bims-mesote Biomed News
on Mesothelioma
Issue of 2022–04–10
eleven papers selected by
Laura Mannarino, Humanitas Research
  1. Pulmonary Asbestos Fiber Burden is Related to Patient Survival in Malignant Pleural Mesothelioma.
  2. Sulfated Glycans Recognized by S1 Monoclonal Antibody can Serve as a Diagnostic Marker for Malignant Pleural Mesothelioma.
  3. Nintedanib and Dasatinib Treatments Induce Protective Autophagy as a Potential Resistance Mechanism in MPM Cells.
  4. First-line nivolumab plus ipilimumab versus chemotherapy for the treatment of unresectable malignant pleural mesothelioma: patient-reported outcomes in CheckMate 743.
  5. Evaluation of DNA/RNA quality from cell block of malignant mesothelioma and lung adenocarcinoma.
  6. Biphasic Peritoneal Mesothelioma: A Lethal Clinical Entity.
  7. Geographic distribution of malignant mesothelioma incidence and survival in Australia.
  8. Current progress of miRNA-derivative nucleotide drugs: Modifications, delivery systems, applications.
  9. Challenging Diagnostic Process for a Malignant Peritoneal Mesothelioma Patient With Ascites and Pleural Effusion: A Case Report and Review of the Literature.
  10. Head and neck cancer and asbestos exposure.
  11. Tazemetostat: EZH2 Inhibitor.
  1. J Thorac Oncol. 2022 Mar 30. pii: S1556-0864(22)00167-8. [Epub ahead of print]
    Pulmonary Asbestos Fiber Burden is Related to Patient Survival in Malignant Pleural Mesothelioma.
    Sanna Laaksonen, Eeva Kettunen, Eva Sutinen, Ilkka Ilonen, Tapio Vehmas, Timo Törmäkangas, Jari Räsänen, Henrik Wolff, Marjukka Myllärniemi.
       INTRODUCTION: Malignant pleural mesothelioma (MPM) is associated with poor prognosis and is strongly associated with occupational asbestos exposure. Given the importance of asbestos exposure in MPM pathogenesis, we retrospectively analyzed the types and concentrations of asbestos fibers within the lung tissues of patients with MPM and investigated their effects on all-cause mortality.
    METHODS: We formed a national dataset of patients with MPM identified from the Finnish Cancer Registry and Statistics Finland. These data were merged with pulmonary asbestos fiber analysis results received from the Finnish Institute of Occupational Health.
    RESULTS: We identified 590 patients with MPM that underwent pulmonary asbestos fiber analysis. The median asbestos concentration within dry lung tissue was 3.20 million fibers/gram (f/g) (range: 0-1700 million f/g). Crocidolite and anthophyllite were the most prevalent asbestos fiber types detected in lung tissue. The multivariable risk of death analyses, where changes over time were accounted for, revealed that total asbestos fiber concentration was associated with increased mortality. However, no difference in mortality was noted between different fiber types.
    CONCLUSION: Our study revealed that pulmonary fiber concentrations correlated with the manner of asbestos usage. Anthophyllite was identified as the sole fiber in a sizable proportion of cases, supporting its independent role in the pathogenesis of MPM. Our findings suggest that asbestos fiber burden, but not fiber type, may have an impact on the prognosis of MPM.
    Keywords:  asbestos fibers; malignant pleural mesothelioma; mortality; pulmonary fiber analysis
    DOI:  https://doi.org/10.1016/j.jtho.2022.03.012
  2. Lung. 2022 Apr 08.
    Sulfated Glycans Recognized by S1 Monoclonal Antibody can Serve as a Diagnostic Marker for Malignant Pleural Mesothelioma.
    Koki Nakashima, Yasuhiro Sakai, Hitomi Hoshino, Yukihiro Umeda, Hiroto Kawashima, Yoshitaka Sekido, Tamotsu Ishizuka, Motohiro Kobayashi.
       PURPOSE: Malignant pleural mesothelioma (MPM) is a malignant neoplasm of the pleura caused by asbestos exposure. For diagnosis of MPM, immunohistochemistry using multiple markers is recommended to rule out differential diagnoses, such as pulmonary adenocarcinoma. However, the specificity of currently used markers is not fully satisfactory. We previously developed a monoclonal antibody named S1, which recognizes 6-sulfo sialyl Lewis x, an L-selectin ligand expressed on high endothelial venules. During the screening process, we discovered that this antibody stained normal pleural mesothelium. This finding prompted us to hypothesize that the epitope recognized by S1 might serve as a new diagnostic marker for MPM.
    METHODS: To test this hypothesis, we immunostained human MPM (n = 22) and lung adenocarcinoma (n = 25) tissues using S1 antibody.
    RESULTS: 77.3% of MPM were S1 positive, and if limited to epithelioid type, the positivity rate was 100%, while that of lung adenocarcinoma was only 36.0%. Statistical analysis revealed a significant difference in the S1 positivity rate between each disease. Furthermore, immunohistochemistry using a series of anti-carbohydrate antibodies combined with glycosidase digestion revealed the structure of sulfated glycans expressed in MPM to be 6-sulfo sialyl N-acetyllactosamine attached to core 2-branched O-glycans.
    CONCLUSION: We propose that the S1 glycoepitope could serve as a new diagnostic marker for MPM.
    Keywords:  Diagnostic marker; Malignant pleural mesothelioma; Sulfated glycan; Thoracic tumor
    DOI:  https://doi.org/10.1007/s00408-022-00531-4
  3. Front Cell Dev Biol. 2022 ;10 852812
    Nintedanib and Dasatinib Treatments Induce Protective Autophagy as a Potential Resistance Mechanism in MPM Cells.
    Luca Hegedüs, Kata D Szücs, Matthias Kudla, Julian Heidenreich, Verena Jendrossek, Samuel Peña-Llopis, Tamas Garay, Andras Czirok, Clemens Aigner, Till Plönes, Silvia Vega-Rubin-de-Celis, Balazs Hegedüs.
      Malignant pleural mesothelioma (MPM) is a rare type of cancer with a grim prognosis. So far, no targetable oncogenic mutation was identified in MPM and biomarkers with predictive value toward drug sensitivity or resistance are also lacking. Nintedanib (BIBF1120) is a small-molecule tyrosine kinase inhibitor that showed promising efficacy preclinically and in phase II trial in MPM as an angiogenesis inhibitor combined with chemotherapy. However, the extended phase III trial failed. In this study, we investigated the effect of nintedanib on one of its targets, the SRC kinase, in two commercial and six novel MPM cell lines. Surprisingly, nintedanib treatment did not inhibit SRC activation in MPM cells and even increased phosphorylation of SRC in several cell lines. Combination treatment with the SRC inhibitor dasatinib could reverse this effect in all cell lines, however, the cellular response was dependent on the drug sensitivity of the cells. In 2 cell lines, with high sensitivity to both nintedanib and dasatinib, the drug combination had no synergistic effect but cell death was initiated. In 2 cell lines insensitive to nintedanib combination treatment reduced cell viability synergisticaly without cell death. In contrast, in these cells both treatments increased the autophagic flux assessed by degradation of the autophagy substrate p62 and increased presence of LC3B-II, increased number of GFP-LC3 puncta and decreased readings of the HiBiT-LC3 reporter. Additionaly, autophagy was synergistically promoted by the combined treatment. At the transcriptional level, analysis of lysosomal biogenesis regulator Transcription Factor EB (TFEB) showed that in all cell lines treated with nintedanib and to a lesser extent, with dasatinib, it became dephosphorylated and accumulated in the nucleus. Interestingly, the expression of certain known TFEB target genes implicated in autophagy or lysosomal biogenesis were significantly modified only in 1 cell line. Finally, we showed that autophagy induction in our MPM cell lines panel by nintedanib and dasatinib is independent of the AKT/mTOR and the ERK pathways. Our study reveals that autophagy can serve as a cytoprotective mechanism following nintedanib or dasatinib treatments in MPM cells.
    Keywords:  TFEB; autophagy; dasatinib; malignant pleural mesothelioma; nintedanib
    DOI:  https://doi.org/10.3389/fcell.2022.852812
  4. Lung Cancer. 2022 Mar 21. pii: S0169-5002(22)00381-6. [Epub ahead of print]167 8-16
    First-line nivolumab plus ipilimumab versus chemotherapy for the treatment of unresectable malignant pleural mesothelioma: patient-reported outcomes in CheckMate 743.
    Arnaud Scherpereel, Scott Antonia, Yolanda Bautista, Francesco Grossi, Dariusz Kowalski, Gérard Zalcman, Anna K Nowak, Nobukazu Fujimoto, Solange Peters, Anne S Tsao, Aaron S Mansfield, Sanjay Popat, Xiaowu Sun, Rachael Lawrance, Xiaoqing Zhang, Melinda J Daumont, Bryan Bennett, Mike McKenna, Paul Baas.
       OBJECTIVE: In CheckMate 743 (NCT02899299), nivolumab + ipilimumab significantly prolonged overall survival in patients with unresectable malignant pleural mesothelioma (MPM). We present patient-reported outcomes (PROs).
    MATERIALS AND METHODS: Patients (N = 605) were randomized to nivolumab + ipilimumab or chemotherapy. Changes in disease-related symptom burden and health-related quality of life (HRQoL) were evaluated descriptively using the Lung Cancer Symptom Scale (LCSS)-Mesothelioma (Meso) average symptom burden index (ASBI), LCSS-Meso 3-item global index (3-IGI), 3-level EuroQol 5-dimensional (EQ-5D-3L) visual analog score (VAS), and EQ-5D-3L utility index. PROs were assessed at baseline and every 2 (nivolumab + ipilimumab) or 3 weeks (chemotherapy) through 12 weeks, every 6 weeks through 12 months, every 12 weeks thereafter, and at specified follow-ups. Mixed-effect model repeated measures (MMRM) and time to deterioration analyses were conducted.
    RESULTS: Completion rates were generally >80%. LCSS-Meso ASBI mean changes from baseline trended to improve over time with nivolumab + ipilimumab and deteriorate with chemotherapy, but did not meet clinically important difference thresholds [±10 score change]. EQ-5D-3L VAS mean scores improved over time with nivolumab + ipilimumab; by week 60, patients had scores consistent with United Kingdom normal population values. MMRM analyses favored nivolumab + ipilimumab for all individual symptoms except cough. Nivolumab + ipilimumab delayed time to definitive deterioration in HRQoL (hazard ratio 0.52 [95% confidence interval 0.36-0.74]) and showed a trend in symptom delay versus chemotherapy.
    CONCLUSIONS: Nivolumab + ipilimumab decreased the risk of deterioration in disease-related symptoms and HRQoL versus chemotherapy and maintained QoL in patients with unresectable MPM.
    Keywords:  Anti-cytotoxic T lymphocyte antigen-4 (CTLA-4); EQ-5D; Immune checkpoint inhibitors; Immuno-oncology; Immunotherapy; Lung Cancer Symptom Scale; Overall survival; Programmed cell death (PD)-1 inhibitor; Quality of life; Symptom burden
    DOI:  https://doi.org/10.1016/j.lungcan.2022.03.012
  5. Diagn Cytopathol. 2022 Apr 05.
    Evaluation of DNA/RNA quality from cell block of malignant mesothelioma and lung adenocarcinoma.
    Shigenobu Tatsumi, Mao Takeuchi, Tomomi Fujii, Aya Sugimoto, Yoko Sekita-Hatakeyama, Takeshi Nishikawa, Tomoko Uchiyama, Kohei Morita, Hiroe Itami, Maiko Takeda, Masaharu Yamazaki, Chiho Ohbayashi.
      Malignant mesothelioma (MM) is a rare and highly lethal tumor that arises from mesothelial tissue on the surface of the chest and abdominal cavity. Cytological examination of body fluids, including pleural fluid and ascites, is essential for the differentiation of malignant mesothelioma from other carcinomas, such as lung and gastrointestinal carcinomas and metastatic tumors. To evaluate the effectiveness of cell block preparation procedures, which are used for immunocytochemical staining and genetic panel analysis of tumor-specific gene mutations, we used various fixatives. We also evaluated the effects of immunostaining, and the quality of nucleic acids for genetic analysis.
    METHODS: Cell blocks were prepared using the malignant mesothelioma cell lines MESO4 and H226 and non-small cell lung carcinoma cell line HCC78. The cells were fixed using 10% neutral buffered formalin and four different fixatives for liquid cytology. Fixed cells were formed into cell clusters using sodium alginate or centrifugation, and paraffin-embedded cell blocks were prepared.
    RESULTS: Cell blocks were morphologically evaluated by hematoxylin and eosin and immunocytological staining, and the nucleic acid quality was evaluated by DNA/RNA extraction, qPCR, and next-generation sequence analysis. D2-40 and WT1 staining differed depending on the fixation solution and the cell cluster formation method; however, the degree of nucleic acid degradation was not impaired by any method.
    CONCLUSION: Although the morphological evaluation of cytology specimens is affected by the method of cell block preparation, it is still useful for nucleic acid extraction and gene panel analysis, as long as there are sufficient amounts of tumor cells.
    Keywords:  NGS; cell block; immunocytochemistry; malignant mesothelioma
    DOI:  https://doi.org/10.1002/dc.24960
  6. Cureus. 2022 Feb;14(2): e22638
    Biphasic Peritoneal Mesothelioma: A Lethal Clinical Entity.
    Abdul Waheed, Shahin Foroutan, Audrey McCloskey, Harmanprit Randhawa, Frederick D Cason.
      Mesotheliomas are a rare malignancy of the serosal membrane. Mainly it affects the pleural surfaces followed by the second most common location, "peritoneum." The disease follows an aggressive pattern of spread, and by the time the diagnosis is established, the condition significantly spreads to distant locations. Diagnosis of malignant peritoneal mesothelioma is typically made by tissue biopsy. The standard treatment is radical resection; however, patients have benefited from several other modalities. The current case report describes a unique case of malignant mesothelioma, biphasic peritoneal mesothelioma (BPM), which comprises less than 25% of all peritoneal mesotheliomas. The diagnosis and treatment do not differ from other subtypes; however, the prognosis is poor, and if untreated, the survival is typically less than six months.
    Keywords:  abdominal; biphasic; mesotheliomas; neoplasms; peritoneal
    DOI:  https://doi.org/10.7759/cureus.22638
  7. Lung Cancer. 2022 Mar 24. pii: S0169-5002(22)00386-5. [Epub ahead of print]167 17-24
    Geographic distribution of malignant mesothelioma incidence and survival in Australia.
    Jessica K Cameron, Joanne Aitken, Alison Reid, Kerrie Mengersen, Susanna Cramb, Paige Preston, Bruce Armstrong, Peter Baade.
       OBJECTIVES: To understand the geographic distribution of and area-level factors associated with malignant mesothelioma incidence and survival in Australia.
    MATERIALS AND METHODS: Generalised linear models and Bayesian spatial models were fitted using population registry data. Area-level covariates were socioeconomic quintile, remoteness category and state or territory. The maximised excess events test was used to test for spatial heterogeneity.
    RESULTS: There was strong evidence of spatial differences in standardised incidence rates for malignant mesothelioma but survival was uniformly poor. Incidence rates varied by state or territory and were lower in remote areas. Patterns in the geographic distribution of modelled incidence counts for malignant mesothelioma differed substantially from patterns of standardised incidence rates.
    CONCLUSIONS: Geographic variation in the modelled incidence counts of malignant mesothelioma demonstrates varying demand for diagnostic and management services. The long latency period for this cancer coupled with migration complicates any associations with patterns of exposure, however some of the geographic distribution of diagnoses can be explained by the location of historical mines and asbestos-related industries.
    Keywords:  Cancer; Incidence; Mesothelioma; Spatial modeling; Statistical modeling; Survival
    DOI:  https://doi.org/10.1016/j.lungcan.2022.03.017
  8. Expert Opin Drug Deliv. 2022 Apr 06.
    Current progress of miRNA-derivative nucleotide drugs: Modifications, delivery systems, applications.
    Charles Asakiya, Liye Zhu, Jieyu Yuhan, Longjiao Zhu, Kunlun Huang, Wentao Xu.
       INTRODUCTION: miRNA-derivative clinical nucleotide drugs (mdCNDs) effectively treat several diseases, with numerous undergoing clinical trials. In early-stage trials in disease therapeutics such as malignant pleural mesothelioma and hepatic virus C infection, mdCND's therapeutic potency is undeniably good for effectiveness and safety.
    AREAS COVERED: 15 mdCNDs undergoing clinical trials are introduced in this review. MiRNA modifications methods have been summarized including phosphorothioate, cholesterol, locked nucleic acid, 2'-O-methyl, N,N-diethyl-4-(4-nitronaphthalen1-ylazo)-phenylamine modifications and many more. Moreover, delivery systems, including self-assembled, inorganic ions nanoparticles, exosomes, and lipid-based nanosystems for mdCNDs targeted delivery, are presented. Among that, EnGeneIC, N-Acetylgalactosamine, liposomal nanoparticles, and cholesterol-conjugated for mdCNDs delivery are currently undergoing clinical trials. The pH, light, temperature, redox-responsive, enzyme, and specific-substance modes to trigger the release of miRNAs to target sites on-demand and the prospects of mdCNDs are discussed in this review.
    EXPERT OPINION: mdNCDs are one type of promising clinical drugs, however, it is still in the infancy. During the development process, it is imperative to advance in modifying miRNAs, especially at the 5'-end, to enhance targetability and stability against nucleases, develop a stimuli-responsive mode to control the release of mdCNDs to tissue cell-type-specific sites.
    Keywords:  Application; Delivery systems; MiRNA-derivative nucleotide drugs; Modifications; Stimuli-responsive system
    DOI:  https://doi.org/10.1080/17425247.2022.2063835
  9. Front Oncol. 2022 ;12 784064
    Challenging Diagnostic Process for a Malignant Peritoneal Mesothelioma Patient With Ascites and Pleural Effusion: A Case Report and Review of the Literature.
    Xiaofeng Zeng, Ke Xu, Liying Zhang, Xiaoli Huang.
      Malignant peritoneal mesothelioma (MPM) is a sporadic and fatal disease of the peritoneal lining. Its diagnosis has been known to be challenging, time-consuming, and money-consuming. In this paper, we report an MPM case of a 58-year-old man with severe abdominal distension. After he had received all kinds of auxiliary examination, including computed tomography scans of the chest and whole abdomen, examinations of peripheral and pleural fluid, positron emission tomography, and twice fine-needle peritoneal biopsies, his disease still could not be confirmed. Eventually, the patient was diagnosed with MPM through laparoscopic biopsy and IHC. From this case, we concluded that clinicians can gradually discover and diagnose the disease through 1) high platelet and CA125 levels and CT imaging results, 2) cytologic examinations of ascites and pleural fluid, 3) peritoneal biopsies (fine-needle biopsy, laparoscopy biopsy), and 4) histopathological examinations and immunohistochemistry findings. The diagnostic process involving this patient can be an example to demonstrate the effectiveness of various auxiliary examination methods in MPM diagnosis.
    Keywords:  ascites; case report; diagnosis; immunohistochemistry; malignant peritoneal mesothelioma; pleural effusion
    DOI:  https://doi.org/10.3389/fonc.2022.784064
  10. Occup Environ Med. 2022 Apr 07. pii: oemed-2021-108047. [Epub ahead of print]
    Head and neck cancer and asbestos exposure.
    Bénédicte Clin, Celine Gramond, Isabelle Thaon, Patrick Brochard, Fleur Delva, Soizick Chammings, Antoine Gislard, François Laurent, Christophe Paris, Aude Lacourt, Jean-Claude Pairon.
       OBJECTIVES: The aim of this study was to analyse, within a French cohort of workers previously occupationally exposed to asbestos, incidence and mortality from various sites of head and neck cancers (larynx excluded) and to examine the potential link of these cancers with pleural plaques.
    METHODS: A 10-year follow-up study was conducted in the 13 481 male subjects included in the cohort between October 2003 and December 2005. Asbestos exposure was assessed by industrial hygienist analysis of a standardised questionnaire. The final cumulative exposure index (CEI; in equivalent fibres.years/mL) for each subject was calculated as the sum of each employment period's four-level CEI. The number of head and neck cancers recorded by the National Health Insurance fund was collected in order to conduct an incidence study. Complementary analysis was restricted to men who had performed at least one chest CT scan (N=4804). A mortality study was also conducted. We used a Cox model with age as the time axis variable adjusted for smoking, time since first exposure, CEI of exposure to asbestos and pleural plaques on CT scans.
    RESULTS: We reported a significant dose-response relationship between CEI of exposure to asbestos and head and neck cancers after exclusion of laryngeal cancers, in the mortality study (HR 1.03, 95% CI (1.01 to 1.06) for an increase of 10 f.years/mL) and a close to significant dose-response relationship in the incidence study (HR 1.02, 95% CI (1.00 to 1.04) for an increase of 10 f.years/mL). No statistically significant association between pleural plaques and head and neck cancer incidence was observed.
    CONCLUSIONS: This large-scale study suggests a relationship between asbestos exposure and head and neck cancers, after exclusion of laryngeal cancers, regardless of whether associated pleural plaques were present.
    Keywords:  Asbestos; Cancer; Occupational Health; Otorhinolaryngologic Diseases
    DOI:  https://doi.org/10.1136/oemed-2021-108047
  11. J Adv Pract Oncol. 2022 Mar;13(2): 158-163
    Tazemetostat: EZH2 Inhibitor.
    Rachael Straining, William Eighmy.
      Epigenetic regulation is a novel approach to cancer treatment. Inhibition of enhancer of zeste homolog 2 (EZH2) is a method to provide targeted epigenetic regulation. Tazemetostat is a first-in-class targeted epigenetic regulator that specifically inhibits EZH2. This new FDA-approved oral treatment received accelerated approval for patients with hematologic and solid malignancies. Tazemetostat was first approved for patients 16 years and older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection based on the results of an international open-label phase II basket trial. Another open-label multicenter phase II trial led to the approval for patients with relapsed or refractory follicular lymphoma with EZH2 mutation who have received at least two prior systemic therapies or patients who have no satisfactory alternative treatment options. Tazemetostat as an oral EZH2 inhibitor provides a new effective and tolerable treatment option for these patients.
    DOI:  https://doi.org/10.6004/jadpro.2022.13.2.7
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