bims-mesote 2022-04-17 papers

bims-mesote

Biomed News

on Mesothelioma

Issue of 2022–04–17
nine papers selected by
Laura Mannarino, Humanitas Research

High Expression of PEA15 Is Associated With Patient Survival in Malignant Pleural Mesothelioma.
Cytoreductive surgery with hyperthermic intrathoracic chemotherapy for malignant pleural mesothelioma: a systematic review.
Long-term benefit of lurbinectedin as palliative chemotherapy in progressive malignant pleural mesothelioma (MPM): final efficacy and translational data of the SAKK 17/16 study.
Predictors of Survival among Male and Female Patients with Malignant Pleural Mesothelioma: A Random Survival Forest Analysis of Data from the 2000-2017 Surveillance, Epidemiology, and End Results Program.
Minimally important differences of EORTC QLQ-C30 scales in patients with lung cancer or malignant pleural mesothelioma - Interpretation guidance derived from two randomized EORTC trials.
Forchlorfenuron and Novel Analogs Cause Cytotoxic Effects in Untreated and Cisplatin-Resistant Malignant Mesothelioma-Derived Cells.
Current treatments for inoperable mesothelioma: indirect comparisons based on individual patient data reconstructed retrospectively from 4 trials.
Asbestos and Other Hazardous Fibrous Minerals: Potential Exposure Pathways and Associated Health Risks.
Multicenter study of diffuse pleural mesothelioma. Histopathological and immunohistochemical features.

Cancer Diagn Progn. 2021 Sep-Oct;1(4):1(4): 371-377

High Expression of PEA15 Is Associated With Patient Survival in Malignant Pleural Mesothelioma.

Shajedul Islam, Takao Kitagawa, Yasuhiro Kuramitsu.

   Background/Aim: Malignant pleural mesothelioma (MPM) is a rare but very aggressive tumor that is primarily pleural in origin. The 5-year overall survival rate of patients with MPM has not improved despite therapeutic advances. Therefore, biomarker discovery to identify premalignant or early malignant tumors of the mesothelium are crucial. PEA15 is a cytoplasmic protein that is involved in various human malignancies, including MPM. However, the clinicopathological involvement of PEA15 in MPM has not yet been documented.
Materials and Methods: The Oncomine database and GEPIA2 platform were used to analyze PEA15 mRNA expression and patient survival in patients with MPM.
Results: PEA15 was found to be significantly up-regulated in MPM, and this up-regulation inversely correlated with prolonged patient survival. Further, PEA15 expression was found to be increased in other cancer tissues without affecting overall survival.
Conclusion: PEA15 may represent a new potential prognostic biomarker in MPM patients.

Keywords:  Mesothelioma; PEA15; bioinformatics; proteomics

DOI:  https://doi.org/10.21873/cdp.10049
Thorax. 2022 Apr 11. pii: thoraxjnl-2021-218214. [Epub ahead of print]

Cytoreductive surgery with hyperthermic intrathoracic chemotherapy for malignant pleural mesothelioma: a systematic review.

Alan G Dawson, Kudzayi Kutywayo, Seid B Mohammed, Dean A Fennell, Apostolos Nakas.

   INTRODUCTION: Cytoreductive surgery has been used a part of multimodality treatment in patients with malignant pleural mesothelioma (MPM). The residual microscopic disease that remains will lead to disease progression in the majority of patients. Delivery of hyperthermic intrathoracic chemotherapy at the time of surgery has been used to address this microscopic disease, however it's effect and place in the multimodality treatment sphere is unknown. The aim of this systematic review was to assess the effect of surgery and hyperthermic intrathoracic chemotherapy in patients with MPM on overall survival and disease-free interval.
METHODS: Ovid MEDLINE, Embase, Web of Science and the Cochrane Database of Systematic Reviews were searched from database inception through to June 2021. Studies reporting overall survival and/or disease-free interval in patients with MPM undergoing cytoreductive surgery with hyperthermic intrathoracic chemotherapy were considered. Study quality was assessed using the Newcastle-Ottawa Scale. A narrative review was performed.
RESULTS: Fifteen studies were eligible for inclusion comprising 598 patients. Surgery with hyperthermic intrathoracic chemotherapy was associated with a median overall survival and disease-free interval ranging from 11 to 75 months and 7.2 to 57 months, respectively. These appeared to be superior to patients not receiving hyperthermic intrathoracic chemotherapy (overall survival: 5-36 months and disease-free interval: 12.1-21 months). A higher dose of hyperthermic intrathoracic chemotherapy was associated with an improvement in overall survival compared with a lower dose: 18-31 months versus 6-18 months, respectively. The most common morbidity was atrial fibrillation followed by renal complications.
CONCLUSION: Surgery with hyperthermic intrathoracic chemotherapy offers a safe and effective therapy with an improvement in disease-free interval and overall survival, particularly when hyperthermic intrathoracic chemotherapy is administered at a higher dose.
PROSPERO REGISTRATION NUMBER: CRD42019129002.

Keywords:  Asbestos Induced Lung Disease; Mesothelioma; Pleural Disease; Thoracic Surgery

DOI:  https://doi.org/10.1136/thoraxjnl-2021-218214
ESMO Open. 2022 Apr 12. pii: S2059-7029(22)00062-X. [Epub ahead of print]7(3): 100446

Long-term benefit of lurbinectedin as palliative chemotherapy in progressive malignant pleural mesothelioma (MPM): final efficacy and translational data of the SAKK 17/16 study.

M Mark, S Rusakiewicz, M Früh, S Hayoz, F Grosso, M Pless, P Zucali, G L Ceresoli, A Maconi, M Schneider, P Froesch, D Tarussio, F Benedetti, J Dagher, L Kandalaft, R von Moos, S Tissot-Renaud, S Schmid, Y Metaxas.

   BACKGROUND: The SAKK 17/16 study showed promising efficacy data with lurbinectedin as second- or third-line palliative therapy in malignant pleural mesothelioma. Here, we evaluated long-term outcome and analyzed the impact of lurbinectedin monotherapy on the tumor microenvironment at the cellular and molecular level to predict outcomes.
MATERIAL AND METHODS: Forty-two patients were treated with lurbinectedin in this single-arm study. Twenty-nine samples were available at baseline, and seven additional matched samples at day one of cycle two of treatment. Survival curves and rates between groups were compared using the log-rank test and Kaplan-Meier method. Statistical significance was set at P value <0.05.
RESULTS: Updated median overall survival (OS) was slightly increased to 11.5 months [95% confidence interval (CI) 8.8-13.8 months]. Thirty-six patients (85%) had died. The OS rate at 12 and 18 months was 47% (95% CI 32.1% to 61.6%) and 31% (95% CI 17.8% to 45.0%), respectively. Median progression-free survival was 4.1 months (95% CI 2.6-5.5 months). No new safety signals were observed. Patients with lower frequencies of regulatory T cells, as well as lower tumor-associated macrophages (TAMs) at baseline, had a better OS. Comparing matched biopsies, a decrease of M2 macrophages was observed in five out of seven patients after exposure to lurbinectedin, and two out of four patients showed increased CD8+ T-cell infiltrates in tumor.
DISCUSSION: Lurbinectedin continues to be active in patients with progressing malignant pleural mesothelioma. According to our very small sample size, we hypothesize that baseline TAMs and regulatory T cells are associated with survival. Lurbinectedin seems to inhibit conversion of TAMs to M2 phenotype in humans.

Keywords:  M2 phenotype; lurbinectedin; malignant pleural mesothelioma; regulatory T cells; tumor-associated macrophages; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.esmoop.2022.100446
J Registry Manag. 2021 ;48(3): 118-125

Predictors of Survival among Male and Female Patients with Malignant Pleural Mesothelioma: A Random Survival Forest Analysis of Data from the 2000-2017 Surveillance, Epidemiology, and End Results Program.

Bian Liu, Li Niu, Francis Boscoe, Furrina F Lee.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy with a dismal prognosis. We aimed to identify predictors of survival among male and female MPM patients in the United States.
METHODS: We identified MPM cases reported by 18 cancer registries in the Surveillance, Epidemiology, and End Results Program (2000-2017). We applied a random survival forest (RSF) algorithm to identify and rank the importance of 10 variables at patient, cancer, and area level in predicting all-cause survival overall and by female and male subgroups.
RESULTS: Approximately 91.4% (n = 11,160) of the MPM patients had died, with better survival among females than males (11.7% vs 7.8%). The median follow-up time was 7 months (interquartile range, 2-17 months). A majority of the patients were male (78.6%), non-Hispanic White (81.8%), and residing in metropolitan counties with a population greater than 1 million (63.7%). The top 3 factors for predicting overall MPM survival were age, histological type, and cancer-directed surgery status. Except for age, the relative ranking of covariates varied by the 3 sample groups. Stage ranked fifth in predicting female survival, while it was replaced by metastasis status for male and overall patients. Race/ethnicity was not a good predictor for survival among MPM patients overall or the male subgroup, but ranked sixth for predicting survival among females. Median household income was not a good predictor for survival among females.
CONCLUSION: We demonstrated that RSF successfully identified predictors of MPM survival. RSF is a viable complement to the commonly used Cox proportional hazard model and a viable alternative, particularly when the proportional hazard assumption is unmet. RSF also identified differences between the sexes, which may help explain the sex differences in MPM survival rates.

Keywords: Surveillance, Epidemiology, and End Results (SEER) Program; machine learning; mesothelioma; survival; variable importance
Lung Cancer. 2022 Mar 29. pii: S0169-5002(22)00387-7. [Epub ahead of print]167 65-72

Minimally important differences of EORTC QLQ-C30 scales in patients with lung cancer or malignant pleural mesothelioma - Interpretation guidance derived from two randomized EORTC trials.

Michael Koller, Jammbe Z Musoro, Krzysztof Tomaszewski, Corneel Coens, Madeleine T King, Mirjam A G Sprangers, Mogens Groenvold, Kim Cocks, Galina Velikova, Hans-Henning Flechtner, Andrew Bottomley.

   OBJECTIVES: A minimally important difference (MID) is the smallest difference in quality of life (QoL) perceived as relevant by patients or clinicians. MIDs aid interpretation of QOL data in research and clinical practice. We aimed to determine MIDs for the EORTC QLQ-C30 for patients with lung cancer or malignant pleural mesothelioma.
MATERIALS AND METHODS: Data were drawn from two EORTC-sponsored randomized clinical trials (RCTs): a three-arm RCT of two cisplatin-based treatments and paclitaxel plus gemcitabine in advanced non-small-cell lung cancer, and an RCT comparing cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma. MIDs for interpreting within-group change and between-group differences in change over time were computed using anchor-based approaches, for improvements and deteriorations separately. Distribution-based approaches provided corroborative evidence.
RESULTS: The combined data from the trials comprised 730 patients. Available data allowed us to determine 8/14 anchor-based MIDs for EORTC scales for improvements, and 9/14 MIDs for deterioration. Furthermore, we provided distribution-based estimates for all 14 QLQ-C30 scales. Most MIDs for improvements ranged between 5 and 10, for both within-group and between-group differences. Outliers were appetite loss and constipation, with MIDs up to 15 score points. MIDs were slightly larger for within-group deterioration, ranging from -5 to - 15, with the largest for Nausea/vomiting (-1 to 4) and Appetite loss (-1 to 5). MIDs for between-group differences in deterioration ranged from - 4 (Physical, Role, and Social functioning, and Global quality of life) to -9 (Nausea/vomiting, Appetite loss and Constipation).
CONCLUSIONS: MIDs vary over scales and for between- versus within-group comparisons; this must be taken into account when interpreting changes. Nevertheless, the majority of MIDs range between 5 and 10 score points, in line with previously used thresholds for QLQ-C30. These findings and those from other tumor-specific MID analyses will inform a planned consensus process identifying commonalities and differences across tumor sites.

Keywords:  Clinical anchors; EORTC QLQ-C30; Lung cancer; Minimally important difference (MID); Pleural mesothelioma; Quality of life (QoL)

DOI:  https://doi.org/10.1016/j.lungcan.2022.03.018
Int J Mol Sci. 2022 Apr 02. pii: 3963. [Epub ahead of print]23(7):

Forchlorfenuron and Novel Analogs Cause Cytotoxic Effects in Untreated and Cisplatin-Resistant Malignant Mesothelioma-Derived Cells.

Thomas Henzi, Kim-Long Diep, Anne Oberson, Valerie Salicio, Christian G Bochet, Beat Schwaller.

  Malignant mesothelioma (MM) is a currently incurable, aggressive cancer derived from mesothelial cells, most often resulting from asbestos exposure. The current first-line treatment in unresectable MM is cisplatin/pemetrexed, which shows very little long-term effectiveness, necessitating research for novel therapeutic interventions. The existing chemotherapies often act on the cytoskeleton, including actin filaments and microtubules, but recent advances indicate the 'fourth' form consisting of the family of septins, representing a novel target. The septin inhibitor forchlorfenuron (FCF) and FCF analogs inhibit MM cell growth in vitro, but at concentrations which are too high for clinical applications. Based on the reported requirement of the chloride group in the 2-position of the pyridine ring of FCF for MM cell growth inhibition and cytotoxicity, we systematically investigated the importance (cell growth-inhibiting capacity) of the halogen atoms fluorine, chlorine, bromine and iodine in the 2- or 3-position of the pyridine ring. The MM cell lines ZL55, MSTO-211H, and SPC212, and-as a control-immortalized Met-5A mesothelial cells were used. The potency of the various halogen substitutions in FCF was mostly correlated with the atom size (covalent radius); the small fluoride analogs showed the least effect, while the largest one (iodide) most strongly decreased the MTT signals, in particular in MM cells derived from epithelioid MM. In the latter, the strongest effects in vitro were exerted by the 2-iodo and, unexpectedly, the 2-trifluoromethyl (2-CF3) FCF analogs, which were further tested in vivo in mice. However, FCF-2-I and, more strongly, FCF-2-CF3 caused rapidly occurring strong symptoms of systemic toxicity at doses lower than those previously obtained with FCF. Thus, we investigated the effectiveness of FCF (and selected analogs) in vitro in MM cells which were first exposed to cisplatin. The slowly appearing population of cisplatin-resistant cells was still susceptible to the growth-inhibiting/cytotoxic effect of FCF and its analogs, indicating that cisplatin and FCF target non-converging pathways in MM cells. Thus, a combination therapy of cisplatin and FCF (analogs) might represent a new avenue for the treatment of repopulating chemo-resistant MM cells in this currently untreatable cancer.

Keywords:  FCF; cisplatin; combination therapy; forchlorfenuron; malignant mesothelioma; septin 7; septin cytoskeleton

DOI:  https://doi.org/10.3390/ijms23073963
J Chemother. 2022 Apr 12. 1-5

Current treatments for inoperable mesothelioma: indirect comparisons based on individual patient data reconstructed retrospectively from 4 trials.

Andrea Messori, Sabrina Trippoli.

  In inoperable pleural mesothelioma, pemetrexed + cisplatin as first line is considered the standard of care, but novel treatments have been recently proposed. Our objective was to comparatively examine the information on overall survival (OS) with these new agents. The Shiny technique was employed for reconstructing individual patient data. Cox statistics was run to estimate hazard ratios (HRs). After a standard literature search, four new treatments were identified (nivolumab + ipilimumab, bevacizumab + pemetrexed + cisplatin, pembrolizumab monotherapy, and durvalumab + pemetrexed + cisplatin). Pemetrexed + ciplatin was the treatment for controls. Nivolumab + ipilimumab and bevacizumab + pemetrexed + cisplatin showed a better OS compared with controls (HR, 0.79 and 0.79, respectively; p < 0.05). Pembrolizumab determined only a numerical improvement (p > 0.05). In contrast, OS worsened with durvalumab + pemetrexed + cisplatin. Our analysis indicates that the novel treatments for inoperable mesothelioma have similar efficacy and, in general, provide a small though significant survival benefit compared with standard of care. Further research is needed to identify agents determining a more substantial OS improvement.

Keywords:  bevacizumab + pemetrexed + cisplatin; cisplatin; durvalumab; nivolumab + ipilimumab; pembrolizumab; pemetrexed; pleural mesothelioma; reconstruction of patient-level data

DOI:  https://doi.org/10.1080/1120009X.2022.2061183
Int J Environ Res Public Health. 2022 Mar 29. pii: 4031. [Epub ahead of print]19(7):

Asbestos and Other Hazardous Fibrous Minerals: Potential Exposure Pathways and Associated Health Risks.

Terri-Ann Berry, Elena Belluso, Ruggero Vigliaturo, Reto Gieré, Edward A Emmett, Joseph R Testa, Gregor Steinhorn, Shannon L Wallis.

  There are six elongate mineral particles (EMPs) corresponding to specific dimensional and morphological criteria, known as asbestos. Responsible for health issues including asbestosis, and malignant mesothelioma, asbestos has been well researched. Despite this, significant exposure continues to occur throughout the world, potentially affecting 125 million people in the workplace and causing thousands of deaths annually from exposure in homes. However, there are other EMPS, such as fibrous/asbestiform erionite, that are classified as carcinogens and have been linked to cancers in areas where it has been incorporated into local building materials or released into the environment through earthmoving activities. Erionite is a more potent carcinogen than asbestos but as it is seldom used for commercial purposes, exposure pathways have been less well studied. Despite the apparent similarities between asbestos and fibrous erionite, their health risks and exposure pathways are quite different. This article examines the hazards presented by EMPs with a particular focus on fibrous erionite. It includes a discussion of the global locations of erionite and similar hazardous minerals, a comparison of the multiple exposure pathways for asbestos and fibrous erionite, a brief discussion of the confusing nomenclature associated with EMPs, and considerations of increasing global mesothelioma cases.

Keywords:  asbestiform; asbestos fibres; erionite; exposure; malignant mesothelioma

DOI:  https://doi.org/10.3390/ijerph19074031
Medicina (B Aires). 2022 ;82(2): 210-216

Multicenter study of diffuse pleural mesothelioma. Histopathological and immunohistochemical features.

Claudia Poleri, Gabriela Acosta Haab, Nora Falcoff, Gabriela Guman, Liliana Dalurzo, Alejandro Iotti, María Eugenia Martín, Gloria Olmedo, Mercedes Rayá, Atilio Reginatto, Andrea Werbach, Gabriela Demelli, María José Labanca, Laura Leguina, María Florencia Mora.

The pathological diagnosis of diffuse pleural mesothelioma (DPM) contributes to treatment selection and clinical trials interpretation. To know its characteristics and evaluate the viability of comprehensive pathological diagnosis of DPM in Argentina we did a retrospective descriptive study of DPM cases reported from 2009 to 2018. We analyzed 398 cases corresponding to 238 (60%) men and 160 (40%) women, median age 66 years, from surgical biopsies (78%), small biopsies (16.5%) and surgical resections (5.5%). The 77% were epithelioid (E-DPM), 12% biphasic, 10% sarcomatoid, and 4 cases transitional variant. In E-DPM the main pattern was tubular in 36% and solid in 33%. There was a second pattern in 179 cases. Considering the main pattern and the second together, 48% presented tubular subtype and 48% solid subtype. Stroma, necrosis, and nuclear score showed significant differences between E-DPM and non-epithelioid mesotheliomas. Overall tumor grade was predominantly low in E-DPM, except for 42% of the solid main pattern. We recognized the transitional variant extensively in 4 cases and focally in 8. The immunohistochemical antibody panel used included pan-cytokeratin, calretinin, WT-1, cytokeratin 5, CEA and TTF-1. The expression of cytokeratin 5, calretinin and WT-1 was lower in the sarcomatoid type (43%, 87 and 37%) than in the epithelioid type (92%, 98% and 93%). This study highlights the tumor heterogeneity of DPM that shows the diagnostic difficulty, and the feasibility of evaluating histological aggressiveness in E-DPM, B-DPM and S-DPM in our country.

Keywords: grading mesothelioma; pathology; pleural mesothelioma