in late phase (difference of contrast between phases 18.5 HU, SD 10.6 HU, p < 0.001). Multiple regression analysis revealed contrast phase and tube voltage to be the only significant independent predictors for tumor contrast.

Conclusions: In contrast enhanced chest-MDCT for MPM late phase scanning seems to provide better conspicuity and higher contrast to surrounding tissue compared to standard arterial phase scans.

© 2021. The Author(s).
Efficacy of second-line treatment and prognostic factors in patients with advanced malignant peritoneal mesothelioma: a retrospective study. R. Kitadai, T. Shimoi, K. Sudo, et al. 2021;21(1):294. PubMed · Publisher · Free full text

Abstract

Background: Standard treatment for malignant peritoneal mesothelioma has not been established, and systemic chemotherapy is administered according to malignant pleural mesothelioma. We previously reported the efficacy of cisplatin plus pemetrexed as first-line chemotherapy; however, the efficacy of second-line chemotherapy remains unknown.

Methods: We retrospectively evaluated patients with malignant peritoneal mesothelioma who started first-line systemic chemotherapy with platinum plus pemetrexed between March 2007 and February 2019 at the National Cancer Center Hospital. Patients who received second-line chemotherapy after failure of platinum plus pemetrexed were identified. We evaluated the efficacy of first- and second-line chemotherapy, and explored the prognostic factors. Survival outcomes were estimated using the Kaplan-Meier method, and between-group differences were compared using the log-rank test. Univariate and multivariate analyses were performed using Cox proportional hazards models.

Results: A total of 54 and 26 patients received platinum plus pemetrexed as first- and second-line chemotherapy, respectively (gemcitabine in 12 patients; taxane, six; nivolumab, three; and others, five). In all patients, the median overall survival and progression-free survival after first-line chemotherapy were 16.6 and 7.3 months, respectively. Among patients who received second-line chemotherapy, the median overall survival, progression-free survival, and second-line overall survival were 16.9, 3.2, and 9.9 months, respectively. Patients who received ≥6 cycles of platinum plus pemetrexed as first-line chemotherapy had longer overall survival after second-line chemotherapy than those who did not (hazard ratio, 0.23; 95% confidence interval: 0.06-0.82; p = 0.02).

Conclusions: Second-line chemotherapy may be an option for refractory malignant peritoneal mesothelioma, especially in patients who have completed 6 cycles of platinum plus pemetrexed as first-line chemotherapy.
Incidence, mortality and survival in malignant pleural mesothelioma before and after asbestos in Denmark, Finland, Norway and Sweden. K. Hemminki, A. Försti, T. Chen, et al. 2021;21(1):1189. Historical article PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is a rare but fatal cancer, which is largely caused by exposure to asbestos. Reliable information about the incidence of MPM prior the influence of asbestos is lacking. The nationwide regional incidence trends for MPM remain poorly characterized. We use nationwide MPM data for Denmark (DK), Finland (FI), Norway (NO) and Sweden (SE) to assess incidence, mortality and survival trends for MPM in these countries.

Methods: We use the NORDCAN database for the analyses: incidence data were available from 1943 in DK, 1953 in FI and NO and 1958 in SE, through 2016. Survival data were available from 1967 through 2016. World standard population was used in age standardization.

Results: The lowest incidence that we recorded for MPM was 0.02/100,000 for NO women and 0.05/100,000 for FI men in 1953-57, marking the incidence before the influence of asbestos. The highest rate of 1.9/100,000 was recorded for DK in 1997. Female incidence was much lower than male incidence. In each country, the male incidence trend for MPM culminated, first in SE around 1990. The regional incidence trends matched with earlier asbestos-related industrial activity, shipbuilding in FI and SE, cement manufacturing and shipbuilding in DK and seafaring in NO. Relative 1-year survival increased from about 20 to 50% but 5-year survival remained at or below 10%.

Conclusion: In the Nordic countries, the male incidence trends for MPM climaxed and started to decrease, indicating that the prevention of exposure was beneficial. Survival in MPM has improved for both sexes but long-term survival remains dismal.

© 2021. The Author(s).
Integrating data from multidisciplinary Management of Malignant Pleural Mesothelioma: a cohort study. L. Saracino, C. Bortolotto, S. Tomaselli, et al. 2021;21(1):762. PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy that most commonly affects the pleural layers. MPM has a strong association with asbestos, mainly caused by exposure to its biopersistent fibers in at least 80% of cases. Individuals with a chronic exposure to asbestos might develop disease with a 20-40-year latency with few or no symptoms. Such has been the case in the Italian regions of Piedmont and Lombardy, where industrial production of materials laden with asbestos, mainly cements, has been responsible for the onset of a large epidemic. Since 2018, a multidisciplinary team at San Matteo hospital in Pavia has been collecting data on over 100 patients with MPM. The main goal of this project is to define and describe an integrated profile for each MPM case at diagnosis by using data mining and partition analysis.

Methods: Here we bring together exhaustive epidemiologic, histologic and radiologic data of 88 MPM patients that came to our observation and draw correlations with predictive and prognostic significance.

Results: The median overall survival (OS) was 15.6 months. Most patients presented with pleural effusion, irrespective of disease stage. Quite unexpectedly, no statistically significant association was demonstrated between OS and TNM disease stage at diagnosis. Although average OS is similar in male and female patients, partition analysis of data underlined a significant differential hierarchy of predictor categories based on patient gender. In females with no smoking history, full chemotherapeutic regimens are associated with better outcomes. Moreover, concerning second line treatments, vinorelbine emerged as the most advantageous choice for female patients, whereas in the male subgroup no statistically significant difference resulted between gemcitabine and vinorelbine.

Conclusion: A multidisciplinary approach to MPM is mandatory to define better therapeutic approaches, personalize the management and improve patient outcomes.
RRM1 and ERCC1 as biomarkers in patients with locally advanced and metastatic malignant pleural mesothelioma treated with continuous infusion of low-dose gemcitabine plus cisplatin. W. Muñoz-Montaño, S. Muñiz-Hernández, A. Avilés-Salas, et al. 2021;21(1):892. PubMed · Publisher · Free full text

Abstract

Background: Malignant Pleural Mesothelioma (MPM) is a rare but aggressive neoplasia that usually presents at advanced stages. Even though some advances have been achieved in the management of patients with MPM, this malignancy continuous to impose a deleterious prognosis for affected patients (12-18 months as median survival, and 5-10% 5-year survival rate), accordingly, the recognition of biomarkers that allow us to select the most appropriate therapy are necessary.

Methods: Immunohistochemistry semi-quantitative analysis was performed to evaluate four different biomarkers (ERCC1, RRM1, RRM2, and hENT-1) with the intent to explore if any of them was useful to predict response to treatment with continuous infusion gemcitabine plus cisplatin. Tissue biopsies from patients with locally advanced or metastatic MPM were analyzed to quantitatively asses the aforementioned biomarkers. Every included patient received treatment with low-dose gemcitabine (250 mg/m2) in a 6-h continuous infusion plus cisplatin 35 mg/m2 on days 1 and 8 every 3 weeks as first-line therapy.

Results: From the 70 eligible patients, the mean and standard deviation (SD) for ERCC1, RRM1, RRM2 and hENT-1 were 286,178.3 (± 219, 019.8); 104,647.1 (± 65, 773.4); 4536.5 (± 5, 521.3); and 2458.7 (± 4, 983.4), respectively. Patients with high expression of RRM1 had an increased median PFS compared with those with lower expression (9.5 vs 4.8 months, p = < 0.001). Furthermore, high expression of RRM1 and ERCC1 were associated with an increased median OS compared with their lower expression counterparts; [(23.1 vs 7.2 months for RRM1 p = < 0.001) and (17.4 vs 9.8 months for ERCC1 p = 0.018)].

Conclusions: ERCC1 and RRM1 are useful biomarkers that predict better survival outcomes in patients with advanced MPM treated with continuous infusion of gemcitabine plus cisplatin.

© 2021. The Author(s).
Systemic characterization of alternative splicing related to prognosis and immune infiltration in malignant mesothelioma. J. Lai, H. Yang, T. Xu. 2021;21(1):848. PubMed · Publisher · Free full text

Abstract

Background: Malignant mesothelioma (MM) is a relatively rare and highly lethal tumor with few treatment options. Thus, it is important to identify prognostic markers that can help clinicians diagnose mesothelioma earlier and assess disease activity more accurately. Alternative splicing (AS) events have been recognized as critical signatures for tumor diagnosis and treatment in multiple cancers, including MM.

Methods: We systematically examined the AS events and clinical information of 83 MM samples from TCGA database. Univariate Cox regression analysis was used to identify AS events associated with overall survival. LASSO analyses followed by multivariate Cox regression analyses were conducted to construct the prognostic signatures and assess the accuracy of these prognostic signatures by receiver operating characteristic (ROC) curve and Kaplan-Meier survival analyses. The ImmuCellAI and ssGSEA algorithms were used to assess the degrees of immune cell infiltration in MM samples. The survival-related splicing regulatory network was established based on the correlation between survival-related AS events and splicing factors (SFs).

Results: A total of 3976 AS events associated with overall survival were identified by univariate Cox regression analysis, and ES events accounted for the greatest proportion. We constructed prognostic signatures based on survival-related AS events. The prognostic signatures proved to be an efficient predictor with an area under the curve (AUC) greater than 0.9. Additionally, the risk score based on 6 key AS events proved to be an independent prognostic factor, and a nomogram composed of 6 key AS events was established. We found that the risk score was significantly decreased in patients with the epithelioid subtype. In addition, unsupervised clustering clearly showed that the risk score was associated with immune cell infiltration. The abundances of cytotoxic T (Tc) cells, natural killer (NK) cells and T-helper 17 (Th17) cells were higher in the high-risk group, whereas the abundances of induced regulatory T (iTreg) cells were lower in the high-risk group. Finally, we identified 3 SFs (HSPB1, INTS1 and LUC7L2) that were significantly associated with MM patient survival and then constructed a regulatory network between the 3 SFs and survival-related AS to reveal potential regulatory mechanisms in MM.

Conclusion: Our study provided a prognostic signature based on 6 key events, representing a better effective tumor-specific diagnostic and prognostic marker than the TNM staging system. AS events that are correlated with the immune system may be potential therapeutic targets for MM.

© 2021. The Author(s).
AHRR methylation in heavy smokers: associations with smoking, lung cancer risk, and lung cancer mortality. L. Grieshober, S. Graw, M.J. Barnett, et al. 2020;20(1):905. PubMed · Publisher · Free full text

Abstract

Background: A low level of methylation at cg05575921 in the aryl-hydrocarbon receptor repressor (AHRR) gene is robustly associated with smoking, and some studies have observed associations between cg05575921 methylation and increased lung cancer risk and mortality. To prospectively examine whether decreased methylation at cg05575921 may identify high risk subpopulations for lung cancer screening among heavy smokers, and mortality in cases, we evaluated associations between cg05575921 methylation and lung cancer risk and mortality, by histotype, in heavy smokers.

Methods: The β-Carotene and Retinol Efficacy Trial (CARET) included enrollees ages 45-69 with ≥ 20 pack-year smoking histories and/or occupational asbestos exposure. A subset of CARET participants had cg05575921 methylation available from HumanMethylationEPIC assays of blood collected on average 4.3 years prior to lung cancer diagnosis in cases. Cg05575921 methylation β-values were treated continuously for a 10% methylation decrease and as quintiles, where quintile 1 (Q1, referent) represents high methylation and Q5, low methylation. We used conditional logistic regression models to examine lung cancer risk overall and by histotype in a nested case-control study including 316 lung cancer cases (diagnosed through 2005) and 316 lung cancer-free controls matched on age (±5 years), sex, race/ethnicity, enrollment year, current/former smoking, asbestos exposure, and follow-up time. Mortality analyses included 372 lung cancer cases diagnosed between 1985 and 2013 with available methylation data. We used Cox proportional hazards models to examine mortality overall and by histotype.

Results: Decreased cg05575921 methylation was strongly associated with smoking, even in our population of heavy smokers. We did not observe associations between decreased pre-diagnosis cg05575921 methylation and increased lung cancer risk, overall or by histotype. We observed linear increasing trends for lung cancer-specific mortality across decreasing cg05575921 methylation quintiles for adenocarcinoma and small cell carcinoma (P-trends = 0.01 and 0.04, respectively).

Conclusions: In our study of heavy smokers, decreased cg05575921 methylation was strongly associated with smoking but not increased lung cancer risk. The observed association between cg05575921 methylation and increased mortality in adenocarcinoma and small cell histotypes requires further examination. Our results do not support using decreased cg05575921 methylation as a biomarker for lung cancer screening risk stratification.
Malignant mesothelioma of the tunica vaginalis testis: a rare case and review of literature. M. Drevinskaite, A. Patasius, L. Kevlicius, et al. 2020;20(1):162. Case report · Review PubMed · Publisher · Free full text

Abstract

Background: Malignant mesothelioma of the tunica vaginalis is a rare tumour which comprises less than 1% of all mesotheliomas.

Case Presentation: 69-years old patient with painful hard mass and hydrocele in the right scrotum to whom a right hydrocelectomy was performed. Any history of scrotal trauma or exposure to asbestos was not present. Excisional biopsy revealed a multinodular tumour with focal areas of necrosis and infiltrative growth. According to morphological and immunohistochemical findings, diagnosis of malignant biphasic mesothelioma of the tunica vaginalis testis was made. Two months after hydrocelectomy, right inguinal orchidectomy was performed. Post-surgical whole body CT scan revealed paraaortic and pararenal lymphadenopathy, likely to be metastatic. Adjuvant treatment with 6 cycles of cisplatin and pemetrexed was applied. After 3 cycles of chemotherapy, CT scan showed progression and the treatment was changed to gemcitabine 1 month after.

Conclusions: Although malignant mesothelioma of the tunica vaginalis is a rare malignancy, it poses a diagnostic challenge which can mimic common inguinal or scrotal diseases such as hydrocele. Despite aggressive surgical procedures or adjuvant therapies, the prognosis remains poor.
Radiological evaluation of malignant pleural mesothelioma - defining distant metastatic disease. D.C. Collins, R. Sundar, A. Constantinidou, et al. 2020;20(1):1210. PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is traditionally characterized by local destructive spread of the pleura and surrounding tissues. Patient outcomes in MPM with distant metastatic dissemination are lacking.

Methods: In this retrospective study, we reviewed a cohort of 164 MPM patients referred to a Phase I trials unit, aiming to describe identified metastatic sites, and correlate with clinical outcomes.

Results: 67% of patients were diagnosed with distant metastatic disease with a high incidence of bone (19%), visceral (14%), contralateral lung (35%) and peritoneal metastases (22%). Peritoneal metastases were more likely in epithelioid versus biphasic/ sarcomatoid MPM (p = 0.015). Overall survival was 23.8 months with no statistical difference in survival between those with distant metastases and those without.

Conclusions: This report highlights the frequency of distant metastases and encourages further radiological investigations in the presence of symptoms. In particular, given the relatively high incidence of bone metastases, bone imaging should be considered in advanced MPM clinical workflow and trial protocols. The presence of distant metastases does not appear to have prognostic implications under existing treatment paradigms. This cohort of MPM patients gives an indication of patterns of metastatic spread that are likely to become prevalent as prognosis improves with emerging treatment paradigms.
Silica and asbestos exposure at work and the risk of bladder cancer in Canadian men: a population-based case-control study. L. Latifovic, P.J. Villeneuve, M.É. Parent, et al. 2020;20(1):171. PubMed · Publisher · Free full text

Abstract

Background: Silica and asbestos are recognized lung carcinogens. However, their role in carcinogenesis at other organs is less clear. Clearance of inhaled silica particles and asbestos fibers from the lungs may lead to translocation to sites such as the bladder where they may initiate carcinogenesis. We used data from a Canadian population-based case-control study to evaluate the associations between these workplace exposures and bladder cancer.

Methods: Data from a population-based case-control study were used to characterize associations between workplace exposure to silica and asbestos and bladder cancer among men. Bladder cancer cases (N = 658) and age-frequency matched controls (N = 1360) were recruited within the National Enhanced Cancer Surveillance System from eight Canadian provinces (1994-97). Exposure concentration, frequency and reliability for silica and asbestos were assigned to each job, based on lifetime occupational histories, using a combination of job-exposure profiles and expert review. Exposure was modeled as ever/never, highest attained concentration, duration (years), highest attained frequency (% worktime) and cumulative exposure. Odds ratios (OR) and their 95% confidence intervals (CI) were estimated using adjusted logistic regression.

Results: A modest (approximately 20%) increase in bladder cancer risk was found for ever having been exposed to silica, highest attained concentration and frequency of exposure but this increase was not statistically significant. Relative to unexposed, the odds of bladder cancer were 1.41 (95%CI: 1.01-1.98) times higher among men exposed to silica at work for ≥27 years. For asbestos, relative to unexposed, an increased risk of bladder cancer was observed for those first exposed ≥20 years ago (OR:2.04, 95%CI:1.25-3.34), those with a frequency of exposure of 5-30% of worktime (OR:1.45, 95%CI:1.06-1.98), and for those with < 10 years of exposure at low concentrations (OR:1.75, 95%CI:1.10-2.77) and the lower tertile of cumulative exposure (OR:1.69, 95%CI:1.07-2.65). However, no clear exposure-response relationships emerged.

Conclusions: Our results indicate a slight increase in risk of bladder cancer with exposure to silica and asbestos, suggesting that the effects of these agents are broader than currently recognized. The findings from this study inform evidence-based action to enhance cancer prevention efforts, particularly for workers in industries with regular exposure.

2010s

BAP1 tumor predisposition syndrome case report: pathological and clinical aspects of BAP1-inactivated melanocytic tumors (BIMTs), including dermoscopy and confocal microscopy. B.C. Soares de Sá, M.P. de Macedo, G.T. Torrezan, et al. 2019;19(1):1077. Case report PubMed · Publisher · Free full text

Abstract

Background: BRCA1 associated-protein 1 (BAP1) tumor predisposition syndrome is associated with an increased risk for malignant mesotheliomas, uveal and cutaneous melanomas, renal cell carcinomas, and singular cutaneous lesions. The latter are referred to as BAP1-inactivated melanocytic tumors (BIMTs). When multiple BIMTs manifest, they are considered potential markers of germline BAP1 mutations.

Case Presentation: Here, we report a novel pathogenic BAP1 germline variant in a family with a history of BIMTs, cutaneous melanomas, and mesotheliomas. We also describe singular pathological aspects of the patient's BIMT lesions and their correlation with dermoscopic and reflectance confocal microscopy findings.

Conclusions: This knowledge is crucial for the recognition of BIMTs by dermatologists and pathologists, allowing the determination of appropriate management for high-risk patients, such as genetic investigations and screening for potentially aggressive tumors.
CDKN2A copy number and p16 expression in malignant pleural mesothelioma in relation to asbestos exposure. E. Kettunen, S. Savukoski, K. Salmenkivi, et al. 2019;19(1):507. PubMed · Publisher · Free full text

Abstract

Background: Deletion of the CDKN2A locus is centrally involved in the development of several malignancies. In malignant pleural mesothelioma (MPM), it is one of the most frequently reported genomic alteration. MPM is strongly associated with a patients' asbestos exposure. However, the status of CDKN2A and the expression of the corresponding protein, p16, in relation to MPM patient's asbestos exposure is poorly known. Copy number alterations in 2p16, 9q33.1 and 19p13 have earlier been shown to accumulate in lung cancer in relation to asbestos exposure but their status in MPM is unclear.

Methods: We studied DNA copy numbers for CDKN2A using fluorescence in situ hybridization (FISH) and p16 expression by immunohistochemistry (IHC) in 92 MPM patients, 75 of which with known asbestos exposure status. We also studied, in MPM, copy number alterations in 2p16, 9q33.1 and 19p13 by FISH.

Results: We were unable to detect an association between p16 expression and pulmonary asbestos fiber count in MPM tumor cells. However, significantly more MPM patients with high pulmonary asbestos fiber count (> 1 million fibers per gram [f/g]) had stromal p16 immunoreactivity than MPM of patients with low exposure (≤ 0.5 million f/g) (51.4% vs 16.7%; p = 0.035, Chi-Square). We found that an abnormal copy number of CDKN2A in MPM tumor cells associated with a high pulmonary asbestos fiber count (p = 0.044, Fisher's Exact test, two-tailed). In contrast to our earlier findings in asbestos associated lung cancer, DNA copy number changes in 2p16, 9q33 and 19p13 were not frequent in MPM although single cases with variable copy numbers on those regions were seen.

Conclusions: We found two instances where the gene locus CDKN2A or its corresponding protein expression, is associated with high asbestos exposure levels. This suggests that there may be biological differences between the mesotheliomas with high pulmonary asbestos fiber count and those with low fiber count.
Correlation of prechemotherapy urinary megalin ectodomain (A-megalin) levels with the development of cisplatin-induced nephrotoxicity: a prospective observational study. S. Shoji, M. Hosojima, H. Kabasawa, et al. 2019;19(1):1170. PubMed · Publisher · Free full text

Abstract

Background: Cisplatin is a potent chemotherapeutic agent used to treat a variety of solid tumors. One of the major side effects of cisplatin is dose-limiting nephrotoxicity. We recently demonstrated that the renal uptake of cisplatin and resultant cisplatin-induced nephrotoxicity are mediated in part by megalin, an endocytic receptor in proximal tubule epithelial cells (PTECs). We also developed sandwich enzyme-linked immunosorbent assays to measure the megalin ectodomain (A-megalin) and full-length megalin (C-megalin) in urine using monoclonal antibodies against the amino- and carboxyl-termini of megalin, respectively. The present study examined the correlation of urinary megalin level with cisplatin-induced nephrotoxicity and its utility as a biomarker in patients with thoracic cancer.

Methods: This prospective observational study involved 45 chemotherapy-naïve patients scheduled to receive chemotherapy with ≥60 mg/m2 cisplatin for histologically diagnosed small cell lung cancer, non-small cell lung cancer, or malignant pleural mesothelioma. Before and after the first course of chemotherapy, we measured urinary A- and C-megalin and other markers of PTEC injury, such as N-acetyl-β-D-glucosaminidase, α1-microglobulin, β2-microglobulin, neutrophil gelatinase-associated lipocalin, and liver-type fatty acid-binding protein, and compared the values with the change in the estimated glomerular filtration rate (eGFR) and clinical risk factors for renal impairment.

Results: A negative correlation was found between baseline urinary A-megalin levels and change in eGFR (r = - 0.458, P = 0.002). According to Kaplan-Meier survival curves, eGFR decline was associated with the baseline urinary A-megalin quartile (P = 0.038). In addition, according to the hazard ratios (HRs) for eGFR decline > 10 mL/min/1.73 m2 calculated using a Cox proportional hazard model, the highest quartile had a significantly higher risk of eGFR decline compared with the lowest quartile (HR 7.243; 95% confidence interval 1.545-33.962). Other baseline urinary markers showed no correlation with eGFR decline.

Conclusions: This is the first report demonstrating that prechemotherapy urinary A-megalin levels are correlated with the development of cisplatin-induced nephrotoxicity. This finding has clinical implications for the identification of patients at risk for cisplatin-induced nephrotoxicity and the development of possible prophylactic therapies.
Gene expression profiling of homologous recombination repair pathway indicates susceptibility for olaparib treatment in malignant pleural mesothelioma in vitro. S. Borchert, M. Wessolly, J. Schmeller, et al. 2019;19(1):108. PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is a tumour arising from pleural cavities with poor prognosis. Multimodality treatment with pemetrexed combined with cisplatin shows unsatisfying response-rates of 40%. The reasons for the rather poor efficacy of chemotherapeutic treatment are largely unknown. However, it is conceivable that DNA repair mechanisms lead to an impaired therapy response. We hypothesize a major role of homologous recombination (HR) for genome stability and survival of this tumour. Therefore, we analysed genes compiled under the term "BRCAness". An inhibition of this pathway with olaparib might abrogate this effect and induce apoptosis.

Methods: We investigated the response of three MPM cell lines and lung fibroblasts serving as a control to treatment with pemetrexed, cisplatin and olaparib. Furthermore, we aimed to find possible correlations between response and gene expression patterns associated with BRCAness phenotype. Therefore, 91 clinical MPM samples were digitally screened for gene expression patterns of HR members.

Results: A BRCAness-dependent increase of apoptosis and senescence during olaparib-based treatment of BRCA-associated-protein 1 (BAP1)-mutated cell lines was observed. The gene expression pattern identified could be found in approx. 10% of patient samples. Against this background, patients could be grouped according to their defects in the HR system. Gene expression levels of Aurora Kinase A (AURKA), RAD50 as well as DNA damage-binding protein 2 (DDB2) could be identified as prognostic markers in MPM.

Conclusions: Defects in HR compiled under the term BRCAness are a common event in MPM. The present data can lead to a better understanding of the underlaying cellular mechanisms and leave the door wide open for new therapeutic approaches for this severe disease with infaust prognosis. Response to Poly (ADP-ribose)-Polymerase (PARP)-Inhibition could be demonstrated in the BAP1-mutated NCI-H2452 cells, especially when combined with cisplatin. Thus, this combination therapy might be effective for up to 2/3 of patients, promising to enhance patients' clinical management and outcome.
Physician requests by patients with malignant pleural mesothelioma in Japan. Y. Nagamatsu, I. Oze, K. Aoe, et al. 2019;19(1):383. PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is a fatal and rare disease that is caused by the inhalation of asbestos. Treatment and care requests made by MPM patients to their physicians were collected and analyzed.

Methods: This cross-sectional survey was part of a larger study (N = 133) regarding the quality of life of MPM patients. Specific responses to two open-ended questions related to patients' requests regarding treatment and care were quantified, analyzed and divided into categories based on content.

Results: Responses (N = 217) from MPM patients (N = 73) were categorized into 24 subcategories and then abstracted into 6 categories. The majority of requests were related to patient-physician communication. Patients wanted clear and understandable explanations about MPM and wanted their physician to deliver treatment based on the patient's perspective by accepting and empathizing with their anxiety and pain. Patients expected physicians to be dedicated to their care and establish an improved medical support system for MPM patients.

Conclusion: Patients with MPM had a variety of unmet needs from their physicians. Physicians who provide care to MPM patients should receive training in both communication skills and stress management. A multidisciplinary care system that includes respiratory and palliative care for MPM patients should be established.
Serum levels of the chemokine CCL2 are elevated in malignant pleural mesothelioma patients. T. Kishimoto, N. Fujimoto, T. Ebara, et al. 2019;19(1):1204. PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is a debilitating disease of the pleural cavity. It is primarily associated with previous inhalation of asbestos fibers. These fibers initiate an oxidant coupled inflammatory response. Repeated exposure to asbestos fibers results in a prolonged inflammatory response and cycles of tissue damage and repair. The inflammation-associated cycles of tissue damage and repair are intimately involved in the development of asbestos-associated cancers. Macrophages are a key component of asbestos-associated inflammation and play essential roles in the etiology of a variety of cancers. Macrophages are also a source of C-C motif chemokine ligand 2 (CCL2), and a variety of tumor-types express CCL2. High levels of CCL2 are present in the pleural effusions of mesothelioma patients, however, CCL2 has not been examined in the serum of mesothelioma patients.

Methods: The present study was carried out with 50 MPM patients and 356 subjects who were possibly exposed to asbestos but did not have disease symptoms and 41 healthy volunteers without a history of exposure to asbestos. The levels of CCL2 in the serum of the study participants was determined using ELISA.

Results: Levels of CCL2 were significantly elevated in the serum of patients with advanced MPM.

Conclusions: Our findings are consistent with the premise that the CCL2/CCR2 axis and myeloid-derived cells play an important role in MPM and disease progression. Therapies are being developed that target CCL2/CCR2 and tumor resident myeloid cells, and clinical trials are being pursued that use these therapies as part of the treatment regimen. The results of trials with patients with a similar serum CCL2 pattern as MPM patients will have important implications for the treatment of MPM.
A prospective study to investigate the role of serial serum mesothelin in monitoring mesothelioma. D. de Fonseka, D.T. Arnold, L. Stadon, et al. 2018;18(1):199. PubMed · Publisher · Free full text

Abstract

Background: Radiological monitoring of malignant pleural mesothelioma (MPM) using modified RECIST criteria is limited by low sensitivity and inter-observer variability. Serial serum mesothelin measurement has shown utility in the assessment of treatment response during chemotherapy but has never been assessed in the longer term follow up of patients.

Methods: This is a single centre study of consecutive patients diagnosed with MPM who received chemotherapy or best supportive care (BSC). Serum mesothelin measurements with paired 6 monthly CT scans were performed following the completion of chemotherapy, or from baseline in the BSC group. Changes in mesothelin were correlated with radiological progression and overall survival.

Results: Forty-one patients with MPM were recruited and followed up for a minimum of 12 months (range 12-21 months). The majority of patients (n = 23) received chemotherapy with pemetrexed and cisplatin. Across the cohort a 10% rise in serum mesothelin could predict radiological progression with a sensitivity of 96% (IQR; 79-100) and specificity of 74% (IQR; 50-91). Sensitivity fell to 80% in sarcomatoid only disease. Patients with a rising mesothelin at 6 months had significantly worse overall survival (175 days) compared to stable/falling levels (448 days) (p = 0.003).

Conclusions: This is the first study to assess serum mesothelin's ability to detect progression of MPM following chemotherapy or during BSC. A 10% rise in serum mesothelin level showed excellent sensitivity at predicting progressive disease. Mesothelin measurement has several advantages over serial CT imaging including reducing hospital visits and cost.
Comparison of Germline versus Somatic BAP1 Mutations for Risk of Metastasis in Uveal Melanoma. K.G. Ewens, E. Lalonde, J. Richards-Yutz, et al. 2018;18(1):1172. PubMed · Publisher · Free full text

Abstract

Background: Germline mutations in BAP1 have been associated with BAP1-Tumor Predisposition Syndrome (BAP1-TPDS), a predisposition to multiple tumors within a family that includes uveal melanoma (UM), cutaneous melanoma, malignant mesothelioma and renal cell carcinoma. Alternatively, somatic mutations in BAP1 in UM have been associated with high risk for metastasis. In this study, we compare the risk of metastasis in UM that carry germline versus somatic BAP1 mutations and mutation-negative tumors.

Methods: DNA extracted from 142 UM and matched blood samples was sequenced using Sanger or next generation sequencing to identify BAP1 gene mutations.

Results: Eleven of 142 UM (8%) carried germline BAP1 mutations, 43 (30%) had somatic mutations, and 88 (62%) were mutation-negative. All BAP1 mutations identified in blood samples were also present in the matched UM. There were 52 unique mutations in 54 tumors. All were pathogenic or likely pathogenic. A comparison of tumors carrying somatic vs. germline mutations, or no mutations, showed a higher frequency of metastasis in tumors carrying somatic mutations: 74% vs. 36%, P=0.03 and 74% vs. 26% P<0.001, respectively. Tumors with a somatic mutation compared to mutation-negative had an older age of diagnosis of (61.8 vs. 52.2 years, P=0.002), and shorter time to metastasis (16 vs. 26 months, P=0.04). Kaplan-Meier analysis further showed that tumors with somatic (vs. germline) mutations demonstrated a greater metastatic risk (P=0.03). Cox multivariate analysis showed in addition to chromosome-3 monosomy and larger tumor diameter, the presence of BAP1 somatic, but not germline mutations, was significantly associated with risk of metastasis(P=0.02). Personal or family history of BAP1-TPDS was available for 79 of the cases. All eight cases with germline mutations reported a history of BAP1-TPDS, which was significantly greater than what was observed in cases with somatic mutations (10 of 23, P=0.009) or mutation-negative cases (11 of 48, P<0.001).

Conclusions: Defining germline vs. somatic nature of BAP1 mutations in UM can inform the individual about both the risk of metastasis, and the time to metastasis, which are critically important outcomes for the individual. This information can also change the cascade screening and surveillance of family members.
Hypoxia promotes acquisition of aggressive phenotypes in human malignant mesothelioma. M.C. Kim, S.H. Hwang, N.Y. Kim, et al. 2018;18(1):819. PubMed · Publisher · Free full text

Abstract

Background: Hypoxia is a hallmark of the solid tumor microenvironment and is associated with poor outcomes in cancer patients. The present study was performed to investigate mechanisms underlying the hypoxia-induced phenotypic changes using human malignant mesothelioma (HMM) cells.

Methods: Hypoxic conditions were achieved by incubating HMM cells in the air chamber. The effect of hypoxia on phenotype changes in HMM cells was investigated by performing in vitro clonogenicity, drug resistance, migration, and invasion assays. Signaling pathways and molecules involved in the more aggressive behaviors of HMM cells under hypoxia were investigated. A two-tailed unpaired Student's t-test or one-way ANOVA with Bonferroni post-test correction was used in this study.

Results: Hypoxic conditions upregulated hypoxia-inducible factor 1 alpha (HIF-1α) and HIF-2α in parallel with the upregulation of its target, Glut-1, in HMM cells. In vitro clonogenicity of HMM cells was significantly increased in hypoxic conditions, but the proliferation of cells at a high density in hypoxia was lower than that in normoxic conditions. The expression levels of HIF-2α and Oct4 were increased in hypoxic HMM cells. The percentage of cells with high CD44 expression was significantly higher in HMM cells cultured in hypoxia than those cultured in normoxia. Hypoxia significantly enhanced the resistance of HMM cells to cisplatin, which occurred through cytoprotection against cisplatin-induced apoptosis. While cisplatin treatment decreased the ratio of Bcl-2 to Bax in normoxic condition, hypoxia conversely increased the ratio in HMM cells treated with cisplatin. Hypoxia increased the mobility and invasiveness of HMM cells. Epithelial to mesenchymal transition was promoted, which was indicated by the repression of E-cadherin and the concomitant increase of vimentin in HMM cells.

Conclusions: The data illustrated that hypoxic conditions augmented the aggressive phenotypes of HMM cells at the biological and molecular levels. The present study provides valuable background information beginning to understand aggressiveness of HMM in tumor microenvironments, suggesting that a control measure for tumor hypoxia may be an effective therapeutic strategy to reduce the aggressiveness of cancer cells in HMM patients.
Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) for the treatment of malignant mesothelioma. U. Giger-Pabst, C. Demtröder, T.A. Falkenstein, et al. 2018;18(1):442. PubMed · Publisher · Free full text

Abstract

Background: Patients with recurrent malignant epithelioid mesothelioma (MM) after surgery and standard chemotherapy with cisplatin and pemetrexed have limited treatment options.

Methods: We performed a retrospective cohort study of patients with recurrent MM undergoing Pressurized IntraPeritoneal/Thoracal Aerosol Chemotherapy (PIPAC/PITAC) with doxorubicin 1.5 mg/m2 and cisplatin 7.5 mg/m2. Data were retrospectively collected in a prospective registry of patients undergoing PIPAC/PITAC. Study outcomes were microscopic tumor regression grade (TRG), survival and adverse events (v4.0 CTCAE).

Results: A total of 29 patients (m/f = 17/12) with MM with a mean age of 62.4 (range: 42 to 84) years were analyzed. A total of 74 PIPAC and 5 PITAC procedures were performed. The mean number of PIPAC applications was 2.5 (range: 0 to 10) per patient. Twenty patients (69%) had > 2 PIPAC procedure and were eligible for TRG analysis. TRG 1 to 4 was observed in 75% (15/20) of patients. Major regression (TRG 3) or complete regression (TRG 4) was observed in 20% and 10%, respectively. PIPAC induced significant tumor regression in 51.7% (15/29) of patients with a cumulative effect after repetitive PIPACs (PIPAC #1 vs. PIPAC #2: p = 0.001; PIPAC #1 vs. PIPAC #3: p = 0.001; PIPAC #1 vs. PIPAC #4: p = 0.001). Postoperative CTCAE grade 4 complications were observed in two patients (6.9%) who had cytoreductive surgery (CC2) and intraoperative PIPAC. One patient (3.4%) died due to postoperative kidney insufficiency. After a follow up of 14.4 (95% CI: 8.1 to 20.7) months after the last PIPAC/PITAC application, median overall survival was 26.6 (95% CI: 9.5 to 43.7) months (from the first application).

Conclusion: After prior abdominal surgery and systemic chemotherapy, repetitive PIPAC applications are feasible and safe for patients with end-stage MM. Furthermore, PIPAC induces significant histological regression of malignant mesothelioma in the majority of patients. PITAC is feasible, but its safety and efficacy to control malignant pleural effusion remain unclear.
Putative cancer stem cells may be the key target to inhibit cancer cell repopulation between the intervals of chemoradiation in murine mesothelioma. L. Wu, W. Blum, C.Q. Zhu, et al. 2018;18(1):471. PubMed · Publisher · Free full text

Abstract

Background: Cancer cell repopulation during chemotherapy or radiotherapy is a major factor limiting the efficacy of treatment. Cancer stem cells (CSC) may play critical roles during this process. We aim to demonstrate the role of mesothelioma stem cells (MSC) in treatment failure and eventually to design specific target therapies against MSC to improve the efficacy of treatment in malignant mesothelioma.

Methods: Murine mesothelioma AB12 and RN5 cells were used to compare tumorigenicity in mice. The expression of CSC-associated genes was evaluated by quantitative real-time PCR in both cell lines treated with chemo-radiation. Stemness properties of MSC-enriched RN5-EOS-Puro2 cells were characterized with flow cytometry and immunostaining. A MSC-specific gene profile was screened by microarray assay and confirmed thereafter. Gene Ontology analysis of the selected genes was performed by GOMiner.

Results: Tumor growth delay of murine mesothelioma AB12 cells was achieved after each cycle of cisplatin treatment, however, tumors grew back rapidly due to cancer cell repopulation between courses of chemotherapy. Strikingly, a 10-times lower number of irradiated cells in both cell lines led to a similar tumor incidence and growth rate as with untreated cells. The expression of CSC-associated genes such as CD24, CD133, CD90 and uPAR was dramatically up-regulated, while others did not change significantly after chemoradiation. Highly enriched MSC after selection with puromycin displayed an increasing GFP-positive population and showed typical properties of stemness. Comparatively, the proportion of MSC significantly increased after RN5-EOS parental cells were treated with either chemotherapy, γ-ray radiation, or a combination of the two, while MSC showed more resistance to the above treatments. A group of identified genes are most likely MSC-specific, and major pathways related to regulation of cell growth or apoptosis are involved. Upregulation of the gene transcripts Tnfsf18, Serpinb9b, Ly6a, and Nppb were confirmed.

Conclusion: Putative MSC possess the property of stemness showing more resistance to chemoradiation, suggesting that MSC may play critical roles in cancer cell repopulation. Further identification of selected genes may be used to design novel target therapies against MSC, so as to eliminate cancer cell repopulation in mesothelioma.
Quality of life of survivors of malignant pleural mesothelioma in Japan: a cross sectional study. Y. Nagamatsu, I. Oze, K. Aoe, et al. 2018;18(1):350. PubMed · Publisher · Free full text

Abstract

Background: Previous studies have indicated that people with malignant pleural mesothelioma (MPM) have a poor quality of life (QOL); however, information about the QOL of people with MPM in Japan is anecdotal. The aims of this study were to investigate the QOL of survivors of MPM in Japan and to determine the factors that correlate with their QOL.

Methods: This was a cross sectional study. The included patients were those diagnosed with MPM in Japan. We created a self-administered questionnaire consisting of 64 questions. The questionnaires were sent to hospitals and patient advocacy groups, distributed to the patients, completed, and sent back to the researchers by postal mail. QOL was assessed with the European Organization for Research and Treatment of Cancer 16 questionnaire (QLQ) and the short version of the core domains of the Comprehensive Quality of Life Outcome questionnaire (CoQoLo).

Results: In total, 133 questionnaires were collected. The QLQ assessments demonstrated that the survivors of MPM most frequently complained of fatigue, pain, sleep disturbances, and dyspnea. The symptom scales were acceptable, but the functional scales were significantly poorer for the patients with poor performance statuses (PSs). The short CoQoLo assessment was very unfavorable for 'Being free from physical pain.' Being a long-term survivor and a survivor with a poor PS were significantly correlated with poor global health status.

Conclusions: Survivors of MPM have impaired function, a variety of symptoms, and lower QOL. Survivors of MPM, even those in good physical condition, need broad support.
Real-life feasibility of home-based pulmonary rehabilitation in chemotherapy-treated patients with thoracic cancers: a pilot study. C. Olivier, J.M. Grosbois, A.B. Cortot, et al. 2018;18(1):178. PubMed · Publisher · Free full text

Abstract

Background: Patients with advanced lung cancer (LC) or malignant pleural mesothelioma (MPM) exhibit limitation of exercise capacities and alteration of quality of life (QoL) induced by cancer and its treatment. Few studies assessed pulmonary rehabilitation (PR) in these chemotherapy-treated patients, and none evaluated a home-based PR program.

Methods: In this prospective uncontrolled observational pilot study, patients treated by chemotherapy for LC or MPM were screened for a home-based PR program combining exercise training with global cares including therapeutic education and psychosocial management. Feasibility and safety were evaluated by attendance and adherence to PR program. Various exercise tolerance tests, including 6-min walk test (6MWT) and 6-min stepper test (6MST), were performed before and after PR associated with, QoL and psychological assessment (VSRQ and HAD, respectively).

Results: 243 patients were considered eligible but only 71 (60.6 ± 8.8 years) started a PR and 47 completed the program. Refusals to participate were mostly related to lack of motivation whereas withdrawals to PR were related to cancer-related medical issues. No adverse event related to PR was observed. Baseline 6MWT distance was associated with performance status (r = - 0.45, p = 0.001) and mMRC dyspnea scale (r = - 0.49, p < 0.001) but not with lung cancer stage. Post-PR reassessment showed 6MWT stability and 6MST improvement in patients who completed the program. Daily physical activity (p = 0.007) and anxiety (p = 0.02) scores were significantly improved.

Conclusions: Home-based PR was feasible and safe in patients with advanced LC or MPM. Exercise capacities stability in patients who completed the PR program suggests that PR might be beneficial. Further studies are warranted to confirm and to improve the potential value of PR in these patients.
Regulation of calretinin in malignant mesothelioma is mediated by septin 7 binding to the CALB2 promoter. W. Blum, L. Pecze, J.W. Rodriguez, et al. 2018;18(1):475. PubMed · Publisher · Free full text

Abstract

Background: The calcium-binding protein calretinin (gene name: CALB2) is currently considered as the most sensitive and specific marker for the diagnosis of malignant mesothelioma (MM). MM is a very aggressive tumor strongly linked to asbestos exposure and with no existing cure so far. The mechanisms of calretinin regulation, as well as its distinct function in MM are still poorly understood.

Methods: We searched for transcription factors binding to the CALB2 promoter and modulating calretinin expression. For this, DNA-binding assays followed by peptide shotgun-mass spectroscopy analyses were used. CALB2 promoter activity was assessed by dual-luciferase reporter assays. Furthermore, we analyzed the effects of CALB2 promoter-binding proteins by lentiviral-mediated overexpression or down-regulation of identified proteins in MM cells. The modulation of expression of such proteins by butyrate was determined by subsequent Western blot analysis. Immunohistochemical analysis of embryonic mouse lung tissue served to verify the simultaneous co-expression of calretinin and proteins interacting with the CALB2 promoter during early development. Finally, direct interactions of calretinin with target proteins were evidenced by co-immunoprecipitation experiments.

Results: Septin 7 was identified as a butyrate-dependent transcription factor binding to a CALB2 promoter region containing butyrate-responsive elements (BRE) resulting in decreased calretinin expression. Accordingly, septin 7 overexpression decreased calretinin expression levels in MM cells. The regulation was found to operate bi-directionally, i.e. calretinin overexpression also decreased septin 7 levels. During murine embryonic development calretinin and septin 7 were found to be co-expressed in embryonic mesenchyme and undifferentiated mesothelial cells. In MM cells, calretinin and septin 7 colocalized during cytokinesis in distinct regions of the cleavage furrow and in the midbody region of mitotic cells. Co-immunoprecipitation experiments revealed this co-localization to be the result of a direct interaction between calretinin and septin 7.

Conclusions: Our results demonstrate septin 7 not only serving as a "cytoskeletal" protein, but also as a transcription factor repressing calretinin expression. The negative regulation of calretinin by septin 7 and vice versa sheds new light on mechanisms possibly implicated in MM formation and identifies these proteins as transcriptional regulators and putative targets for MM therapy.
Satisfactory results of a psychometric analysis and calculation of minimal clinically important differences of the World Health Organization quality of life-BREF questionnaire in an observational cohort study with lung cancer and mesothelioma patients. M. de Mol, S. Visser, J.G.J.V. Aerts, et al. 2018;18(1):1173. PubMed · Publisher · Free full text

Abstract

Background: To determine the psychometric properties and minimal clinically important differences (MCIDs) of the World Health Organization Quality of Life-BREF (WHOQOL-BREF) in advanced stage lung cancer patients.

Methods: Patients (n = 153) completed the WHOQOL-BREF and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Confirmatory factor analysis (CFA) was performed and reliability and construct validity determined. MCIDs were estimated with two distribution-based methods (0.5 standard deviation (SD) and 1 standard error of measurement (1 SEM)).

Results: CFA confirmed WHOQOL-BREF domain structure. All domains demonstrated good internal consistency (α > 0.70), except Social Relationships (α = 0.57). Nineteen of the 24 WHOQOL-BREF items had correlations of ≥ 0.40 with their intended domain. Four items had higher correlations with a domain other than their intended domain. Moderate to strong correlations were observed for corresponding domains of the two questionnaires, except for the social domains (r = 0.07). For 0.5 SD, MCIDs ranged from 0.88 to 1.55, and for 1 SEM MCIDs ranged from 1.76 to 2.72.

Conclusions: The WHOQOL-BREF has satisfactory psychometric properties in patients with advanced stage lung cancer, whereas the observed MCIDs provide a method for interpretation of scores.
Systematic review of quality of life following pleurectomy decortication and extrapleural pneumonectomy for malignant pleural mesothelioma. R.M. Schwartz, W. Lieberman-Cribbin, A. Wolf, et al. 2018;18(1):1188. Meta-analysis · Systematic review PubMed · Publisher · Free full text

Abstract

Background: Few studies have focused on quality of life (QoL) after treatment of malignant pleural mesothelioma (MPM). There are still questions as to which surgical procedure, extrapleural pneumonectomy (EPP) or pleurectomy decortication (P/D) is most effective and results in better survival outcomes, involves fewer complications, and results in better QoL. Here we performed a literature review on MPM patients to assess and compare QoL changes after P/D and EPP.

Methods: Research articles concerning QoL after mesothelioma surgery were identified through May 2018 in Medline. For inclusion, studies were 1) cohort or randomized controlled trials (RCT) design, 2) included standardized QoL instruments, 3) reported QoL measurement after surgery, 4) described the type of surgery performed (EPP or P/D), 5) were written in English. Measures of lung function (FEV1, FVC) and measures from the EORTC-C30 were compared 6 months following surgery with preoperative values.

Results: QoL data was extracted from 17 articles (14 datasets), encompassing 659 patients (102 EPP, 432 P/D); the available evidence was of low quality. While two studies directly compared QoL between the two surgical procedures, additional data was available from one arm of two RCTs, as the RCTs were not comparing EPP and P/D. The remaining data was reported from observational studies. While QoL was still compromised 6 months following surgery, from the limited and low quality data available it would appear that P/D patients had better QoL than EPP patients across all measures. Physical function, social function and global health were better at follow-up for P/D than for EPP, while other indicators such as pain and cough were similar. Forced Expiratory Volume (FEV1) and Forced Vital Capacity (FVC) were reported in one study only, and were higher at follow-up for P/D compared to EPP.

Conclusions: Although the existing evidence is limited and of low quality, it suggests that P/D patients have better QoL than EPP patients following surgery. QoL outcomes should be factored into the choice of surgical procedure for MPM patients, and the possible effects on lung function and QoL should be discussed with patients when presenting surgical treatment options.
Calretinin as a blood-based biomarker for mesothelioma. G. Johnen, K. Gawrych, I. Raiko, et al. 2017;17(1):386. PubMed · Publisher · Free full text

Abstract

Background: Malignant mesothelioma (MM) is a deadly cancer mainly caused by previous exposure to asbestos. With a latency period up to 50 years the incidence of MM is still increasing, even in countries that banned asbestos. Secondary prevention has been established to provide persons at risk regular health examinations. An earlier detection with tumor markers might improve therapeutic options. Previously, we have developed a new blood-based assay for the protein marker calretinin. Aim of this study was the verification of the assay in an independent study population and comparison with the established marker mesothelin.

Methods: For a case-control study in men, a total of 163 cases of pleural MM and 163 controls were available from Australia, another 36 cases and 72 controls were recruited in Germany. All controls had asbestosis and/or plaques. Calretinin and mesothelin were determined by ELISA (enzyme-linked immunosorbent assay) in serum or plasma collected prior to therapy. We estimated the performance of both markers and tested factors potentially influencing marker concentrations like age, sample storage time, and MM subtype.

Results: Calretinin was able to detect all major subtypes except for sarcomatoid MM. Calretinin showed a similar performance in Australian and German men. At a pre-defined specificity of 95% the sensitivity of calretinin reached 71% and that of mesothelin 69%, when excluding sarcomatoid MM. At 97% specificity, the combination with calretinin increased the sensitivity of mesothelin from 66% to 75%. Sample storage time did not influence the results. In controls the concentrations of calretinin increased 1.87-fold (95% CI 1.10-3.20) per 10 years of age and slightly more for mesothelin (2.28, 95% CI 1.30-4.00).

Conclusions: Calretinin could be verified as a blood-based marker for MM. The assay is robust and shows a performance that is comparable to that of mesothelin. Retrospective analyses would not be limited by storage time. The high specificity supports a combination of calretinin with other markers. Calretinin is specific for epithelioid and biphasic MM but not the rarer sarcomatoid form. Molecular markers like calretinin and mesothelin are promising tools to improve and supplement the diagnosis of MM and warrant further validation in a prospective study.
Cytotoxicity of replication-competent adenoviruses powered by an exogenous regulatory region is not linearly correlated with the viral infectivity/gene expression or with the E1A-activating ability but is associated with the p53 genotypes. S. Yamauchi, B. Zhong, K. Kawamura, et al. 2017;17(1):622. PubMed · Publisher · Free full text

Abstract

Background: Replication-competent adenoviruses (Ad) produced cytotoxic effects on infected tumors and have been examined for the clinical applicability. A biomarkers to predict the cytotoxicity is valuable in a clinical setting.

Methods: We constructed type 5 Ad (Ad5) of which the expression of E1A gene was activated by a 5' regulatory sequences of survivin, midkine or cyclooxygenase-2, which were highly expressed in human tumors. We also produced the same replication-competent Ad of which the fiber-knob region was replaced by that of Ad35 (AdF35). The cytotoxicity was examined by a colorimetric assay with human tumor cell lines, 4 kinds of pancreatic, 9 esophageal carcinoma and 5 mesothelioma. Ad infectivity and Ad-mediated gene expression were examined with replication-incompetent Ad5 and AdF35 which expressed the green fluorescence protein gene. Expression of cellular receptors for Ad5 and AdF35 was also examined with flow cytometry. A transcriptional activity of the regulatory sequences was investigated with a luciferase assay in the tumor cells. We then investigated a possible correlation between Ad-mediated cytotoxicity and the infectivity/gene expression, the transcriptional activity or the p53 genotype.

Results: We found that the cytotoxicity was greater with AdF35 than with Ad5 vectors, but was not correlated with the Ad infectivity/gene expression irrespective of the fiber-knob region or the E1A-activating transcriptional activity. In contrast, replication-competent Ad produced greater cytotoxicity in p53 mutated than in wild-type esophageal carcinoma cells, suggesting a possible association between the cytotoxicity and the p53 genotype.

Conclusions: Sensitivity to Ad-mediated cytotoxic activity was linked with the p53 genotype but was not lineally correlated with the infectivity/gene expression or the E1A expression.
Metformin produces growth inhibitory effects in combination with nutlin-3a on malignant mesothelioma through a cross-talk between mTOR and p53 pathways. K. Shimazu, Y. Tada, T. Morinaga, et al. 2017;17(1):309. PubMed · Publisher · Free full text

Abstract

Background: Mesothelioma is resistant to conventional treatments and is often defective in p53 pathways. We then examined anti-tumor effects of metformin, an agent for type 2 diabetes, and combinatory effects of metformin and nutlin-3a, an inhibitor for ubiquitin-mediated p53 degradation, on human mesothelioma.

Methods: We examined the effects with a colorimetric assay and cell cycle analyses, and investigated molecular events in cells treated with metformin and/or nutlin-3a with Western blot analyses. An involvement of p53 was tested with siRNA for p53.

Results: Metformin suppressed cell growth of 9 kinds of mesothelioma including immortalized cells of mesothelium origin irrespective of the p53 functional status, whereas susceptibility to nutlin-3a was partly dependent on the p53 genotype. We investigated combinatory effects of metformin and nutlin-3a on, nutlin-3a sensitive MSTO-211H and NCI-H28 cells and insensitive EHMES-10 cells, all of which had the wild-type p53 gene. Knockdown of p53 expression with the siRNA demonstrated that susceptibility of MSTO-211H and NCI-H28 cells to nutlin-3a was p53-dependent, whereas that of EHMES-10 cells was not. Nevertheless, all the cells treated with both agents produced additive or synergistic growth inhibitory effects. Cell cycle analyses also showed that the combination increased sub-G1 fractions greater than metformin or nutlin-3a alone in MSTO-211H and EHMES-10 cells. Western blot analyses showed that metformin inhibited downstream pathways of the mammalian target of rapamycin (mTOR) but did not activate the p53 pathways, whereas nutlin-3a phosphorylated p53 and suppressed mTOR pathways. Cleaved caspase-3 and conversion of LC3A/B were also detected but it was dependent on cells and treatments. The combination of both agents in MSTO-211H cells rather suppressed the p53 pathways that were activated by nutrin-3a treatments, whereas the combination rather augmented the p53 actions in NCI-H28 and EHMES-10 cells.

Conclusion: These data collectively indicated a possible interactions between mTOR and p53 pathways, and the combinatory effects were attributable to differential mechanisms induced by a cross-talk between the pathways.
Midkine is a potential novel marker for malignant mesothelioma with different prognostic and diagnostic values from mesothelin. G. Ak, Y. Tada, H. Shimada, et al. 2017;17(1):212. PubMed · Publisher · Free full text

Abstract

Background: We evaluated possible diagnostic and prognostic values of serum midkine in malignant pleural mesothelioma in comparison with those of serum mesothelin, a well-established diagnostic biomarker.

Methods: Serum mesothelin and midkine levels were determined with an enzyme-linked immunosorbent assay. We examined specimens from 95 Turkish cases with malignant pleural mesothelioma, 56 metastatic cancers to pleura, 27 other types of benign pleural diseases and 20 benign asbestos pleurisy. The cut-off values were 1.5 nmol/L for mesothelin and 421 pg/mL for midkine.

Results: Sensitivity and specificity of mesothelin were 51.6 and 71.4%, 51.6 and 85.2%, and 51.6 and 85% for differentiating mesothelioma from metastatic cancers to pleura, other benign pleural diseases and benign asbestos pleurisy, respectively. Sensitivity and specificity of midkine were 61.1 and 41.1%, 61.1 and 48.1%, and 61.1 and 75% to distinguish mesothelioma from metastatic cancers to pleura, other benign pleural diseases and benign asbestos pleurisy, respectively. Combination of both biomarkers did not improve the differential diagnostic efficacy. Mesothelin levels were elevated in the epitheloid type and in the advanced cases, but were not related to the prognosis. In contrast, elevated baseline levels of midkine were independently associated with a poor prognosis of mesothelioma patients after adjusting for the stage, the histological subtypes and treatment schedules (HR = 1.84; 95% CI: 1.09-3.09) (p = 0.022).

Conclusions: Serum mesothelin showed moderate sensitivity and high specificity to differentiate malignant pleural mesothelioma from metastatic malignancy to pleura and from benign pleural diseases. In contrast, midkine was a useful marker for predicting prognosis of mesothelioma patients.
Renal failure during chemotherapy: renal biopsy for assessing subacute nephrotoxicity of pemetrexed. M. Assayag, P. Rouvier, M. Gauthier, et al. 2017;17(1):770. Case report PubMed · Publisher · Free full text

Abstract

Background: Pemetrexed, a multitargeted antifolate cytotoxic agent, is currently used primarily in combination with cisplatin for metastatic non-small cell lung cancer and for malignant mesothelioma. Acute renal toxicity of pemetrexed has been recently described with polychemotherapy, in which the individual responsibility of each drug is difficult to establish. Only one recent report documents renal involvement in long-term exposed patients.

Case Presentation: We report on a case of rapidly progressive nephropathy leading to the cessation of platinum salts and the secondary interruption of pemetrexed and bevacizumab. Acute tubular necrosis shown on the renal biopsy could potentially be due to pemetrexed. Persistent severe renal failure after the resumption of all drugs led to new treatment lines with gemcitabine (while the glomerular filtration rate was below 30 ml/min/1.73m2), then followed by Taxol.

Conclusions: The optimal strategy with regard to renal complications in cancer patients is not clear. Acute or chronic loss in renal function generally leads to a new treatment line, possibly impairing the overall success of the treatment. The use of chemotherapy in patients with a glomerular filtration rate below 30 ml/min/1.73m2 is usually associated with an increased risk of side effects when not contraindicated by renal elimination of the drug.
Serial immunomonitoring of cancer patients receiving combined antagonistic anti-CD40 and chemotherapy reveals consistent and cyclical modulation of T cell and dendritic cell parameters. A.M. McDonnell, A. Cook, B.W.S. Robinson, et al. 2017;17(1):417. PubMed · Publisher · Free full text

Abstract

Background: CD40 signalling can synergise with chemotherapy in preclinical cancer models, and early clinical studies are promising. We set out to define the immunological changes associated with this therapeutic combination to identify biomarkers for a response to the therapy. Here, we present serial immunomonitoring examining dendritic cell and T cell subpopulations over sequential courses of chemoimmunotherapy.

Methods: Fifteen patients with mesothelioma received up to six 21-day cycles of pemetrexed plus cisplatin chemotherapy and anti-CD40 (CP-870,893). Peripheral blood was collected weekly, and analysed by flow cytometry. Longitudinal immunophenotyping data was analysed by linear mixed modelling, allowing for variation between patients. Exploratory analyses testing for any correlation between overall survival and immunophenotyping data were undertaken up to the third cycle of treatment.

Results: Large statistically significant cyclical variations in the proportions of BDCA-1+, BDCA-2+ and BDCA-3+ dendritic cells were observed, although all subsets returned to baseline levels after each cycle and no significant changes were observed between start and end of treatment. Expression levels of CD40 and HLA-DR on dendritic cells were also cyclically modulated, again without significant change between start and end of treatment. CD8 and CD4 T cell populations, along with regulatory T cells, effector T cells, and markers of proliferation and activation, showed similar patterns of statistically significant cyclical modulation in response to therapy without changes between start and end of treatment. Exploratory analysis of endpoints revealed that patients with a higher than average proportion of BDCA-2+ dendritic cells (p = 0.010) or a higher than average proportion of activated (ICOS+) CD8 T cells (0.022) in pretreatment blood samples had better overall survival. A higher than average proportion of BDCA-3+ dendritic cells was associated with poorer overall survival at both the second (p = 0.008) and third (p = 0.014) dose of anti-CD40.

Conclusions: Substantial cyclical variations in DC and T cell populations during sequential cycles of chemoimmunotherapy highlight the critical importance of timing of immunological biomarker assessments in interpretation of results and the value of linear mixed modelling in interpretation of longitudinal change over a full treatment course.

Trial Registration: Australia New Zealand Clinical Trials Registry number ACTRN12609000294257 (18th May 2009).
Whole exome sequencing of an asbestos-induced wild-type murine model of malignant mesothelioma. S. Sneddon, A.M. Patch, I.M. Dick, et al. 2017;17(1):396. PubMed · Publisher · Free full text

Abstract

Background: Malignant mesothelioma (MM) is an aggressive cancer of the pleural and peritoneal cavities caused by exposure to asbestos. Asbestos-induced mesotheliomas in wild-type mice have been used extensively as a preclinical model because they are phenotypically identical to their human counterpart. However, it is not known if the genetic lesions in these mice tumours are similar to in the human disease, a prerequisite for any new preclinical studies that target genetic abnormalities.

Methods: We performed whole exome sequencing of fifteen asbestos-induced murine MM tumour cell lines from BALB/c, CBA and C57BL/6 mouse strains and compared the somatic mutations and copy number variations with those recurrently reported in human MM. We then catalogued and characterised the mutational landscape of the wild-type murine MM tumours. Quantitative RT-PCR was used to interrogate the expression of key MM genes of interest in the mRNA.

Results: Consistent with human MM tumours, we identified homozygous loss of the tumour suppressor Cdkn2a in 14/15 tumours. One tumour retained the first exon of both of the p16INK4a and p19ARF isoforms though this tumour also contained genetic amplification of Myc resulting in increased expression of the c-Myc proto-oncogene in the mRNA. There were no chromosomal losses in either the Bap1 or Nf2 regions. One tumour harbored homozygous loss of Trp53 in the DNA. Mutation rates were similar in tumours generated in the CBA and C57BL/6 strains when compared to human MM. Interestingly, all BALB/c tumour lines displayed high mutational loads, consistent with the known mutator phenotype of the host strain. The Wnt, MAPK and Jak-STAT signaling pathways were found to be the most commonly affected biological pathways. Mutations and copy number deletions also occurred in the Hedgehog and Hippo pathways.

Conclusions: These data suggest that in the wild-type murine model asbestos causes mesotheliomas in a similar way to in human MM. This further supports the notion that the murine model of MM represents a genuine homologue of the human disease, something uncommon in cancer, and is thus a valuable tool to provide insight into MM tumour development and to aide the search for novel therapeutic strategies.
A phase Ia/Ib clinical trial of metronomic chemotherapy based on a mathematical model of oral vinorelbine in metastatic non-small cell lung cancer and malignant pleural mesothelioma: rationale and study protocol. X. Elharrar, D. Barbolosi, J. Ciccolini, et al. 2016;16:278. PubMed · Publisher · Free full text

Abstract

Background: Metronomic oral vinorelbine is effective in metastatic NSCLC and malignant pleural mesothelioma, but all the studies published thus far were based upon a variety of empirical and possibly suboptimal schedules, with inconsistent results. Mathematical modelling showed by simulation that a new metronomic protocol could lead to a better safety and efficacy profile.

Design: This phase Ia/Ib trial was designed to confirm safety (phase Ia) and evaluate efficacy (phase Ib) of a new metronomic oral vinorelbine schedule. Patients with metastatic NSCLC or malignant pleural mesothelioma in whom standard treatments failed and who exhibited ECOG performance status 0-2 and adequate organ function will be eligible. Our mathematical PK-PD model suggested an alternative weekly D1, D2 and D4 schedule (named Vinorelbine Theoretical Protocol) with a respective dose of 60, 30 and 60 mg. Trial recruitment will be two-staged, as 12 patients are planned to participate in phase Ia to confirm safety and consolidate the calibration of the model parameters. Depending on the phase Ia results and after a favourable decision from a consultative committee, the extension phase (phase Ib) will be an efficacy study including 20 patients who will receive the Optimal Vinorelbine Theoretical Protocol. The primary endpoint is the tolerance (assessed by CTC v4.0) for the phase Ia and the objective response according to RECIST 1.1 for phase Ib. An ancillary study on circulating angiogenesis biomarkers will be a subproject of the trial.

Discussion: This ongoing trial is the first to prospectively test a mathematically optimized schedule in metronomic chemotherapy. As such, this trial can be considered as a proof-of-concept study demonstrating the feasibility to run a computational-driven protocol to ensure an optimal efficacy/toxicity balance in patients with cancer.

Trial Registration: EudraCT N°: 2015-000138-31.
Combination of a third generation bisphosphonate and replication-competent adenoviruses augments the cytotoxicity on mesothelioma. Y. Jiang, B. Zhong, K. Kawamura, et al. 2016;16:455. PubMed · Publisher · Free full text

Abstract

Background: Approximately 80 % of mesothelioma specimens have the wild-type p53 gene, whereas they contain homozygous deletions in the INK4A/ARF locus that encodes p14 (ARF) and the 16 (INK4A) genes. Consequently, the majority of mesothelioma is defective of the p53 pathways. We examined whether zoledronic acid (ZOL), a third generation bisphosphonate, and adenoviruses with a deletion of the E1B-55kD gene (Ad-delE1B55), which augments p53 levels in the infected tumors, could produce combinatory anti-tumor effects on human mesothelioma cells bearing the wild-type p53 gene.

Methods: Cytotoxicity of ZOL and Ad-delE1B55 was assessed with a WST assay. Cell cycle changes were tested with flow cytometry. Expression levels of relevant molecules were examined with western blot analysis to investigate a possible mechanism of cytotoxicity. Furthermore, the expressions of Ad receptors on target cells and infectivity were estimated with flow cytometry. Viral replication was assayed with the tissue culture infection dose method.

Results: A combinatory use of ZOL and Ad-delE1B55 suppressed cell growth and increased sub-G1 or S-phase populations compared with a single agent, depending on cells tested. The combinatory treatment up-regulated p53 levels and subsequently enhanced the cleavage of caspase-3, 8, 9 and poly (ADP-ribose) polymerase, but expression of molecules involved in autophagy pathways were inconsistent. ZOL-treated cells also increased Ad infectivity with a dose-dependent manner and augmented Ad replication although the expression levels of integrin molecules, one of the Ad receptors, were down-regulated.

Conclusions: These findings indicated that ZOL and Ad-delE1B55 achieved combinatory anti-tumor effects through augmented apoptotic pathways or increased viral replication.
HOX transcription factors are potential targets and markers in malignant mesothelioma. R. Morgan, G. Simpson, S. Gray, et al. 2016;16:85. PubMed · Publisher · Free full text

Abstract

Background: The HOX genes are a family of homeodomain-containing transcription factors that determine cellular identity during development and which are dys-regulated in some cancers. In this study we examined the expression and oncogenic function of HOX genes in mesothelioma, a cancer arising from the pleura or peritoneum which is associated with exposure to asbestos.

Methods: We tested the sensitivity of the mesothelioma-derived lines MSTO-211H, NCI-H28, NCI-H2052, and NCI-H226 to HXR9, a peptide antagonist of HOX protein binding to its PBX co-factor. Apoptosis was measured using a FACS-based assay with Annexin, and HOX gene expression profiles were established using RT-QPCR on RNA extracted from cell lines and primary mesotheliomas. The in vivo efficacy of HXR9 was tested in a mouse MSTO-211H flank tumor xenograft model.

Results: We show that HOX genes are significantly dysregulated in malignant mesothelioma. Targeting HOX genes with HXR9 caused apoptotic cell death in all of the mesothelioma-derived cell lines, and prevented the growth of mesothelioma tumors in a mouse xenograft model. Furthermore, the sensitivity of these lines to HXR9 correlated with the relative expression of HOX genes that have either an oncogenic or tumor suppressive function in cancer. The analysis of HOX expression in primary mesothelioma tumors indicated that these cells could also be sensitive to the disruption of HOX activity by HXR9, and that the expression of HOXB4 is strongly associated with overall survival.

Conclusion: HOX genes are a potential therapeutic target in mesothelioma, and HOXB4 expression correlates with overall survival.
Malignant mesothelioma of the pleura with desmoplastic histology: a case series and literature review. K. Hashimoto, Y. Okuma, Y. Hosomi, et al. 2016;16(1):718. Case report · Review PubMed · Publisher · Free full text

Abstract

Background: Desmoplastic malignant pleural mesothelioma (DMM) is rare histological subtype of diffuse malignant pleural mesothelioma (MPM), accounting for 5-10 % of cases. It has a poor prognosis, with direct invasion of the chest wall or lungs and distant metastases. Its pathological characteristics include dense collagen fibers in a storiform pattern. Its pretreatment pathological diagnosis is difficult, with fibrous pleuritis and reactive mesothelial hyperplasia as potential differential diagnoses.

Case Presentation: We retrospectively reviewed the medical charts of patients with MPM from 1996 to 2012. Among 60 patients with MPM, four patients with the desmoplastic subtype were identified and their clinical characteristics, including asbestos exposure, treatment, and prognosis, were reviewed. All of the patients with DMM were men, with a median age of 69 years (range: 63-74 years). All four patients had been exposed to asbestos. The definitive diagnosis was made histologically and the International Mesothelioma Interest Group classification was advanced (III/IV: 2/3) in all four patients. Three patients were treated with chemotherapy (two with cisplatin/pemetrexed and one with cisplatin/gemcitabine) and one patient underwent surgery. The median survival time in the patients with DMM was 3.8 months (range: 0.9-11.5 months), compared with 10.5 months in patients with other subtypes of MPM in our institution.

Conclusions: DMM continues to have a poor prognosis. It is important to recognize this variant and distinguish it from pleural plaques, non-specific reactive pleural fibrosis, pleurisy, and other lung diseases.
Pembrolizumab-associated minimal change disease in a patient with malignant pleural mesothelioma. A. Bickel, I. Koneth, A. Enzler-Tschudy, et al. 2016;16:656. Case report PubMed · Publisher · Free full text

Abstract

Background: Pembrolizumab is an anti- Programmed Death 1 (PD-1) antibody approved in melanoma, non-small cell lung cancer and investigated in malignant pleural mesothelioma. The most frequent immunotherapy related autoimmune reactions include dermatitis, pneumonitis, colitis, hypophysitis, uveitis, hypothyreodism, hepatitis and interstitial nephritis.

Case Presentation: We describe a 62-year old patient diagnosed with malignant pleural mesothelioma who experienced ten days after the second dose of third line therapy with pembrolizumab sudden onset of generalized edema including legs and eyelids and weight gain of 15 kg resulting from nephrotic syndrome and acute renal failure. Pembrolizumab was discontinued and prednisone, diuretics and angiotensin II receptor blocker were initiated with full recovery of symptoms and renal function. Pembrolizumab-associated minimal change disease (MCD) was confirmed by electron microscopy in the renal biopsy.

Conclusion: We are the first to describe pembrolizumab-related minimal change disease (MCD). Physicians should be aware of this side effect in patients presenting with edema and weight gain and initiate prompt renal function testing, serum albumin and urinalysis followed by steroid treatment if pembrolizumab-related MCD is suspected.
Consistent gene expression profiles in MexTAg transgenic mouse and wild type mouse asbestos-induced mesothelioma. C. Robinson, I.M. Dick, M.J. Wise, et al. 2015;15:983. PubMed · Publisher · Free full text

Abstract

Background: The MexTAg transgenic mouse model of mesothelioma replicates many aspects of human mesothelioma, including induction by asbestos, pathogenicity and response to cytotoxic chemotherapy, despite high levels of the SV40 large T Antigen (TAg) in the mesothelial compartment. This model enables analysis of the molecular events associated with asbestos induced mesothelioma and is utilised here to investigate the molecular dynamics of tumours induced in these mice, using gene expression patterns as a read out.

Methods: Gene expression of MexTAg mesothelioma cell lines bearing a high or low number of copies of the TAg transgene were compared to wild type mouse mesotheliomas and normal mouse mesothelial cells using Affymetrix microarray. These data were then compared to a similar published human microarray study using the same platform.

Results: The main expression differences between transgenic mouse and wild type mouse mesotheliomas occurred for genes involved in cell cycle regulation and DNA replication, as would be expected from overexpression of the TAg oncogene. Quantitative PCR confirmed that E2F and E2F regulated genes were significantly more upregulated in MexTAg mesotheliomas and MexTAg mesothelial cells compared to wild type mesotheliomas. Like human mesothelioma, both MexTAg and wild type mesotheliomas had more genes underexpressed than overexpressed compared to normal mouse mesothelial cells. Most notably, the cdkn2 locus was deleted in the wild type mouse mesotheliomas, consistent with 80 % human mesotheliomas, however, this region was not deleted in MexTAg mesotheliomas. Regardless of the presence of TAg, all mouse mesotheliomas had a highly concordant set of deregulated genes compared to normal mesothelial cells that overlapped with the deregulated genes between human mesotheliomas and mesothelial cells.

Conclusions: This investigation demonstrates that the MexTAg mesotheliomas are comparable with wild type mouse mesotheliomas in their representation of human mesothelioma at the molecular level, with some key gene expression differences that are attributable to the TAg transgene expression. Of particular note, MexTAg mesothelioma development was not dependent on cdkn2 deletion.
Epidemiological patterns of asbestos exposure and spatial clusters of incident cases of malignant mesothelioma from the Italian national registry. M. Corfiati, A. Scarselli, A. Binazzi, et al. 2015;15:286. PubMed · Publisher · Free full text

Abstract

Background: Previous ecological spatial studies of malignant mesothelioma cases, mostly based on mortality data, lack reliable data on individual exposure to asbestos, thus failing to assess the contribution of different occupational and environmental sources in the determination of risk excess in specific areas. This study aims to identify territorial clusters of malignant mesothelioma through a Bayesian spatial analysis and to characterize them by the integrated use of asbestos exposure information retrieved from the Italian national mesothelioma registry (ReNaM).

Methods: In the period 1993 to 2008, 15,322 incident cases of all-site malignant mesothelioma were recorded and 11,852 occupational, residential and familial histories were obtained by individual interviews. Observed cases were assigned to the municipality of residence at the time of diagnosis and compared to those expected based on the age-specific rates of the respective geographical area. A spatial cluster analysis was performed for each area applying a Bayesian hierarchical model. Information about modalities and economic sectors of asbestos exposure was analyzed for each cluster.

Results: Thirty-two clusters of malignant mesothelioma were identified and characterized using the exposure data. Asbestos cement manufacturing industries and shipbuilding and repair facilities represented the main sources of asbestos exposure, but a major contribution to asbestos exposure was also provided by sectors with no direct use of asbestos, such as non-asbestos textile industries, metal engineering and construction. A high proportion of cases with environmental exposure was found in clusters where asbestos cement plants were located or a natural source of asbestos (or asbestos-like) fibers was identifiable. Differences in type and sources of exposure can also explain the varying percentage of cases occurring in women among clusters.

Conclusions: Our study demonstrates shared exposure patterns in territorial clusters of malignant mesothelioma due to single or multiple industrial sources, with major implications for public health policies, health surveillance, compensation procedures and site remediation programs.
Management of malignant pleural mesothelioma: a French multicenter retrospective study (GFPC 0802 study). C. Raynaud, L. Greillier, J. Mazieres, et al. 2015;15:857. PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is a rare disease with poor prognosis in spite of significant improvement in survival, due to new chemotherapy regimens. We describe here patients' profiles and management in daily practice in France.

Methods: Observational retrospective study. Data were collected from medical files. All patients with histologically proven MPM diagnosed from January 2005 to December 2008 were included in the participating sites.

Results: Four hundred and six patients were included in 37 sites: mean age 68.9 ± 9.8 years, male predominance (sex ratio 3.27), latency of the disease 45.7 years, epithelioïd type 83 %. Diagnosis was made using thoracoscopy in 80.8 % of patients. Radical surgery was performed in 6.2 % of cases. Chemotherapy was administered to 74.6 % of patients. First line regimens consisted mainly of platinum + pemetrexed (91 %) or pemetrexed alone (7 %). Objective response rate was 17.2 % and another 41.6 % of patients experienced disease stabilization. Half of these patients underwent second line chemotherapy (platinium + pemetrexed 31.6 %, pemetrexed alone 24.6 %), resulting in a 6 % response rate. Third-line chemotherapy (56 patients) yielded disease control in 5.4 % of cases.

Conclusions: The management of MPM in France is usually in accordance with guidelines. Response rates are somewhat lower than those described in clinical trials.
Mesothelioma patient derived tumor xenografts with defined BAP1 mutations that mimic the molecular characteristics of human malignant mesothelioma. N. Kalra, J. Zhang, A. Thomas, et al. 2015;15:376. PubMed · Publisher · Free full text

Abstract

Background: The development and evaluation of new therapeutic approaches for malignant mesothelioma has been sparse due, in part, to lack of suitable tumor models.

Methods: We established primary mesothelioma cultures from pleural and ascitic fluids of five patients with advanced mesothelioma. Electron microscopy and immunohistochemistry (IHC) confirmed their mesothelial origin. Patient derived xenografts were generated by injecting the cells in nude or SCID mice, and malignant potential of the cells was analyzed by soft agar colony assay. Molecular profiles of the primary patient tumors, early passage cell cultures, and patient derived xenografts were assessed using mutational analysis, fluorescence in situ hybridization (FISH) analysis and IHC.

Results: Primary cultures from all five tumors exhibited morphologic and IHC features consistent to those of mesothelioma cells. Mutations of BAP1 and CDKN2A were each detected in four tumors. BAP1 mutation was associated with the lack of expression of BAP1 protein. Three cell cultures, all of which were derived from BAP1 mutant primary tumors, exhibited anchorage independent growth and also formed tumors in mice, suggesting that BAP1 loss may enhance tumor growth in vivo. Both early passage cell cultures and mouse xenograft tumors harbored BAP1 mutations and CDKN2A deletions identical to those found in the corresponding primary patient tumors.

Conclusions: The mesothelioma patient derived tumor xenografts with mutational alterations that mimic those observed in patient tumors which we established can be used for preclinical development of novel drug regimens and for studying the functional aspects of BAP1 biology in mesothelioma.
Molecular characteristics of endometrial cancer coexisting with peritoneal malignant mesothelioma in Li-Fraumeni-like syndrome. A. Chao, C.H. Lai, Y.S. Lee, et al. 2015;15:8. Case report PubMed · Publisher · Free full text

Abstract

Background: Endometrial cancer that occurs concurrently with peritoneal malignant mesothelioma (PMM) is difficult to diagnose preoperatively.

Case Presentation: A postmenopausal woman had endometrial cancer extending to the cervix, vagina and pelvic lymph nodes, and PMM in bilateral ovaries, cul-de-sac, and multiple peritoneal sites. Adjuvant therapies included chemotherapy and radiotherapy. Targeted, massively parallel DNA sequencing and molecular inversion probe microarray analysis revealed a germline TP53 mutation compatible with Li-Fraumeni-like syndrome, somatic mutations of PIK3CA in the endometrial cancer, and a somatic mutation of GNA11 and JAK3 in the PMM. Large-scale genomic amplifications and some deletions were found in the endometrial cancer. The patient has been stable for 24 months after therapy. One of her four children was also found to carry the germline TP53 mutation.

Conclusions: Molecular characterization of the coexistent tumors not only helps us make the definite diagnosis, but also provides information to select targeted therapies if needed in the future. Identification of germline TP53 mutation further urged us to monitor future development of malignancies in this patient and encourage cancer screening in her family.
The combination of sorafenib and everolimus shows antitumor activity in preclinical models of malignant pleural mesothelioma. Y. Pignochino, C. Dell'Aglio, S. Inghilleri, et al. 2015;15:374. PubMed · Publisher · Free full text

Abstract

Background: Malignant Pleural Mesothelioma (MPM) is an aggressive tumor arising from mesothelial cells lining the pleural cavities characterized by resistance to standard therapies. Most of the molecular steps responsible for pleural transformation remain unclear; however, several growth factor signaling cascades are known to be altered during MPM onset and progression. Transducers of these pathways, such as PIK3CA-mTOR-AKT, MAPK, and ezrin/radixin/moesin (ERM) could therefore be exploited as possible targets for pharmacological intervention. This study aimed to identify 'druggable' pathways in MPM and to formulate a targeted approach based on the use of commercially available molecules, such as the multikinase inhibitor sorafenib and the mTOR inhibitor everolimus.

Methods: We planned a triple approach based on: i) analysis of immunophenotypes and mutational profiles in a cohort of thoracoscopic MPM samples, ii) in vitro pharmacological assays, ii) in vivo therapeutic approaches on MPM xenografts. No mutations were found in 'hot spot' regions of the mTOR upstream genes (e.g. EGFR, KRAS and PIK3CA).

Results: Phosphorylated mTOR and ERM were specifically overexpressed in the analyzed MPM samples. Sorafenib and everolimus combination was effective in mTOR and ERM blockade; exerted synergistic effects on the inhibition of MPM cell proliferation; triggered ROS production and consequent AMPK-p38 mediated-apoptosis. The antitumor activity was displayed when orally administered to MPM-bearing NOD/SCID mice.

Conclusions: ERM and mTOR pathways are activated in MPM and 'druggable' by a combination of sorafenib and everolimus. Combination therapy is a promising therapeutic strategy against MPM.
The effectiveness and safety of platinum-based pemetrexed and platinum-based gemcitabine treatment in patients with malignant pleural mesothelioma. G. Ak, S. Metintas, M. Akarsu, et al. 2015;15:510. PubMed · Publisher · Free full text

Abstract

Background: We aimed to evaluate the efficiency and safety of cis/carboplatin plus gemcitabine, which was previously used for mesothelioma but with no recorded proof of its efficiency, compared with cis/carboplatin plus pemetrexed, which is known to be effective in mesothelioma, in comparable historical groups of malignant pleural mesothelioma.

Methods: One hundred and sixteen patients received cis/carboplatin plus pemetrexed (group 1), while 30 patients received cis/carboplatin plus gemcitabine (group 2) between June 1999 and June 2012. The two groups were compared in terms of median survival and adverse events to chemotherapy.

Results: The mean ages of groups 1 and 2 were 60.7 and 60.8 years, respectively. Most of the patients (78.1%) had epithelial type tumors, and 47% of the patients had stage IV disease. There was no difference between the two groups in terms of age, gender, asbestos exposure, histology, stage, Karnofsky performance status, presence of pleurodesis, prophylactic radiotherapy, second-line chemotherapy and median hemoglobin and serum albumin levels. The median survival time from diagnosis to death or the last day of follow up with a 95% confidence interval was 12 ± 0.95 months (95% CI: 10.15-13.85) for group 1 and 11.0 ± 1.09 months (95% CI: 8.85-13.15) for group 2 (Log-Rank: 0.142; p = 0.706). The median survival time from treatment to death or the last day of follow-up with a 95% confidence interval was 11.0 ± 0.99 months (95% CI: 9.06-12.94) for group 1 and 11.0 ± 1.52 months (95% CI: 8.02-13.97) for group 2 (Log-Rank: 0.584; p = 0.445). The stage and Karnofsky performance status were found to be significant variables on median survival time by univariate analysis. After adjusting for the stage and Karnofsky performance status, the chemotherapy schema was not impressive on median survival time (OR: 0.837; 95% CI: 0.548-1.277; p = 0.409). The progression free survival was 7.0 ± 0.61 months for group I and 6.0 ± 1.56 months for group II (Log-Rank: 0.522; p = 0.470). The treatment was generally well tolerated, and the side effects were similar in both groups.

Conclusions: The study indicates that platinum-based gemcitabine is effective and a safe schema in malignant pleural mesothelioma. Further research should include large randomized phase III trials comparing these agents.
A serum mesothelin level is a prognostic indicator for patients with malignant mesothelioma in routine clinical practice. M. Linch, S. Gennatas, S. Kazikin, et al. 2014;14:674. PubMed · Publisher · Free full text

Abstract

Background: Malignant mesothelioma (MM) carries a poor prognosis and response rates to palliative chemotherapy remain low. Identifying patients with MM that are unlikely to respond to chemotherapy could prevent futile treatments and improve patient quality of life. Studies have suggested that soluble mesothelin is a potential biomarker for early diagnosis and prognosis of MM. We set out to explore the utility of serum mesothelin in routine clinical practice.

Methods: We conducted a prospective exploratory study of serum mesothelin levels in 53 consecutive patients with MM at our institution between April 2009 and February 2011. Survival was assessed and analysed by mesothelin level as both continuous and categorical variables using Cox regression models. Differences in response rate between treatment groups were assessed by the Kruskal-Wallis Test.

Results: All 53 patients, who had been given study information agreed to participate. The patients' median age was 69 (range 24-90). Median mesothelin level was 2.7 nM and this value was used to dichotomize categories: ≤2.7 nM (low) and >2.7 nM (high). The progression free survival (PFS) for low vs high mesothelin was 8.0 vs 5.1 months (HR 1.8, p-0.058). When mesothelin was accessed as a continuous variable for PFS the HR was 1.03 (95% CI: 1.01-1.06; p=0.013). The overall survival (OS) for low vs high mesothelin was 17.2 vs 11.3 months (HR 1.9, p=0.088). When mesothelin was assessed as a continuous variable for OS the HR was 1.02 (95% CI: 0.99 - 1.04; p=0.073). Thirty patients received chemotherapy of which 18 had a pre-chemotherapy serum mesothelin level. In these 18 patients, the pre-chemotherapy mesothelin level did not correlate with response.

Conclusions: A single random sample provides information about patient prognosis but does not predict treatment response. We suggest further prospective validation of mesothelin testing as a prognostic biomarker.
Characterization and drug sensitivity profiling of primary malignant mesothelioma cells from pleural effusions. A. Szulkin, R. Otvös, C.O. Hillerdal, et al. 2014;14:709. PubMed · Publisher · Free full text

Abstract

Background: Patients with malignant mesothelioma have a poor prognosis and only 40% respond to first line treatment; a combination of pemetrexed and cisplatin or carboplatin. We used primary malignant mesothelioma cells and an ex vivo chemosensitivity assay with future purpose to predict best choice of treatment. The clinical outcome of these patients might be predicted by measuring drug sensitivity.

Methods: Pleural effusions containing primary malignant mesothelioma cells were received from the diagnostic routine. We characterized and tested the chemosensitivity of 18 malignant samples and four benign samples from 16 different patients with pleural effusions. Cells were seeded in a 384-well plate for a robotized ex vivo testing of drug sensitivity to 32 different drugs. The primary cells were further characterized by immunocytochemistry to evaluate the proportion of malignant cells and to study the RRM1 and ERCC1 reactivity, two proteins associated with drug resistance.

Results: We observed great individual variability in the drug sensitivity. Primary cell isolates were affected by between one and ten drugs, and resistant to the remaining tested drugs. Actinomycin D and daunorubicin were the two drugs effective in most cases. Adjusting efficiency of individual drugs for varying proportion of tumor cells and to the average effect on benign cells correlated with effect of pemetrexed, cisplatin and survival time. General drug sensitivity, proportion of malignant cells and reactivity to RRM1 correlated to each other and to survival time of the patients.

Conclusions: The proportion of malignant cells and RRM1 reactivity in the pleural effusions correlate to drug sensitivity and survival time. The variability in response to the commonly used chemotherapies emphasizes the need for tests that indicate best individual choice of cytotoxic drugs. The efficiency of the obtained results should preferably be corrected for admixture of benign cells and effects of given drugs on benign cells.
Cisplatin-resistant cells in malignant pleural mesothelioma cell lines show ALDH(high)CD44(+) phenotype and sphere-forming capacity. L. Cortes-Dericks, L. Froment, R. Boesch, et al. 2014;14:304. PubMed · Publisher · Free full text

Abstract

Background: Conventional chemotherapy in malignant pleural mesothelioma (MPM) has minimal impact on patient survival due to the supposed chemoresistance of cancer stem cells (CSCs). We sought to identify a sub-population of chemoresistant cells by using putative CSC markers, aldehyde dehydrogenase (ALDH) and CD44 in three MPM cell lines; H28, H2052 and Meso4.

Methods: The Aldefluor assay was used to measure ALDH activity and sort ALDH(high) and ALDH(low) cells. Drug-resistance was evaluated by cell viability, anchorage-independent sphere formation, flow-cytometry and qRT-PCR analyses.

Results: The ALDH(high) - and ALDH(low) -sorted fractions were able to demonstrate phenotypic heterogeneity and generate spheres, the latter being less efficient, and both showed an association with CD44. Cis- diamminedichloroplatinum (II) (cisplatin) treatment failed to reduce ALDH activity and conferred only a short-term inhibition of sphere generation in both ALDH(high) and ALDH(low) fractions of the three MPM cell lines. Induction of drug sensitivity by an ALDH inhibitor, diethylaminobenzaldehyde (DEAB) resulted in significant reductions in cell viability but not a complete elimination of the sphere-forming cells, suggestive of the presence of a drug-resistant subpopulation. At the transcript level, the cisplatin + DEAB-resistant cells showed upregulated mRNA expression levels for ALDH1A2, ALDH1A3 isozymes and CD44 indicating the involvement of these markers in conferring chemoresistance in both ALDH(high) and ALDH(low) fractions of the three MPM cell lines.

Conclusions: Our study shows that ALDH(high) CD44(+) cells are implicated in conveying tolerance to cisplatin in the three MPM cell lines. The combined use of CD44 and ALDH widens the window for identification and targeting of a drug-resistant population which may improve the current treatment modalities in mesothelioma.
The efficacy of tumor debulking surgery is improved by adjuvant immunotherapy using imiquimod and anti-CD40. A. Khong, A.L. Cleaver, M. Fahmi Alatas, et al. 2014;14:969. PubMed · Publisher · Free full text

Abstract

Background: Tumor debulking surgery followed by adjuvant chemotherapy or radiotherapy is a standard treatment for many solid malignancies. Although this approach can be effective, it often has limited success against recurrent or metastatic cancers and new multimodality approaches are needed. Adjuvant immunotherapy is another potentially effective approach. We therefore tested the efficacy of the TLR7 agonist imiquimod (IMQ) combined with agonistic anti-CD40 in an incomplete debulking model of malignant mesothelioma.

Methods: Established subcutaneous murine ABA-HA mesothelioma tumors in BALB/c mice were surgically debulked by 75% and treated with either: i) saline; ii) intratumoral IMQ; iii) systemic anti-CD40 antibody, or using a combination of IMQ and anti-CD40. Tumour growth and survival were monitored, and the role of anti-tumor CD4 and CD8 T cells in therapeutic responses was determined.

Results: The combination therapy of partial debulking surgery, IMQ and anti-CD40 significantly delayed tumor growth in a CD8 T cell dependent manner, and promoted tumor regression in 25% of animals with establishment of immunological memory. This response was associated with an increase in ICOS+ CD8 T cells and tumor-specific CTL activity in tumor draining lymph nodes along with an increase in ICOS+ CD8 T cells in responding tumours.

Conclusions: We show that the post-surgical environment can be significantly altered by the co-administration of adjuvant IMQ and anti-CD40, resulting in strong, systemic anti-tumor activity. Both adjuvants are available for clinical use/trial, hence this treatment regimen has clear translational potential.
Activity ex vivo of cytotoxic drugs in patient samples of peritoneal carcinomatosis with special focus on colorectal cancer. P.H. Cashin, H. Mahteme, W. Graf, et al. 2013;13:435. PubMed · Publisher · Free full text

Abstract

Background: The optimal choice of cytotoxic drugs for intraperitoneal chemotherapy (IPC) in conjunction with cytoreductive surgery (CRS) for treatment of peritoneal carcinomatosis (PC) is poorly defined. We investigated drug sensitivity ex vivo in patient samples of various PC tumor types and correlated clinical outcome to drug sensitivity within the subset of PC from colorectal cancer (CRC).

Methods: PC tissue samples (n = 174) from mesothelioma, pseudomyxoma peritonei (PMP), ovarian cancer, CRC or appendix cancer were analyzed ex vivo for sensitivity to oxaliplatin, cisplatin, mitomycin C, melphalan, irinotecan, docetaxel, doxorubicin and 5-FU. Clinicopathological variables and outcome data were collected for the CRC subset.

Results: Mesothelioma and ovarian cancer were generally more drug sensitive than CRC, appendix cancer and PMP. Oxaliplatin showed the most favorable ratio between achievable IPC concentration and ex vivo drug sensitivity. Drug sensitivity in CRC varied considerably between individual samples. Ex vivo drug sensitivity did not obviously correlate to time-to-progression (TTP) in individual patients.

Conclusions: Drug-sensitivity varies considerably between PC diagnoses and individual patients arguing for individualized therapy in IPC rather than standard diagnosis-specific therapy. However, in the current paradigm of treatment according to diagnosis, oxaliplatin is seemingly the preferred drug for IPC from a drug sensitivity and concentration perspective. In the CRC subset, analysis of correlation between ex vivo drug sensitivity and TTP was inconclusive due to the heterogeneous nature of the data.
Defect in recruiting effector memory CD8+ T-cells in malignant pleural effusions compared to normal pleural fluid. A. Scherpereel, B.D. Grigoriu, M. Noppen, et al. 2013;13:324. PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural effusions (MPE) are a common and fatal complication in cancers including lung or breast cancers, or malignant pleural mesothelioma (MPM). MPE animal models and immunotherapy trials in MPM patients previously suggested defects of the cellular immunity in MPE. However only few observational studies of the immune response were done in MPM patients, using questionable control groups (transudate…).

Methods: We compared T cell populations evaluated by flow cytometry from blood and pleural effusion of untreated patients with MPM (n = 58), pleural metastasis of adenocarcinoma (n = 30) or with benign pleural lesions associated with asbestos exposure (n = 23). Blood and pleural fluid were also obtained from healthy subjects, providing normal values for T cell populations.

Results: Blood CD4+ or CD8+ T cells percentages were similar in all groups of patients or healthy subjects. Whereas pleural fluid from healthy controls contained mainly CD8+ T cells, benign or malignant pleural effusions included mainly CD4+ T cells. Effector memory T cells were the main T cell subpopulation in pleural fluid from healthy subjects. In contrast, there was a striking and selective recruitment of central memory CD4+ T cells in MPE, but not of effector cells CD8+ T cells or NK cells in the pleural fluid as one would expect in order to obtain an efficient immune response.

Conclusions: Comparing for the first time MPE to pleural fluid from healthy subjects, we found a local defect in recruiting effector CD8+ T cells, which may be involved in the escape of tumor cells from immune response. Further studies are needed to characterize which subtypes of effector CD8+ T cells are involved, opening prospects for cell therapy in MPE and MPM.
EphB4 as a therapeutic target in mesothelioma. R. Liu, B.D. Ferguson, Y. Zhou, et al. 2013;13:269. PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) often develops decades following exposure to asbestos. Current best therapy produces a response in only half of patients, and the median survival with this therapy remains under a year. A search for novel targets and therapeutics is underway, and recently identified targets include VEGF, Notch, and EphB4-Ephrin-B2. Each of these targets has dual activity, promoting tumor cell growth as well as tumor angiogenesis.

Methods: We investigated EphB4 expression in 39 human mesothelioma tissues by immunohistochemistry. Xenograft tumors established with human mesothelioma cells were treated with an EphB4 inhibitor (monomeric soluble EphB4 fused to human serum albumin, or sEphB4-HSA). The combinatorial effect of sEphB4-HSA and biologic agent was also studied.

Results: EphB4 was overexpressed in 72% of mesothelioma tissues evaluated, with 85% of epithelioid and 38% of sarcomatoid subtypes demonstrating overexpression. The EphB4 inhibitor sEphB4-HSA was highly active as a single agent to inhibit tumor growth, accompanied by tumor cell apoptosis and inhibition of PI3K and Src signaling. Combination of sEphB4-HSA and the anti-VEGF antibody (Bevacizumab) was superior to each agent alone and led to complete tumor regression.

Conclusion: EphB4 is a potential therapeutic target in mesothelioma. Clinical investigation of sEphB4-HSA as a single agent and in combination with VEGF inhibitors is warranted.
Microspheres targeted with a mesothelin antibody and loaded with doxorubicin reduce tumor volume of human mesotheliomas in xenografts. S.L. Macura, J.L. Steinbacher, M.B. Macpherson, et al. 2013;13:400. PubMed · Publisher · Free full text

Abstract

Background: Malignant mesotheliomas (MMs) are chemoresistant tumors related to exposure to asbestos fibers. The long latency period of MM (30-40 yrs) and heterogeneity of tumor presentation make MM difficult to diagnose and treat at early stages. Currently approved second-line treatments following surgical resection of MMs include a combination of cisplatin or carboplatin (delivered systemically) and pemetrexed, a folate inhibitor, with or without subsequent radiation. The systemic toxicities of these treatments emphasize the need for more effective, localized treatment regimens.

Methods: Acid-prepared mesoporous silica (APMS) microparticles were loaded with doxorubicin (DOX) and modified externally with a mesothelin (MB) specific antibody before repeated intraperitoneal (IP) injections into a mouse xenograft model of human peritoneal MM. The health/weight of mice, tumor volume/weight, tumor necrosis and cell proliferation were evaluated in tumor-bearing mice receiving saline, DOX high (0.2 mg/kg), DOX low (0.05 mg/kg), APMS-MB, or APMS-MB-DOX (0.05 mg/kg) in saline.

Results: Targeted therapy (APMS-MB-DOX at 0.05 mg/kg) was more effective than DOX low (0.05 mg/kg) and less toxic than treatment with DOX high (0.2 mg/kg). It also resulted in the reduction of tumor volume without loss of animal health and weight, and significantly decreased tumor cell proliferation. High pressure liquid chromatography (HPLC) of tumor tissue confirmed that APMS-MB-DOX particles delivered DOX to target tissue.

Conclusions: Data suggest that targeted therapy results in greater chemotherapeutic efficacy with fewer adverse side effects than administration of DOX alone. Targeted microparticles are an attractive option for localized drug delivery.
Phase II trial of neoadjuvant pemetrexed plus cisplatin followed by surgery and radiation in the treatment of pleural mesothelioma. R. Federico, F. Adolfo, M. Giuseppe, et al. 2013;13:22. PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma is an aggressive tumor that has a poor prognosis and is resistant to unimodal approaches. Multimodal treatment has provided encouraging results.

Methods: Phase II, open-label study of the combination of chemotherapy (pemetrexed 500 mg/m²+cisplatin 75 mg/m² IV every 21 days × 3 cycles), followed by surgery (en-bloc extrapleural pneumonectomy, 3-8 weeks after chemotherapy) and hemithoracic radiation (total radiation beam 54 Gy, received 4-8 weeks post-surgery). The primary endpoint was event-free survival, defined as the time from enrollment to time of first observation of disease progression, death due to any cause, or early treatment discontinuation.

Results: Fifty-four treatment-naïve patients with T1-3 N0-2 malignant pleural mesothelioma were enrolled, 52 (96.3%) completed chemotherapy, 45 (83.3%) underwent surgery, 22 (40.7%) completed the whole treatment including 90-day post-radiation follow-up. The median event-free survival was 6.9 months (95%CI: 5.0-10.5), median overall survival was 15.5 months (95%CI 11.0-NA) while median time-to-tumor response was 4.8 months (95%CI: 2.5-8.0). Eighteen (33.3%) and 13 (24.1%) patients were still event-free after 1 and 2 years, respectively. The most common treatment-emergent adverse events were nausea (63.0%), anemia (51.9%) and hypertension (42.6%).Following two cardiopulmonary radiation-related deaths the protocol was amended (21 [38.9%] patients were already enrolled in the study): the total radiation beam was reduced from 54 Gy to 50.4 Gy and a more accurate selection of patients was recommended.

Conclusions: The combination of pemetrexed plus cisplatin followed by surgery and hemithoracic radiation is feasible and has a manageable toxicity profile in carefully selected patients. It may be worthy of further investigation.

Trial Registration: Clinicaltrial.com registrationID #NCT00087698.
Pleural cancer mortality in Spain: time-trends and updating of predictions up to 2020. G. López-Abente, M. García-Gómez, A. Menéndez-Navarro, et al. 2013;13:528. Historical article PubMed · Publisher · Free full text

Abstract

Background: A total of 2,514,346 metric tons (Mt) of asbestos were imported into Spain from 1906 until the ban on asbestos in 2002. Our objective was to study pleural cancer mortality trends as an indicator of mesothelioma mortality and update mortality predictions for the periods 2011-2015 and 2016-2020 in Spain.

Methods: Log-linear Poisson models were fitted to study the effect of age, period of death and birth cohort (APC) on mortality trends. Change points in cohort- and period-effect curvatures were assessed using segmented regression. Fractional power-link APC models were used to predict mortality until 2020. In addition, an alternative model based on national asbestos consumption figures was also used to perform long-term predictions.

Results: Pleural cancer deaths increased across the study period, rising from 491 in 1976-1980 to 1,249 in 2006-2010. Predictions for the five-year period 2016-2020 indicated a total of 1,319 pleural cancer deaths (264 deaths/year). Forecasts up to 2020 indicated that this increase would continue, though the age-adjusted rates showed a levelling-off in male mortality from 2001 to 2005, corresponding to the lower risk in post-1960 generations. Among women, rates were lower and the mortality trend was also different, indicating that occupational exposure was possibly the single factor having most influence on pleural cancer mortality.

Conclusion: The cancer mortality-related consequences of human exposure to asbestos are set to persist and remain in evidence until the last surviving members of the exposed cohorts have disappeared. It can thus be assumed that occupationally-related deaths due to pleural mesothelioma will continue to occur in Spain until at least 2040.
Serum HMGB1 as a prognostic marker for malignant pleural mesothelioma. C. Tabata, E. Shibata, R. Tabata, et al. 2013;13:205. PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor of mesothelial origin that shows a limited response to conventional chemotherapy and radiotherapy. Therefore, diagnosing MPM early is very important. Some researchers have previously reported that high-mobility group box 1 (HMGB1) was correlated with pulmonary fibrosis. MPM involves the malignant transformation of mesothelial cells, which originate from mesenchymal cells similar to lung fibroblasts. Here, we investigated serum levels of HMGB1 in patients with MPM and compared them with those of a population that had been exposed to asbestos without developing MPM.

Methods: HMGB1 production from MPM cell lines was measured using ELISA. Serum HMGB1 levels were also examined in 61 MPM patients and 45 individuals with benign asbestos-related diseases.

Results: HMGB1 concentrations of 2 out of 4 MPM cell lines were higher than that of normal mesothelial cell line, Met-5A. We demonstrated that patients with MPM had significantly higher serum levels of HMGB1 than the population who had been exposed to asbestos but had not developed MPM. The difference in overall survival between groups with serum HMGB1 levels that were lower and higher than assumed cut-off values was significant.

Conclusions: Our data suggest that serum HMGB1 concentration is a useful prognostic factor for MPM.
TRAIL and proteasome inhibitors combination induces a robust apoptosis in human malignant pleural mesothelioma cells through Mcl-1 and Akt protein cleavages. B.Z. Yuan, J. Chapman, M. Ding, et al. 2013;13:140. PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is an aggressive malignancy closely associated with asbestos exposure and extremely resistant to current treatments. It exhibits a steady increase in incidence, thus necessitating an urgent development of effective new treatments.

Methods: Proteasome inhibitors (PIs) and TNFα-Related Apoptosis Inducing Ligand (TRAIL), have emerged as promising new anti-MPM agents. To develop effective new treatments, the proapoptotic effects of PIs, MG132 or Bortezomib, and TRAIL were investigated in MPM cell lines NCI-H2052, NCI-H2452 and NCI-H28, which represent three major histological types of human MPM.

Results: Treatment with 0.5-1 μM MG132 alone or 30 ng/mL Bortezomib alone induced a limited apoptosis in MPM cells associated with the elevated Mcl-1 protein level and hyperactive PI3K/Akt signaling. However, whereas 10-20 ng/ml TRAIL alone induced a limited apoptosis as well, TRAIL and PI combination triggered a robust apoptosis in all three MPM cell lines. The robust proapoptotic activity was found to be the consequence of a positive feedback mechanism-governed amplification of caspase activation and cleavage of both Mcl-1 and Akt proteins, and exhibited a relative selectivity in MPM cells than in non-tumorigenic Met-5A mesothelial cells.

Conclusion: The combinatorial treatment using TRAIL and PI may represent an effective new treatment for MPMs.
Occupational exposure to asbestos and lung cancer in men: evidence from a population-based case-control study in eight Canadian provinces. P.J. Villeneuve, M.É. Parent, S.A. Harris, et al. 2012;12:595. PubMed · Publisher · Free full text

Abstract

Background: Asbestos is classified as a human carcinogen, and studies have consistently demonstrated that workplace exposure to it increases the risk of developing lung cancer. Few studies have evaluated risks in population-based settings where there is a greater variety in the types of occupations, and exposures.

Methods: This was a population based case-control study with 1,681 incident cases of lung cancer, and 2,053 controls recruited from 8 Canadian provinces between 1994 and 1997. Self-reported questionnaires were used to elicit a lifetime occupational history, including general tasks, and information for other risk factors. Occupational hygienists, who were blinded to case-control status, assigned asbestos exposures to each job on the basis of (i) concentration (low, medium, high), (ii) frequency (<5%, 5-30%, and >30% of the time in a normal work week), and (iii) reliability (possible, probable, definite). Logistic regression was used to estimate odds ratios (ORs) and their corresponding 95% confidence intervals (CI).

Results: Those occupationally exposed to (i) low, and (ii) medium or high concentrations of asbestos had ORs for lung cancer of 1.17 (95% CI=0.92 - 1.50) and 2.16 (95% CI=1.21-3.88), respectively, relative to those who were unexposed. Medium or high exposure to asbestos roughly doubled the risk for lung cancer across all three smoking pack-year categories. The joint relationship between smoking and asbestos was consistent with a multiplicative risk model.

Conclusions: Our findings provide further evidence that exposure to asbestos has contributed to an increased risk of lung cancer in Canadian workplaces, and suggests that nearly 3% of lung cancers among Canadian men are caused by occupational exposure to asbestos.
Pleural fluid cell-free DNA integrity index to identify cytologically negative malignant pleural effusions including mesotheliomas. K.B. Sriram, V. Relan, B.E. Clarke, et al. 2012;12:428. PubMed · Publisher · Free full text

Abstract

Background: The diagnosis of malignant pleural effusions (MPE) is often clinically challenging, especially if the cytology is negative for malignancy. DNA integrity index has been reported to be a marker of malignancy. The aim of this study was to evaluate the utility of pleural fluid DNA integrity index in the diagnosis of MPE.

Methods: We studied 75 pleural fluid and matched serum samples from consecutive subjects. Pleural fluid and serum ALU DNA repeats [115bp, 247bp and 247bp/115bp ratio (DNA integrity index)] were assessed by real-time quantitative PCR. Pleural fluid and serum mesothelin levels were quantified using ELISA.

Results: Based on clinico-pathological evaluation, 52 subjects had MPE (including 16 mesotheliomas) and 23 had benign effusions. Pleural fluid DNA integrity index was higher in MPE compared with benign effusions (1.2 vs. 0.8; p<0.001). Cytology had a sensitivity of 55% in diagnosing MPE. If cytology and pleural fluid DNA integrity index were considered together, they exhibited 81% sensitivity and 87% specificity in distinguishing benign and malignant effusions. In cytology-negative pleural effusions (35 MPE and 28 benign effusions), elevated pleural fluid DNA integrity index had an 81% positive predictive value in detecting MPEs. In the detection of mesothelioma, at a specificity of 90%, pleural fluid DNA integrity index had similar sensitivity to pleural fluid and serum mesothelin (75% each respectively).

Conclusion: Pleural fluid DNA integrity index is a promising diagnostic biomarker for identification of MPEs, including mesothelioma. This biomarker may be particularly useful in cases of MPE where pleural aspirate cytology is negative, and could guide the decision to undertake more invasive definitive testing. A prospective validation study is being undertaken to validate our findings and test the clinical utility of this biomarker for altering clinical practice.
Re-directed T cells for the treatment of fibroblast activation protein (FAP)-positive malignant pleural mesothelioma (FAPME-1). U. Petrausch, P.C. Schuberth, C. Hagedorn, et al. 2012;12:615. PubMed · Publisher · Free full text

Abstract

Background: Asbestos is the main cause of MPM in industrialized countries. Even since asbestos is banned in most developed countries, the peak wave of MPM incidence is anticipated for the next years due to the long latency of asbestos induced MPM. MPM patients not eligible for surgical procedures like decortication or pleuro-pneumectomie have a median survival of 12 months with palliative chemotherapy. Therefore, new therapeutic approaches are of crucial need in this clinical situation.

Methods/Design: This is a phase I trial for patients with malignant pleural mesothelioma with pleural effusion testing the safety of a fixed single dose of 1x106 adoptively transferred FAP-specific re-directed T cells given directly in the pleural effusion. Lymphocytes will be taken 21 days before transfer from peripheral blood. CD8 positive T cells will be isolated and re-programmed by retroviral transfer of a chimeric antigen receptor recognizing FAP which serves as target structure in MPM. At day 0 of the protocol, re-directed T cells will be injected in the pleural effusion and patients will be monitored for 48h under intermediate care conditions. AE, SAE, SADR and SUSAR will be monitored for 35 days and evaluated by an independent safety board to define any dose limiting toxicity (DLT). No further patient can be treated before the previous patient passed day 14 after T cell transfer. The protocol will be judged as save when no DLT occurred in the first 3 patients, or 1 DLT in 6 patients. Secondary objectives are feasibility and immune monitoring.

Discussion: Adoptive T cell transfer is a new and rapidly expanding branch of immunotherapies focusing on cancer treatment. Recently, objective responses could be observed in patients with chronic lymphatic leukemia treated with adoptively transferred CD19-specific re-directed T cells. The choice of the target antigen determines the possible on-target off-tissue toxicity of such approaches. There are reports of severe toxicity in patients who received T cells intravenously due to unexpected expression of the target antigen (on-target) in other tissues than the tumor (off-tissue). To minimize the risk of on-target off-tissue toxicity and to maximize the on-target anti-tumor effect we propose a clinical protocol with loco-regional administration of re-directed T cells. FAP-specific T cells will be directly injected in the pleural effusion of patients with MPM.

Trial Registration: ClinicalTrials.gov (NCT01722149).
Risk factors for nasal malignancies in German men: the South-German Nasal cancer study. E.M. Greiser, K.H. Greiser, W. Ahrens, et al. 2012;12:506. PubMed · Publisher · Free full text

Abstract

Background: There are few studies of the effects of nasal snuff and environmental factors on the risk of nasal cancer. This study aimed to investigate the impact of using nasal snuff and of other risk factors on the risk of nasal cancer in German men.

Methods: A population-based case-control study was conducted in the German Federal States of Bavaria and Baden-Württemberg. Tumor registries and ear, nose and throat departments provided access to patients born in 1926 or later.

Results: Telephone interviews were conducted with 427 cases (mean age 62.1 years) and 2.401 population-based controls (mean age 60.8 years). Ever-use of nasal snuff was associated with an odds ratio (OR) for nasal cancer of 1.45 (95% confidence interval [CI] 0.88-2.38) in the total study population, whereas OR in smokers was 2.01 (95% CI 1.00-4.02) and in never smokers was 1.10 (95% CI 0.43-2.80). The OR in ever-smokers vs. never-smokers was 1.60 (95% CI 1.24-2.07), with an OR of 1.06 (95% CI 1.05-1.07) per pack-year smoked, and the risk was significantly decreased after quitting smoking. Exposure to hardwood dust for at least 1 year resulted in an OR of 2.33 (95% CI 1.40-3.91) in the total population, which was further increased in never-smokers (OR 4.89, 95% CI 1.92-12.49) in analyses stratified by smoking status. The OR for nasal cancer after exposure to organic solvents for at least 1 year was 1.53 (1.17-2.01). Ever-use of nasal sprays/nasal lavage for at least 1 month rendered an OR of 1.59 (1.04-2.44). The OR after use of insecticides in homes was 1.48 (95% CI 1.04-2.11).

Conclusions: Smoking and exposure to hardwood dust were confirmed as risk factors for nasal carcinoma. There is evidence that exposure to organic solvents, and in-house use of insecticides could represent novel risk factors. Exposure to asbestos and use of nasal snuff were risk factors in smokers only.
Starvation-induced activation of ATM/Chk2/p53 signaling sensitizes cancer cells to cisplatin. Y. Shi, E. Felley-Bosco, T.M. Marti, et al. 2012;12:571. PubMed · Publisher · Free full text

Abstract

Background: Optimizing the safety and efficacy of standard chemotherapeutic agents such as cisplatin (CDDP) is of clinical relevance. Serum starvation in vitro and short-term food starvation in vivo both stress cells by the sudden depletion of paracrine growth stimulation.

Methods: The effects of serum starvation on CDDP toxicity were investigated in normal and cancer cells by assessing proliferation, cell cycle distribution and activation of DNA-damage response and of AMPK, and were compared to effects observed in cells grown in serum-containing medium. The effects of short-term food starvation on CDDP chemotherapy were assessed in xenografts-bearing mice and were compared to effects on tumor growth and/or regression determined in mice with no diet alteration.

Results: We observed that serum starvation in vitro sensitizes cancer cells to CDDP while protecting normal cells. In detail, in normal cells, serum starvation resulted in a complete arrest of cellular proliferation, i.e. depletion of BrdU-incorporation during S-phase and accumulation of the cells in the G0/G1-phase of the cell cycle. Further analysis revealed that proliferation arrest in normal cells is due to p53/p21 activation, which is AMPK-dependent and ATM-independent. In cancer cells, serum starvation also decreased the fraction of S-phase cells but to a minor extent. In contrast to normal cells, serum starvation-induced p53 activation in cancer cells is both AMPK- and ATM-dependent. Combination of CDDP with serum starvation in vitro increased the activation of ATM/Chk2/p53 signaling pathway compared to either treatment alone resulting in an enhanced sensitization of cancer cells to CDDP. Finally, short-term food starvation dramatically increased the sensitivity of human tumor xenografts to cisplatin as indicated not only by a significant growth delay, but also by the induction of complete remission in 60% of the animals bearing mesothelioma xenografts, and in 40% of the animals with lung carcinoma xenografts.

Conclusion: In normal cells, serum starvation in vitro induces a cell cycle arrest and protects from CDDP induced toxicity. In contrast, proliferation of cancer cells is only moderately reduced by serum starvation whereas CDDP toxicity is enhanced. The combination of CDDP treatment with short term food starvation improved outcome in vivo. Therefore, starvation has the potential to enhance the therapeutic index of cisplatin-based therapy.
Testing of human papillomavirus in lung cancer and non-tumor lung tissue. A. Galvan, S. Noci, F. Taverna, et al. 2012;12:512. PubMed · Publisher · Free full text

Abstract

Background: Risk factors for lung cancer, such as cigarette smoking, environmental pollution, asbestos, and genetic determinants, are well-known, whereas involvement of the human papillomavirus (HPV) is still unclear.

Methods: We examined a series of 100 lung cancer patients from Italy and the UK for the presence of HPV DNA in both lung tumor specimens and adjacent non-tumoral specimens from the same patients. Thirty-five of the most clinically relevant HPV types were assayed using PCR amplification of the highly conserved L1 region of the viral genome followed by hybridization with specific probes.

Results: No HPV was detected in tumor specimens nor in normal lung tissue of any patient.

Conclusions: These data indicate that, in this Western series, HPV is not associated with the risk of lung cancer. Our findings will help refine estimates of lung cancer risk in patients affected by a common viral infection involved in other types of human cancer.
The role of TGFBI in mesothelioma and breast cancer: association with tumor suppression. B. Li, G. Wen, Y. Zhao, et al. 2012;12:239. PubMed · Publisher · Free full text

Abstract

Background: Transforming growth factor β induced (TGFBI) product, an extracellular matrix (ECM) protein, has been implicated as a putative tumor suppressor in recent studies. Our previous findings revealed that expression of TGFBI gene is down-regulated in a variety of cancer cell lines and clinical tissue samples. In this study, ectopic expression of TGFBI was used to ascertain its role as a tumor suppressor and to determine the underlying mechanism of mesothelioma and breast cancer.

Methods: Cells were stably transfected with pRc/CMV2-TGFBI and pRc/CMV2-empty vector with Lipofectamine Plus. Ectopic expression of TGFBI was quantified by using quantitative PCR and Western-blotting. Characterization of cell viability was assessed using growth curve, clonogenic survival and soft agar growth. The potential of tumor formation was evaluated by an in vivo mouse model. Cell cycle was analyzed via flow cytometry. Expressions of p21, p53, p16 and p14 were examined using Western-blotting. Senescent cells were sorted by using a Senescence β-Galactosidase Staining Kit. Telomerase activity was measured using quantitative telomerase detection kit.

Results: In this study, an ectopic expression of TGFBI in two types of cancer cell lines, a mesothelioma cell line NCI-H28 and a breast cancer cell line MDA-MB-231 was found to have reduced the cellular growth, plating efficiency, and anchorage-independent growth. The tumorigenicity of these cancer cell lines as determined by subcutaneous inoculation in nude mice was similarly suppressed by TGFBI expression. Likewise, TGFBI expression reduced the proportion of S-phase while increased the proportion of G1 phase in these cells. The redistribution of cell cycle phase after re-expression of TGFBI was correspondent with transiently elevated expression of p21 and p53. The activities of senescence-associated β-galactosidase and telomerase were enhanced in TGFBI-transfected cells.

Conclusion: Collectively, these results imply that TGFBI plays a suppressive role in the development of mesothelioma and breast cancer cells, possibly through inhibitions of cell proliferation, delaying of G1-S phase transition, and induction of senescence.
Genes associated with prognosis after surgery for malignant pleural mesothelioma promote tumor cell survival in vitro. G.J. Gordon, R. Bueno, D.J. Sugarbaker. 2011;11:169. PubMed · Publisher · Free full text

Abstract

Background: Mesothelioma is an aggressive neoplasm with few effective treatments, one being cytoreductive surgery. We previously described a test, based on differential expression levels of four genes, to predict clinical outcome in prospectively consented mesothelioma patients after surgery. In this study, we determined whether any of these four genes could be linked to a cancer relevant phenotype.

Methods: We conducted a high-throughput RNA inhibition screen to knockdown gene expression levels of the four genes comprising the test (ARHGDIA, COBLL1, PKM2, TM4SF1) in both a human lung-derived normal and a tumor cell line using three different small inhibitory RNA molecules per gene. Successful knockdown was confirmed using quantitative RT-PCR. Detection of statistically significant changes in apoptosis and mitosis was performed using immunological assays and quantified using video-assisted microscopy at a single time-point. Changes in nuclear shape, size, and numbers were used to provide additional support of initial findings. Each experiment was conducted in triplicate. Specificity was assured by requiring that at least 2 different siRNAs produced the observed change in each cell line/time-point/gene/assay combination.

Results: Knockdown of ARHGDIA, COBLL1, and TM4SF1 resulted in 2- to 4-fold increased levels of apoptosis in normal cells (ARHGDIA only) and tumor cells (all three genes). No statistically significant changes were observed in apoptosis after knockdown of PKM2 or for mitosis after knockdown of any gene.

Conclusions: We provide evidence that ARHGDIA, COBLL1, and TM4SF1 are negative regulators of apoptosis in cultured tumor cells. These genes, and their related intracellular signaling pathways, may represent potential therapeutic targets in mesothelioma.
COX-2 inhibition improves immunotherapy and is associated with decreased numbers of myeloid-derived suppressor cells in mesothelioma. Celecoxib influences MDSC function. J.D. Veltman, M.E. Lambers, M. van Nimwegen, et al. 2010;10:464. PubMed · Publisher · Free full text

Abstract

Background: Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature cells that accumulates in tumour-bearing hosts. These cells are induced by tumour-derived factors (e.g. prostaglandins) and have a critical role in immune suppression. MDSC suppress T and NK cell function via increased expression of arginase I and production of reactive oxygen species (ROS) and nitric oxide (NO). Immune suppression by MDSC was found to be one of the main factors for immunotherapy insufficiency. Here we investigate if the in vivo immunoregulatory function of MDSC can be reversed by inhibiting prostaglandin synthesis by specific COX-2 inhibition focussing on ROS production by MDSC subtypes. In addition, we determined if dietary celecoxib treatment leads to refinement of immunotherapeutic strategies.

Methods: MDSC numbers and function were analysed during tumour progression in a murine model for mesothelioma. Mice were inoculated with mesothelioma tumour cells and treated with cyclooxygenase-2 (COX-2) inhibitor celecoxib, either as single agent or in combination with dendritic cell-based immunotherapy.

Results: We found that large numbers of infiltrating MDSC co-localise with COX-2 expression in those areas where tumour growth takes place. Celecoxib reduced prostaglandin E2 levels in vitro and in vivo. Treatment of tumour-bearing mice with dietary celecoxib prevented the local and systemic expansion of all MDSC subtypes. The function of MDSC was impaired as was noticed by reduced levels of ROS and NO and reversal of T cell tolerance; resulting in refinement of immunotherapy.

Conclusions: We conclude that celecoxib is a powerful tool to improve dendritic cell-based immunotherapy and is associated with a reduction in the numbers and suppressive function of MDSC. These data suggest that immunotherapy approaches benefit from simultaneously blocking cyclooxygenase-2 activity.
Development of an enzyme-linked immunosorbent assay for the detection of human calretinin in plasma and serum of mesothelioma patients. I. Raiko, I. Sander, D.G. Weber, et al. 2010;10:242. PubMed · Publisher · Free full text

Abstract

Background: Calretinin is one of the well-established immunohistochemical markers in the diagnostics of malignant mesothelioma (MM). Its utility as a diagnostic tool in human blood, however, is scarcely investigated. The aim of this study was to develop an enzyme-linked immunosorbent assay (ELISA) for human calretinin in blood and to assess its usefulness as a potential minimally invasive diagnostic marker for MM.

Methods: Initially, attempts were made to establish an assay using commercially available antibodies and to optimize it by including a biotin-streptavidin complex into the assay protocol. Subsequently, a novel ELISA based on polyclonal antibodies raised in rabbit immunized with human recombinant calretinin was developed. The assay performance in human serum and plasma (EDTA/heparin) and the influence of calcium concentrations on antibody recognition were studied. Stability of spiked-in calretinin in EDTA plasma under different storage conditions was also examined. In preliminary studies serum and plasma samples from 97 healthy volunteers, 35 asbestos-exposed workers, and 42 MM patients were analyzed.

Results: The mean detection range of the new ELISA was 0.12 to 8.97 ng/ml calretinin. The assay demonstrated markedly lower background and significantly higher sensitivity compared to the initially contrived assay that used commercial antibodies. Recovery rate experiments confirmed dependence of calretinin antibody recognition on calcium concentration. Calcium adjustment is necessary for calretinin measurement in EDTA plasma. Spiked-in calretinin revealed high stability in EDTA plasma when stored at room temperature, 4 degrees C, or after repeated freeze/thaw cycles. Median calretinin values in healthy volunteers, asbestos workers, and MM patients were 0.20, 0.33, and 0.84 ng/ml, respectively (p < 0.0001 for healthy vs. MM, p = 0.0036 for healthy vs. asbestos-exposed, p < 0.0001 for asbestos-exposed vs. MM). Median values in patients with epithelioid and biphasic MM were similar. No influence of age, gender, smoking status, or type of medium (plasma/serum) on calretinin values was found.

Conclusions: The novel assay is highly sensitive and applicable to human serum and plasma. Calretinin appears to be a promising marker for the blood-based detection of MM and might complement other markers. However, further studies are required to prove its usefulness in the diagnosis of MM patients.
In vitro and in vivo characterization of highly purified human mesothelioma derived cells. A. Melotti, A. Daga, D. Marubbi, et al. 2010;10:54. PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma is a rare disease known to be resistant to conventional therapies. A better understanding of mesothelioma biology may provide the rationale for new therapeutic strategies. In this regard, tumor cell lines development has been an important tool to study the biological properties of many tumors. However all the cell lines established so far were grown in medium containing at least 10% serum, and it has been shown that primary cell lines cultured under these conditions lose their ability to differentiate, acquire gene expression profiles that differ from that of tissue specific stem cells or the primary tumor they derive from, and in some cases are neither clonogenic nor tumorigenic. Our work was aimed to establish from fresh human pleural mesothelioma samples cell cultures maintaining tumorigenic properties.

Methods: The primary cell cultures, obtained from four human pleural mesotheliomas, were expanded in vitro in a low serum proliferation-permissive medium and the expression of different markers as well as the tumorigenicity in immunodeficient mice was evaluated.

Results: The established mesothelioma cell cultures are able to engraft, after pseudo orthotopic intraperitoneal transplantation, in immunodeficient mouse and maintain this ability to after serial transplantation. Our cell cultures were strongly positive for CD46, CD47, CD56 and CD63 and were also strongly positive for some markers never described before in mesothelioma cell lines, including CD55, CD90 and CD99. By real time PCR we found that our cell lines expressed high mRNA levels of typical mesothelioma markers as mesothelin (MSLN) and calretinin (CALB2), and of BMI-1, a stemness marker, and DKK1, a potent Wingless [WNT] inhibitor.

Conclusions: These cell cultures may provide a valuable in vitro and in vivo model to investigate mesothelioma biology. The identification of new mesothelioma markers may be useful for diagnosis and/or prognosis of this neoplasia as well as for isolation of mesothelioma tumor initiating cells.
Onconase responsive genes in human mesothelioma cells: implications for an RNA damaging therapeutic agent. D.A. Altomare, S.M. Rybak, J. Pei, et al. 2010;10:34. PubMed · Publisher · Free full text

Abstract

Background: Onconase represents a new class of RNA-damaging drugs. Mechanistically, Onconase is thought to internalize, where it degrades intracellular RNAs such as tRNA and double-stranded RNA, and thereby suppresses protein synthesis. However, there may be additional or alternative mechanism(s) of action.

Methods: In this study, microarray analysis was used to compare gene expression profiles in untreated human malignant mesothelioma (MM) cell lines and cells exposed to 5 microg/ml Onconase for 24 h. A total of 155 genes were found to be regulated by Onconase that were common to both epithelial and biphasic MM cell lines. Some of these genes are known to significantly affect apoptosis (IL-24, TNFAIP3), transcription (ATF3, DDIT3, MAFF, HDAC9, SNAPC1) or inflammation and the immune response (IL-6, COX-2). RT-PCR analysis of selected up- or down-regulated genes treated with varying doses and times of Onconase generally confirmed the expression array findings in four MM cell lines.

Results: Onconase treatment consistently resulted in up-regulation of IL-24, previously shown to have tumor suppressive activity, as well as ATF3 and IL-6. Induction of ATF3 and the pro-apoptotic factor IL-24 by Onconase was highest in the two most responsive MM cell lines, as defined by DNA fragmentation analysis. In addition to apoptosis, gene ontology analysis indicated that pathways impacted by Onconase include MAPK signaling, cytokine-cytokine-receptor interactions, and Jak-STAT signaling.

Conclusions: These results provide a broad picture of gene activity after treatment with a drug that targets small non-coding RNAs and contribute to our overall understanding of MM cell response to Onconase as a therapeutic strategy. The findings provide insights regarding mechanisms that may contribute to the efficacy of this novel drug in clinical trials of MM patients who have failed first line chemotherapy or radiation treatment.

2000s

Certified causes of death in patients with mesothelioma in South East England. C. Okello, T. Treasure, A.G. Nicholson, et al. 2009;9:28. PubMed · Publisher · Free full text

Abstract

Background: Mesothelioma is a highly fatal cancer that is caused by exposure to asbestos fibres. In many populations, the occurrence of mesothelioma is monitored with the use of mortality data from death certification. We examine certified causes of death of patients who have been diagnosed with mesothelioma, and assess the validity of death certification data as a proxy for mesothelioma incidence.

Methods: We extracted mesothelioma registrations in the South East of England area between 2000 and 2004 from the Thames Cancer Registry database. We retained for analysis 2200 patients who had died at the time of analysis, after having excluded seven dead cases where the causes of death were not known to the cancer registry. The 2200 deaths were classified hierarchically to identify (1) mesothelioma deaths, (2) deaths certified as lung cancer deaths or (3) deaths from unspecified cancer, and (4) deaths from other causes.

Results: 87% of the patients had mesothelioma mentioned on the death certificate. 6% had no mention of mesothelioma but included lung cancer as a cause of death. Another 6% had no mention of mesothelioma or lung cancer, but included an unspecified cancer as a cause of death. Lastly, 2% had other causes of death specified on the death certificate.

Conclusion: This analysis suggests that official mortality data may underestimate the true occurrence of mesothelioma by around 10%.
Chrysotile effects on human lung cell carcinoma in culture: 3-D reconstruction and DNA quantification by image analysis. B.A. Cortez, G.M. Machado-Santelli. 2008;8:181. PubMed · Publisher · Free full text

Abstract

Background: Chrysotile is considered less harmful to human health than other types of asbestos fibers. Its clearance from the lung is faster and, in comparison to amphibole forms of asbestos, chrysotile asbestos fail to accumulate in the lung tissue due to a mechanism involving fibers fragmentation in short pieces. Short exposure to chrysotile has not been associated with any histopathological alteration of lung tissue.

Methods: The present work focuses on the association of small chrysotile fibers with interphasic and mitotic human lung cancer cells in culture, using for analyses confocal laser scanning microscopy and 3D reconstructions. The main goal was to perform the analysis of abnormalities in mitosis of fibers-containing cells as well as to quantify nuclear DNA content of treated cells during their recovery in fiber-free culture medium.

Results: HK2 cells treated with chrysotile for 48 h and recovered in additional periods of 24, 48 and 72 h in normal medium showed increased frequency of multinucleated and apoptotic cells. DNA ploidy of the cells submitted to the same chrysotile treatment schedules showed enhanced aneuploidy values. The results were consistent with the high frequency of multipolar spindles observed and with the presence of fibers in the intercellular bridge during cytokinesis.

Conclusion: The present data show that 48 h chrysotile exposure can cause centrosome amplification, apoptosis and aneuploid cell formation even when long periods of recovery were provided. Internalized fibers seem to interact with the chromatin during mitosis, and they could also interfere in cytokinesis, leading to cytokinesis failure which forms aneuploid or multinucleated cells with centrosome amplification.
National Mesothelioma Virtual Bank: a standard based biospecimen and clinical data resource to enhance translational research. W. Amin, A.V. Parwani, L. Schmandt, et al. 2008;8:236. PubMed · Publisher · Free full text

Abstract

Background: Advances in translational research have led to the need for well characterized biospecimens for research. The National Mesothelioma Virtual Bank is an initiative which collects annotated datasets relevant to human mesothelioma to develop an enterprising biospecimen resource to fulfill researchers' need.

Methods: The National Mesothelioma Virtual Bank architecture is based on three major components: (a) common data elements (based on College of American Pathologists protocol and National North American Association of Central Cancer Registries standards), (b) clinical and epidemiologic data annotation, and (c) data query tools. These tools work interoperably to standardize the entire process of annotation. The National Mesothelioma Virtual Bank tool is based upon the caTISSUE Clinical Annotation Engine, developed by the University of Pittsburgh in cooperation with the Cancer Biomedical Informatics Grid (caBIG, see http://cabig.nci.nih.gov). This application provides a web-based system for annotating, importing and searching mesothelioma cases. The underlying information model is constructed utilizing Unified Modeling Language class diagrams, hierarchical relationships and Enterprise Architect software.

Result: The database provides researchers real-time access to richly annotated specimens and integral information related to mesothelioma. The data disclosed is tightly regulated depending upon users' authorization and depending on the participating institute that is amenable to the local Institutional Review Board and regulation committee reviews.

Conclusion: The National Mesothelioma Virtual Bank currently has over 600 annotated cases available for researchers that include paraffin embedded tissues, tissue microarrays, serum and genomic DNA. The National Mesothelioma Virtual Bank is a virtual biospecimen registry with robust translational biomedical informatics support to facilitate basic science, clinical, and translational research. Furthermore, it protects patient privacy by disclosing only de-identified datasets to assure that biospecimens can be made accessible to researchers.
The development and deployment of Common Data Elements for tissue banks for translational research in cancer - an emerging standard based approach for the Mesothelioma Virtual Tissue Bank. S.K. Mohanty, A.T. Mistry, W. Amin, et al. 2008;8:91. PubMed · Publisher · Free full text

Abstract

Background: Recent advances in genomics, proteomics, and the increasing demands for biomarker validation studies have catalyzed changes in the landscape of cancer research, fueling the development of tissue banks for translational research. A result of this transformation is the need for sufficient quantities of clinically annotated and well-characterized biospecimens to support the growing needs of the cancer research community. Clinical annotation allows samples to be better matched to the research question at hand and ensures that experimental results are better understood and can be verified. To facilitate and standardize such annotation in bio-repositories, we have combined three accepted and complementary sets of data standards: the College of American Pathologists (CAP) Cancer Checklists, the protocols recommended by the Association of Directors of Anatomic and Surgical Pathology (ADASP) for pathology data, and the North American Association of Central Cancer Registry (NAACCR) elements for epidemiology, therapy and follow-up data. Combining these approaches creates a set of International Standards Organization (ISO) - compliant Common Data Elements (CDEs) for the mesothelioma tissue banking initiative supported by the National Institute for Occupational Safety and Health (NIOSH) of the Center for Disease Control and Prevention (CDC).

Methods: The purpose of the project is to develop a core set of data elements for annotating mesothelioma specimens, following standards established by the CAP checklist, ADASP cancer protocols, and the NAACCR elements. We have associated these elements with modeling architecture to enhance both syntactic and semantic interoperability. The system has a Java-based multi-tiered architecture based on Unified Modeling Language (UML).

Results: Common Data Elements were developed using controlled vocabulary, ontology and semantic modeling methodology. The CDEs for each case are of different types: demographic, epidemiologic data, clinical history, pathology data including block level annotation, and follow-up data including treatment, recurrence and vital status. The end result of such an effort would eventually provide an increased sample set to the researchers, and makes the system interoperable between institutions.

Conclusion: The CAP, ADASP and the NAACCR elements represent widely established data elements that are utilized in many cancer centers. Herein, we have shown these representations can be combined and formalized to create a core set of annotations for banked mesothelioma specimens. Because these data elements are collected as part of the normal workflow of a medical center, data sets developed on the basis of these elements can be easily implemented and maintained.
Characterization of human malignant mesothelioma cell lines orthotopically implanted in the pleural cavity of immunodeficient mice for their ability to grow and form metastasis. D. Martarelli, A. Catalano, A. Procopio, et al. 2006;6:130. PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is a tumor known to be resistant to conventional therapies. Thus, an in vivo model can represent an important tool for assessing the efficacy of novel approaches in the treatment of MPM.Presently, human MPM cells have been grown orthotopically in mice upon transplantation of tumor masses or tumor cell suspensions following surgery. In these models however, surgery can interfere with the tumor growth and the early stages of tumor development cannot be easily explored. Finally, results may not be so accurate due to implantation of potentially different tumor samples in different experimental groups.Our work aimed at establishing a nude mouse model xenotransplanted with human MPM cell lines in which tumor progression exhibits some features of the human disease.

Methods: Three distinct human MPM cell lines previously established from MPM patients displaying two different phenotypes, biphasic (MM-B1 and IST-Mes3) and epithelioid (IST-Mes2), were directly injected into the pleural cavity of nude mice. At different times, mice were sacrificed for autopsy, tumor nodules were counted and then removed for histology. Presence of metastases in visceral organs was also monitored.

Results: IST-Mes2 cells were unable to grow in nude mice. MM-B1 and IST-Mes3 cells were capable of growing in nude mice and formed tumor nodules in the pleura. Post-mortem examination showed that MPM cells progressively colonized the parietal and visceral pleura, the diaphragm, the mediastinum and, lastly the lung parenchyma. No pneumo-thorax was evidenced in the mice. Pleural effusions as well as lymph node metastases were observed only at later times.

Conclusion: This model mimics the progression of human malignant mesothelioma and it is easy to perform and reproducible; therefore it can be useful to study human MPM biology and evaluate the efficacy of novel therapies.
Dramatic tumour response to pemetrexed single-agent in an elderly patient with malignant peritoneal mesothelioma: a case report. G. Fasola, F. Puglisi, A. Follador, et al. 2006;6:289. Case report PubMed · Publisher · Free full text

Abstract

Background: To date, there is no standard treatment for unresectable malignant peritoneal mesothelioma; either best supportive care or systemic chemotherapy with palliative intent are accepted options.

Case Presentation: Here, we report the case of a 79-year old patient with malignant peritoneal mesothelioma who was treated with pemetrexed single-agent and obtained an impressive long-lasting response.

Conclusion: Single-agent pemetrexed is a treatment option for malignant peritoneal mesothelioma in selected elderly patients or in patients with unpaired performance status.
Plasma osteopontin levels in patients with head and neck cancer and cervix cancer are critically dependent on the choice of ELISA system. D. Vordermark, H.M. Said, A. Katzer, et al. 2006;6:207. PubMed · Publisher · Free full text

Abstract

Background: The tumor-associated glycoprotein osteopontin (OPN) is discussed as a plasma surrogate marker of tumor hypoxia and as an indicator of the presence of pleural mesothelioma in asbestos-exposed individuals. The clinical introduction of plasma OPN measurements requires the availability of a reliable enzyme-linked immunosorbence assay (ELISA).

Methods: We compared previously described and currently available ELISA systems on 88 archival plasma samples obtained from patients with head and neck or cervix cancer between 20 days before and 171 after the start of radiotherapy.

Results: Median (range) plasma OPN levels were 667 (148.8-2095) ng/ml and 9.8 (3.5-189.5) ng/ml for a previously described and a newly marketed assay, respectively. Although results for different assays were significantly correlated (r = 0.38, p < 0.05, Spearman rank test), between-assay factors ranged from 2.0 to 217.9 (median 74.6) in individual patients. OPN levels in cervix cancer patients were comparable to those of head and neck cancer patients.

Conclusion: Commercially available OPN ELISA systems produce different absolute plasma OPN levels, compromising a comparison of individual patient data with published results. However, different assays appear to have a similar capacity to rank patients according to plasma OPN level. A review of literature data suggests that plasma OPN levels measured even with identical ELISA systems can only be compared with caution.

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