bims-mesote 2023-02-05 papers

Issue of 2023–02–05
six papers selected by
Laura Mannarino, Humanitas Research

Asian Pac J Cancer Prev. 2023 Jan 01. pii: 90449. [Epub ahead of print]24(1): 195-205

The Predictive Value of ERCC1, RRM1, and Thymidylate Synthase in Advanced Malignant Pleural Mesothelioma Patients Treated with Platinum-Based Chemotherapy.

Nagwa Ismail Wahba, Ola Khorshid, Fatma Abo Elkasem, Abeer Bahnassy, Rabab Gaafer.

BACKGROUND: A rare yet severe neoplasia called malignant pleural mesothelioma (MPM) typically manifests itself in advanced stages. Despite some improvements in the treatment of patients with MPM, this malignancy continues to have a detrimental prognosis . The primary goal of the present study was to assess the associatin between ERCC1, RRM1, and thymidylate synthase (TS) expression and disease outcome in patients with malignant pleural mesothelioma (MPM) treated with either pemetrexed plus cisplatin or gemcitabine plus cisplatin.
METHODS: This prospective cohort study was done on ninety-one advanced MPM patients. The patients received either pemetrexed plus platinum (55 of 91) or gemcitabine plus platinum chemotherapy (36 of 91). Tissue biopsy was taken at time of diagnosis. Immunohistochemistry was used to assess the levels of ERCC1, RRM1, and TS transcription in tissue biopsies (paraffin embedded).
RESULTS: Based on the findings, 70% of patients with low expression of TS had low expression of ERCC1, and 68% of patients with high expression of TS had high expression of ERCC1, suggesting a significat association between ERCC1 expression and TS expression (p=0.005). However, there was no relation between ERCC1 and RRM1 expression patterns (p= 0.296). In patients underwen platinum-based theraphy (n 91), a significant correlation was detected between low ERCC1 median High-scoring and longer progression time (TTP;9.6 v 5.3 months;P< .001) or overall survival (OS) (OS;18.1 v 9.1 months; P<0.001). A significant correlation was found between low TS protein expression and longer time progression (TTP; 11.8 v 5.4 months; P< .001) or OS (OS; 19.8 v 8.5 months; P <0.001) in patients undergoing pemetrexed plus platinum chemotherapy (n 55). Low RRM1 expression was accompanied by high progression free survival (TTP; 10.6 v 3.8 months) and OS (OS; 20.6 v 8.6 months) in patients receiving gemcitabine plus platinum chemotherapy. Based on the multivariate test results, the independent variables significantly affecting OS were tumor stage (HR: 2.3; 95% CI: 1.1-4.9; p= 0.021) and ERCC1 (HR: 2.7; 95% CI: 1.7-4.3; p < 0.001).
CONCLUSION: Decreased TS protein expression can be indicative of greater responsivness to pemtrexed and of longer TTP and OS in individuals with advanced MPM (locally progressed or metastatic) who are receiving pemetrexed-based chemotheraphy. Low ERCC1 expressions in individuals with advanced MPM can predict increased PFS and OS, as well as a better responsivness to platinum-based chemotherapy. In patients with progressed MPM receiving gemcitabine plus cisplatin chemotherapy, lower RRM1 expression was associated with a better prognosis, longer PFS, and longer OS.

Keywords: Biomarkers; ERCC1; Mesothelioma; RRM1; immunohistochemistry

DOI: https://doi.org/10.31557/APJCP.2023.24.1.195

Thorac Cardiovasc Surg. 2023 Feb 03.

Importance of Histopathological Grading for Treatment Selection in Malignant Mesothelioma.

İlteriş Türk, Gokturk Findik, Mehmet Çetin, Pinar Bicakcioglu, Selim Şakir Erkmen Gülhan, Koray Aydoğdu, Ülkü Yılmaz, Funda Demirağ.

BACKGROUND: Complexities in TNM staging in epithelioid malignant pleural mesothelioma (MPM) may lead to errors in treatment selection, leading to major surgical interventions in patients with low survival expectations.
METHODS: Sixty-nine stage I epithelioid MPM patients, including 27 patients treated with pleurectomy/decortication (P/D) and multimodal therapy (MMT) (the P/D [MMT] group), and 42 patients treated with chemotherapy or chemoradiotherapy (the CRT group), were included in the study. After an initial evaluation of overall survival, all patients were grouped in terms of histopathological parameters and treatment types, and then, a secondary survival evaluation was performed for the groups.
RESULTS: Forty-one patients were male, the mean age was 61.8 years. The median survival time was 26 months in the P/D (MMT) group, and 19.6 months in the CRT group, but the difference was not statistically significant. After grouping according to pathological criteria, a median survival time of 32.4 ± 2.9 months in the P/D (MMT) group and 21.9 ± 3.2 months in the CRT group was obtained among patients with histopathological low-grade tumors. Among patients with high-grade tumors, the median survival time was 18.3 ± 2.6 months in the P/D (MMT) group and 17 ± 4.4 months in the CRT group. Among patients with low-grade tumors, the P/D (MMT) group had longer survival. Median survival times were similar among patients with high-grade tumors.
CONCLUSION: In epithelioid MPM, histopathological grading by video-assisted thoracic surgery pleural biopsy can prove accurate in selecting patients for P/D and MMT.

DOI: https://doi.org/10.1055/s-0043-1761209

Pathobiology. 2023 Feb 01. 1-11

miR-142-3p Suppresses Invasion and Adhesion of Mesothelioma Cells by Downregulating ITGAV.

Ihiro Endo, Vishwa Jeet Amatya, Kei Kushitani, Tetsuya Nakagiri, Kohei Aoe, Yukio Takeshima.

INTRODUCTION: Malignant mesothelioma is an aggressive cancer associated with asbestos exposure. Currently, the efficacy of therapeutics is limited in malignant mesothelioma, and developing more effective therapies is the need of the hour. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), have attracted attention as therapeutic targets. To explore potential therapeutic targets, we focused on miR-142-3p expression, which was found to be significantly downregulated in mesothelioma cell lines in our previous study.
METHODS: Mesothelioma cell lines and tissues were validated for expression of miR-142-3p or integrin subunit alpha-V (ITGAV). We transfected mesothelioma cell lines with miR-142-3p mimic and ITGAV siRNA and analyzed their biological functions.
RESULTS: We found that miR-142-3p was significantly downregulated in mesothelioma tissues. Transfection with miR-142-3p mimic significantly suppressed cell proliferation, migration, and invasion. Bioinformatics analysis of potential targets of miR-142-3p identified ITGAV. Membrane ITGAV expression in mesothelioma cell lines was confirmed using immunocytochemistry. ITGAV was significantly upregulated in mesothelioma tissues. Moreover, transfection of miR-142-3p mimics into mesothelioma cell lines significantly suppressed ITGAV expression, indicating that miR-142-3p targets ITGAV. Next, ITGAV siRNA transfection into mesothelioma cell lines inhibited cell proliferation, migration, and invasion. Further investigation of cell adhesion mechanisms showed that the miR-142-3p/ITGAV axis specifically affects mesothelioma cell adhesion via vitronectin in the extracellular matrix.
CONCLUSION: This study proposed that the miR-142-3p/ITGAV axis is involved in tumor progression in malignant mesothelioma.

Keywords: Adhesion; ITGAV; Invasion; Malignant mesothelioma; miR-142-3p

DOI: https://doi.org/10.1159/000528670

Curr Cancer Drug Targets. 2023 Feb 01.

Micro-Fragmented Fat Inhibits the Progression of Human Mesothelioma Xenografts in Mice.

Silvia La Monica, Valentina Coccé, Mara Bonelli, Giulio Alessandri, Roberta Alfieri, Costanza Annamaria Lagrasta, Caterina Frati, Lisa Flammini, Aldo Gianni, Francesco Petrella, Francesca Paino, Augusto Pessina.

BACKGROUND: Malignant pleural mesothelioma is a pathology with no effective therapy and a poor prognosis. Our previous study demonstrated an in vitro inhibitory effect on mesothelioma cell lines of both the lysate and secretome of adipose tissue-derived Mesenchymal Stromal Cells. The inhibitory activity on tumor growth has been demonstrated also in vivo: five million Mesenchymal Stromal Cells, injected "in situ", produced a significant therapeutic efficacy against MSTO-211H xenograft equivalent to that observed after the systemic administration of paclitaxel.
OBJECTIVE: The objective of this study is to evaluate the efficacy of less (half a million) Mesenchymal Stromal Cells and micro-fragmented adipose tissues (the biological tissue from which the Mesenchymal Stromal Cells were isolated) on mesothelioma cells growth.
METHODS: Tumor cells growth inhibition was evaluated in vitro and in a xenograft model of mesothelioma.
RESULTS: The inhibitory effect of micro-fragmented fat from adipose-tissue has been firstly confirmed in vitro on MSTO-211H cell growth. Then the efficacy against the growth of mesothelioma xenografts in mice of both micro-fragmented fat and low amount of Mesenchymal Stromal Cells has been evaluated. Our results confirmed that both Mesenchymal Stromal Cells and micro-fragmented fat, injected "in situ", did not stimulate mesothelioma cell growth. By contrast, micro-fragmented fat produced a significant inhibition of tumor growth and progression, comparable to that observed by the treatment with paclitaxel. Low amount of Mesenchymal Stromal Cells exerted only a little anticancer activity.
CONCLUSION: Micro-fragmented fat inhibited mesothelioma cell proliferation in vitro and exerted a significant control of the mesothelioma xenograft growth in vivo.

Keywords: Adipose Tissue.; Mesenchymal Stromal Cells; Mesothelioma; Micro-fragmented fat; Paclitaxel; Xenograft

DOI: https://doi.org/10.2174/1568009623666230201092302

J Thorac Cardiovasc Surg. 2022 Dec 14. pii: S0022-5223(22)01337-X. [Epub ahead of print]

Tumor thickness in mesothelioma predicts differential response to neoadjuvant therapy and survival.

Mesothelioma Immune Genomic Group

OBJECTIVE: Neoadjuvant systemic therapy in resectable malignant pleural mesothelioma remains controversial and demonstrates variable responses. We sought to evaluate tumor thickness as a predictor of response to neoadjuvant therapy and as a prognostic marker for overall survival.
METHODS: Data from patients who underwent neoadjuvant therapy followed by cytoreductive surgery from 2002 to 2019 were reviewed. Baseline and postneoadjuvant therapy tumor thickness were measured on computed tomography. Radiological tumor response was categorized as progressive disease (≥20% increase), partial response (≥30% decrease), or stable disease (in between). Tumor response outcomes were modeled using logistic regression and multinomial regression models. Overall survival was evaluated based on tumor thickness and tumor response.
RESULTS: Of the 143 patients reviewed, 36 (25%) had progressive disease, 54 (38%) had stable disease, and 56 (39%) had partial response. The baseline tumor thickness of the progressive disease group (36 mm) was lower than in both stable disease and partial response groups (both 63 mm; P < .001). Both logistic regression and multinomial regression analyses demonstrated that thicker baseline tumor thickness was associated with decreased probability of progressive disease and increased probability of partial response. In a multivariable Cox model, thicker postneoadjuvant therapy tumor thickness was associated with worse overall survival (hazard ratio, 1.01, 95% confidence interval, 1.00-1.01, P = .008). The same trend was observed for thicker baseline tumor thickness (hazard ratio, 1.02, 95% confidence interval, 1.01-1.04, P = .008), and the risk was decreased in tumors with partial response (hazard ratio, 0.98, 95% confidence interval, 0.96-0.100, P = .014).
CONCLUSIONS: We present the first study demonstrating the relationship between baseline tumor thickness and differential radiographic response to neoadjuvant therapy and survival. Further studies are needed to validate tumor thickness as both a prognostic and predictive biomarker.

Keywords: RECIST; chemotherapy; mesothelioma; neoadjuvant; surgery; tumor thickness

DOI: https://doi.org/10.1016/j.jtcvs.2022.12.003