bims-mesote Biomed News
on Mesothelioma
Issue of 2021‒06‒06
nineteen papers selected by
Laura Mannarino
Humanitas Research
  1. Pathological Characterization of Tumor Immune Microenvironment (TIME) in Malignant Pleural Mesothelioma.
  2. NIPU: a randomised, open-label, phase II study evaluating nivolumab and ipilimumab combined with UV1 vaccination as second line treatment in patients with malignant mesothelioma.
  3. New DNA Methylation Signals for Malignant Pleural Mesothelioma Risk Assessment.
  4. Oncological Frontiers in the Treatment of Malignant Pleural Mesothelioma.
  5. Update on Diagnosing and Reporting Malignant Pleural Mesothelioma.
  6. Nose in malignant mesothelioma-Prediction of response to immune checkpoint inhibitor treatment.
  7. Evaluation of the Preclinical Efficacy of Lurbinectedin in Malignant Pleural Mesothelioma.
  8. Surgical Management and Reconstruction of Diaphragm, Pericardium and Chest Wall in Mesothelioma Surgery: A Review.
  9. Diagnostic Challenges in Epithelioid Pleural Mesothelioma: Case Series with Support from Electron Microscopy.
  10. Old Borders and New Horizons in Multimodality Imaging of Malignant Pleural Mesothelioma.
  11. Potential airborne asbestos exposures in dentistry: a comprehensive review and risk assessment.
  12. Development of unenhanced CT-based imaging signature for BAP1 mutation status prediction in malignant pleural mesothelioma: Consideration of 2D and 3D segmentation.
  13. Essential role of the histone lysine demethylase KDM4A in the biology of malignant pleural mesothelioma (MPM).
  14. Surgical Diagnosis of Malignant Pleural Mesothelioma: 20 Years' Experience at a High-Volume Referral Center.
  15. DNA methylation as a diagnostic biomarker for malignant mesothelioma: a systematic review and meta-analysis.
  16. Meta-Analysis of Survival and Development of a Prognostic Nomogram for Malignant Pleural Mesothelioma Treated with Systemic Chemotherapy.
  17. Precision Therapy for Mesothelioma: Feasibility and New Opportunities.
  18. Therapeutic Synergy in Esophageal Cancer and Mesothelioma is Predicted by Dynamic BH3 Profiling.
  19. When the Diagnosis of Mesothelioma Challenges Textbooks and Guidelines.
  1. Cancers (Basel). 2021 May 24. pii: 2564. [Epub ahead of print]13(11):
    Pathological Characterization of Tumor Immune Microenvironment (TIME) in Malignant Pleural Mesothelioma.
    Francesca Napoli, Angela Listì, Vanessa Zambelli, Gianluca Witel, Paolo Bironzo, Mauro Papotti, Marco Volante, Giorgio Scagliotti, Luisella Righi.
      Malignant pleural mesothelioma (MPM) is a rare and highly aggressive disease that arises from pleural mesothelial cells, characterized by a median survival of approximately 13-15 months after diagnosis. The primary cause of this disease is asbestos exposure and the main issues associated with it are late diagnosis and lack of effective therapies. Asbestos-induced cellular damage is associated with the generation of an inflammatory microenvironment that influences and supports tumor growth, possibly in association with patients' genetic predisposition and tumor genomic profile. The chronic inflammatory response to asbestos fibers leads to a unique tumor immune microenvironment (TIME) composed of a heterogeneous mixture of stromal, endothelial, and immune cells, and relative composition and interaction among them is suggested to bear prognostic and therapeutic implications. TIME in MPM is known to be constituted by immunosuppressive cells, such as type 2 tumor-associated macrophages and T regulatory lymphocytes, plus the expression of several immunosuppressive factors, such as tumor-associated PD-L1. Several studies in recent years have contributed to achieve a greater understanding of the pathogenetic mechanisms in tumor development and pathobiology of TIME, that opens the way to new therapeutic strategies. The study of TIME is fundamental in identifying appropriate prognostic and predictive tissue biomarkers. In the present review, we summarize the current knowledge about the pathological characterization of TIME in MPM.
    Keywords:  dendritic cells; immunohistochemistry; mesothelioma; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.3390/cancers13112564
  2. J Transl Med. 2021 May 31. 19(1): 232
    NIPU: a randomised, open-label, phase II study evaluating nivolumab and ipilimumab combined with UV1 vaccination as second line treatment in patients with malignant mesothelioma.
    Vilde Drageset Haakensen, Anna K Nowak, Espen Basmo Ellingsen, Saima Jamil Farooqi, Maria Moksnes Bjaanæs, Henrik Horndalsveen, Tine Mcculloch, Oscar Grundberg, Susana M Cedres, Åslaug Helland.
      BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare and aggressive tumour. For patients with inoperable disease, few treatment options are available after first line chemotherapy. The combination of ipilimumab and nivolumab has recently shown increased survival compared to standard chemotherapy, but most patients do not respond and improvements are called for. Telomerase is expressed in mesothelioma cells, but only sparsely in normal tissues and is therefore an attractive target for therapeutic vaccination. Vaccination against telomerase is tolerable and has shown to induce immune responses associated with increased survival in other cancer types. There is a well-founded scientific rationale for the combination of a telomerase vaccine and checkpoint inhibition to improve treatment response in MPM patients.METHODS: NIPU is a randomized, multi-centre, open-label, phase II study comparing the efficacy and safety of nivolumab and ipilimumab with or without telomerase vaccine in patients with inoperable malignant pleural mesothelioma after first-line platinum-based chemotherapy. Participants (n = 118) are randomized 1:1 into two treatment arms. All participants receive treatment with nivolumab (240 mg every 2 weeks) and ipilimumab (1 mg/kg every 6 weeks) until disease progression, unacceptable toxicity or for a maximum of 2 years. Patients randomised to the experimental arm receive 8 intradermal injections of UV1 vaccine during the first three months of treatment. Tumour tissue, blood, urine, faeces and imaging will be collected for biomarker analyses and exploration of mechanisms for response and resistance to therapy.
    DISCUSSION: Checkpoint inhibition is used for treatment of mesothelioma, but many patients still do not respond. Increasing therapy response to immunotherapy is an important goal. Possible approaches include combination with chemotherapy, radiotherapy, targeted therapy and other immunotherapeutic agents. Predictive biomarkers are necessary to ensure optimal treatment for each patient and to prevent unnecessary side effects. This trial seeks to improve treatment response by combining checkpoint inhibition with a telomerase vaccine and also to explore mechanisms for treatment response and resistance. Knowledge gained in the NIPU study may be transferred to the first line setting and to other cancers with limited benefit from immunotherapy.
    TRIAL REGISTRATION: ClinicalTrials.gov: NCT04300244, registered March 8th, 2020, https://clinicaltrials.gov/ct2/show/NCT04300244?term=NIPU&draw=2&rank=1 .
    Keywords:  Biomarker; Immune response; Immunotherapy; Ipilimumab; Malignant pleural mesothelioma; Nivolumab; Telomerase vaccine; hTERT
    DOI:  https://doi.org/10.1186/s12967-021-02905-3
  3. Cancers (Basel). 2021 May 27. pii: 2636. [Epub ahead of print]13(11):
    New DNA Methylation Signals for Malignant Pleural Mesothelioma Risk Assessment.
    Giovanni Cugliari, Alessandra Allione, Alessia Russo, Chiara Catalano, Elisabetta Casalone, Simonetta Guarrera, Federica Grosso, Daniela Ferrante, Marika Sculco, Marta La Vecchia, Chiara Pirazzini, Roberta Libener, Dario Mirabelli, Corrado Magnani, Irma Dianzani, Giuseppe Matullo.
      Malignant pleural mesothelioma (MPM) is a rare and aggressive neoplasm. Patients are usually diagnosed when current treatments have limited benefits, highlighting the need for noninvasive tests aimed at an MPM risk assessment tool that might improve life expectancy. Three hundred asbestos-exposed subjects (163 MPM cases and 137 cancer-free controls), from the same geographical region in Italy, were recruited. The evaluation of asbestos exposure was conducted considering the frequency, the duration and the intensity of occupational, environmental and domestic exposure. A genome-wide methylation array was performed to identify novel blood DNA methylation (DNAm) markers of MPM. Multiple regression analyses adjusting for potential confounding factors and interaction between asbestos exposure and DNAm on the MPM odds ratio were applied. Epigenome-wide analysis (EWAS) revealed 12 single-CpGs associated with the disease. Two of these showed high statistical power (99%) and effect size (>0.05) after false discovery rate (FDR) multiple comparison corrections: (i) cg03546163 in FKBP5, significantly hypomethylated in cases (Mean Difference in beta values (MD) = -0.09, 95% CI = -0.12|-0.06, p = 1.2 × 10-7), and (ii) cg06633438 in MLLT1, statistically hypermethylated in cases (MD = 0.07, 95% CI = 0.04|0.10, p = 1.0 × 10-6). Based on the interaction analysis, asbestos exposure and epigenetic profile together may improve MPM risk assessment. Above-median asbestos exposure and hypomethylation of cg03546163 in FKBP5 (OR = 20.84, 95% CI = 8.71|53.96, p = 5.5 × 10-11) and hypermethylation of cg06633438 in MLLT1 (OR = 11.71, 95% CI = 4.97|29.64, p = 5.9 × 10-8) genes compared to below-median asbestos exposure and hyper/hypomethylation of single-CpG DNAm, respectively. Receiver Operation Characteristics (ROC) for Case-Control Discrimination showed a significant increase in MPM discrimination when DNAm information was added in the model (baseline model, BM: asbestos exposure, age, gender and white blood cells); area under the curve, AUC = 0.75; BM + cg03546163 at FKBP5. AUC = 0.89, 2.1 × 10-7; BM + cg06633438 at MLLT1. AUC = 0.89, 6.3 × 10-8. Validation and replication procedures, considering independent sample size and a different DNAm analysis technique, confirmed the observed associations. Our results suggest the potential application of DNAm profiles in blood to develop noninvasive tests for MPM risk assessment in asbestos-exposed subjects.
    Keywords:  DNA methylation; asbestos exposure; epigenome-wide analysis; interaction analysis; malignant pleural mesothelioma
    DOI:  https://doi.org/10.3390/cancers13112636
  4. J Clin Med. 2021 May 25. pii: 2290. [Epub ahead of print]10(11):
    Oncological Frontiers in the Treatment of Malignant Pleural Mesothelioma.
    Emanuele Vita, Alessio Stefani, Mariantonietta Di Salvatore, Marco Chiappetta, Filippo Lococo, Stefano Margaritora, Giampaolo Tortora, Emilio Bria.
      Malignant pleural mesothelioma (MPM) is a rare malignancy characterized by very poor prognosis and lack of treatment options. Immunotherapy has rapidly emerged as an effective tool for MPM, particularly for tumors of non-epithelioid histology. At the same time, comprehensive genomic sequencing may open the way to new-generation targeted-drugs able to hit specific MPM molecular vulnerabilities. These innovations will possibly enrich, but also dramatically complicate, the elucidation of treatment algorithms. Multidisciplinary integration is urgently needed.
    Keywords:  immunotherapy; malignant pleural mesothelioma; target therapy
    DOI:  https://doi.org/10.3390/jcm10112290
  5. Acta Med Acad. 2021 Apr;50(1): 197-208
    Update on Diagnosing and Reporting Malignant Pleural Mesothelioma.
    Ivana Savic, Jeffrey Myers.
      In this review, we summarize current approaches to diagnosis of malignant pleural mesothelioma, focusing on the distinction from benign mesothelial proliferations and other malignant tumors. Current recommendations for reporting histological sub-type and tumor grade are also reviewed. Particular emphasis is placed on immunohistochemical and molecular tools that may help in establishing the diagnosis of mesothelioma with greater confidence. Immunohistochemical stains for BRCA1-associated protein (BAP1) and methylthioadenosine phosphorylase (MTAP) and homozygous deletion of p16 using fluorescence in situ hybridization (FISH) are emphasized as important methods for distinguishing benign from malignant mesothelial proliferations. CONCLUSIONS: Diffuse malignant pleural mesothelioma is a heterogeneous group of aggressive pleural tumors for which histological classification plays an increasingly important role in patient management. Stage and resectability remain key drivers of therapeutic strategies and outcomes. There is an increasingly robust suite of diagnostic tools, including immunohistochemical stains for BAP1 and MTAP and p16 FISH, for differentiating benign from malignant mesothelial proliferations in cytology and tissue specimens.
    Keywords:  Diagnostics; Fluorescence in Situ Hybridization; Immunohistochemistry; Malignant Pleural Mesothelioma
    DOI:  https://doi.org/10.5644/ama2006-124.335
  6. Eur J Cancer. 2021 Jun 01. pii: S0959-8049(21)00270-7. [Epub ahead of print]152 60-67
    Nose in malignant mesothelioma-Prediction of response to immune checkpoint inhibitor treatment.
    Maria J Disselhorst, Rianne de Vries, Josine Quispel-Janssen, Marguerite Wolf-Lansdorf, Peter J Sterk, Paul Baas.
      INTRODUCTION: Recent clinical trials with immune checkpoint inhibitors (ICIs) have shown that a subgroup of patients with malignant pleural mesothelioma (MPM) could benefit from these agents. However, there are no accurate biomarkers to predict who will respond. The aim of this study was to assess the accuracy of exhaled breath analysis using electronic technology (eNose) for discriminating between responders to ICI and non-responders.METHODS: This proof-of-concept prospective observational study was part of an intervention study (INITIATE) in patients with recurrent MPM who were treated with nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA-4). At baseline and after six weeks of treatment, breath profiles were collected by an eNose. Modified Response Evaluation Criteria in Solid Tumors were used to assess efficacy at 6-month follow-up. For data processing and statistics, we used independent t-test analyses followed by linear discriminant and receiver-operating characteristic (ROC) analysis.
    RESULTS: Exhaled breath data of 31 MPM patients who received nivolumab plus ipilimumab were available at baseline. There were 16 with and 15 without a response after 6 months of treatment. At baseline, breath profiles significantly differed between responders and non-responders, with a cross validation value of 71%. The ROC-AUC after internal cross-validation was 0.90 (confidence interval: 0.80-1.00).
    CONCLUSION: An eNose is able to discriminate at baseline between responders and non-responders to nivolumab plus ipilimumab in MPM, thereby potentially identifying a subgroup of patients that will benefit from ICI treatment.
    Keywords:  Malignant pleural mesothelioma (MPM); Volatile organic compound (VOC); eNose
    DOI:  https://doi.org/10.1016/j.ejca.2021.04.024
  7. Cancers (Basel). 2021 May 12. pii: 2332. [Epub ahead of print]13(10):
    Evaluation of the Preclinical Efficacy of Lurbinectedin in Malignant Pleural Mesothelioma.
    Dario P Anobile, Paolo Bironzo, Francesca Picca, Marcello F Lingua, Deborah Morena, Luisella Righi, Francesca Napoli, Mauro G Papotti, Alessandra Pittaro, Federica Di Nicolantonio, Chiara Gigliotti, Federico Bussolino, Valentina Comunanza, Francesco Guerrera, Alberto Sandri, Francesco Leo, Roberta Libener, Pablo Aviles, Silvia Novello, Riccardo Taulli, Giorgio V Scagliotti, Chiara Riganti.
      BACKGROUND: Malignant pleural mesothelioma (MPM) is a highly aggressive cancer generally diagnosed at an advanced stage and characterized by a poor prognosis. The absence of alterations in druggable kinases, together with an immune-suppressive tumor microenvironment, limits the use of molecular targeted therapies, making the treatment of MPM particularly challenging. Here we investigated the in vitro susceptibility of MPM to lurbinectedin (PM01183), a marine-derived drug that recently received accelerated approval by the FDA for the treatment of patients with metastatic small cell lung cancer with disease progression on or after platinum-based chemotherapy.METHODS: A panel of primary MPM cultures, resembling the three major MPM histological subtypes (epithelioid, sarcomatoid, and biphasic), was characterized in terms of BAP1 status and histological markers. Subsequently, we explored the effects of lurbinectedin at nanomolar concentration on cell cycle, cell viability, DNA damage, genotoxic stress response, and proliferation.
    RESULTS: Stabilized MPM cultures exhibited high sensitivity to lurbinectedin independently from the BAP1 mutational status and histological classification. Specifically, we observed that lurbinectedin rapidly promoted a cell cycle arrest in the S-phase and the activation of the DNA damage response, two conditions that invariably resulted in an irreversible DNA fragmentation, together with strong apoptotic cell death. Moreover, the analysis of long-term treatment indicated that lurbinectedin severely impacts MPM transforming abilities in vitro.
    CONCLUSION: Overall, our data provide evidence that lurbinectedin exerts a potent antitumoral activity on primary MPM cells, independently from both the histological subtype and BAP1 alteration, suggesting its potential activity in the treatment of MPM patients.
    Keywords:  DNA damage response; MPM; lurbinectedin
    DOI:  https://doi.org/10.3390/cancers13102332
  8. J Clin Med. 2021 May 26. pii: 2330. [Epub ahead of print]10(11):
    Surgical Management and Reconstruction of Diaphragm, Pericardium and Chest Wall in Mesothelioma Surgery: A Review.
    Pietro Bertoglio, Elena Garelli, Jury Brandolini, Kenji Kawamukai, Filippo Antonacci, Sara Ricciardi, Alessandro Cipolli, Barbara Bonfanti, Sergio Nicola Forti Parri, Niccolò Daddi, Giampiero Dolci, Piergiorgio Solli.
      Mesothelioma is an aggressive disease arising from parietal pleura. Surgery is a valuable option in the frame of a multimodality treatment. Several surgical approaches have been standardized with the aim of a macroscopic complete resection; these often require homolateral diaphragm and pericardial resection and reconstruction. Extrapleural pneumonectomy (EPP) and extended pleurectomy decortication (EPD) have been recognized as radical surgical procedures. Nevertheless, both operations are technically challenging and associated with a significant rate of peri-operative morbidity and non-negligible mortality. The diaphragmatic and pericardial reconstruction technique is mandatory to avoid respiratory impairment and to reduce post-operative complications like gastric and cardiac herniation. Moreover, in the case of localized chest wall recurrence, surgery might be considered a valuable therapeutical option for highly selected and fit patients. All the technical aspects of the resection and reconstruction of the diaphragm, pericardium, and chest wall are described as well as the possible use of new minimally invasive techniques. In addition, the choice of different prosthetic materials, considering the most recent innovations in the field, are discussed.
    Keywords:  chest wall; diaphragm; malignant pleural mesothelioma; pericardium; surgery
    DOI:  https://doi.org/10.3390/jcm10112330
  9. Diagnostics (Basel). 2021 May 07. pii: 841. [Epub ahead of print]11(5):
    Diagnostic Challenges in Epithelioid Pleural Mesothelioma: Case Series with Support from Electron Microscopy.
    Francesco Fortarezza, Mila Della Barbera, Federica Pezzuto, Francesca Lunardi, Eleonora Faccioli, Giulia Pasello, Federico Rea, Stefania Rizzo, Fiorella Calabrese.
      The histological diagnosis of pleural epithelioid mesothelioma can be difficult in the case of rare variants or in the definition of neoplasm origin in patients with previous or concomitant tumours. Currently, several immunohistochemical reactions are available in the surgical pathologist's armamentarium that allow us to obtain a more sensitive and specific diagnosis of malignant pleural mesothelioma. However, in some cases, the final interpretation remains inconclusive. Historically, ultrastructural examination has represented a useful tool for the definition of the mesothelial nature of neoplastic cells due to their peculiar morphological characteristics. The recent international guidelines for pathological diagnosis of pleural mesothelioma suggest the use of electron microscopy when the immunohistochemical reactions are equivocal or when further support of a diagnosis of mesothelioma is needed. This paper presents three cases of pleural epithelioid mesothelioma whose diagnoses were finally supported by ultrastructural examination.
    Keywords:  histology; immunohistochemistry; mesothelioma; transmission electron microscopy
    DOI:  https://doi.org/10.3390/diagnostics11050841
  10. Thorac Cardiovasc Surg. 2021 Jun 01.
    Old Borders and New Horizons in Multimodality Imaging of Malignant Pleural Mesothelioma.
    Katharina Martini, Thomas Frauenfelder.
      BACKGROUND:  The purpose of this article is to describe the various imaging techniques involved in detection, staging, and preoperative planning in malignant pleural mesothelioma (MPM) focusing on new imaging modalities.METHODS:  For this purpose, first a brief summary of the etiology of MPM is given. Second, not only the commonly known, but also novel imaging modalities used in MPM will be discussed.
    RESULTS:  A wide range of imaging methods, from conventional chest radiography, through computed tomography and hybrid imaging to radiomics and artificial intelligence, can be used to evaluate MPM.
    CONCLUSION:  Nowadays multimodality imaging is considered the cornerstone in MPM diagnosis and staging.
    DOI:  https://doi.org/10.1055/s-0041-1728714
  11. Crit Rev Toxicol. 2021 Jun 01. 1-27
    Potential airborne asbestos exposures in dentistry: a comprehensive review and risk assessment.
    A Michael Ierardi, Claire Mathis, Ania Urban, Neva Jacobs, Brent Finley, Shannon Gaffney.
      Chrysotile was formerly used in the manufacture of casting ring liner (CRL) and periodontal dressing powder (PDP). The purpose of this study was to describe the potential for airborne asbestos exposure among dental professionals who may have used these products and to assess their risk of asbestos-related disease (ARD). Task-specific exposure data associated with CRL and PDP were identified and compared to regulatory standards for asbestos and health-based benchmarks. Personal airborne fiber concentrations ranged from 0.008-3.5 f/cc by PCM (duration: 3-420 minutes) for CRL (tearing, placement), and from <0.0044-<0.297 f/cc by PCM (duration: 5-28 minutes) for PDP (mixing). Eight-hour time-weighted average (TWA) exposures were calculated using the reported task-based airborne fiber concentrations and associated sampling durations. For CRL tasks, the upper-bound calculated 8-hour TWA of 0.022 f/cc (tearing, placement) did not exceed regulatory standards for asbestos (≥0.1 f/cc). All samples collected during the mixing of PDP resulted in non-measurable fiber concentrations. The greatest estimated cumulative asbestos exposure for dental professionals using CRL (tearing, placement) of 0.33 f/cc-years is well below "best estimate", published chrysotile no-observed-adverse-effect-levels (NOAEL) for ARD (lung cancer = 89-168 f/cc-years; pleural mesothelioma = 208-415 f/cc-years). As such, the use of asbestos-containing CRL and/or PDP is not expected to pose an increased risk of ARD among dental professionals. This conclusion is consistent with the lack of an increased risk of ARD reported in epidemiological studies of these occupations.
    Keywords:  Dental professional; casting ring liner; dental assistant; dental hygienist; dental laboratory technician; dental tape; dentist; investment material; lost-wax casting process; lung cancer; mesothelioma; periodontal dressing powder
    DOI:  https://doi.org/10.1080/10408444.2021.1910624
  12. Lung Cancer. 2021 Apr 29. pii: S0169-5002(21)00164-1. [Epub ahead of print]157 30-39
    Development of unenhanced CT-based imaging signature for BAP1 mutation status prediction in malignant pleural mesothelioma: Consideration of 2D and 3D segmentation.
    Xiao-Jie Xie, Si-Yun Liu, Jian-You Chen, Yi Zhao, Jie Jiang, Li Wu, Xing-Wen Zhang, Yi Wu, Hui Duan, Bing He, Heng Luo, Dan Han.
      OBJECTIVES: We aimed to explore the feasibility of 2D and 3D radiomics signature based on the unenhanced computed tomography (CT) images to predict BRCA1-associated protein 1 (BAP1) gene mutation status for malignant pleural mesothelioma (MPM) patients.MATERIALS AND METHODS: 74 patients with MPM were retrospectively enrolled (22 mutant BAP1, 52 wild-type BAP1 demonstrated by Sanger sequencing). The radiomic features were extracted respectively from the 2D and 3D segmentation of unenhanced pre-treatment CT images, and the dataset was randomly divided into training (n = 51) and test (n = 23) sets for radiomics model development and internal validation. The synthetic minority over-sampling technique (SMOTE) was used for data balancing in the training set. 2D or 3D features were sequentially selected by ICC > 0.8, correlation analysis (cut-value 0.7), univariate analysis or univariate logistic regression (LR), which were involved into multivariate LR for LR model construction. Following the comparison of the 2D and 3D models by the ROC analysis and Delong test for AUC, the calibration and clinical utility of 2D and 3D models were evaluated.
    RESULTS: 3D radiomic features showed better ICCs compared with 2D in both intra- (P < 0.001) and inter-observer (P <  0.001) analysis. 3D radiomic model based on selected features developed from a balanced training dataset presented a favorable predictive performance with AUC of 0.786 and 0.768 in the training and test sets, respectively. The predictive performance of 3D model was superior to 2D model (1 feature) both in the training (AUC 0.786 vs. 0.683, P = 0.036) and the test (AUC 0.768 vs.0.652, P = 0.441) set. The calibration curve and decision curves also indicate a better BAP1 prediction performance and clinical benefit for 3D model than that of 2D model.
    CONCLUSION: The developed unenhanced CT-based 3D radiomics signature is potential as a noninvasive marker for predicting BAP1 mutation status.
    Keywords:  BRCA1-associtaed protein 1; Gene mutation; Malignant pleural mesothelioma; Radiomics; Tomography; X-ray computed
    DOI:  https://doi.org/10.1016/j.lungcan.2021.04.023
  13. Br J Cancer. 2021 Jun 04.
    Essential role of the histone lysine demethylase KDM4A in the biology of malignant pleural mesothelioma (MPM).
    Moshe Lapidot, Abigail E Case, Ellen L Weisberg, Chengcheng Meng, Sarah R Walker, Swati Garg, Wei Ni, Klaus Podar, Yin P Hung, Ruben D Carrasco, Aine Knott, Prafulla C Gokhale, Sunil Sharma, Alex Pozhitkov, Prakash Kulkarni, David A Frank, Ravi Salgia, James D Griffin, Srinivas V Saladi, Raphael Bueno, Martin Sattler.
      BACKGROUND: Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with a dismal prognosis. There is increasing interest in targeting chromatin regulatory pathways in difficult-to-treat cancers. In preliminary studies, we found that KDM4A (lysine-specific histone demethylase 4) was overexpressed in MPM.METHODS: KDM4A protein expression was determined by immunohistochemistry or immunoblotting. Functional inhibition of KDM4A by targeted knockdown and small molecule drugs was correlated to cell growth using cell lines and a xenograft mouse model. Gene expression profiling was performed to identify KDM4A-dependent signature pathways.
    RESULTS: Levels of KDM4A were found to be significantly elevated in MPM patients compared to normal mesothelial tissue. Inhibiting the enzyme activity efficiently reduced cell growth in vitro and reduced tumour growth in vivo. KDM4A inhibitor-induced apoptosis was further enhanced by the BH3 mimetic navitoclax. KDM4A expression was associated with pathways involved in cell growth and DNA repair. Interestingly, inhibitors of the DNA damage and replication checkpoint regulators CHK1 (prexasertib) and WEE1 (adavosertib) within the DNA double-strand break repair pathway, cooperated in the inhibition of cell growth.
    CONCLUSIONS: The results establish a novel and essential role for KDM4A in growth in preclinical models of MPM and identify potential therapeutic approaches to target KDM4A-dependent vulnerabilities.
    DOI:  https://doi.org/10.1038/s41416-021-01441-7
  14. J Clin Med. 2021 May 04. pii: 1973. [Epub ahead of print]10(9):
    Surgical Diagnosis of Malignant Pleural Mesothelioma: 20 Years' Experience at a High-Volume Referral Center.
    Amedeo Iaffaldano, Thomas Charrier, Filippo Lococo, Diane Damotte, Antonio Bobbio, Marco Alifano, Ludovic Fournel.
      Despite advances, malignant pleural mesothelioma (MPM) remains a challenging disease in terms of diagnosis, treatment, and overall management. Herein, we analyzed, in a large-scale single-center cohort, the characteristics and perioperative course of patients undergoing surgical diagnosis of MPM. We identified a total of 514 consecutive patients, 71.4% male and 28.6% female, with mean age 71.3 +/- 13.6 years. Most exhibited pleural, respiratory, or general symptoms and American Society of Anesthesiologists (ASA) score was ≥3 in 68.3% of cases. Thoracoscopy was the most frequent approach (92.0%) and short open thoracotomy was performed in the remaining patients. Pleurodesis was simultaneously performed in 74.3% of cases. Diagnostic failure led to redo surgery in 3.7% of patients. Non-epithelioid histology was found in 19.5% of MPMs and was significantly more frequent in right-sided MPM (p = 0.04), and in patients without history of cancer (p = 0.03), or pleural nodules at thoracoscopy (p = 0.01). Minor only or major complications occurred in respectively 7.8% and 3.6% of cases. They were more frequent in patients ≥ 70 years (p = 0.05) and Performance Status > 2 (p = 0.05). The mean hospital stay was 7.5 days. The 30-day and 90-day early mortality rates were 2.3% and 6.4%, respectively. Surgical diagnosis of MPM is a reliable procedure but is associated with significant morbidity and hospital-stay duration.
    Keywords:  diagnosis; mesothelioma; morbidity; pleurodesis; thoracoscopy
    DOI:  https://doi.org/10.3390/jcm10091973
  15. J Thorac Oncol. 2021 May 31. pii: S1556-0864(21)02186-9. [Epub ahead of print]
    DNA methylation as a diagnostic biomarker for malignant mesothelioma: a systematic review and meta-analysis.
    Janah Vandenhoeck, Jan P van Meerbeeck, Erik Fransen, Jo Raskin, Guy Van Camp, Ken Op de Beeck, Kevin Lamote.
      BACKGROUND: Malignant mesothelioma is an aggressive cancer type linked to asbestos exposure. Due to several intrinsic challenges, mesothelioma is often diagnosed in an advanced disease stage. Therefore, there is need for diagnostic biomarkers that may contribute to early detection. Recently, the epigenome of tumours is extensively being investigated to identify biomarkers. This manuscript is a systematic review summarizing the state-of-the-art research investigating DNA methylation in mesothelioma.METHODS: Four literature databases (Pubmed, Scopus, Web of Science, Medline) were systematically searched for studies investigating DNA methylation in mesothelioma up to October 16, 2020. A meta-analysis was performed per gene investigated in at least two independent studies.
    RESULTS: Fifty-three studies investigated DNA methylation of 97 genes in mesothelioma and are described in a qualitative overview. Ten studies investigating 13 genes (APC, CDH1, CDKN2A, DAPK, ESR1, MGMT, miR-34b/c, PGR, RARβ, RASSF1, SFRP1, SFRP4, WIF1) were included in the quantitative meta-analysis. In this meta-analysis, the APC gene is significantly hypomethylated in mesothelioma, while CDH1, ESR1, miR-34b/c, PGR, RARβ, SFRP1 and WIF1 are significantly hypermethylated in mesothelioma. The three genes that are the most appropriate candidate biomarkers from this meta-analysis are APC, miR-34b/c and WIF1. However, both study number and study objects comprised in this meta-analysis are too low to draw final conclusions about their clinical applications.
    CONCLUSION: The elucidation of the genome-wide DNA methylation profile of mesothelioma is desirable in the future, using a standardized genome-wide methylation analysis approach. The most informative CpG sites from this signature could then form the basis of a panel of highly sensitive and specific biomarkers that can be used for the diagnosis of mesothelioma and even for the screening of an at high-risk population of asbestos-exposed individuals.
    Keywords:  DNA methylation; Mesothelioma; biomarker; epigenetics
    DOI:  https://doi.org/10.1016/j.jtho.2021.05.015
  16. Cancers (Basel). 2021 May 02. pii: 2186. [Epub ahead of print]13(9):
    Meta-Analysis of Survival and Development of a Prognostic Nomogram for Malignant Pleural Mesothelioma Treated with Systemic Chemotherapy.
    Rupesh Kotecha, Raees Tonse, Muni Rubens, Haley Appel, Federico Albrecht, Paul Kaywin, Evan W Alley, Martin C Tom, Minesh P Mehta.
      (1) Purpose: Malignant pleural mesothelioma (MPM) is a rare cancer with an aggressive course. For patients who are medically inoperable or surgically unresectable, multi-agent systemic chemotherapy remains an accepted standard-of-care. The purpose of this meta-analysis is to provide baseline summative survival estimates as well as evaluate the influence of prognostic variables to provide comparative estimates for future trial designs. (2) Methods: Using PRISMA guidelines, a systematic review and meta-analysis was performed of MPM studies published from 2002-2019 obtained from the Medline database evaluating systemic therapy combinations for locally advanced or metastatic disease. Weighted random effects models were used to calculate survival estimates. The influence of proportions of known prognostic factors on overall survival (OS) were evaluated in the creation of a prognostic nomogram to estimate survival. The performance of this model was evaluated against data generated from one positive phase II study and two positive randomized trials. (3) Results: Twenty-four phase II studies and five phase III trials met the eligibility criteria; 2534 patients were treated on the included clinical studies. Ten trials included a platinum-pemetrexed-based treatment regimen, resulting in a pooled estimate of progression-free survival (PFS) of 6.7 months (95% CI: 6.2-7.2 months) and OS of 14.2 months (95% CI: 12.7-15.9 months). Fifteen experimental chemotherapy regimens have been tested in phase II or III studies, with a pooled median survival estimate of 13.5 months (95% CI: 12.6-14.6 months). Meta-regression analysis was used to estimate OS with platinum-pemetrexed using a variety of features, such as pathology (biphasic vs. epithelioid), disease extent (locally advanced vs. metastatic), ECOG performance status, age, and gender. The nomogram-predicted estimates and corresponding 95% CIs performed well when applied to recent randomized studies. (4) Conclusions: Given the rarity of MPM and the aggressive nature of the disease, innovative clinical trial designs with significantly greater randomization to experimental regimens can be performed using robust survival estimates from prior studies. This study provides baseline comparative values and also allows for accounting for differing proportions of known prognostic variables.
    Keywords:  first line; mesothelioma; meta-analysis; systematic review
    DOI:  https://doi.org/10.3390/cancers13092186
  17. Cancers (Basel). 2021 May 13. pii: 2347. [Epub ahead of print]13(10):
    Precision Therapy for Mesothelioma: Feasibility and New Opportunities.
    Sean Dulloo, Aleksandra Bzura, Dean Anthony Fennell.
      Malignant pleural mesotheliomas (MPMs) are characterised by their wide variation in natural history, ranging from minimally to highly aggressive, associated with both interpatient and intra-tumour genomic heterogeneity. Recent insights into the nature of this genetic variation, the identification of drivers, and the emergence of novel strategies capable of targeting vulnerabilities that result from the inactivation of key tumour suppressors suggest that new approaches to molecularly strategy therapy for mesothelioma may be feasible.
    Keywords:  BAP1; CDKN2A; Hippo pathway; MTAP; NF2; PTCH1; SETD2; histotype; mesothelioma
    DOI:  https://doi.org/10.3390/cancers13102347
  18. Mol Cancer Ther. 2021 Jun 04. pii: molcanther.0887.2020. [Epub ahead of print]
    Therapeutic Synergy in Esophageal Cancer and Mesothelioma is Predicted by Dynamic BH3 Profiling.
    Deborah R Surman, Yuan Xu, Min-Jung Lee, Jane Trepel, Kate Brown, Maheshwari Ramineni, Taylor G Splawn, Laurence P Diggs, H Courtney Hodges, Jeremy L Davis, Hyun-Sung Lee, Bryan M Burt, Robert Taylor Ripley.
      Approximately 20,000 patients per year are diagnosed with esophageal adenocarcinoma (EAC) and malignant pleural mesothelioma (MPM); fewer than 20% survive five years. Effective therapeutic strategies are limited even though patients receive a combination of chemotherapeutics. These tumors harbor thousands of mutations that contribute to tumor development. Downstream of oncogenic driving mutations, altered tumor mitochondria promote resistance to apoptosis. Dynamic Bcl-2 homology-3 profiling (DBP) is a functional assay of live cells that identifies the mitochondrial proteins responsible for resistance to apoptosis. We hypothesized that DBP will predict which protein to target to overcome resistance thereby enhancing combinatorial therapy. DBP predicted that targeting either Mcl-1 or Bcl-xL increases the efficacy of the chemotherapeutic agent, cisplatin, whereas targeting Bcl-2 does not. We performed these assays by treating EAC and MPM cells with a combination of BH3 mimetics and cisplatin. Following treatments, we performed efficacy assessments including apoptosis assays, IC50 calculations, and generation of a combinatorial index. DBP confirmed that targeting mitochondria with BH3 mimetics alters the threshold of apoptosis. These apoptotic effects were abolished when the mitochondrial pathway was disrupted. We validated our findings by developing knockdown models of anti-apoptotic proteins Mcl-1, Bcl-xL, and the mitochondrial effector proteins Bax/Bak. Knockdown of Mcl-1 or Bcl-xL recapitulated the results of BH3 mimetics. Additionally, we report an approach for BH3 profiling directly from patient tumor samples. We demonstrate that the DBP assay on living tumor cells measures the dynamic changes of resistance mechanisms, assesses response to combinatorial therapy, and provides results in a clinically feasible timeframe.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-20-0887
  19. J Clin Med. 2021 May 30. pii: 2434. [Epub ahead of print]10(11):
    When the Diagnosis of Mesothelioma Challenges Textbooks and Guidelines.
    Giulio Rossi, Fabio Davoli, Venerino Poletti, Alberto Cavazza, Filippo Lococo.
      The diagnosis of malignant mesothelioma (MPM) does not pose difficulties when presenting with usual clinico-radiologic features and morphology. Pathology textbooks and national/international guidelines generally describe the findings of classic MPM, underlining common clinical presentation, the gold standard of sampling techniques, usual morphologic variants, immunohistochemical results of several positive and negative primary antibodies in the differential diagnosis, and the role of novel molecular markers. Nevertheless, MPM often does not follow the golden rules in routine practice, while the literature generally does not sufficiently emphasize unusual features of its manifestation. This gap may potentially create problems for patients in sustaining a difficult diagnosis of MPM in clinical practice and during legal disputes. Indeed, the guidelines accidentally tend to favor the job of lawyers and pathologists defending asbestos-producing industries against patients suffering from MPM characterized by uncommon features. The current review is aimed at underlining the wide spectrum of clinical and radiological presentation of MPM, the possibility to consistently use cytology for diagnostic intent, the aberrant immunohistochemical expression using so-called specific negative and positive primary antibodies, and finally proposing some alternative and more unbiased approaches to the diagnosis of MPM.
    Keywords:  BAP1; cell block; cytology; histology; immunohistochemistry; mesothelioma; pleura
    DOI:  https://doi.org/10.3390/jcm10112434
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