bims-mesote Biomed News
on Mesothelioma
Issue of 2022–02–27
ten papers selected by
Laura Mannarino, Humanitas Research
  1. Salvage debulking surgery and hyperthermic intrathoracic chemotherapy for massive recurrent mesothelioma in the mediastinum.
  2. Fibrosis in Mesothelioma: Potential Role of Lysyl Oxidases.
  3. Identification of Novel Diagnostic Markers for Malignant Pleural Mesothelioma Using a Reverse Translational Approach Based on a Rare Synchronous Tumor.
  4. SKP2 drives the sensitivity to neddylation inhibitors and cisplatin in malignant pleural mesothelioma.
  5. Current Management and Future Perspective in Pleural Mesothelioma.
  6. Dynamic contrast-enhanced MRI in malignant pleural mesothelioma: prediction of outcome based on DCE-MRI measurements in patients undergoing cytotoxic chemotherapy.
  7. Unusual Histology in Mesothelioma: A Report of Two Cases with a Brief Review.
  8. Big and Free Fractions of Gamma-Glutamyltransferase: New Diagnostic Biomarkers for Malignant Mesothelioma?
  9. Quantitative Assessment of Asbestos Fibers in Normal and Pathological Pleural Tissue-A Scoping Review.
  10. Follow the leader? Can malignant pleural mesothelioma follow non-small cell lung cancer's lead with immunotherapy?
  1. Interact Cardiovasc Thorac Surg. 2022 Feb 26. pii: ivac034. [Epub ahead of print]
    Salvage debulking surgery and hyperthermic intrathoracic chemotherapy for massive recurrent mesothelioma in the mediastinum.
    Shi Sum Poon, Caterina Alberti, Marco Nardini, Marcello Migliore.
      Mediastinal malignant pleural mesothelioma with signs of tamponade is rare. Indication for reoperation for recurrent malignant pleural mesothelioma is a controversial but viable option in selected patients. We report a case of a 68-year-old man presenting with epithelioid malignant pleural mesothelioma who underwent a total of three debulking surgeries (pleurectomy/decortication) combined with hyperthermic intrathoracic chemotherapy. Five years after the first procedure, a third urgent operation was performed for recurrence of a large mediastinal mesothelioma causing acute symptoms of pericardial constriction and tamponade. The patient was alive for eight years since the first treatment and 36 months after the second reoperation.
    Keywords:  Debulking surgery; Decortication; Hyperthermic intrathoracic chemotherapy; Mesothelioma; Pleurectomy
    DOI:  https://doi.org/10.1093/icvts/ivac034
  2. Cancers (Basel). 2022 Feb 15. pii: 981. [Epub ahead of print]14(4):
    Fibrosis in Mesothelioma: Potential Role of Lysyl Oxidases.
    Lara Perryman, Steven G Gray.
      Immunotherapies (such as checkpoint inhibitors) and standard chemotherapies (such as cisplatin) have limitations in the successful treatment of malignant pleural mesothelioma (MPM). Fibrosis is the accumulation of collagen in the extracellular matrix (ECM) of tissues, making them denser than that of healthy tissues and thereby affecting drug delivery and immune cell infiltration. Moreover, fibrosis severely affects the patient's breathing and quality of life. The production of collagen and its assembly is highly regulated by various enzymes such as lysyl oxidases. Many solid tumors aberrantly express the family of lysyl oxidases (LOX/LOXL). This review examines how LOX/LOXLs were found to be dysregulated in noncancerous and cancerous settings, discusses their roles in solid tumor fibrosis and pathogenesis and explores the role of fibrosis in the development and poor clinical outcomes of patients with MPM. We examine the current preclinical status of drugs targeting LOX/LOXLs and how the incorporation of such drugs may have therapeutic benefits in the treatment and management of patients with MPM.
    Keywords:  biomarker; collagen; extracellular matrix; fibrosis; lysyl oxidase; malignant pleural mesothelioma; stroma; therapy
    DOI:  https://doi.org/10.3390/cancers14040981
  3. Diagnostics (Basel). 2022 Jan 27. pii: 316. [Epub ahead of print]12(2):
    Identification of Novel Diagnostic Markers for Malignant Pleural Mesothelioma Using a Reverse Translational Approach Based on a Rare Synchronous Tumor.
    Tomoaki Naka, Yutaka Hatanaka, Yukiko Tabata, Akira Takasawa, Hideo Akiyama, Yasuhiro Hida, Hiromi Okada, Kanako C Hatanaka, Tomoko Mitsuhashi, Kei Kushitani, Vishwa Jeet Amatya, Yukio Takeshima, Kouki Inai, Kichizo Kaga, Yoshihiro Matsuno.
      Although the routine use of immunohistochemistry has improved the accuracy of histopathologic diagnosis in clinical practice, new methods for discovering novel diagnostic markers are still needed. We sought new diagnostic markers for malignant pleural mesothelioma (MPM) using a reverse translational approach with limited archival tissues from a very rare case. Total RNA extracted from formalin-fixed paraffin-embedded (FFPE) tissues of a synchronous collision tumor consisting of MPM and pulmonary adenocarcinoma (PAC) was employed for gene expression profiling (GEP) analysis. Among the 54 genes selected by GEP analysis, we finally identified the following two candidate MPM marker genes: PHGDH and TRIM29. Immunohistochemical analysis of 48 MM and 20 PAC cases showed that both PHGDH and TRIM29 had sensitivity and specificity almost equivalent to those of calretinin (sensitivity 50% and 46% vs. 63%, and specificity 95% and 100% vs. 100%, respectively). Importantly, of the 23 epithelioid MMs, all 3 calretinin-negative cases were positive for TRIM29. These two markers may be diagnostically useful for immunohistochemical distinction between MPMs and PACs. This successful reverse translational approach based on FFPE samples from one very rare case encourages the further use of such samples for the development of novel diagnostic markers.
    Keywords:  gene expression profiling; immunohistochemistry; malignant pleural mesothelioma
    DOI:  https://doi.org/10.3390/diagnostics12020316
  4. J Exp Clin Cancer Res. 2022 Feb 23. 41(1): 75
    SKP2 drives the sensitivity to neddylation inhibitors and cisplatin in malignant pleural mesothelioma.
    Iris Chiara Salaroglio, Dimas Carolina Belisario, Paolo Bironzo, Preeta Ananthanarayanan, Luisa Ricci, Sabrina Digiovanni, Simona Fontana, Francesca Napoli, Alberto Sandri, Chiara Facolmatà, Roberta Libener, Valentina Comunanza, Federica Grosso, Elena Gazzano, Francesco Leo, Riccardo Taulli, Federico Bussolino, Luisella Righi, Mauro Giulio Papotti, Silvia Novello, Giorgio Vittorio Scagliotti, Chiara Riganti, Joanna Kopecka.
       BACKGROUND: The combination of pemetrexed and cisplatin remains the reference first-line systemic therapy for malignant pleural mesothelioma (MPM). Its activity is moderate because of tumor aggressiveness, immune-suppressive environment and resistance to chemotherapy-induced immunogenic cell death (ICD). Preliminary and limited findings suggest that MPM cells have deregulated ubiquitination and proteasome activities, although proteasome inhibitors achieved disappointing clinical results.
    METHODS: Here, we investigated the role of the E3-ubiquitin ligase SKP/Cullin/F-box (SCF) complex in cell cycle progression, endoplasmic reticulum (ER)/proteostatic stress and ICD in MPM, and the therapeutic potential of the neddylation/SCF complex inhibitor MLN4924/Pevonedistat.
    RESULTS: In patient-derived MPM cultures and syngenic murine models, MLN4924 and cisplatin showed anti-tumor effects, regardless of MPM histotype and BAP1 mutational status, increasing DNA damage, inducing S- and G2/M-cell cycle arrest, and apoptosis. Mechanistically, by interfering with the neddylation of cullin-1 and ubiquitin-conjugating enzyme UBE2M, MLN4924 blocks the SCF complex activity and triggers an ER stress-dependent ICD, which activated anti-MPM CD8+T-lymphocytes. The SKP2 component of SCF complex was identified as the main driver of sensitivity to MLN4924 and resistance to cisplatin. These findings were confirmed in a retrospective MPM patient series, where SKP2 high levels were associated with a worse response to platinum-based therapy and inferior survival.
    CONCLUSIONS: We suggest that the combination of neddylation inhibitors and cisplatin could be worth of further investigation in the clinical setting for MPM unresponsive to cisplatin. We also propose SKP2 as a new stratification marker to determine the sensitivity to cisplatin and drugs interfering with ubiquitination/proteasome systems in MPM.
    Keywords:  Malignant pleural mesothelioma; Pevonedistat; SKP/Cullin/F-box complex; endoplasmic reticulum stress; immunogenic cell death
    DOI:  https://doi.org/10.1186/s13046-022-02284-7
  5. Cancers (Basel). 2022 Feb 18. pii: 1044. [Epub ahead of print]14(4):
    Current Management and Future Perspective in Pleural Mesothelioma.
    Rajiv Shah, Laura V Klotz, Julia Glade.
      Pleural mesothelioma is an aggressive malignancy arising from pleural mesothelial cell lining, predominantly associated with prior exposure to asbestos. The ban on asbestos use has led to its lower incidence in many countries, but globally the disease burden is expected to rise. Therefore, well-planned research is needed to develop more effective, tolerable and affordable drugs. The development of novel treatment has been too slow, with only two regimens of systemic therapy with robust phase 3 data approved formally to date. The treatment scenario for resectable disease remains controversial. However, recent developments in the understanding of disease and clinical trials have been encouraging, and may add better treatment options in the coming years. In this review, we discuss the current treatment options for pleural mesothelioma and shed light on some recent studies and ongoing trials.
    Keywords:  biomarker; checkpoint; chemotherapy; immunotherapy; mesothelioma; multimodal treatment; surgery
    DOI:  https://doi.org/10.3390/cancers14041044
  6. BMC Cancer. 2022 Feb 20. 22(1): 191
    Dynamic contrast-enhanced MRI in malignant pleural mesothelioma: prediction of outcome based on DCE-MRI measurements in patients undergoing cytotoxic chemotherapy.
    Martina Vivoda Tomšič, Peter Korošec, Viljem Kovač, Sotirios Bisdas, Katarina Šurlan Popovič.
       BACKGROUND: The malignant pleural mesothelioma (MPM) response rate to chemotherapy is low. The identification of imaging biomarkers that could help guide the most effective therapy approach for individual patients is highly desirable. Our aim was to investigate the dynamic contrast-enhanced (DCE) MR parameters as predictors for progression-free (PFS) and overall survival (OS) in patients with MPM treated with cisplatin-based chemotherapy.
    METHODS: Thirty-two consecutive patients with MPM were enrolled in this prospective study. Pretreatment and intratreatment DCE-MRI were scheduled in each patient. The DCE parameters were analyzed using the extended Tofts (ET) and the adiabatic approximation tissue homogeneity (AATH) model. Comparison analysis, logistic regression and ROC analysis were used to identify the predictors for the patient's outcome.
    RESULTS: Patients with higher pretreatment ET and AATH-calculated Ktrans and ve values had longer OS (P≤.006). Patients with a more prominent reduction in ET-calculated Ktrans and kep values during the early phase of chemotherapy had longer PFS (P =.008). No parameter was identified to predict PFS. Pre-treatment ET-calculated Ktrans was found to be an independent predictive marker for longer OS (P=.02) demonstrating the most favourable discrimination performance compared to other DCE parameters with an estimated sensitivity of 89% and specificity of 78% (AUC 0.9, 95% CI 0.74-0.98, cut off > 0.08 min-1).
    CONCLUSIONS: In the present study, higher pre-treatment ET-calculated Ktrans values were associated with longer OS. The results suggest that DCE-MRI might provide additional information for identifying MPM patients that may respond to chemotherapy.
    Keywords:  Cisplatin; Magnetic resonance imaging; Mesothelioma diagnostic imaging; Mesothelioma drug therapy; Perfusion; Prognosis; Progression free survival; Survival
    DOI:  https://doi.org/10.1186/s12885-022-09277-x
  7. Diagnostics (Basel). 2022 Feb 01. pii: 371. [Epub ahead of print]12(2):
    Unusual Histology in Mesothelioma: A Report of Two Cases with a Brief Review.
    Francesca Bono, Stefano Ceola, Carlo Beretta, Marta Jaconi.
      Mesothelioma is often difficult to diagnose due to its rarity and its unusual histopathological features that could lend to diagnostic pitfalls and misdiagnosis. The WHO histological classification of pleural tumors in 2021 recommended a pathologic grading system for malignant pleural mesothelioma. Architectural aspects and cytological features, with nuclear grading, bent on a neoplastic score with fundamental prognostic and diagnostic value. Unusual features must be correctly assigned in the grading system to avoid misdiagnosis, especially toward metastatic lesions or reactive pleural processes. In this paper, we present two cases as examples of unusual morphological and architectural features with a brief literature review.
    Keywords:  adenomatoid mesothelioma; mesothelioma; signet ring cell mesothelioma; unusual variant epithelioid mesothelioma
    DOI:  https://doi.org/10.3390/diagnostics12020371
  8. Diagnostics (Basel). 2022 Jan 26. pii: 311. [Epub ahead of print]12(2):
    Big and Free Fractions of Gamma-Glutamyltransferase: New Diagnostic Biomarkers for Malignant Mesothelioma?
    Rudy Foddis, Maria Franzini, Alessandra Bonotti, Riccardo Marino, Roberto Silvestri, Poupak Fallahi, Dante Chiappino, Michele Emdin, Aldo Paolicchi, Alfonso Cristaudo.
      Malignant pleural mesothelioma (MPM) is a cancer mainly caused by asbestos fiber inhalation, characterized by an extremely long latency and poor prognosis. Recently, researchers have focused on testing the diagnostic ability of several biomarkers. Gamma-Glutamyltransferase (GGT) has been demonstrated to be the sum of several GGT sub-fractions activity, classified based on their molecular weight in big-GGT, medium-GGT, small-GGT, and free-GGT. This work aims to evaluate whether specific GGT fractional enzymatic activity patterns could be helpful in MPM diagnosis. We analyzed blood samples from 175 workers previously exposed to asbestos, 157 non-exposed healthy subjects, and 37 MPM patients through a molecular exclusion chromatographic method. We found a specific profile of GGT fractions activity, significantly associated with MPM, resulting in an increase in b-, m- activity, along with an evident, yet not significant, decrease in f-activity. Receiver-operating characteristic (ROC) analysis showed that the best Area Under Curve (AUC) value resulted from the combined index b/f (0.679, 95% CI: 0.582-0.777). Combining the b-/f-GGT activity with the levels of serum mesothelin-related protein (SMRP; another promising MPM biomarker) improved the diagnostic accuracy, increasing the AUC value to 0.875 (95% CI: 0.807-0.943, p = <0.0001). Since MPM has a specific pattern of GGT enzymatic activity, we could hypothesize that GGT fractions play different specific biochemical roles. The improvement in the diagnostic power given by the combination of these two biomarkers confirms that the strategy of biomarkers combination might be a better approach for MPM diagnosis.
    Keywords:  biomarkers; diagnosis; gamma-glutamyltransferase; mesothelioma
    DOI:  https://doi.org/10.3390/diagnostics12020311
  9. Life (Basel). 2022 Feb 16. pii: 296. [Epub ahead of print]12(2):
    Quantitative Assessment of Asbestos Fibers in Normal and Pathological Pleural Tissue-A Scoping Review.
    Yohama Caraballo-Arias, Paola Caffaro, Paolo Boffetta, Francesco Saverio Violante.
       BACKGROUND: pleural mesothelioma is a rare cancer in the general population, but it is more common in subjects occupationally exposed to asbestos. Studies with asbestos fiber quantification in pleural tissue are scarce: for this reason, we aimed at undertaking a scoping review to summarize the evidence provided by studies in which asbestos fibers were determined by electron microscopy (SEM or TEM) in human pleural tissues, whether normal or pathologic.
    MATERIALS AND METHODS: A scoping review of articles that quantified asbestos fibers in human pleural tissue (normal or pathologic) by electron microscopy (SEM or TEM), in subjects with asbestos exposure (if any) was performed.
    RESULTS: The 12 studies selected comprised 137 cases, out of which 142 samples were analyzed. Asbestos fibers were detected in 111 samples (78%) and were below the detectable limit in 31 samples (22%). The concentration of asbestos fibers detected in the positive samples was distributed from as low as 0.01 mfgdt (millions of fibers per gram of dry tissue) up to 240 mfgdt. However, the minimum concentration of fibers overlaps in the three types of tissues (normal pleura, pleural plaque, mesothelioma) in terms of magnitude; therefore, it is not possible to distinguish a definite pattern which differentiates one tissue from the other.
    CONCLUSIONS: The studies included were heterogeneous as to the representativeness of the samples and analytical techniques; the possibility of false negatives must be considered. It would be desirable to systematically search for asbestos fibers to fill the knowledge gap about the presence of asbestos fibers in normal or pathological pleural tissue in order to better understand the development of the different pleural diseases induced by this mineral.
    Keywords:  amphiboles; asbestos fibers; chrysotile; electron microscopy; occupational diseases; pleural mesothelioma; scoping review
    DOI:  https://doi.org/10.3390/life12020296
  10. Ann Thorac Surg. 2022 Feb 19. pii: S0003-4975(22)00213-2. [Epub ahead of print]
    Follow the leader? Can malignant pleural mesothelioma follow non-small cell lung cancer's lead with immunotherapy?
    Nicolas Contreras, Virginia Ruth Litle.
      
    DOI:  https://doi.org/10.1016/j.athoracsur.2022.02.008
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