bims-mesote Biomed News
on Mesothelioma
Issue of 2021‒02‒14
fourteen papers selected by
Laura Mannarino
Mario Negri Institute


  1. Cancers (Basel). 2021 Feb 06. pii: 658. [Epub ahead of print]13(4):
    Vogl M, Rosenmayr A, Bohanes T, Scheed A, Brndiar M, Stubenberger E, Ghanim B.
      Malignant pleural mesothelioma (MPM) is an aggressive disease with limited treatment response and devastating prognosis. Exposure to asbestos and chronic inflammation are acknowledged as main risk factors. Since immune therapy evolved as a promising novel treatment modality, we want to reevaluate and summarize the role of the inflammatory system in MPM. This review focuses on local tumor associated inflammation on the one hand and systemic inflammatory markers, and their impact on MPM outcome, on the other hand. Identification of new biomarkers helps to select optimal patient tailored therapy, avoid ineffective treatment with its related side effects and consequently improves patient's outcome in this rare disease. Additionally, a better understanding of the tumor promoting and tumor suppressing inflammatory processes, influencing MPM pathogenesis and progression, might also reveal possible new targets for MPM treatment. After reviewing the currently available literature and according to our own research, it is concluded that the suppression of the specific immune system and the activation of its innate counterpart are crucial drivers of MPM aggressiveness translating to poor patient outcome.
    Keywords:  immune therapy; infiltrating immune cells; inflammation; malignant pleural mesothelioma; predictive biomarker; prognostic biomarker
    DOI:  https://doi.org/10.3390/cancers13040658
  2. Oncol Lett. 2021 Feb;21(2): 128
    Fontana V, Pistillo MP, Vigani A, Canessa PA, Berisso G, Giannoni U, Ferro P, Franceschini MC, Carosio R, Tonarelli M, Dessanti P, Roncella S.
      Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor survival rates. Therefore, it is essential to have effective biological markers predicting the course of the disease and prognosis. The aim of the present study was to highlight the prognostic significance of serum soluble mesothelin-related protein (Se-SMRP) in patients with MPM at diagnosis. Se-SMRP was determined in 60 patients using an ELISA commercial kit. Se-SMRP levels were subdivided into three tertile-based categories and in each category overall survival (OS) indexes were determined using the Kaplan-Meier and Cox regression analyses. The association between Se-SMRP levels and OS was also assessed by restricted cubic spline (RCS) analysis. No notable differences in the Kaplan-Meier probabilities were identified across the Se-SMRP categories (<0.66 nM, 0.66-1.46 nM, >1.46 nM) although an upward trend in death rate ratios (RR) was pointed out by comparing the higher (RR=1.95) and intermediate (RR=1.86) categories with the lower category (RR=1.00). In addition, such an increasing tendency, particularly when the biomarker exceeded 1.0 nM, was confirmed by an RCS function of Se-SMPR levels fitted to survival data using the Cox regression equation. The present study provided evidence in favor of a prognostic value of Se-SMRP in patients with MPM.
    Keywords:  mesothelin; mesothelioma; prognosis; serum; survival
    DOI:  https://doi.org/10.3892/ol.2020.12389
  3. J Clin Med. 2021 Feb 08. pii: 648. [Epub ahead of print]10(4):
    Lococo F.
      Malignant pleural mesothelioma (MPM) is a rare but highly malignant disease of the pleura usually related to asbestos exposure [...].
    DOI:  https://doi.org/10.3390/jcm10040648
  4. Pleura Peritoneum. 2020 Nov;5(4): 20200131
    Aujayeb A, Jackson K.
      Objectives: Local anesthetic medical thoracoscopy (LAT) is a well-established diagnostic, therapeutic, and preventative intervention in undiagnosed pleural effusions with a high diagnostic sensitivity and low complication rates. There is a large variability in practice. We describe a nine-year experience in a large district general hospital in England.Methods: Two hundred seventy-five patients had LAT between January 2010 and December 2018. Data on outcomes and complications were obtained from the patients' notes, electronic records, laboratory, and radiographic findings.
    Results: The main diagnoses were malignant pleural mesothelioma (MPM) (n=110, 40%), chronic inflammation/fibrinous pleuritis (77, 28%), lung cancer (26, 9.5%), and breast cancer (16, 6%). LAT failed to diagnose cancer in 7/275 patients (false-negative rate 2.5%, diagnostic sensitivity 97.5%). Out of the 105 patients with chronic inflammation/fibrinous pleuritis or atypical proliferative processes, 21 (20%) were subsequently diagnosed with malignancy. Talcum pleurodesis was performed in 146 patients, and was successful in 86%. Seventy eight (28%) patients had trapped lung; 27 of those had a repeat procedure. The median length of stay was 3.96 days. There was one hospital death (0.3% mortality). Complications of LAT included pleural (3, 1%) and wound infections (4, 1.4%), persistent air leaks (9, 3.2%), subcutaneous emphysema (10, 3.6%), and tumor extension to the access port (1, 0.3%).
    Conclusions: In this cohort, LAT was safe, effective, and enabled high diagnostic sensitivity. Further areas of study include optimal sedation and anesthetic pathways and combining LAT with indwelling pleural catheters (IPC).
    Keywords:  mesothelioma; pleural effusion; thoracoscopy
    DOI:  https://doi.org/10.1515/pp-2020-0131
  5. Lung Cancer. 2021 Jan 14. pii: S0169-5002(21)00029-5. [Epub ahead of print]154 5-12
    Katz SI, Roshkovan L, Berger I, Friedberg JS, Alley EW, Simone CB, Haas AR, Cengel KA, Sterman DH, Albelda SM.
      OBJECTIVES: Soluble mesothelin-related protein (SMRP) and fibulin-3 serum levels may serve as diagnostic and prognostic biomarkers of malignant pleural mesothelioma (MPM). Here, we evaluate these markers for correlation to tumor volume, prognosis and response assessment in a clinical trial of immunogene therapy in combination with chemotherapy.MATERIALS AND METHODS: Serial serum levels of SMRP and fibulin-3 were measured in adult patients with biopsy-proven MPM enrolled in two prospective clinical trials. Pre-therapy computed tomography (CT) measurements of tumor burden were calculated and correlated with pre-therapy serum SMRP and fibulin-3 levels in these two trials. Serological data were also correlated with radiological assessment of response using Modified RECIST criteria over the first 6 months of intrapleural delivery of adenovirus-IFN alpha (Ad.IFN-α) combined with chemotherapy.
    RESULTS: A cohort of 58 patients who enrolled in either a photodynamic therapy trial or immunotherapy clinical trial had available imaging and SMRP serological data for analysis of whom 45 patients had serological fibulin-3 data. The cohort mean total tumor volume was 387 cm3 (STD 561 cm3). Serum SMRP was detectable in 57 of 58 patients (mean 3.8 nM, STD 6.0). Serum fibulin-3 was detected in 44 of 45 patients (mean 23 ng/mL, STD 14). At pre-therapy baseline in these two trials, there was a strong correlation between tumor volume and serum SMRP levels (r = 0.61, p < 0.001), and a moderate correlation between tumor volume and serum fibulin-3 levels (r = 0.36, p = 0.014). Twenty-eight patients in the immunotherapy trial had longitudinal serologic and radiographic data. Fold-changes in SMRP and fibulin-3 did not show significant correlations with modified RECIST measurements.
    CONCLUSIONS: Although our data show correlations of SMRP and fibulin-3 with initial tumor volumes as measured by CT scanning, the use of SMRP and fibulin-3 as serological biomarkers in the immunotherapy trial were not useful in following tumor response longitudinally.
    Keywords:  Ad.IFN; Biomarkers; Computed tomography; Fibulin; Mesothelin; Mesothelioma; Volumes
    DOI:  https://doi.org/10.1016/j.lungcan.2021.01.011
  6. Cancers (Basel). 2021 Jan 29. pii: 508. [Epub ahead of print]13(3):
    Di Gregorio E, Miolo G, Saorin A, Muraro E, Cangemi M, Revelant A, Minatel E, Trovò M, Steffan A, Corona G.
      Radical hemithoracic radiotherapy (RHRT) represents an advanced therapeutic option able to improve overall survival of malignant pleural mesothelioma patients. This study aims to investigate the systemic effects of this radiotherapy modality on the serum metabolome and their potential implications in determining the individual clinical outcome. Nineteen patients undergoing RHRT at the dose of 50 Gy in 25 fractions were enrolled. Serum targeted metabolomics profiles were investigated at baseline and the end of radiotherapy by liquid chromatography and tandem mass spectrometry. Univariate and multivariate OPLS-DA analyses were applied to study the serum metabolomics changes induced by RHRT while PLS regression analysis to evaluate the association between such changes and overall survival. RHRT was found to affect almost all investigated metabolites classes, in particular, the amino acids citrulline and taurine, the C14, C18:1 and C18:2 acyl-carnitines as well as the unsaturated long chain phosphatidylcholines PC ae 42:5, PC ae 44:5 and PC ae 44:6 were significantly decreased. The enrichment analysis showed arginine metabolism and the polyamine biosynthesis as the most perturbed pathways. Moreover, specific metabolic changes encompassing the amino acids and acyl-carnitines resulted in association with the clinical outcome accounting for about 60% of the interpatients overall survival variability. This study highlighted that RHRT can induce profound systemic metabolic effects some of which may have a significant prognostic value. The integration of metabolomics in the clinical assessment of the malignant pleural mesothelioma could be useful to better identify the patients who can achieve the best benefit from the RHRT treatment.
    Keywords:  biomarkers; cancers; mesothelioma; metabolomics; radiotherapy
    DOI:  https://doi.org/10.3390/cancers13030508
  7. Virchows Arch. 2021 Feb 11.
    Piao ZH, Zhou XC, Chen JY.
      Sarcomatoid malignant mesothelioma (SMM) tends to occur in the pleura and is morphologically similar to lung sarcomatoid carcinoma (LSC) and organizing pleuritis (OP). Because SMM often does not express mesothelial markers, it is very difficult to distinguish from LSC and OP. GATA-binding protein 3 (GATA3) is a specific immunohistochemical (IHC) marker of breast and urothelial carcinoma. We routinely find that GATA is expressed in MM; however, GATA3 expression in SMM and its reference value for distinguishing SMM from LSC and OP remain unclear. Here, we used IHC methods to detect the expression of GATA3 and classic mesothelial markers in 17 SMM, 12 LSC, and 7 OP cases. We detected the following expression rates in SMM versus LSC cases: GATA3 (70.6% vs. 16.7%, p = 0.008), calretinin (52.9% vs. 8.3%, p = 0.019), Wilms tumor (WT)-1 (64.7% vs. 0%, p = 0.000), D2-40 (47.1% vs. 16.7%, p = 0.126), CK5/6 (35.3% vs. 25.0%, p = 0.694), and pan-cytokeratin (CKpan) (88.2% vs. 100.0%, p = 0.498). The specificities of calretinin, WT-1, and GATA3 in distinguishing SMM from LSC were 91.7%, 100%, and 83.3%, respectively, and combinations of any two of these three markers exhibited 100% specificity for SMM. Notably, the sensitivity of calretinin+/WT1+ staining for SMM was only 23.5%, which increased to 64.7% after including GATA3. Furthermore, all OP cases showed partial or diffuse expression of CKpan, WT-1, and D2-40 but no GATA3 and calretinin expression. In conclusion, GATA3 is an IHC marker with excellent sensitivity and specificity for SMM, and the combined consideration of GATA3, calretinin, and WT-1 was best for distinguishing SMM from LSC. Moreover, CKpan, WT-1, and D2-40 had no value for distinguishing SMM from OP, and GATA3 and calretinin were the most specific markers for distinguishing these two lesions.
    Keywords:  GATA3; Immunohistochemistry; Lung sarcomatoid carcinoma; Organizing pleuritis; Pathologic diagnosis; Sarcomatoid malignant mesothelioma
    DOI:  https://doi.org/10.1007/s00428-021-03048-y
  8. Cancers (Basel). 2021 Feb 08. pii: 685. [Epub ahead of print]13(4):
    Keller M, Reis K, Hjerpe A, Dobra K, Aspenström P.
      Malignant mesothelioma (MM) is a rare but highly aggressive cancer that primarily originates from the pleura, peritoneum or pericardium. There is a well-established link between asbestos exposure and progression of MM. Direct invasion of the surrounding tissues is the main feature of MM, which is dependent on dysregulated communication between the mesothelium and the microenvironment. This communication is dependent on the dynamic organization of the cytoskeleton. We have analyzed the organization and function of key cytoskeletal components in MM cell lines of increasing malignancies measured as migratory and invasive properties, and we show that highly malignant and invasive MM cells have an organization of the actin filament and vimentin systems that is distinct from the less malignant MM cell lines. In addition, the Hippo tumor suppressor pathway was inactivated in the invasive MM cells, which was seen as increased YAP nuclear localization.
    Keywords:  YAP; actin dynamics; cytoskeleton; malignant mesothelioma; vimentin
    DOI:  https://doi.org/10.3390/cancers13040685
  9. Mol Cancer Res. 2021 Feb 11. pii: molcanres.MCR-20-0637-E.2020. [Epub ahead of print]
    Sato T, Mukai S, Ikeda H, Mishiro-Sato E, Akao K, Kobayashi T, Hino O, Shimono W, Shibagaki Y, Hattori S, Sekido Y.
      Malignant mesothelioma (MM) is an aggressive tumor that typically develops after a long latency following asbestos exposure. Although mechanistic target of rapamycin complex 1 (mTORC1) activation enhances MM cell growth, the mTORC1 inhibitor everolimus has shown limited efficacy in clinical trials of MM patients. We explored the mechanism underlying mTORC1 activation in MM cells and its effects on cell proliferation and progression. Analysis of the expression profiles of 87 MMs from The Cancer Genome Atlas revealed that 40 samples (46%) displayed altered expression of RPTOR (mTORC1 component) and genes immediately upstream that activate mTORC1. Among them, we focused on RHEB and RHEBL1, which encode direct activators of mTORC1. Exogenous RHEBL1 expression enhanced MM cell growth, indicating that RHEB-mTORC1 signaling acts as a pro-oncogenic cascade. We investigated molecules that directly activate RHEBs, identifying SmgGDS as a novel RHEB-binding protein. SmgGDS knockdown reduced mTORC1 activation and inhibited the proliferation of MM cells with mTORC1 activation. Interestingly, SmgGDS displayed high binding affinity with inactive GDP-bound RHEBL1, and its knockdown reduced cytosolic RHEBL1 without affecting its activation. These findings suggest that SmgGDS retains GDP-bound RHEBs in the cytosol, whereas GTP-bound RHEBs are localized on intracellular membranes to promote mTORC1 activation. We revealed a novel role for SmgGDS in the RHEB-mTORC1 pathway and its potential as a therapeutic target in MM with aberrant mTORC1 activation. Implications: Our data showing that SmgGDS regulates RHEB localization to activate mTORC1 indicate that SmgGDS can be used as a new therapeutic target for MM exhibiting mTORC1 activation.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-20-0637
  10. Cancers (Basel). 2021 Feb 06. pii: 655. [Epub ahead of print]13(4):
    Javadi J, Heidari-Hamedani G, Schmalzl A, Szatmári T, Metintas M, Aspenström P, Hjerpe A, Dobra K.
      Malignant mesothelioma (MM) is an aggressive tumor of the serosal cavities. Angiogenesis is important for mesothelioma progression, but so far, anti-angiogenic agents have not improved patient survival. Our hypothesis is that better understanding of the regulation of angiogenesis in this tumor would largely improve the success of such a therapy. Syndecan-1 (SDC-1) is a transmembrane heparan sulfate proteoglycan that acts as a co-receptor in various cellular processes including angiogenesis. In MM, the expression of SDC-1 is generally low but when present, SDC-1 associates to epithelioid differentiation, inhibition of tumor cell migration and favorable prognosis, meanwhile SDC-1 decrease deteriorates the prognosis. In the present study, we studied the effect of SDC-1 overexpression and silencing on MM cells ability to secrete angiogenic factors and monitored the downstream effect of SDC-1 modulation on endothelial cells proliferation, wound healing, and tube formation. This was done by adding conditioned medium from SDC-1 transfected and SDC-1 silenced mesothelioma cells to endothelial cells. Moreover, we investigated the interplay and molecular functional changes in angiogenesis in a co-culture system and characterized the soluble angiogenesis-related factors secreted to the conditioned media. We demonstrated that SDC-1 over-expression inhibited the proliferation, wound healing, and tube formation of endothelial cells. This effect was mediated by a multitude of angiogenic factors comprising angiopoietin-1 (Fold change ± SD: 0.65 ± 0.07), FGF-4 (1.45 ± 0.04), HGF (1.33 ± 0.07), NRG1-β1 (1.35 ± 0.08), TSP-1 (0.8 ± 0.02), TIMP-1 (0.89 ± 0.01) and TGF-β1 (1.35 ± 0.01). SDC-1 silencing increased IL8 (1.33 ± 0.06), promoted wound closure, but did not influence the tube formation of endothelial cells. Pleural effusions from mesothelioma patients showed that Vascular Endothelial Growth Factor (VEGF) levels correlate to soluble SDC-1 levels and have prognostic value. In conclusion, SDC-1 over-expression affects the angiogenic factor secretion of mesothelioma cells and thereby inhibits endothelial cells proliferation, tube formation, and wound healing. VEGF could be used in prognostic evaluation of mesothelioma patients together with SDC-1.
    Keywords:  angiogenesis; endothelial cells; mesothelioma; syndecan-1; tubulogenesis
    DOI:  https://doi.org/10.3390/cancers13040655
  11. Int J Gynecol Pathol. 2021 Feb 11.
    Malpica A, Euscher ED, Marques-Piubelli ML, Miranda RN, Fournier KF, Raghav KP, Ramalingam P.
      Only a few cases of malignant peritoneal mesothelioma (MPeM) associated with endometriosis have been published; with chronic inflammation of the peritoneum associated with the latter being postulated as an inducing factor in the pathogenesis of this tumor. We assessed the clinicopathologic characteristics of MPeM associated with endometriosis to determine if there were other factors besides inflammation that may contribute to the pathogenesis in this patient population. Fifteen MPeM associated with endometriosis were retrieved from our files. Most presented with abdominal/pelvic pain, mass or distention; median age was 45 yr. Only 16% of patients had a history of asbestos exposure. In contrast, a third of the patients had a personal history of other neoplasms, and >80% had a family history of malignancies. Although most tumors had gross and microscopic features typical of MPeM, some had confounding features including "adhesion-like" appearance or gelatinous cysts/nodules, and signet ring cells. Tumors were epithelioid (9) and biphasic (6). MPeM was misdiagnosed as Müllerian carcinoma in 40% of cases. All patients (n=15) had cytoreductive surgery in addition to other therapies. Only 2/12 patients died of disease (17%). The 3- and 5-yr overall survival was 90%. MPeM associated with endometriosis tends to occur in patients with personal/familial history of malignancies, which may be a predisposing factor. In light of this finding, the role of endometriosis in the pathogenesis of MPeM is likely less relevant. The favorable outcome seen in these patients may be related to germline mutations or the hormonal milieu and needs further investigation.
    DOI:  https://doi.org/10.1097/PGP.0000000000000762
  12. Oncologist. 2021 Feb 08.
    Miyagawa C, Takaya H, Sakai K, Nishio K, Konishi M, Minamiguchi S, Shimada T, Matsumura N.
      Recently, several malignant peritoneal mesothelioma (MPMs) that occur in young women without asbestos exposure and with fusion genes such as anaplastic lymphoma kinase (ALK) and Ewing sarcoma breakpoint region 1 (EWSR1) have been reported. In the present case, we encountered MPM with STRN-ALK fusion in a 17-year-old female. The case did not respond to chemotherapy and is currently in a clinical trial of alectinib. This is the fourth reported case of MPM with STRN-ALK fusion. Of the 45 cancer cases with STRN-ALK fusion in which the fusion partners were examined, all cases except for the current case showed fusion of exon 3 of STRN and exon 20 of ALK. This is first case with fusion of exon 2 of STRN and exon 20 of ALK. Further advances in cancer genomic medicine may help clarify the clinical significance of this new fusion. KEY POINTS: Malignant peritoneal mesothelioma (MPMs) can occur in young women without asbestos exposure and show fusion genes that activate anaplastic lymphoma kinase (ALK) by gene rearrangement. ALK rearrangement and the fusion partner can be detected by companion diagnostics and by next generation sequencing. MPM patients with ALK rearrangement may benefit from target therapy.
    Keywords:  ALK fusion; Malignant; Mesothelioma; Peritoneal; STRN
    DOI:  https://doi.org/10.1002/onco.13714
  13. Hepatoma Res. 2021 ;pii: 8. [Epub ahead of print]7
    Kwee SA, Tiirikainen M.
      Mutations involving CTNNB1, the gene encoding beta-catenin, and other molecular alterations that affect the Wnt/beta-catenin signaling pathway are exceptionally common in hepatocellular carcinoma. Several of these alterations have also been associated with scarcity of immune cells in the tumor microenvironment and poor clinical response to immune checkpoint inhibitor therapy. In light of these associations, tumor biomarkers of beta-catenin status could have the potential to serve as clinical predictors of immunotherapy outcome. This editorial review article summarizes recent pre-clinical and clinical research pertaining to associations between beta-catenin activation and diminished anti-tumor immunity. Potential non-invasive biomarkers that may provide a window into this oncogenic mechanism of immune evasion are also presented and discussed.
    Keywords:  Hepatocellular carcinoma; beta-catenin; biomarkers; immune checkpoint; immunotherapy; positron emission tomography
    DOI:  https://doi.org/10.20517/2394-5079.2020.124
  14. Drug Dev Res. 2021 Feb 09.
    Pyziak K, Sroka-Porada A, Rzymski T, Dulak J, Łoboda A.
      Enhancer of zeste homolog 2 (EZH2), a catalytic component of polycomb repressive complex 2 (PRC2), is commonly overexpressed or mutated in many cancer types, both of hematological and solid nature. Till now, plenty of EZH2 small molecule inhibitors have been developed and some of them have already been tested in clinical trials. Most of these inhibitors, however, are effective only in limited cases in the context of EZH2 gain-of-function mutated tumors such as lymphomas. Other cancer types with aberrant EZH2 expression and function require alternative approaches for successful treatment. One possibility is to exploit synthetic lethal strategy, which is based on the phenomenon that concurrent loss of two genes is detrimental but the deletion of either of them leaves cell viable. In the context of EZH2/PRC2, the most promising synthetic lethal target seems to be SWItch/Sucrose Non-Fermentable chromatin remodeling complex (SWI/SNF), which is known to counteract PRC2 functions. SWI/SNF is heavily involved in carcinogenesis and its subunits have been found mutated in approximately 20% of tumors of different kinds. In the current review, we summarize the existing knowledge of synthetic lethal relationships between EZH2/PRC2 and components of the SWI/SNF complex and discuss in detail the potential application of existing EZH2 inhibitors in cancer patients harboring mutations in SWI/SNF proteins. We also highlight recent discoveries of EZH2 involvement in tumor microenvironment regulation and consequences for future therapies. Although clinical studies are limited, the fundamental research might help to understand which patients are most likely to benefit from therapies using EZH2 inhibitors.
    Keywords:  EZH2; PRC2; SWI/SNF; epigenetics; synthetic lethality
    DOI:  https://doi.org/10.1002/ddr.21796