bims-mesote Biomed News
on Mesothelioma
Issue of 2021–04–04
eightteen papers selected by
Laura Mannarino, Humanitas Research
  1. Identification of Redox-Sensitive Transcription Factors as Markers of Malignant Pleural Mesothelioma.
  2. NF2 and Canonical Hippo-YAP Pathway Define Distinct Tumor Subsets Characterized by Different Immune Deficiency and Treatment Implications in Human Pleural Mesothelioma.
  3. Relapse Patterns and Tailored Treatment Strategies for Malignant Pleural Mesothelioma Recurrence after Multimodality Therapy.
  4. The Evolving Landscape of the Molecular Epidemiology of Malignant Pleural Mesothelioma.
  5. BAP1-Altered Malignant Pleural Mesothelioma: Outcomes With Chemotherapy, Immune Check-Point Inhibitors and Poly(ADP-Ribose) Polymerase Inhibitors.
  6. Identification of Overexpressed Genes in Malignant Pleural Mesothelioma.
  7. Utility of SOX6 and DAB2 for the Diagnosis of Malignant Mesothelioma.
  8. The concept of mesothelioma in situ, with consideration of its potential impact on cytology diagnosis.
  9. VATS Pleurectomy Decortication Is a Reasonable Alternative for Higher Risk Patients in the Management of Malignant Pleural Mesothelioma: An Analysis of Short-Term Outcomes.
  10. Diaphragm reconstruction by GORE DUALMESH in patients undergoing resection for thoracic malignancies.
  11. Assessment of the Carcinogenicity of Carbon Nanotubes in the Respiratory System.
  12. Response to Immune Checkpoint Inhibitor Therapy in Patients with Unresectable Recurrent Malignant Pleural Mesothelioma Shown by FDG-PET and CT.
  13. Interobserver Variability of Quantitative and Qualitative Assessment Using MRI in Malignant Pleural Mesothelioma.
  14. Bisecting-GlcNAc on Asn388 is characteristic to ERC/mesothelin expressed on epithelioid mesothelioma cells.
  15. CD26/Dipeptidyl Peptidase IV and Its Multiple Biological Functions.
  16. [Asbestos exposure and asbestos-related malignant diseases:an epidemiological review].
  17. Orphan Designation and Cisplatin/Hyaluronan Complex in an Intracavitary Film for Malignant Mesothelioma.
  18. Transcriptional perturbation of protein arginine methyltransferase-5 exhibits MTAP-selective oncosuppression.
  1. Cancers (Basel). 2021 Mar 07. pii: 1138. [Epub ahead of print]13(5):
    Identification of Redox-Sensitive Transcription Factors as Markers of Malignant Pleural Mesothelioma.
    Martina Schiavello, Elena Gazzano, Loredana Bergandi, Francesca Silvagno, Roberta Libener, Chiara Riganti, Elisabetta Aldieri.
      Although asbestos has been banned in most countries around the world, malignant pleural mesothelioma (MPM) is a current problem. MPM is an aggressive tumor with a poor prognosis, so it is crucial to identify new markers in the preventive field. Asbestos exposure induces oxidative stress and its carcinogenesis has been linked to a strong oxidative damage, event counteracted by antioxidant systems at the pulmonary level. The present study has been focused on some redox-sensitive transcription factors that regulate cellular antioxidant defense and are overexpressed in many tumors, such as Nrf2 (Nuclear factor erythroid 2-related factor 2), Ref-1 (Redox effector factor 1), and FOXM1 (Forkhead box protein M1). The research was performed in human mesothelial and MPM cells. Our results have clearly demonstrated an overexpression of Nrf2, Ref-1, and FOXM1 in mesothelioma towards mesothelium, and a consequent activation of downstream genes controlled by these factors, which in turn regulates antioxidant defense. This event is mediated by oxidative free radicals produced when mesothelial cells are exposed to asbestos fibers. We observed an increased expression of Nrf2, Ref-1, and FOXM1 towards untreated cells, confirming asbestos as the mediator of oxidative stress evoked at the mesothelium level. These factors can therefore be considered predictive biomarkers of MPM and potential pharmacological targets in the treatment of this aggressive cancer.
    Keywords:  asbestos; biomarkers; malignant pleural mesothelioma; mesothelium; oxidative stress; redox-sensitive factors
    DOI:  https://doi.org/10.3390/cancers13051138
  2. Cancers (Basel). 2021 Mar 29. pii: 1561. [Epub ahead of print]13(7):
    NF2 and Canonical Hippo-YAP Pathway Define Distinct Tumor Subsets Characterized by Different Immune Deficiency and Treatment Implications in Human Pleural Mesothelioma.
    Haitang Yang, Sean R R Hall, Beibei Sun, Liang Zhao, Yanyun Gao, Ralph A Schmid, Swee T Tan, Ren-Wang Peng, Feng Yao.
      (1) Inactivation of the tumor suppressor NF2 is believed to play a major role in the pathogenesis of malignant pleural mesothelioma (MPM) by deregulating the Hippo-YAP signaling pathway. However, NF2 has functions beyond regulation of the Hippo pathway, raising the possibility that NF2 contributes to MPM via Hippo-independent mechanisms. (2) We performed weighted gene co-expression analysis (WGCNA) in transcriptomic and proteomic datasets obtained from The Cancer Gene Atlas (TCGA) MPM cohort to identify clusters of co-expressed genes highly correlated with NF2 and phospho (p)-YAP protein, surrogate markers of active Hippo signaling and YAP inactivation. The potential targets are experimentally validated using a cell viability assay. (3) MPM tumors with NF2 loss-of-function are not associated with changes in p-YAP level nor YAP/TAZ activity score, but are characterized by a deficient B-cell receptor (BCR) signaling pathway. Conversely, MPM tumors with YAP activation display exhausted CD8 T-cell-mediated immunity together with significantly upregulated PD-L1, which is validated in an independent MPM cohort, suggesting a potential benefit of immune-checkpoint inhibitors (ICI) in this patient subset. In support of this, mutations in core Hippo signaling components including LATS2, but not NF2, are independently associated with better overall survival in response to ICI in patients. Additionally, based on cancer cell line models, we show that MPM cells with a high Hippo-YAP activity are particularly sensitive to inhibitors of BCR-ABL/SRC, stratifying a unique MPM patient subset that may benefit from BCR-ABL/SRC therapies. Furthermore, we observe that NF2 physically interacts with a considerable number of proteins that are not involved in the canonical Hippo-YAP pathway, providing a possible explanation for its Hippo-independent role in MPM. Finally, survival analyses show that YAP/TAZ scores together with p-YAP protein level, but not NF2, predict the prognosis of MPM patients. (4) NF2 loss-of-function and dysregulated Hippo-YAP pathway define distinct MPM subsets that differ in their molecular features and prognosis, which has important clinical implications for precision oncology in MPM patients.
    Keywords:  Hippo pathway; LATS2; NF2; YAP; immunotherapy; mesothelioma; targeted therapy
    DOI:  https://doi.org/10.3390/cancers13071561
  3. J Clin Med. 2021 Mar 08. pii: 1134. [Epub ahead of print]10(5):
    Relapse Patterns and Tailored Treatment Strategies for Malignant Pleural Mesothelioma Recurrence after Multimodality Therapy.
    Alice Bellini, Andrea Dell'Amore, Stefano Terzi, Giovanni Zambello, Andrea Zuin, Giulia Pasello, Fiorella Calabrese, Marco Schiavon, Federico Rea.
      To date, there have been no established therapies for recurrent malignant pleural mesothelioma (MPM) after multimodality treatment. Aims of this retrospective study are to analyze the recurrence pattern, its treatment and to identify the predictors of best oncological outcomes for relapsed MPM, comparing extrapleural pneumonectomy (EPP) vs. pleurectomy/decortication (PD). Study population: 94 patients with recurrence of MPM after multimodality treatment underwent macroscopic complete resection (52.1% with EPP and 47.9% with PD) between July 1994 and February 2020. Distant spread was the most frequent pattern of recurrence (71.3%), mostly in the EPP group, while the PD group showed a higher local-only failure rate. Post-recurrence treatment was administered in 86.2%, whereas best supportive care was administered in 13.8%. Median post-recurrence survival (PRS) was 12 months (EPP 14 vs. PD 8 months, p = 0.4338). At multivariate analysis, predictors of best PRS were epithelial histology (p = 0.026, HR 0.491, IC95% 0.263-0.916), local failure (p = 0.027, HR 0.707, IC95% 0.521-0.961), DFS ≥ 12 months (p = 0.006, HR 0.298, IC95% 0.137-0.812) and post-recurrence medical treatment (p = 0.046, HR 0.101, IC95% 0.897-0.936). The type of surgical intervention seems not to influence the PRS if patients are fit enough to face post-recurrence treatments. In patients with a prolonged disease-free interval, in the case of recurrence the most appropriate treatment seems to be the systemic medical therapy, even in the case of local-only relapse.
    Keywords:  mesothelioma; multimodality therapy; thoracic surgery
    DOI:  https://doi.org/10.3390/jcm10051134
  4. J Clin Med. 2021 Mar 03. pii: 1034. [Epub ahead of print]10(5):
    The Evolving Landscape of the Molecular Epidemiology of Malignant Pleural Mesothelioma.
    Sara Lettieri, Chandra Bortolotto, Francesco Agustoni, Filippo Lococo, Andrea Lancia, Patrizia Comoli, Angelo G Corsico, Giulia M Stella.
      Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy that most commonly affects the pleural lining of the lungs. It has a strong association with exposure to biopersistent fibers, mainly asbestos (80% of cases) and-in specific geographic regions-erionite, zeolites, ophiolites, and fluoro-edenite. Individuals with a chronic exposure to asbestos generally have a long latency with no or few symptoms. Then, when patients do become symptomatic, they present with advanced disease and a worse overall survival (about 13/15 months). The fibers from industrial production not only pose a substantial risk to workers, but also to their relatives and to the surrounding community. Modern targeted therapies that have shown benefit in other human tumors have thus far failed in MPM. Overall, MPM has been listed as orphan disease by the European Union. However, molecular high-throughput profiling is currently unveiling novel biomarkers and actionable targets. We here discuss the natural evolution, mainly focusing on the novel concept of molecular epidemiology. The application of innovative endpoints, quantification of genetic damages, and definition of genetic susceptibility are reviewed, with the ultimate goal to point out new tools for screening of exposed subject and for designing more efficient diagnostic and therapeutic strategies.
    Keywords:  genetics; mesothelioma; molecular epidemiology; personalized medicine
    DOI:  https://doi.org/10.3390/jcm10051034
  5. Front Oncol. 2021 ;11 603223
    BAP1-Altered Malignant Pleural Mesothelioma: Outcomes With Chemotherapy, Immune Check-Point Inhibitors and Poly(ADP-Ribose) Polymerase Inhibitors.
    Elizabeth Dudnik, Jair Bar, Assaf Moore, Teodor Gottfried, Mor Moskovitz, Julia Dudnik, Tzippy Shochat, Aaron M Allen, Alona Zer, Ofer Rotem, Nir Peled, Damien Urban.
       Objectives: Little is known regarding the outcomes of systemic treatments in BAP1-altered malignant pleural mesothelioma (MPM).
    Materials and Methods: Forty five patients with MPM [group A: eight MPM patients with BAP1 inactivating mutation/copy number loss (FoundationOne® CDx/TEMPUSxT), selected from the electronic databases of four Israeli cancer centers (ICC); group B: 37 consecutive (years 2016-2018) MPM patients selected from the electronic databases of two ICC-of those six patients without a BAP1 alteration (group B1) and 31 patients not tested for BAP1 (group B2)] were analyzed for ORR, PFS (mRECIST), and OS with 1st-line platinum/pemetrexed+/-antiangiogenic drug (CT, n-28), immune check-point inhibitors (ICPi, n-16) and poly (ADP-ribose) polymerase inhibitors (PARPi, n-4). OS since diagnosis (OSDx) was assessed.
    Results: There were no differences in ORR or mPFS with CT between the groups: ORR-50% vs. 47% vs. 50% vs. 47% (p>0.9), mPFS-9.1mo (95% CI, 1.2-16.1) vs. 9.2mo (95% CI, 2.9-13.3) vs. 7.2mo (95% CI, 2.3-NR) vs. 10.9mo (95% CI, 2.9-20.3) (p>0.8) in groups A, B, B1, and B2, respectively. There were no differences in ORR or mPFS with ICPi between the groups: ORR-0% vs. 27% vs. 33% vs. 25% (p>0.2), mPFS-2.5mo (95% CI, 1.4-3.7) vs. 3.0mo (95% CI, 1.3-10.5) vs. 2.0mo (95% CI, 1.9-NR) vs. 4.5mo (95% CI, 0.3-10.5) (p>0.3) in groups A, B, B1, and B2, respectively. In group A, no responses were seen with PARPi; mPFS with PARPi was 1.8mo (95% CI, 1.8-NR). OSDx was 98.3mo (95% CI, 9.7-98.3) vs. 19.4mo (95% CI, 9.7-47.3) vs. 18.8mo (95% CI, 8.5-NR) vs. 19.5mo (95% CI, 8.3-82.2) in groups A, B, B1, and B2, respectively (p>0.3).
    Conclusions: BAP1-altered MPM, as compared to non-selected MPM, is characterized by similar efficacy of CT and ICPi. Numerically longer OS in BAP1-altered MPM may reflect favorable tumor biology. No responses were observed with PARPi.
    Keywords:  BAP1; PARP inhibitors; chemotherapy; immune check-point inhibitors; mesothelioma
    DOI:  https://doi.org/10.3389/fonc.2021.603223
  6. Int J Mol Sci. 2021 Mar 08. pii: 2738. [Epub ahead of print]22(5):
    Identification of Overexpressed Genes in Malignant Pleural Mesothelioma.
    Federica Morani, Luisa Bisceglia, Giulia Rosini, Luciano Mutti, Ombretta Melaiu, Stefano Landi, Federica Gemignani.
      Malignant pleural mesothelioma (MPM) is a fatal tumor lacking effective therapies. The characterization of overexpressed genes could constitute a strategy for identifying drivers of tumor progression as targets for novel therapies. Thus, we performed an integrated gene-expression analysis on RNAseq data of 85 MPM patients from TCGA dataset and reference samples from the GEO. The gene list was further refined by using published studies, a functional enrichment analysis, and the correlation between expression and patients' overall survival. Three molecular signatures defined by 15 genes were detected. Seven genes were involved in cell adhesion and extracellular matrix organization, with the others in control of the mitotic cell division or apoptosis inhibition. Using Western blot analyses, we found that ADAMTS1, PODXL, CIT, KIF23, MAD2L1, TNNT1, and TRAF2 were overexpressed in a limited number of cell lines. On the other hand, interestingly, CTHRC1, E-selectin, SPARC, UHRF1, PRSS23, BAG2, and MDK were abundantly expressed in over 50% of the six MPM cell lines analyzed. Thus, these proteins are candidates as drivers for sustaining the tumorigenic process. More studies with small-molecule inhibitors or silencing RNAs are fully justified and need to be undertaken to better evaluate the cancer-driving role of the targets herewith identified.
    Keywords:  MPM; RNAseq; gene signature; malignant pleural mesothelioma; overexpressed genes; therapeutic targets
    DOI:  https://doi.org/10.3390/ijms22052738
  7. Am J Surg Pathol. 2021 Mar 29.
    Utility of SOX6 and DAB2 for the Diagnosis of Malignant Mesothelioma.
    Julia R Naso, Simon Cheung, Diana N Ionescu, Andrew Churg.
      The separation of malignant mesothelioma from non-small cell lung carcinomas can be a difficult problem. Sex-determining region Y box 6 (SOX6) and disabled homolog 2 (DAB2) have recently been proposed as sensitive/specific markers of mesothelial lineage, but have not yet been independently tested for utility in mesothelioma diagnosis. Using tissue microarrays containing mesotheliomas (epithelioid: n=40, sarcomatoid: n=23) and non-small cell lung carcinomas (adenocarcinoma: n=52, squamous cell carcinoma: n=57, large cell carcinoma: n=12) we evaluated the performance of SOX6 and DAB2 by themselves, in conjunction with other established mesothelioma markers (calretinin, WT1, D2-40, CK5/6, HEG1) and combined with 3 broad-spectrum established carcinoma markers: claudin-4, MOC31, and BerEP4. For epithelioid mesothelioma, SOX6 and DAB2 had sensitivities of 85% and 98%, respectively. For sarcomatoid mesothelioma, SOX6 had a sensitivity of 13% and DAB2 could not be assessed due to background stromal staining. For SOX6 alone, specificity for mesothelioma versus adenocarcinoma, squamous cell carcinoma, and large cell carcinoma was 94%, 79%, and 92%, respectively, while for DAB2 specificity was 77%, 86%, and 67%. Combinations of SOX6 and established mesothelioma markers produced sensitivities of 95% or greater. A combination of SOX6 positive/claudin-4 negative staining was 95% to 100% specific for mesothelioma versus carcinoma with a sensitivity of 85%. SOX6 is a promising marker for the diagnosis of mesothelioma and potentially could be combined with other mesothelial markers or a broad-spectrum carcinoma marker to reach an accurate diagnosis with relatively few immunostains, The relatively low specificity and difficulty of interpreting DAB2 staining limits its utility for mesothelioma diagnosis.
    DOI:  https://doi.org/10.1097/PAS.0000000000001712
  8. Pathology. 2021 Mar 25. pii: S0031-3025(21)00062-3. [Epub ahead of print]
    The concept of mesothelioma in situ, with consideration of its potential impact on cytology diagnosis.
    Sonja Klebe, Yukio Nakatani, Katalin Dobra, Kelly J Butnor, Anja C Roden, Andrew G Nicholson, Alberto M Marchevsky, Aliya N Husain, Amanda Segal, Ann E Walts, Birgit Weynand, Claire W Michael, Sanja Dacic, David Godbolt, Richard Attanoos, Eric Santoni-Rugiu, Françoise Galateau-Salle, Kenzo Hiroshima, Andre L Moreira, Juliet Burn, Kazuki Nabeshima, Allen R Gibbs, Andrew Churg, Leslie A Litzky, Luka Brcic, Ming Sound Tsao, Mari Mino-Kenudson, Sara B Rørvig, Henry D Tazelaar, Thomas Krausz, Yu Zhi Zhang, Lucian R Chirieac, Mary B Beasley, Anders Hjerpe.
      Diffuse malignant mesothelioma (MM) is an incurable tumour of the serosal membranes, which is often caused by exposure to asbestos and commonly diagnosed at advanced stage. Malignant mesothelioma in situ (MMIS) is now included as diagnostic category by the World Health Organization (WHO). However, our international survey of 34 pulmonary pathologists with an interest in MM diagnosis highlights inconsistency regarding how the diagnosis is being made by experts, despite published guidelines. Whilst the WHO restricts the diagnosis to surgical samples, the very concept has implication for cytological diagnosis, which is already regarded as controversial in itself by some. MMIS is currently only applicable as precursor to MM with an epithelioid component, and raises the possibility for different molecular pathways for different histological MM subtypes. The clinical implications of MMIS at this stage are uncertain, but aggressive therapies are being initiated in some instances. Based on the results of the survey we here present a critical appraisal of the concept, its clinical and conceptual implications and provide practice suggestions for diagnosis. A low threshold for ancillary testing is suggested. The designations of 'malignant mesothelioma, cannot exclude MMIS' or 'atypical mesothelial proliferation with molecular indicators of malignancy, so-called MMIS' could be used on cytology samples, adding 'no evidence of invasion in sample provided' for surgical samples. Clinical and radiological correlation are integral to diagnosis and best done at multidisciplinary meetings. Finally, collaborative studies are required to improve our understanding of MMIS.
    Keywords:  Diffuse malignant mesothelioma; WHO; cytology diagnosis; early diagnosis; mesothelioma in situ
    DOI:  https://doi.org/10.1016/j.pathol.2020.12.005
  9. Cancers (Basel). 2021 Mar 03. pii: 1068. [Epub ahead of print]13(5):
    VATS Pleurectomy Decortication Is a Reasonable Alternative for Higher Risk Patients in the Management of Malignant Pleural Mesothelioma: An Analysis of Short-Term Outcomes.
    Dong-Seok Lee, Andrea Carollo, Naomi Alpert, Emanuela Taioli, Raja Flores.
      Surgery is a mainstay of treatment allowing for debulking of tumor and expansion of the lung for improvement in median survival and quality of life for patients with malignant pleural mesothelioma (MPM). Although optimal surgical technique remains open for debate-extrapleural pneumonectomy (EPP) vs. pleurectomy/decortication (P/D)-minimally invasive surgery (VATS-P/D) remains underutilized in the management of MPM. We examined whether VATS-P/D is a feasible alternative to EPP and P/D. We evaluated the New York Statewide Planning and Research Cooperative System (SPARCS) from 2007-2017 to assess the short-term complications of EPP vs. P/D, including a subanalysis of open P/D vs. VATS-P/D. There were 331 patients with open surgery; 269 with P/D and 62 with EPP. There were 384 patients with P/D; 269 were open and 115 VATS. Rates of any complication were similar between EPP and P/D patients, but EPP had significantly higher rates of cardiovascular complications. After adjusting for confounders, those with a VATS approach were less likely to have any complication, compared to an open approach and significantly less likely to have a pulmonary complication. VATS-P/D remains a viable alternative to radical surgery in MPM patients allowing for improved short-term outcomes.
    Keywords:  VATS; extrapleural pneumonectomy; malignant mesothelioma; pleurectomy decortication
    DOI:  https://doi.org/10.3390/cancers13051068
  10. J Cardiothorac Surg. 2021 Mar 31. 16(1): 65
    Diaphragm reconstruction by GORE DUALMESH in patients undergoing resection for thoracic malignancies.
    Atsushi Sano, Yoko Azuma, Takashi Sakai, Satoshi Koezuka, Hajime Otsuka, Akira Iyoda.
       BACKGROUND: We used GORE DUALMESH for the reconstruction of diaphragms in patients with thoracic malignancies. Here, we report the results.
    METHODS: Between July 2015 and August 2017, diaphragm reconstruction using 2-mm GORE DUALMESH was performed in 7 patients undergoing surgical resection for thoracic malignancies. After resection of the diaphragm, the mesh was trimmed to the size of defect and placed with the smooth surface facing the chest cavity and the rough surface facing the abdomen. It was fixed with interrupted sutures consisting of synthetic monofilament nonabsorbable 1-0 to 2 threads.
    RESULTS: Indications for resection were malignant pleural mesothelioma and primary lung cancer in 5 and 2 patients, respectively. Patients with malignant pleural mesothelioma underwent pleurectomy with decortication; patients with primary lung cancer underwent lung lobectomy. Right and left diaphragm reconstruction was performed for 4 and 3 patients, respectively. Neither complications related to diaphragm reconstruction nor displacement of mesh occurred during a follow-up period ranging from 11 days to 37 months.
    CONCLUSIONS: GORE DUALMESH is a good synthetic material for diaphragm reconstruction, because its smooth surface prevents adhesions to the lung and its rough surface allows adherence to abdominal tissue.
    Keywords:  Diaphragm; Lung cancer; Malignant pleural mesothelioma; Prosthesis; Reconstruction
    DOI:  https://doi.org/10.1186/s13019-021-01449-3
  11. Cancers (Basel). 2021 Mar 15. pii: 1318. [Epub ahead of print]13(6):
    Assessment of the Carcinogenicity of Carbon Nanotubes in the Respiratory System.
    Marcella Barbarino, Antonio Giordano.
      In 2014, the International Agency for Research on Cancer (IARC) classified the first type of carbon nanotubes (CNTs) as possibly carcinogenic to humans, while in the case of other CNTs, it was not possible to ascertain their toxicity due to lack of evidence. Moreover, the physicochemical heterogeneity of this group of substances hamper any generalization on their toxicity. Here, we review the recent relevant toxicity studies produced after the IARC meeting in 2014 on an homogeneous group of CNTs, highlighting the molecular alterations that are relevant for the onset of mesothelioma. Methods: The literature was searched on PubMed and Web of Science for the period 2015-2020, using different combinations keywords. Only data on normal cells of the respiratory system after exposure to fully characterized CNTs for their physico-chemical characteristics were included. Recent studies indicate that CNTs induce a sustained inflammatory response, oxidative stress, fibrosis and histological alterations. The development of mesothelial hyperplasia, mesothelioma, and lungs tumors have been also described in vivo. The data support a strong inflammatory potential of CNTs, similar to that of asbestos, and provide evidence that CNTs exposure led to molecular alterations known to have a key role in mesothelioma onset. These evidences call for an urgent improvement of studies on exposed human populations and adequate systems for monitoring the health of workers exposed to this putative carcinogen.
    Keywords:  asbestos exposure; carbon nanotubes; carcinogenesis; malignant mesothelioma
    DOI:  https://doi.org/10.3390/cancers13061318
  12. Cancers (Basel). 2021 Mar 04. pii: 1098. [Epub ahead of print]13(5):
    Response to Immune Checkpoint Inhibitor Therapy in Patients with Unresectable Recurrent Malignant Pleural Mesothelioma Shown by FDG-PET and CT.
    Kazuhiro Kitajima, Mitsunari Maruyama, Hiroyuki Yokoyama, Toshiyuki Minami, Takashi Yokoi, Akifumi Nakamura, Masaki Hashimoto, Nobuyuki Kondo, Kozo Kuribayashi, Takashi Kijima, Seiki Hasegawa, Koichiro Yamakado.
       BACKGROUND: To compare three FDG-PET criteria (EORTC, PERCIST, imPERCIST) with CT criteria (combined modified RECIST and RECIST 1.1) for response evaluation and prognosis prediction in patients with recurrent MPM treated with ICI monotherapy.
    METHODS: Thirty MPM patients underwent FDG-PET/CT and contrast-enhanced CT at the baseline and during nivolumab therapy (median 10 cycles). Therapeutic response was evaluated according to EORTC, PERCIST, imPERCIST, and CT criteria. PFS and OS were examined using log-rank and Cox methods.
    RESULTS: CMR/PMR/SMD/PMD numbered 5/3/4/18 for EORTC, 5/1/7/17 for PERCIST, and 5/3/9/13 for imPERCIST. With CT, CR/PR/SD/PD numbered 0/6/10/14. There was high concordance between EORTC and PERCIST (κ = 0.911), and PERCIST and imPERCIST (κ = 0.826), while that between EORTC and imPERCIST (κ = 0.746) was substantial, and between CT and the three PET criteria moderate (κ = 0.516-0.544). After median 14.9 months, 26 patients showed progression and nine died. According to both PET and CT findings, patients with no progression (CMR/PMR/SMD or CR/PR/SD) showed significantly longer PFS and somewhat longer OS than PMD and PD patients (EORTC p = 0.0004 and p = 0.055, respectively; PERCIST p = 0.0003 and p = 0.052; imPERCIST p < 0.0001 and p = 0.089; CT criteria p = 0.0015 and p = 0.056).
    CONCLUSIONS: Both FDG-PET and CT criteria are accurate for response evaluation of ICI therapy and prediction of MPM prognosis. In comparison with CT, all three FDG-PET/CT criteria judged a greater percentage of patients (16.7%) as CMR, while two (EORTC, PERCIST) judged a greater percentage (10-13.3%) as PMD. For predicting PFS, the three FDG-PET criteria were superior to the CT criteria, and imPERCIST demonstrated the highest rate of accurate prediction.
    Keywords:  FDG; PET-CT; immunotherapy; mesothelioma; survival; therapy response
    DOI:  https://doi.org/10.3390/cancers13051098
  13. Radiol Cardiothorac Imaging. 2020 Apr;2(2): e190066
    Interobserver Variability of Quantitative and Qualitative Assessment Using MRI in Malignant Pleural Mesothelioma.
    Ritu R Gill, David J Murphy, Ravi T Seethamraju, Emanuele Mazzola, Raphael Bueno, William G Richards.
       Purpose: To evaluate the interobserver variability associated with quantitative and qualitative MRI assessments of malignant pleural mesothelioma (MPM).
    Materials and Methods: Patients with MPM who underwent uniform-protocol preoperative MRI between 2009 and 2014 were included. The MRI-derived tumor volume was estimated. Unidimensional measurements of maximal pleural thickness (P max) and average pleural thickness (P avg) on axial MR images; maximal fissural thickness (F max); maximal diaphragmatic thickness (D max); and average diaphragmatic thickness (D avg) on sagittal reconstructed images were acquired. Interobserver agreement regarding the American Joint Committee on Cancer (AJCC) tumor stage at each criterion level was assessed by using Cohen κ statistics. Agreement between quantitative measurements was assessed by using Bland-Altman plots and intraclass correlation coefficients (ICCs).
    Results: The study cohort included 349 patients (median age, 68 years [age range, 30-90 years), 273 (78%) of whom were men and 203 (58%) of whom had epithelioid-subtype tumors. Qualitative assessment performed by using the AJCC staging criteria (eighth edition) was concordant in 31% of cases and yielded considerable disagreement (κ = 0.177). Inspection of the Bland-Altman plots led to decisive agreement between the two reviewers regarding MRI-derived tumor volume (ICC, 0.979). There was also a good degree of agreement between the two reviewers regarding unidimensional measurements of D max (ICC, 0.807), D avg (ICC, 0.823), P max (ICC, 0.787), P avg (ICC, 0.787), and F max (ICC, 0.659).
    Conclusion: Quantitative assessment can enhance the clinical staging of MPM. Compared with qualitative assessment, quantitative assessment has low interobserver variability and could yield a tumor size criterion that is currently lacking in the AJCC clinical staging of MPM.Supplemental material is available for this article.© RSNA, 2020.
    DOI:  https://doi.org/10.1148/ryct.2020190066
  14. J Biochem. 2021 Apr 01. pii: mvab044. [Epub ahead of print]
    Bisecting-GlcNAc on Asn388 is characteristic to ERC/mesothelin expressed on epithelioid mesothelioma cells.
    Haruhiko Fujihira, Daisuke Takakura, Atsushi Matsuda, Masaaki Abe, Michiyo Miyazaki, Tomomi Nakagawa, Kazunori Kajino, Kaori Denda-Nagai, Miki Noji, Okio Hino, Tatsuro Irimura.
      Mesothelioma is a highly aggressive tumor associated with asbestos exposure and is histologically classified into three types: epithelioid-type, sarcomatoid-type, and biphasic-type. The prognosis of mesothelioma patients is poor and there is no effective molecular-targeting therapy as yet. ERC/mesothelin is a glycoprotein that is highly expressed on several types of cancers including epithelioid mesothelioma, but also expressed on normal mesothelial cells. This is a predicted reason why there is no clinically approved therapeutic antibody targeting ERC/mesothelin. In the present study, we focused on the differential glycosylation between ERC/mesothelin present on epithelioid mesothelioma and that on normal mesothelial cells and aimed to reveal a distinct feature of epithelioid mesothelioma cells. Lectin microarray analysis of ERC/mesothelin using cells and patient specimens showed significantly stronger binding of PHA-E4 lectin, which recognizes complex-type N-glycans having a so-called bisecting-GlcNAc structure, to ERC/mesothelin from epithelioid mesothelioma cells than that from normal mesothelial cells. Further, LC/MS analysis on ERC/mesothelin from epithelioid mesothelioma cells confirmed the presence of a bisecting-GlcNAc attached to Asn388 of ERC/mesothelin. These results suggest that this glycoproteome could serve as a potential target for the generation of a highly selective and safe therapeutic antibody for epithelioid mesothelioma.
    Keywords:  ERC/mesothelin; bisecting-GlcNAc; epithelioid mesothelioma; glycosylation
    DOI:  https://doi.org/10.1093/jb/mvab044
  15. Cureus. 2021 Feb 22. 13(2): e13495
    CD26/Dipeptidyl Peptidase IV and Its Multiple Biological Functions.
    Kelsey Pan, Kei Ohnuma, Chikao Morimoto, Nam H Dang.
      CD26/Dipeptidyl peptidase IV (DPPIV) is a cell surface glycoprotein with numerous roles including glucose metabolism, immunomodulation, and tumorigenesis. CD26/DPPIV is well recognized in diabetes, with DPPIV inhibitors being a class of oral hypoglycemic drugs called gliptins that are commonly used to treat type two diabetes mellitus. Recent work also indicated a potential role for CD26 in infectious diseases, including COVID-19, and immune-mediated disorders such as rheumatoid arthritis, inflammatory bowel disease, and graft-versus-host disease. In cancer, CD26/DPPIV expression has been characterized in numerous tumors such as hematologic malignancies, malignant pleural mesothelioma (MPM), renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), gastrointestinal stromal tumor (GIST), and prostate, lung, colorectal, and ovarian (PLCO) cancer. Hence, CD26 has been frequently studied as a tumor biomarker and therapeutic target. CD26/DPPIV-targeted therapies have been evaluated in various cancers, including the use of anti-CD26 monoclonal antibodies as anticancer treatment in selected neoplasms. This review highlights our current understanding of the role of CD26 in cancer, diabetes, immune-mediated diseases, and infectious diseases. Enhanced understanding of CD26 biology and function may lead to novel therapeutic approaches in multiple human diseases.
    Keywords:  cancer; cd26; covid; diabetes; dipeptidyl peptidase iv; immunology; infectious disease
    DOI:  https://doi.org/10.7759/cureus.13495
  16. Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi. 2021 Mar 20. 39(3): 233-236
    [Asbestos exposure and asbestos-related malignant diseases:an epidemiological review].
    X Y Huang, Q Ye.
      Asbestos has high fire resistance, electrical insulation and thermal insulation. It is an important fire prevention, insulation and insulation material. It is widely used in industrial production and daily life. In 1987, the international agency for research on cancer (IARC) has listed asbestos as a class I carcinogen; in 2012, IARC confirmed that all types of asbestos have carcinogenic effect. By 2019, asbestos has been banned in 66 countries and regions around the world. Asbestos exposure increases the risk of human malignant tumor. Lung cancer and mesothelioma are known asbestos induced tumors. Epidemiological studies also support that asbestos exposure is related to the incidence of malignant tumors in reproductive system, digestive system, urinary system, nasopharynx head and neck. We summarized the epidemiological studies of asbestos induced tumors in order to provide reference for further research.
    Keywords:  Asbestos; Epidemiology; Lung cancer; Mesothelioma; Tumor
    DOI:  https://doi.org/10.3760/cma.j.cn121094-20200226-00089
  17. Pharmaceutics. 2021 Mar 09. pii: 362. [Epub ahead of print]13(3):
    Orphan Designation and Cisplatin/Hyaluronan Complex in an Intracavitary Film for Malignant Mesothelioma.
    Sabrina Banella, Eride Quarta, Paolo Colombo, Fabio Sonvico, Antonella Pagnoni, Fabrizio Bortolotti, Gaia Colombo.
      Pleural mesothelioma is a lung diffuse tumor, whose complete resection is unlikely. Consequently, metastases reappear where the primary tumor was removed. This paper illustrates the orphan medicine designation procedure of an intracavitary cisplatin film and related pharmaceutical development aspects requested by the European Medicines Agency (EMA) in its Scientific Advice. Since cisplatin pharmacokinetics from the implanted film in sheep resulted substantially modified compared to intravenous administration, the formation of a cisplatin/hyaluronan complex had been hypothesized. Here, the interaction between sodium hyaluronate (NaHA) and cisplatin (CisPt) was demonstrated. Size exclusion chromatography qualitatively evidenced the complex in the film-forming mixture, only showing the NaHA peak. Atomic absorption spectroscopy of the corresponding fraction revealed platinum, confirming the interaction. Reverse phase HPLC quantified about 5% free cisplatin in the film-forming mixture, indirectly meaning that 95% was complexed. Finally, a study of CisPt release from the film assessed how CisPt/NaHA complex affected drug availability. In water, a medium without chloride ions, there was no release and the film remained intact for 48 h and longer, whereas the placebo film dissolved in 15 min. In 0.9% NaCl medium, the film became more soluble, dissolving within 3-4 h. However, cisplatin release was still controlled by the existing complex in solution until chloride ions displaced it. While the film modified its dissolution with aging, CisPt release remained unaffected (90% released in 48 h).
    Keywords:  cisplatin; complex; film; intracavitary; intrapleural; mesothelioma; orphan designation; sodium hyaluronate
    DOI:  https://doi.org/10.3390/pharmaceutics13030362
  18. Sci Rep. 2021 Apr 01. 11(1): 7434
    Transcriptional perturbation of protein arginine methyltransferase-5 exhibits MTAP-selective oncosuppression.
    Sara Busacca, Qi Zhang, Annabel Sharkey, Alan G Dawson, David A Moore, David A Waller, Apostolos Nakas, Carolyn Jones, Kelvin Cain, Jin-Li Luo, Adriana Salcedo, Iris Chiara Salaroglio, Chiara Riganti, John Le Quesne, Tom John, Paul C Boutros, Shu-Dong Zhang, Dean A Fennell.
      We hypothesized that small molecule transcriptional perturbation could be harnessed to target a cellular dependency involving protein arginine methyltransferase 5 (PRMT5) in the context of methylthioadenosine phosphorylase (MTAP) deletion, seen frequently in malignant pleural mesothelioma (MPM). Here we show, that MTAP deletion is negatively prognostic in MPM. In vitro, the off-patent antibiotic Quinacrine efficiently suppressed PRMT5 transcription, causing chromatin remodelling with reduced global histone H4 symmetrical demethylation. Quinacrine phenocopied PRMT5 RNA interference and small molecule PRMT5 inhibition, reducing clonogenicity in an MTAP-dependent manner. This activity required a functional PRMT5 methyltransferase as MTAP negative cells were rescued by exogenous wild type PRMT5, but not a PRMT5E444Q methyltransferase-dead mutant. We identified c-jun as an essential PRMT5 transcription factor and a probable target for Quinacrine. Our results therefore suggest that small molecule-based transcriptional perturbation of PRMT5 can leverage a mutation-selective vulnerability, that is therapeutically tractable, and has relevance to 9p21 deleted cancers including MPM.
    DOI:  https://doi.org/10.1038/s41598-021-86834-7
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