bims-mesote 2023-04-16 papers

bims-mesote

Biomed News

on Mesothelioma

Issue of 2023–04–16
seven papers selected by
Laura Mannarino, Humanitas Research

KRAS Mutations Are Associated with Shortened Survival in Patients with Epithelioid Malignant Pleural Mesothelioma.
A Selective ALDH1A3 Inhibitor Impairs Mesothelioma 3-D Multicellular Spheroid Growth and Neutrophil Recruitment.
Immunotherapy vs. Chemotherapy in Subsequent Treatment of Malignant Pleural Mesothelioma: Which Is Better?
Damage-associated molecular patterns and sensing receptors based molecular subtypes in malignant pleural mesothelioma and implications for immunotherapy.
One Third of Malignant Pleural Mesothelioma Shows High Immunohistochemical Expression of MSLN or CXCR4 Which Indicates Potent Candidates for Endo-Radiotherapy.
High mesothelin expression by immunohistochemistry predicts improved survival in pleural mesothelioma.
Surgical phenotype of patients with peritoneal mesothelioma and a germline mutation.

Cancers (Basel). 2023 Mar 30. pii: 2072. [Epub ahead of print]15(7):

KRAS Mutations Are Associated with Shortened Survival in Patients with Epithelioid Malignant Pleural Mesothelioma.

Margherita Vannucchi, Veronica Pennati, Clelia Mencaroni, Chiara Defraia, Ledi Bardhi, Francesca Castiglione, Cristiana Bellan, Camilla Eva Comin.

  Malignant pleural mesothelioma (MPM) is an aggressive malignancy of the pleural surface that includes three major histologic subtypes, epitheliod, sarcomatoid and biphasic. Epithelioid mesothelioma is usually associated with better prognosis. The genetic mechanisms driving MPM, the possible target mutations and the correlation with overall survival remain largely unsettled. We performed target exome sequencing in 29 cases of MPM aimed at identifying somatic mutations and, eventually, their correlation with phenotypic traits and prognostic significance. We found that KRAS mutations, occurring in 13.7% of cases, were associated with shortened median survival (7.6 versus 32.6 months in KRAS wild-type; p = 0.005), as it was the occurrence of any ≥3 mutations (7.6 versus 37.6 months; p = 0.049). Conversely, the presence of KDR single nucleotide polymorphism p.V297I (rs2305948) resulted in a favorable variable for survival (NR versus 23.4 months; p = 0.026). With the intrinsic limitations of a small number of cases and patient heterogeneity, results of this study contribute to the characterization of the mutation profile of MPM and the impact of selected somatic mutations, and possibly KDR polymorphism, on prognosis.

Keywords:  KDR gene; KRAS mutation; MPM prognosis; epithelioid mesothelioma; pleural mesothelioma

DOI:  https://doi.org/10.3390/cancers15072072
Int J Mol Sci. 2023 Apr 03. pii: 6689. [Epub ahead of print]24(7):

A Selective ALDH1A3 Inhibitor Impairs Mesothelioma 3-D Multicellular Spheroid Growth and Neutrophil Recruitment.

Sara Boumya, Silvia Fallarini, Sonia Siragusa, Giovanni Petrarolo, Silvio Aprile, Valentina Audrito, Concettina La Motta, Silvia Garavaglia, Laura Moro, Giulia Pinton.

  Aldehyde dehydrogenase 1A3 (ALDH1A3), one of the three members of the aldehyde dehydrogenase 1A subfamily, has been associated with increased progression and drug resistance in various types of solid tumours. Recently, it has been reported that high ALDH1A3 expression is prognostic of poor survival in patients with malignant pleural mesothelioma (MPM), an asbestos-associated chemoresistant cancer. We treated MPM cells, cultured as multicellular spheroids, with NR6, a potent and highly selective ALDH1A3 inhibitor. Here we report that NR6 treatment caused the accumulation of toxic aldehydes, induced DNA damage, CDKN2A expression and cell growth arrest. We observed that, in CDKN2A proficient cells, NR6 treatment induced IL6 expression, but abolished CXCL8 expression and IL-8 release, preventing both neutrophil recruitment and generation of neutrophil extracellular traps (NETs). Furthermore, we demonstrate that in response to ALDH1A3 inhibition, CDKN2A loss skewed cell fate from senescence to apoptosis. Dissecting the role of ALDH1A3 isoform in MPM cells and tumour microenvironment can open new fronts in the treatment of this cancer.

Keywords:  ALDH1A3; CDKN2A; malignant pleural mesothelioma; tumour-associated neutrophils

DOI:  https://doi.org/10.3390/ijms24076689
J Clin Med. 2023 Mar 27. pii: 2531. [Epub ahead of print]12(7):

Immunotherapy vs. Chemotherapy in Subsequent Treatment of Malignant Pleural Mesothelioma: Which Is Better?

Xiaotong Guo, Lede Lin, Jiang Zhu.

  (1) Background: Malignant pleural mesothelioma (MPM) is a rare but aggressive tumor arising from the pleural surface. For relapsed MPM, there is no accepted standard of- are for subsequent treatment. Thus, we aimed to compare the efficacy of chemotherapy, targeting drugs, and immune-checkpoint inhibitors (ICIs) as subsequent therapy for relapsed MPM. (2) Methods: The study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We searched several acknowledged databases. Primary outcomes were defined as overall median progressive survival (mPFS) and median overall survival (mOS) in different treatment groups. Secondary outcomes were defined as objective response rate (ORR), the proportion of stable disease (SD), and progressive disease (PD). (3) Results: Ultimately, 43 articles were selected for the meta-analysis. According to the results of a pooled analysis of single-arm studies, ICIs showed a slight advantage in mOS, while chemotherapy showed a slight advantage in mPFS (mOS: 11.2 m vs. 10.39 m and mPFS: 4.42 m vs. 5.08 m for ICIs group and chemotherapy group, respectively). We identified only a few studies that directly compared the efficacy of ICIs with that of chemotherapy, and ICIs did not show significant benefits over chemotherapy based on mOS. (4) Conclusions: Based on current evidence, we considered that immunotherapy might not be superior to chemotherapy as a subsequent therapy for relapsed MPM. Although several studies investigated the efficacy of ICIs, targeting drugs, and chemotherapy in relapsed MPM, there was still no standard of care. Further randomized control trials with consistent criteria and outcomes are recommended to guide subsequent therapy in relapsed MPM and identify patients with certain characteristics that might benefit from such subsequent therapy.

Keywords:  chemotherapy; immune checkpoint inhibitors; malignant pleural mesothelioma; subsequent treatment

DOI:  https://doi.org/10.3390/jcm12072531
Front Immunol. 2023 ;14 1104560

Damage-associated molecular patterns and sensing receptors based molecular subtypes in malignant pleural mesothelioma and implications for immunotherapy.

Zheng Liu, Rui Wan, Hua Bai, Jie Wang.

   Objectives: Malignant pleural mesothelioma (MPM) is characterized as an incredibly aggressive form of cancer with a dismal diagnosis and a dearth of specific biomarkers and therapeutic options. For MPM patients, the effectiveness of immunotherapy may be influenced by damage-associated molecular pattern (DAMP)-induced immunogenic cell death (ICD).The objective of this work is to create a molecular profile associated with DAMPs to categorize MPM patients and predict their prognosis and response to immunotherapy.
Methods: The RNA-seq of 397 patients (263 patients with clinical data, 57.2% male, 73.0% over 60 yrs.) were gathered from eight public datasets as a training cohort to identify the DAMPs-associated subgroups of MPMs using K-means analysis. Three validation cohorts of patients or murine were established from TCGA and GEO databases. Comparisons were made across each subtype's immune status, gene mutations, survival prognosis, and predicted response to therapy.
Results: Based on the DAMPs gene expression, MPMs were categorized into two subtypes: the nuclear DAMPs subtype, which is classified by the upregulation of immune-suppressed pathways, and the inflammatory DAMPs subtype, which is distinguished by the enrichment of proinflammatory cytokine signaling. The inflammatory DAMPs subgroup had a better prognosis, while the nuclear DAMPs subgroup exhibited a worse outcome. In validation cohorts, the subtyping system was effectively verified. We further identified the genetic differences between the two DAMPs subtypes. It was projected that the inflammatory DAMPs subtype will respond to immunotherapy more favorably, suggesting that the developed clustering method may be implemented to predict the effectiveness of immunotherapy.
Conclusion: We constructed a subtyping model based on ICD-associated DAMPs in MPM, which might serve as a signature to gauge the outcomes of immune checkpoint blockades. Our research may aid in the development of innovative immunomodulators as well as the advancement of precision immunotherapy for MPM.

Keywords:  damage-associated molecular patterns; immunogenic cell death; immunotherapy; malignant mesothelioma; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2023.1104560
Int J Mol Sci. 2023 Mar 28. pii: 6356. [Epub ahead of print]24(7):

One Third of Malignant Pleural Mesothelioma Shows High Immunohistochemical Expression of MSLN or CXCR4 Which Indicates Potent Candidates for Endo-Radiotherapy.

Thomas Hager, Sabrina Borchert, Michael Wessolly, Alexander Mathilakathu, Elena Mairinger, Jens Kollmeier, Thomas Mairinger, Balazs Hegedus, Kristina Greimelmaier, Jeremias Wohlschlaeger, Ken Herrmann, Fabian Dominik Mairinger.

  Malignant pleural mesothelioma (MPM) is a mainly asbestos-related tumour associated with a very poor prognosis. Therapeutic approaches include multimodal therapy and chemotherapeutics, with cisplatin being the drug of choice, but response rates of only up to 14% indicate very poor outcomes. Effective treatment options are lacking. Besides the diagnostic usage of radioligands in positron emission tomography (PET)/computed tomography (CT), the endo-radioligand therapy with Lu177 has been proven as a powerful tool in cancer therapy. Mesothelin (MSLN) and C-XC chemokine receptor 4 (CXCR4) are membrane-bound proteins, expressed in certain cancers, and thus are promising targets for endo-radiotherapy. A significant portion of high MSLN- or CXCR4-expressing tumors within the MPM may open the field for this sophisticated treatment approach in the near future. Formalin-fixed, paraffin-embedded (FFPE) tumour specimens from 105 patients suffering from MPM and treated at the Lung Cancer Centre of Essen and at the Helios Klinikum Emil von Behring Berlin were screened. The tumour samples were arranged in tissue microarrays. We immunohistochemically stained the tumour samples against MSLN and CXCR4. The protein expressions of the stainings were scored by a pathologist by using a semiquantitative method. The data obtained were correlated with the clinical outcome. Overall, 77.1% of the analysed tumours showed CXCR4 protein expression (25.7% of them at high expression level (Score 3)). 48.6% of all samples showed an overall strong staining (Score ≥ 2), 59% of the investigated tumours showed MSLN protein expression (10.5% of them at high expression (Score 3)), and 36.2% of all samples showed an overall strong staining (Score ≥ 2). Our results show significant tissue expression levels, for both CXCR4 and MSLN protein, in a major portion of clinical MPM samples. One-third of patients showed outstanding immunoexpression of at least one of these markers, making them interesting candidates for radioligand-based PET/CT diagnostics and follow-up and furthermore may profit from endo-radiotherapy.

Keywords:  CXCR4; MSLN; biomarkers; endo-radiotherapy; methylation; pleural mesothelioma; radioligand; theranostics

DOI:  https://doi.org/10.3390/ijms24076356
Histopathology. 2023 Apr 11.

High mesothelin expression by immunohistochemistry predicts improved survival in pleural mesothelioma.

Gerard J Chu, Anthony Linton, Steven Kao, Sonja Klebe, Stephen Adelstein, Dannel Yeo, John E J Rasko, Wendy A Cooper.

   AIMS: Mesothelin (MSLN) is a cancer-associated antigen that is overexpressed in malignancies such as mesothelioma, pancreatic and ovarian cancer. It is also a target for novel personalised therapies, including antibodies, antibody-drug conjugates and chimeric antigen receptor T cells. Immunohistochemistry may predict those who would best respond to anti-mesothelin therapies and guide decisions in therapeutic strategy. This study aimed to assess the intensity and distribution of MSLN immunostaining in mesothelioma, and to determine the prognostic value of MSLN expression by histochemical-score (H-score).
METHODS AND RESULTS: The MN1 anti-MSLN antibody was used to stain a formalin-fixed paraffin-embedded tissue microarray of histologically confirmed mesothelioma from 75 consecutive patients who had undergone pleurectomy with or without decortication. MSLN positivity, the staining intensity, distribution of staining and H-score were evaluated. The correlation of H-score with prognosis was investigated. Sixty-six per cent of epithelioid tumours were MSLN-positive (with expression in > 5% tumour cells). Of MSLN-expressing epithelioid tumours, 70.4% had moderate (2+) or strong (3+) intensity MSLN immunostaining, although only 37% of samples had staining in ≥ 50% of tumour cells. In multivariate analysis, MSLN H-score as a continuous variable and an H-score ≥ 33 were independent predictors of improved survival (P = 0.04 and P < 0.001, respectively).
CONCLUSIONS: MSLN expression was more heterogenous in epithelioid mesothelioma than reported previously. Therefore, it would be appropriate to perform an immunohistochemical assessment of MSLN expression to stratify and assess patient suitability for mesothelin-targeted personalised therapies, such as chimeric antigen receptor T cells.

Keywords:  antibodies; chimeric antigen receptor T cells; epithelioid; expression; immunohistochemistry; mesothelin; mesothelioma; prognosis

DOI:  https://doi.org/10.1111/his.14916
Cancer. 2023 Apr 12.

Surgical phenotype of patients with peritoneal mesothelioma and a germline mutation.

Yaniv Berger, Meghana Gadiraju, Ankit Dhiman, Katie Gilliam, Buerkley Opalecky, Heather Chen, Maria Helgeson, Oliver S Eng, Aliya N Husain, Michael W Drazer, Hedy L Kindler, Jane E Churpek, Kiran K Turaga.

   BACKGROUND: This study aimed to investigate if peritoneal mesothelioma (PM) patients with germline mutations (GM) have distinct surgical characteristics when compared to those without GM.
METHODS: PM patients were selected from an ongoing prospective study that conducts germline testing of 82 susceptibility genes. Germline status was correlated with surgical data obtained from a prospectively collected database using univariate, multivariate, and receiver operating characteristic (ROC) analyses.
RESULTS: Out of 88 PM patients enrolled between 2009 and 2019, 18 GMs (20.5%) were identified in BRCA1-associated protein 1 (BAP1) (n = 11, 12.5% of all patients), SDHA (n = 2) and WT1, CDKN2A, CHEK2, ATM, and BRCA2 (n = 1 patient each). Surgical procedures were performed in 71 patients, the most common of which were cytoreductive surgeries with hyperthermic intraperitoneal chemotherapy (n = 61). Patients with GM presented with a higher prevalence of other prior cancers (61.1% vs. 31.4%, p = .02) and lower platelet count (251 [160-413] vs. 367 [196-780] K/µL, p = .005) compared to those without GM (n = 70). Survival outcomes did not differ significantly between the groups. Patients with BAP1 GMs were more likely to develop bicavitary disease and to present with lower platelet count and mitotic count score, and higher peritoneal cancer index (PCI, all p ≤ .04) compared with those without GM. On ROC analysis, the combination of PCI, platelet count and mitotic score yielded an area under the curve of 0.96 (95% CI, 0.91-1.0) for BAP1 GM detection among operated PM patients.
CONCLUSION: Higher intraoperative tumor burden and lower platelet count and mitotic score are suggestive of BAP1 GMs in surgical PM patients and should prompt germline testing.

Keywords:  cytoreduction; germ-line mutation; mesothelioma; peritoneum; surgery

DOI:  https://doi.org/10.1002/cncr.34763