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Diagnostic and prognostic biomarkers for malignant mesothelioma: an update
Chen, Zhongjian; Gaudino, Giovanni; Pass, Harvey I; Carbone, Michele; Yang, Haining
Malignant mesothelioma (MM) is an aggressive and lethal cancer, mostly related to inhalation of asbestos and erionite fibers. MM is associated with poor prognosis, because of its resistance to current therapies, even if higher survival occurs in patients diagnosed and treated when at stage I of the disease. However, these do not exceed 5% of the total number of cases, due to the inadequacy of the existing biomarkers for early and accurate diagnosis. Therefore, new effective biomarkers are needed for MM detection at earlier stages and to develop tailored therapies. Here we review the most promising biomarkers in MM to date: mesothelin, soluble mesothelin-related peptides (SMRPs), megakaryocyte potentiating factor (MPF), Osteopontin (OPN), Fibulin-3, high mobility group B1 (HMGB1), microRNAs (miRNAs), multiplex protein signatures. The validation of these biomarkers will allow their use, alone or in combination, for monitoring individuals from cohorts at risk of MM and attaining early detection of MM that is instrumental in improving patient survival.
PMCID:5504120
PMID: 28713671
ISSN: 2218-6751
CID: 2639912
Pleural IMRT after Lung-Sparing Cytoreduction for Mesothelioma: Mature Enough to Randomize [Editorial]
Pass, Harvey I
PMID: 28532562
ISSN: 1556-1380
CID: 2574672
Computed Tomography Screening for Lung Cancer: Mediastinal Lymph Node Resection in Stage IA Nonsmall Cell Lung Cancer Manifesting as Subsolid and Solid Nodules
Flores, Raja M; Nicastri, Daniel; Bauer, Thomas; Aye, Ralph; Andaz, Shahriyour; Kohman, Leslie; Sheppard, Barry; Mayfield, William; Thurer, Richard; Korst, Robert; Straznicka, Michaela; Grannis, Fred; Pass, Harvey; Connery, Cliff; Yip, Rowena; Smith, James P; Yankelevitz, David F; Henschke, Claudia I; Altorki, Nasser K
OBJECTIVE: To compare long-term survival rates of patients with first, primary, clinical stage IA nonsmall cell lung cancer from a large cohort undergoing computed tomography screening with and without mediastinal lymph node resection (MLNR) under an Institutional Review Board-approved common protocol from 1992 to 2014. BACKGROUND: Assessing survival differences of patients with and without MLNR manifesting as solid and subsolid nodules. METHODS: Long-term Kaplan-Meier (K-M) survival rates for those with and without MLNR were compared and Cox regression analyses were used to adjust for demographic, computed tomography, and surgical covariates. RESULTS: The long-term K-M rates for 462 with and 145 without MLNR was 92% versus 96% (P = 0.19), respectively. For 203 patients with a subsolid nodule, 151 with and 52 without MLNR, the rate was 100%. For the 404 patients with a solid nodule, 311 with and 93 without MLNR, the rate was 87% versus 94% (P = 0.24) and Cox regression showed no statistically significant difference (P = 0.28) when adjusted for all covariates. Risk of dying increased significantly with increasing decades of age (hazard ratio [HR] 2.3, 95% confidence interval [CI] 1.4-3.8), centrally located tumor (HR 2.5, 95% CI 1.2-5.2), tumor size 21 to 30 mm (HR 2.7, 95% CI 1.2-6.0), and invasion beyond the lung stroma (HR 3.0, 95% CI 1.4-6.1). For the 346 patients with MLNR, tumor size was 20 mm or less; K-M rates for the 269 patients with and 169 patients without MLNR were also not significantly different (HR 2.1, P = 0.24). CONCLUSIONS: It is not mandatory to perform MLNR when screen-diagnosed nonsmall cell lung cancer manifests as a subsolid nodule.
PMCID:5995117
PMID: 27232256
ISSN: 1528-1140
CID: 2115192
HMGB1 targeting by ethyl pyruvate suppresses malignant phenotype of human mesothelioma
Pellegrini, Laura; Xue, Jiaming; Larson, David; Pastorino, Sandra; Jube, Sandro; Forest, Kelly H; Saad-Jube, Zeyana Salim; Napolitano, Andrea; Pagano, Ian; Negi, Vishal S; Bianchi, Marco E; Morris, Paul; Pass, Harvey I; Gaudino, Giovanni; Carbone, Michele; Yang, Haining
Human malignant mesothelioma (MM) is an aggressive cancer linked to asbestos and erionite exposure. We previously reported that High-Mobility Group Box-1 protein (HMGB1), a prototypic damage-associated molecular pattern, drives MM development and sustains MM progression. Moreover, we demonstrated that targeting HMGB1 inhibited MM cell growth and motility in vitro, reduced tumor growth in vivo, and prolonged survival of MM-bearing mice. Ethyl pyruvate (EP), the ethyl ester of pyruvic acid, has been shown to be an effective HMGB1 inhibitor in inflammation-related diseases and several cancers. Here, we studied the effect of EP on the malignant phenotype of MM cells in tissue culture and on tumor growth in vivo using an orthotopic MM xenograft model. We found that EP impairs HMGB1 secretion by MM cells leading to reduced RAGE expression and NF-kappaB activation. As a consequence, EP impaired cell motility, cell proliferation, and anchorage-independent growth of MM cells. Moreover, EP reduced HMGB1 serum levels in mice and inhibited the growth of MM xenografts.Our results indicate that EP effectively hampers the malignant phenotype of MM, offering a novel potential therapeutic approach to patients afflicted with this dismal disease.
PMCID:5410252
PMID: 28186988
ISSN: 1949-2553
CID: 2437592
Association of Asbestos Exposure With Malignant Mesothelioma Incidence in Eastern China
Mao, Weimin; Zhang, Xing; Guo, Zhenying; Gao, Zhibin; Pass, Harvey I; Yang, Haining; Carbone, Michele
PMCID:5569880
PMID: 27918607
ISSN: 2374-2445
CID: 2354192
Targeting the RON/MET/TAM signalling network in mesothelioma [Meeting Abstract]
Baird, A-M; Jarzabek, M; Shiels, L; Raeppel, S; Finn, S; Cuffe, S; Pass, HI; Schmitt-Opitz, I; Byrne, AT; Gray, SG
ISI:000405512800146
ISSN: 1569-8041
CID: 2650262
Improving the accuracy of mesothelioma diagnosis in China
Guo, Zhenying; Carbone, Michele; Zhang, Xing; Su, Dan; Sun, Wenyong; Lou, Jianlin; Gao, Zhibin; Shao, Dichu; Chen, Junqiang; Zhang, Gu; Hu, Jinlin; Chen, Kaiyan; Wang, Fang; Pass, Harvey I; Yu, Herbert; Napolitano, Andrea; Yang, Haining; Mao, Weiming
BACKGROUND: In the Western World malignant mesothelioma (MM) is most prevalent in the pleura of older males professionally exposed to asbestos. Information about MM from rapidly industrializing countries, such as China, is minimal. There is concern that a proportion of MM diagnoses in China may be incorrect because most Chinese physicians do not have experience diagnosing this rare cancer. We recently reported an unusual high incidence of peritoneal MM among Eastern Chinese female patients. Here, we review the accuracy of MM diagnoses in China and provide suggestions to improve the accuracy of diagnosis. METHODS: We reviewed 92 pathological diagnosis of MM during 2002-2015 from two reference centers in the province of Zhejiang, Eastern China. We performed, a large set of immunohistochemical (IHC) analyses to increase the reliability of the diagnosis. RESULTS: We confirmed the MM diagnosis in 12/34 (35.3%) of the pleural tumors, in 38/56 (67.9%) of the peritoneal tumors, and in 2/2 (100%) of the MM of the tunica vaginalis. MM were characterized by tumor cells showing nuclear WT1 and calretinin staining and by strong membranous staining for cytokeratin (CK) CAM5.2. The epithelial markers, CEA, TTF1, MOC31, BerEP4, p63, p40, PAX8, ER and PR were negative. BAP1 nuclear staining was lost in percentages similar to what reported for samples from Western countries. CONCLUSIONS: Our findings suggest that MM -especially in its pleural localization- is often misdiagnosed in Eastern China. Identifying pitfalls and possible solutions in the pathological diagnosis of MM will impact both standard of care and research in China.
PMCID:5567857
PMID: 28007630
ISSN: 1556-1380
CID: 2374542
FTY720 inhibits mesothelioma growth in vitro and in a syngeneic mouse model
Szymiczek, Agata; Pastorino, Sandra; Larson, David; Tanji, Mika; Pellegrini, Laura; Xue, Jiaming; Li, Shuangjing; Giorgi, Carlotta; Pinton, Paolo; Takinishi, Yasutaka; Pass, Harvey I; Furuya, Hideki; Gaudino, Giovanni; Napolitano, Andrea; Carbone, Michele; Yang, Haining
BACKGROUND: Malignant mesothelioma (MM) is a very aggressive type of cancer, with a dismal prognosis and inherent resistance to chemotherapeutics. Development and evaluation of new therapeutic approaches is highly needed. Immunosuppressant FTY720, approved for multiple sclerosis treatment, has recently raised attention for its anti-tumor activity in a variety of cancers. However, its therapeutic potential in MM has not been evaluated yet. METHODS: Cell viability and anchorage-independent growth were evaluated in a panel of MM cell lines and human mesothelial cells (HM) upon FTY720 treatment to assess in vitro anti-tumor efficacy. The mechanism of action of FTY720 in MM was assessed by measuring the activity of phosphatase protein 2A (PP2A)-a major target of FTY720. The binding of the endogenous inhibitor SET to PP2A in presence of FTY720 was evaluated by immunoblotting and immunoprecipitation. Signaling and activation of programmed cell death were evaluated by immunoblotting and flow cytometry. A syngeneic mouse model was used to evaluate anti-tumor efficacy and toxicity profile of FTY720 in vivo. RESULTS: We show that FTY720 significantly suppressed MM cell viability and anchorage-independent growth without affecting normal HM cells. FTY720 inhibited the phosphatase activity of PP2A by displacement of SET protein, which appeared overexpressed in MM, as compared to HM cells. FTY720 promoted AKT dephosphorylation and Bcl-2 degradation, leading to induction of programmed cell death, as demonstrated by caspase-3 and PARP activation, as well as by cytochrome c and AIF intracellular translocation. Moreover, FTY720 administration in vivo effectively reduced tumor burden in mice without apparent toxicity. CONCLUSIONS: Our preclinical data indicate that FTY720 is a potentially promising therapeutic agent for MM treatment.
PMCID:5353897
PMID: 28298211
ISSN: 1479-5876
CID: 2488692
Proteomic analysis of paired malignant and non-malignant tissues from patients with NSCLC adenocarcinoma identified changes in translation initiation factors potentially important in oncogenesis [Meeting Abstract]
Miyamoto, Suzanne; Fahrmann, Johannes F; Grapov, Dmitry; Phinney, Brett; Pass, Harvey
ISI:000397860300011
ISSN: 1538-7445
CID: 2528982
Integrated Metabolomics and Proteomics Highlight Altered Nicotinamide- and Polyamine Pathways in Lung Adenocarcinoma
Fahrmann, Johannes F; Grapov, Dmitry D; Wanichthanarak, Kwanjeera; DeFelice, Brian C; Salemi, Michelle R; Rom, William N; Gandara, David R; Phinney, Brett S; Fiehn, Oliver; Pass, Harvey; Miyamoto, Suzanne
Lung cancer is the leading cause of cancer mortality in the United States with non-small cell lung cancer (NSCLC) adenocarcinoma being the most common histological type. Early perturbations in cellular metabolism are a hallmark of cancer, but the extent of these changes in early stage lung adenocarcinoma remains largely unknown. In the current study, an integrated metabolomics and proteomics approach was utilized to characterize the biochemical and molecular alterations between malignant and matched control tissue from 27 subjects diagnosed with early stage lung adenocarcinoma. Differential analysis identified 71 metabolites and 1102 proteins that delineated tumor from control tissue. Integrated results indicated four major metabolic changes in early stage adenocarcinoma: (1) increased glycosylation and glutaminolysis; (2) elevated Nrf2 activation; (3) increase in nicotinic and nicotinamide salvaging pathways; and (4) elevated polyamine biosynthesis linked to differential regulation of the SAM/nicotinamide methyl-donor pathway. Genomic data from publicly available databases were included to strengthen proteomic findings. Our findings provide insight into the biochemical and molecular biological reprogramming that may accompanies early stage lung tumorigenesis and highlight potential therapeutic targets.
PMCID:5862279
PMID: 28049629
ISSN: 1460-2180
CID: 2692712