bims-mesote 2022-06-12 papers

bims-mesote

Biomed News

on Mesothelioma

Issue of 2022–06–12
nine papers selected by
Laura Mannarino, Humanitas Research

Asbestos lung burden does not predicts survival in malignant pleural mesothelioma. A necropsy-based study of 185 cases.
Sneaky Diagnosis of Pleural Malignant Mesothelioma in Thoracic Surgery: All That Glitters Is Not Gold.
Genomics of Tumor Origin and Characteristics for Adenocarcinoma and Malignant Pleural Mesothelioma: A Case Report.
A prognostic score for patients with malignant pleural mesothelioma (MPM) receiving second-line immunotherapy or chemotherapy in the ETOP 9-15 PROMISE-meso phase III trial.
NFE2L3 as a Novel Biomarker Associated With IL-2/STAT5/NLRP3 Signaling Pathway in Malignant Pleural Mesothelioma and Other Cancers.
YAP1 is essential for malignant mesothelioma tumor maintenance.
Phase I Study of Tremelimumab Monotherapy or in Combination With Durvalumab in Japanese Patients With Advanced Solid Tumors or Malignant Mesothelioma.
Correction to: Micro-RNA-215 and -375 regulate thymidylate synthase protein expression in pleural mesothelioma and mediate epithelial to mesenchymal transition.
EWSR1::YY1 fusion positive peritoneal epithelioid mesothelioma harbors mesothelioma epigenetic signature: report of 3 cases in support of an emerging entity.

J Thorac Oncol. 2022 Jun 01. pii: S1556-0864(22)00270-2. [Epub ahead of print]

Asbestos lung burden does not predicts survival in malignant pleural mesothelioma. A necropsy-based study of 185 cases.

Pietro Gino Barbieri, Dario Consonni, Anna Somigliana.

   INTRODUCTION: Malignant pleural mesothelioma (MPM) is an asbestos-related disease with poor survival. The prognostic role of histological subtype is well established. Some studies (without a biological hypothesis) suggested that higher asbestos lung burden is associated with reduced survival.
OBJECTIVES: We performed a necropsy-based study of MPM patients to analyze the relationship between asbestos lung burden and survival.
METHODS: We selected subjects from two series of necropsies: residents in Brescia province (North-West Italy) and workers (or persons living with them) employed in the Monfalcone shipyards (North-East Italy). Asbestos fibers (AF) and bodies (AB) in lung samples were counted using a scanning electron and an optical microscope respectively. Separately in the two series, we analyzed median survival time and fitted multivariable Cox regression models (adjusted for gender, period and age at diagnosis, and morphology) to calculate hazard ratios (HR) and 95% confidence intervals (CI) for three levels of AF counts (reference: <1 million fibers per gram of dry lung tissue).
RESULTS: We analyzed 185 necropsies, 83 in Brescia and 102 in Monfalcone. Despite a much higher lung burden in Monfalcone patients, median survival was slightly shorter in Brescia (8.3 months) than in Monfalcone (10.2 months). In Brescia, for medium (1-9.9) and high (10+) fiber burden HRs were 0.91 (95% CI 0.54-1.53) and 1.23 (95% CI 0.41-3.70). In Monfalcone, the corresponding HRs were 1.18 (95% CI 0.59-2.35) and 1.63 (95% CI 0.77-3.45).
CONCLUSION: No relationship between asbestos lung burden and survival was found. Histological subtype was the strongest prognostic determinant.

Keywords:  Pleural mesothelioma; asbestos lung burden; survival

DOI:  https://doi.org/10.1016/j.jtho.2022.05.010
J Clin Med. 2022 Jun 06. pii: 3225. [Epub ahead of print]11(11):

Sneaky Diagnosis of Pleural Malignant Mesothelioma in Thoracic Surgery: All That Glitters Is Not Gold.

Riccardo Orlandi, Francesca Bono, Diego Luigi Cortinovis, Giuseppe Cardillo, Ugo Cioffi, Angelo Guttadauro, Emanuele Pirondini, Stefania Canova, Enrico Mario Cassina, Federico Raveglia.

  Malignant Pleural Mesothelioma (MPM) is a highly aggressive disease whose diagnosis could be challenging and confusing. It could occur with atypical presentations on every examined level. Here, we present three unconventional cases of the complex diagnostic process of MPM that we have experienced during routine practice: a patient with reactive mesothelial hyperplasia mimicking MPM, an unexpected presentation of MPM with persistent unilateral hydropneumothorax, a rare case of MPM in situ. Then, we review the relevant literature on each of these topics. Definitive biomarkers to confidently distinguish MPM from other pleural affections are still demanded. Patients presenting with persistent hydropneumothorax must always be investigated for MPM. MPM in situ is now a reality, and this raises questions about its management.

Keywords:  BAP1; hydropneumothorax; immunohistochemistry; in situ; mesothelioma; pleura

DOI:  https://doi.org/10.3390/jcm11113225
Front Oncol. 2022 ;12 858094

Genomics of Tumor Origin and Characteristics for Adenocarcinoma and Malignant Pleural Mesothelioma: A Case Report.

Katsuo Usuda, Yo Niida, Masahito Ishikawa, Shun Iwai, Aika Yamagata, Yoshihito Iijima, Nozomu Motono, Sohsuke Yamada, Hidetaka Uramoto.

  A female underwent a right middle lobectomy for a pulmonary adenocarcinoma (AD). She eventually died of a right malignant pleural mesothelioma (MPM; sarcomatoid type) 4 years and 7 months after the removal of the AD even though she did not have any history of asbestos exposure, smoking, or radiation exposure. Her chest CT revealed multiple pulmonary nodules and bilateral pleural effusion with a right pleural tumor directly invading into the abdominal cavity. The genomics of tumor origin and characteristics were examined for the AD and the MPM. As a result, 50 somatic variants were detected in the AD, and 29 somatic variants were detected in the MPM. The variants which were common in both the AD and the MPM were not present, which suggested that the AD and the MPM had occurred independently in different origins. The MPM had two driver oncogenes of TP53 and EP300, but the AD did not. Two driver oncogenes of TP53 and EP300 were hypothesized to make the MPM aggressive. The speed at which the MPM progressed without the patient having a history of asbestos exposure, smoking, or radiation exposure was alarming.

Keywords:  adenocarcinoma; genomics; lung cancer; malignant pleural mesothelioma; oncogene

DOI:  https://doi.org/10.3389/fonc.2022.858094
Lung Cancer. 2022 May 28. pii: S0169-5002(22)00463-9. [Epub ahead of print]169 77-83

A prognostic score for patients with malignant pleural mesothelioma (MPM) receiving second-line immunotherapy or chemotherapy in the ETOP 9-15 PROMISE-meso phase III trial.

Giuseppe Luigi Banna, Alfredo Addeo, Panagiota Zygoura, Zoi Tsourti, Sanjay Popat, Alessandra Curioni-Fontecedro, Ernest Nadal, Riyaz Shah, Anthony Pope, Patricia Fisher, James Spicer, Amy Roy, David Gilligan, Oliver Gautschi, Wolf-Dieter Janthur, Rafael López-Castro, Heidi Roschitzki-Voser, Urania Dafni, Solange Peters, Rolf A Stahel.

   INTRODUCTION: Clinical and laboratory parameters associated with response for patients with advanced pre-treated malignant pleural mesothelioma (MPM) are lacking. We aimed to identify prognostic and predictive markers among patients with relapsed MPM who were randomised into the ETOP 9-15 PROMISE-meso phase III trial, evaluating pembrolizumab and chemotherapy.
METHODS: Baseline clinical and laboratory parameters were investigated for prognostic or predictive value on progression-free survival (PFS) and overall survival (OS) in a retrospective analysis, based on the full cohort of 144 MPM patients. These consisted of immune-inflammatory indexes (neutrophil-lymphocyte ratio [NLR], systemic immune-inflammatory index [SII], lactate dehydrogenase [LDH]) along with other already known prognostic baseline characteristics and laboratory values. Cut-offs were chosen independently of outcome. Based on Cox multivariable analysis for PFS in the whole cohort, a risk factor model was built to illustrate the prognostic stratification of patients by the combination of the derived independent prognostic factors, taking into account the EORTC score, a validated prognostic score in MPM. All models were stratified by histology and adjusted by treatment.
RESULTS: In the stratified multivariable analysis in the whole cohort, high SII (hazard ratio (HR) 2.06; 95%CI 1.39-3.05) and low haemoglobin (HR 1.62; 95%CI 1.06-2.50) were associated with worse PFS. Based on these two prognostic factors, a mesothelioma risk score (MRS) was constructed with three PFS risk prognosis categories: favourable, intermediate and poor with 0, 1 and 2 risk factors, respectively (corresponding percent of cohort: 24%, 34% and 42% and median PFS: 5.8, 4.2 and 2.1 months). The derived MRS stratified the prognosis for PFS and OS, overall and within each of the EORTC groups. No significant predictors of treatment benefit were identified.
CONCLUSIONS: The proposed MRS is prognostic of patient outcome and it fine-tunes the prognosis of patients with pre-treated MPM alone or when used with the already established EORTC score.

Keywords:  Chemotherapy; MPM; Malignant pleural mesothelioma; Mesothelioma risk score; Pembrolizumab

DOI:  https://doi.org/10.1016/j.lungcan.2022.05.018
Front Genet. 2022 ;13 805256

NFE2L3 as a Novel Biomarker Associated With IL-2/STAT5/NLRP3 Signaling Pathway in Malignant Pleural Mesothelioma and Other Cancers.

Zhen Wang, Han Yang, Bin Luo, Pengfei Duan, Peng Lin.

  Background: Malignant pleural mesothelioma (MPM) is a malignant tumor originating from pleural mesothelial cells and has a high mortality rate worldwide. With the advent of immunotherapy in MPM treatment, there is an urgent need to elucidate the immune-related mechanisms in this caner. Methods: Single-sample gene set enrichment analysis (ssGSEA) was used to score the immunocytes infiltration of data from different database sources. Identification of immunocyte-related genes was performed with weighted gene co-expression network analysis (WGCNA), differentially expressed genes (DEGs) analysis, and correlation analysis. Pan-caner analysis was performed using "DiffExp" and "Correlation" modules in TIMER. Results: T-helper 2 (Th2) cell was found to be a poor prognostic factor for patients with MPM. Then a transcription factor, NFE2L3, was identified as a biomarker that showed a strong positive correlation with Th2 cell infiltration, and was highly expressed in MPM tissues and was related to the poor prognosis of these patients. At the same time, multiple NFE2L3 methylation sites were negatively correlated with Th2 cell infiltration, and patients with a high degree of methylation enjoy a better prognosis. Pan-caner analysis indicated that NFE2L3 might promote the differentiation of Th2 cells through the IL-2/STAT5/NLRP3 signaling pathway in MPM and many other cancers. Conclusion: We believe that NFE2L3 can serve as a potential biomarker related to the diagnosis and prognosis of patients with MPM, and speculate that NFE2L3 could promote Th2 cell differentiation via IL-2/STAT5/NLRP3 signaling pathway in MPM and many other cancers.

Keywords:  IL-2; NFE2L3; NLRP3; Stat5; malignant pleural mesothelioma; t-helper 2 cell

DOI:  https://doi.org/10.3389/fgene.2022.805256
BMC Cancer. 2022 Jun 10. 22(1): 639

YAP1 is essential for malignant mesothelioma tumor maintenance.

Loreley Calvet, Odette Dos-Santos, Emmanuel Spanakis, Véronique Jean-Baptiste, Jean-Christophe Le Bail, Armelle Buzy, Pascal Paul, Christophe Henry, Sandrine Valence, Colette Dib, Jack Pollard, Sukhvinder Sidhu, Jürgen Moll, Laurent Debussche, Iris Valtingojer.

  Malignant pleural mesothelioma, a tumor arising from the membrane covering the lungs and the inner side of the ribs, is a cancer in which genetic alterations of genes encoding proteins that act on or are part of the Hippo-YAP1 signaling pathway are frequent. Dysfunctional Hippo signaling may result in aberrant activation of the transcriptional coactivator protein YAP1, which binds to and activates transcription factors of the TEAD family. Recent studies have associated elevated YAP1 protein activity with a poor prognosis of malignant mesothelioma and its resistance to current therapies, but its role in tumor maintenance is unclear. In this study, we investigate the dependence of malignant mesothelioma on YAP1 signaling to maintain fully established tumors in vivo. We show that downregulation of YAP1 in a dysfunctional Hippo genetic background results in the inhibition of YAP1/TEAD-dependent gene expression, the induction of apoptosis, and the inhibition of tumor cell growth in vitro. The conditional downregulation of YAP1 in established tumor xenografts leads to the inhibition of YAP1-dependent gene transcription and eventually tumor regression. This effect is only seen in the YAP1-activated MSTO-211H mesothelioma xenograft model, but not in the Hippo-independent HCT116 colon cancer xenograft model. Our data demonstrate that, in the context of a Hippo pathway mutated background, YAP1 activity alone is enough to maintain the growth of established tumors in vivo, thus validating the concept of inhibiting the activated YAP1-TEAD complex for the treatment of malignant pleural mesothelioma patients.

Keywords:  Malignant mesothelioma; Tumor maintenance; YAP-TEAD transcription signature; YAP1

DOI:  https://doi.org/10.1186/s12885-022-09686-y
Oncologist. 2022 Jun 07. pii: oyac099. [Epub ahead of print]

Phase I Study of Tremelimumab Monotherapy or in Combination With Durvalumab in Japanese Patients With Advanced Solid Tumors or Malignant Mesothelioma.

Yutaka Fujiwara, Yasuo Takahashi, Morihito Okada, Takumi Kishimoto, Shunsuke Kondo, Koshi Fujikawa, Manabu Hayama, Masatoshi Sugeno, Shinya Ueda, Keiko Komuro, Mark Lanasa, Takashi Nakano.

   BACKGROUND: The primary objective of this phase I, open-label trial was to assess safety and tolerability of tremelimumab monotherapy and combination therapy with durvalumab in Japanese patients with advanced cancer. Tremelimumab is a fully human monoclonal antibody against CTLA-4 in clinical trials; durvalumab is a monoclonal antibody against PD-L1 for the treatment of bladder and lung cancer.
METHODS: In part 1, tremelimumab 3 or 10 mg/kg was given every 4 weeks (Q4W) for 6 doses, and thereafter every 12 weeks until discontinuation (n = 8); subsequently tremelimumab 10 mg/kg Q4W for 6 doses/Q12W and thereafter until discontinuation was administered in 41 patients with malignant pleural or peritoneal mesothelioma (MPM). In part 2, tremelimumab 10 mg/kg (Q4W for 6 doses followed by Q12W for 3 doses) was given in combination with durvalumab 15 mg/kg (Q4W for 13 doses) in cohort 1 (n = 4). In cohort 2 (n = 6), tremelimumab 1 mg/kg (Q4W for 4 doses) was given in combination with durvalumab 20 mg/kg (Q4W for 4 doses followed by 10 mg/kg Q2W for 22 doses), while in cohort 3 (n = 6), fixed-dose tremelimumab 75 mg Q4W for 4 doses plus durvalumab 1500 mg Q4W for 13 doses was given.
RESULTS: In part 1, no dose-limiting toxicities (DLTs) for tremelimumab 3 or 10 mg/kg (Q4W for 6 doses/Q12W thereafter until discontinuation) were observed. Six (75%) patients reported treatment-related adverse events (trAEs). In the MPM dose-expansion cohort, 38 (92.7%) patients reported trAEs. In part 2, one DLT (Grade 4 myasthenia gravis) was reported for tremelimumab 10 mg/kg (Q4W for 6 doses/Q12W for 3 doses) plus durvalumab 15 mg/kg (Q4W for 13 doses). One DLT (Grade 4 hyperglycemia) was reported for tremelimumab 75 mg (Q4W for 4 doses) plus durvalumab 1500 mg (Q4W for 13 doses). Fourteen (87.5%) patients reported trAEs. Tremelimumab demonstrated low immunogenicity; 1 (16.7%) patient developed antidrug antibodies.
CONCLUSION: Tremelimumab 10 mg/kg (Q4W/Q12W), tremelimumab 1 mg/kg (Q4W) plus durvalumab 20 mg/kg (Q4W/10 mg/kg Q2W), and fixed-dose tremelimumab 75 mg (Q4W) plus durvalumab 1500 mg (Q4W) were safe and tolerable.ClinicalTrials.gov Identifier: NCT02141347 (https://clinicaltrials.gov/ct2/show/NCT02141347).

Keywords:  Japanese; durvalumab; immunotherapy; malignant mesothelioma; tremelimumab

DOI:  https://doi.org/10.1093/oncolo/oyac099
Virchows Arch. 2022 Jun 07.

Correction to: Micro-RNA-215 and -375 regulate thymidylate synthase protein expression in pleural mesothelioma and mediate epithelial to mesenchymal transition.

Francesca Napoli, Ida Rapa, Stefania Izzo, Angelica Rigutto, Roberta Libener, Chiara Riganti, Paolo Bironzo, Riccardo Taulli, Mauro Papotti, Marco Volante, Giorgio Scagliotti, Luisella Righi.

DOI: https://doi.org/10.1007/s00428-022-03355-y
Genes Chromosomes Cancer. 2022 Jun 04.

EWSR1::YY1 fusion positive peritoneal epithelioid mesothelioma harbors mesothelioma epigenetic signature: report of 3 cases in support of an emerging entity.

Josephine K Dermawan, Dianne Torrence, Cheng-Han Lee, Liliana Villafania, Kerry A Mullaney, Sara DiNapoli, Purvil Sukhadia, Ryma Benayed, Laetitia Borsu, Narasimhan P Agaram, Garrett M Nash, Brendan C Dickson, Jamal Benhamida, Cristina R Antonescu.

  Mesothelioma is a rare, aggressive malignant neoplasm of mesothelial origin. A small subset of peritoneal mesothelioma is driven by recurrent gene fusions, mostly EWSR1/FUS::ATF1 fusions, with predilection for young adults. To date, only two cases of mesothelioma harboring EWSR1::YY1 fusions have been described. We present three additional cases of EWSR1::YY1-fused peritoneal mesotheliomas, two localized and one diffuse, all occurring in the peritoneum of middle-aged adults (2 females and 1 male), and discovered incidentally by imaging or during surgery performed for unrelated reasons. None presented with symptoms or had a known history of asbestos exposure. All three cases were cellular epithelioid neoplasms with heterogeneous architectural patterns comprising mostly solid nests and sheets with variably papillary and trabecular areas against collagenous stroma. Cytologically, the cells were monomorphic, polygonal, epithelioid cells with dense eosinophilic cytoplasm and centrally located nuclei. Overt mitotic activity or tumor necrosis was absent. All cases showed strong diffuse immunoreactivity for pancytokeratin, CK7, and nuclear WT1, patchy to negative calretinin, retained BAP1 expression, and were negative for Ber-EP4 and MOC31. RNA-sequencing confirmed in-frame gene fusion transcripts involving EWSR1 exon 7/8 and YY1 exon 2/3. By unsupervised clustering analysis, the methylation profiles of EWSR1::YY1-fused mesotheliomas clustered similarly with EWSR1/FUS::ATF1-fused mesotheliomas and conventional mesotheliomas, suggesting a mesothelioma epigenetic signature. All three patients underwent surgical resection or cytoreductive surgery of the masses. On follow-up imaging, no recurrence or progression of disease was identified. Our findings suggest that EWSR1::YY1-fusion defines a small subset of peritoneal epithelioid mesothelioma in middle-aged adults without history of asbestos exposure. This article is protected by copyright. All rights reserved.

Keywords:  EWSR1; YY1; gene fusion; methylation profiling; peritoneal mesothelioma

DOI:  https://doi.org/10.1002/gcc.23074