bims-mesote 2021-05-09 papers

bims-mesote

Biomed News

on Mesothelioma

Issue of 2021–05–09
nine papers selected by
Laura Mannarino, Humanitas Research

Emerging avenues in immunotherapy for the management of malignant pleural mesothelioma.
Does the LENT score risk-stratify patients with malignant pleural mesothelioma? An observational study.
Sarcomatoid Mesothelioma: A Clinicopathological and Immunohistochemical Study of 64 Cases.
Malignant pleural mesothelioma: Comparison of surgery-based trimodality therapy to medical therapy at two tertiary academic institutions.
High tumor cell platelet-derived growth factor receptor beta expression is associated with shorter survival in malignant pleural epithelioid mesothelioma.
Efficacy, Safety, and Cost-Minimization Analysis of Continuous Infusion of Low-Dose Gemcitabine Plus Cisplatin in Patients With Unresectable Malignant Pleural Mesothelioma.
Quality of life and lung function after pleurectomy/decortication for malignant pleural mesothelioma.
Overexpression of microRNA‑486 affects the proliferation and chemosensitivity of mesothelioma cell lines by targeting PIM1.
Emerging biological therapies for the treatment of malignant pleural mesothelioma.

BMC Pulm Med. 2021 May 05. 21(1): 148

Emerging avenues in immunotherapy for the management of malignant pleural mesothelioma.

Steven G Gray.

BACKGROUND: The role of immunotherapy in cancer is now well-established, and therapeutic options such as checkpoint inhibitors are increasingly being approved in many cancers such as non-small cell lung cancer (NSCLC). Malignant pleural mesothelioma (MPM) is a rare orphan disease associated with prior exposure to asbestos, with a dismal prognosis. Evidence from clinical trials of checkpoint inhibitors in this rare disease, suggest that such therapies may play a role as a treatment option for a proportion of patients with this cancer.
MAIN TEXT: While the majority of studies currently focus on the established checkpoint inhibitors (CTLA4 and PD1/PDL1), there are many other potential checkpoints that could also be targeted. In this review I provide a synopsis of current clinical trials of immunotherapies in MPM, explore potential candidate new avenues that may become future targets for immunotherapy and discuss aspects of immunotherapy that may affect the clinical outcomes of such therapies in this cancer.
CONCLUSIONS: The current situation regarding checkpoint inhibitors in the management of MPM whilst encouraging, despite impressive durable responses, immune checkpoint inhibitors do not provide a long-term benefit to the majority of patients with cancer. Additional studies are therefore required to further delineate and improve our understanding of both checkpoint inhibitors and the immune system in MPM. Moreover, many new potential checkpoints have yet to be studied for their therapeutic potential in MPM. All these plus the existing checkpoint inhibitors will require the development of new biomarkers for patient stratification, response and also for predicting or monitoring the emergence of resistance to these agents in MPM patients. Other potential therapeutic avenues such CAR-T therapy or treatments like oncolytic viruses or agents that target the interferon pathway designed to recruit more immune cells to the tumor also hold great promise in this hard to treat cancer.

DOI: https://doi.org/10.1186/s12890-021-01513-7
Thorac Cancer. 2021 May 05.

Does the LENT score risk-stratify patients with malignant pleural mesothelioma? An observational study.

Bertrand Chollet, Julien Guinde, Sophie Laroumagne, Hervé Dutau, Philippe Astoul.

   BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare, highly aggressive and deadly disease with a poor patient life expectancy. A few years ago, the main challenge was the histological diagnosis of this disease; at present, the search for the best therapeutic strategy is now a priority. However, an optimal therapeutic strategy is not yet clear, despite growing efforts in the treatment armamentarium and research, and at the era of tailored and individualized treatment, tools to predict patient survival are needed for therapeutic decision-making. Among them, the LENT scoring system was developed to predict prognosis in patients with malignant pleural effusion. The aim of this study was to assess the performance of the LENT score in predicting prognosis in patients with MPM.
METHODS: A retrospective observational study was conducted by analyzing the prospective collected databases of patients undergoing medical thoracoscopy in a single center with a final diagnosis of MPM confirmed by the MESOPATH National Reference Center.
RESULTS: A total of 41 patients with MPM were studied. All patients underwent platinum-based chemotherapy combined with pemetrexed ± bevacizumab. No high-risk category patients were found using the LENT scoring system in this cohort. The median (range) LENT score at the time of medical thoracoscopy was 0 (0-3) and the median survival was 15.5 (2-54) months for the entire cohort. The median survival of low-risk and moderate-risk category patients was 21.4 months (2-54, 32 patients) and 6.7 months (2-19, nine patients), respectively. A total of 27 patients with MPM of epithelial subgroup had a median LENT score of 1 (0-2) with a 26 (2-54) months median survival. The median LENT score and median survival of nonepithelial mesothelioma patients (biphasic MPM subgroup, eight patients; sarcomatoid MPM subgroup, six patients) were 0 (0-3) and 11 (2-52) months, respectively.
CONCLUSIONS: Applied to a homogenous cohort of MPM patients, the LENT score underestimated prognosis and was not useful per se for the management of this disease, as evidenced in the epithelial mesothelioma subgroup of patients in our study.

Keywords:  pleural effusion; pleural mesothelioma; predictive medicine; survival

DOI:  https://doi.org/10.1111/1759-7714.13987
Int J Surg Pathol. 2021 May 03. 10668969211014256

Sarcomatoid Mesothelioma: A Clinicopathological and Immunohistochemical Study of 64 Cases.

Diana M Oramas, Michael Zaleski, Cesar A Moran.

  Sixty-four cases of sarcomatoid pleural mesothelioma represent the basis of this study. The patients are 51 men and 13 women between the ages of 42 and 79 years, who presented with symptoms of chest pain, cough, and weight loss. Diagnostic imaging showed the presence of diffuse pleural thickening with encasement of the lung parenchyma in all the cases. All patients had surgical resection via extrapleural pneumonectomy. By immunohistochemistry, all cases were positive for cytokeratin AE1/AE3; however, reactivity with other markers including keratin 5/6, calretinin, and D2-40 was seen in different proportions, whereas a few cases showed positive staining for GATA3, WT1, and p40. All tumors were negative for carcinomatous epitopes (carcinoembryonic antigen, CD15, and TTF1). Our findings show that even though the use of immunohistochemical stains plays an important role in the final interpretation, the best results are accomplished by a global interpretation of clinical, radiographical, and immunohistochemical findings. It is also important to highlight that it does not seem to be a single immunohistochemical stain that is pathognomonic of sarcomatoid mesothelioma and that some other stains that are commonly used for other tumors may also show positive staining in a small percentage of sarcomatoid mesotheliomas.

Keywords:  immunohistochemistry; lung; mesothelioma; pleura; thorax

DOI:  https://doi.org/10.1177/10668969211014256
Lung Cancer. 2021 May 03. pii: S0169-5002(21)00167-7. [Epub ahead of print]

Malignant pleural mesothelioma: Comparison of surgery-based trimodality therapy to medical therapy at two tertiary academic institutions.

Frédéric Larose, Nicholas Quigley, Yves Lacasse, Simon Martel, Loïc Lang-Lazdunski.

   OBJECTIVES: Medical management based on palliative chemotherapy is currently the standard of care in malignant pleural mesothelioma (MPM). Median survival of 12-16 months has been reported with modern chemotherapy regimens with or without anti-angiogenic agents. Multimodality therapy incorporating cytoreductive surgery, systemic chemotherapy and radiotherapy has been offered for years to fit patients with early-stage disease, but its role remains debated. Our objective was to compare overall survival in patients offered multimodality therapy in a specialized clinic setting in London, UK to that of patients offered exclusively medical treatment at another academic institution in Quebec, Canada.
MATERIALS AND METHODS: We retrospectively compared the survival rates of 2 separate cohorts of patients treated consecutively: Cohort 1 (n = 106) received multimodality therapy including systemic chemotherapy, extended pleurectomy/decortication (P/D) and prophylactic radiotherapy in London (United Kingdom) between 2009 and 2016, while Cohort 2 (n = 98) received medical treatment at the Quebec Heart and Lung Institute (Canada) during the same period.
RESULTS: In Cohort 1, all patients but two completed trimodality therapy. In cohort 2, 51 % received palliative care only and 40 % received systemic chemotherapy. Median survival was 32 months vs 10 months in Cohort 1 and Cohort 2, respectively (hazard ratio with age, gender, pathology and TNM staging as covariates: 3.81; 95 % CI: 2.67-5.45; p < 0.0001). Similar results were obtained in sensitivity analyses, after excluding those who received best supportive care only and in a propensity score-matched analysis.
CONCLUSION: Aggressive therapy of MPM using cancer-directed surgery, systemic chemotherapy and prophylactic radiotherapy may provide a significant survival benefit in selected patients.

Keywords:  Chemotherapy; Malignant mesothelioma; Mesothelioma; Palliative therapy; Pleural disease; Pleurectomy; Radiation therapy; Surgery; Trimodality therapy

DOI:  https://doi.org/10.1016/j.lungcan.2021.04.025
J Pathol Clin Res. 2021 May 06.

High tumor cell platelet-derived growth factor receptor beta expression is associated with shorter survival in malignant pleural epithelioid mesothelioma.

Hely Ollila, Juuso Paajanen, Henrik Wolff, Ilkka Ilonen, Eva Sutinen, Katja Välimäki, Arne Östman, Sisko Anttila, Eeva Kettunen, Jari Räsänen, Olli Kallioniemi, Marjukka Myllärniemi, Mikko I Mäyränpää, Teijo Pellinen.

  Malignant pleural mesothelioma (MPM) has a rich stromal component containing mesenchymal fibroblasts. However, the properties and interplay of MPM tumor cells and their surrounding stromal fibroblasts are poorly characterized. Our objective was to spatially profile known mesenchymal markers in both tumor cells and associated fibroblasts and correlate their expression with patient survival. The primary study cohort consisted of 74 MPM patients, including 16 patients who survived at least 60 months. We analyzed location-specific tissue expression of seven fibroblast markers in clinical samples using multiplexed fluorescence immunohistochemistry (mfIHC) and digital image analysis. Effect on survival was assessed using Cox regression analyses. The outcome measurement was all-cause mortality. Univariate analysis revealed that high expression of secreted protein acidic and cysteine rich (SPARC) and fibroblast activation protein in stromal cells was associated with shorter survival. Importantly, high expression of platelet-derived growth factor receptor beta (PDGFRB) in tumor cells, but not in stromal cells, was associated with shorter survival (hazard ratio [HR] = 1.02, p < 0.001). A multivariable survival analysis adjusted for clinical parameters and stromal mfIHC markers revealed that tumor cell PDGFRB and stromal SPARC remained independently associated with survival (HR = 1.01, 95% confidence interval [CI] = 1.00-1.03 and HR = 1.05, 95% CI = 1.00-1.11, respectively). The prognostic effect of PDGFRB was validated with an artificial intelligence-based analysis method and further externally validated in another cohort of 117 MPM patients. In external validation, high tumor cell PDGFRB expression associated with shorter survival, especially in the epithelioid subtype. Our findings suggest PDGFRB and SPARC as potential markers for risk stratification and as targets for therapy.

Keywords:  fibroblast; mesothelioma; platelet-derived growth factor receptor beta; prognosis

DOI:  https://doi.org/10.1002/cjp2.218
Front Oncol. 2021 ;11 641975

Efficacy, Safety, and Cost-Minimization Analysis of Continuous Infusion of Low-Dose Gemcitabine Plus Cisplatin in Patients With Unresectable Malignant Pleural Mesothelioma.

Oscar Arrieta, Wendy Muñoz-Montaño, Sae Muñiz-Hernández, Saul Campos, Rodrigo Catalán, Herman Soto-Molina, Silvia Guzmán Vázquez, Osvaldo Díaz-Álvarez, Victor Martínez-Pacheco, Jenny G Turcott, Maritza Ramos-Ramírez, Luis Cabrera-Miranda, Feliciano Barrón, Andrés F Cardona.

   Background: Malignant pleural mesothelioma (MPM) is rare and aggressive neoplasia, with a poor prognosis; furthermore, the monetary cost of its treatment represents a major challenge for many patients. The economic burden this malignancy imposes is underscored by the fact that asbestos exposure, which is the most frequent risk factor, is much more prevalent in the lower socioeconomic population of developing countries. The aims of the present study were to evaluate the efficacy, safety, and cost of continuous infusion of low-dose Gemcitabine plus Cisplatin (CIGC) as a treatment strategy for patients with unresectable MPM.
Methods: We performed a prospective cohort study to determine efficacy and safety of continuous infusion gemcitabine at a dose of 250 mg/m2 in a 6-h continuous infusion plus cisplatin 35 mg/m2 on days 1 and 8 of a 21-day cycle in patients with unresectable MPM. We also performed a cost-minimization analysis to determine if this chemotherapy regimen is less expensive than other currently used regimens.
Results: The median number of chemotherapy cycles was six (range 1-11 cycles); objective response rate was documented in 46.2%, and disease control rate was seen in 81.2%. Median PFS was 8.05 months (CI 95% 6.97-9.13); median OS was 16.16 months (CI 95% 12.5-19.9). The cost minimization analysis revealed savings of 66.4, 61.9, and 97.7% comparing CIGC with short-infusion gemcitabine plus cisplatin (SIGC), cisplatin plus pemetrexed (CP), and cisplatin plus pemetrexed and bevacizumab (CPB), respectively. Furthermore, this chemotherapy regimen proved to be safe at the administered dosage.
Conclusion: CIGC is an effective and safe treatment option for patients with unresectable MPM; besides, this combination is a cost-saving option when compared with other frequently used chemotherapy schemes. Therefore, this treatment scheme should be strongly considered for patients with unresectable MPM and limited economic resources.

Keywords:  chemotherapy; cisplatin; cost minimization analysis; low-dose gemcitabine; pleural mesothelioma; prolonged gemcitabine infusion

DOI:  https://doi.org/10.3389/fonc.2021.641975
Interact Cardiovasc Thorac Surg. 2021 May 08. pii: ivab139. [Epub ahead of print]

Quality of life and lung function after pleurectomy/decortication for malignant pleural mesothelioma.

Toru Nakamichi, Masaki Hashimoto, Akifumi Nakamura, Ayumi Kuroda, Takashi Tanaka, Jiro Takeuchi, Seiji Matsumoto, Takeshi Morimoto, Nobuyuki Kondo, Kazuhisa Domen, Seiki Hasegawa.

   OBJECTIVES: Impact of pleurectomy/decortication (P/D) on quality of life (QOL) is not widely reported. We investigated QOL and lung function after P/D.
METHODS: A single-centre, retrospective cohort study was performed among patients who underwent P/D for malignant mesothelioma between June 2014 and June 2018 at Hyogo College of Medicine. Data at 4 points before and 3, 6 and 12 months on QOL and lung function were evaluated with the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and pulmonary function tests.
RESULTS: Forty-five out of 65 patients completed SF-36. Physical function and role physical decreased from 78 to 65 and 69 to 41 and did not recover. Body pain decreased from 74 to 52. It increased to 62 at 12 months but was lower than before. General health perceptions, vitality and social function decreased from 56 to 49, 50 to 47 and 63 to 50, respectively, but returned to baseline. Role emotional decreased from 75 to 54, then once increased to 63, but decreased again to 58. Mental health tended to improve from 58 to 70. Thirty-eight patients out of 45 completed pulmonary function tests. Forced vital capacity and forced expiratory volume in 1 s decreased from 98% to 61% and 93% to 67% and did not increase. Right-sided surgery or complications was the risk factors of poor lung function but no significant risk factors in QOL.
CONCLUSIONS: This study suggests that P/D had an impact on QOL. Despite the lack of recovery in lung function QOL in mental aspects tended to improve, suggesting that pulmonary function tests alone are limited in assessing QOL.

Keywords:  Lung function; Malignant pleural mesothelioma; Pleurectomy/decortication; Quality of life; The Medical Outcomes Study 36-Item Short-Form Health Survey

DOI:  https://doi.org/10.1093/icvts/ivab139
Int J Mol Med. 2021 Jun;pii: 117. [Epub ahead of print]47(6):

Overexpression of microRNA‑486 affects the proliferation and chemosensitivity of mesothelioma cell lines by targeting PIM1.

Silvana Pinelli, Rossella Alinovi, Diana Poli, Massimo Corradi, Giorgio Pelosi, Marcello Tiseo, Matteo Goldoni, Delia Cavallo, Paola Mozzoni.

  Dysregulated levels of microRNAs (miRNAs or miRs), involved in oncogenic pathways, have been proposed to contribute to the aggressiveness of malignant pleural mesothelioma (MPM). Previous studies have highlighted the downregulation of miRNA miR‑486‑5p in patients with mesothelioma and the introduction of miRNA mimics to restore their reduced or absent functionality in cancer cells is considered an important therapeutic strategy. The aim of the present study was to evaluate the mechanisms through which miRNAs may influence the functions, proliferation and sensitivity to cisplatin of MPM cells. In the present study, a miR‑486‑5p mimic was transfected into the H2052 and H28 MPM cell lines, and cell viability, proliferation, apoptosis and mitochondrial membrane potential were monitored. miR‑486‑5p overexpression led to a clear impairment of cell proliferation, targeting CDK4 and attenuating cell cycle progression. In addition, transfection with miR‑486‑5p mimic negatively regulated the release of inflammatory factors and the expression of Provirus integration site for Moloney murine leukaemia virus 1 (PIM1). The sensitivity of the cells to cisplatin was enhanced by enhancing the apoptotic effects of the drug and impairing mitochondrial function. On the whole, the present study demonstrates that miR‑486‑5p may play an important role in MPM treatment by targeting multiple pathways involved in tumour development and progression. These activities may be mostly related to the downregulation of PIM1, a crucial regulator of cell survival and proliferation. Furthermore, these results provide support for the combined use of miR‑486‑5p with chemotherapy as a therapeutic strategy for MPM.

Keywords:  CDK4; PIM1; cisplatin sensitivity; malignant pleural mesothelioma; miRNA‑486‑5p

DOI:  https://doi.org/10.3892/ijmm.2021.4950
Expert Opin Emerg Drugs. 2021 May 04.

Emerging biological therapies for the treatment of malignant pleural mesothelioma.

Alexander P Davis, Steven C Kao, Stephen J Clarke, Michael Boyer, Nick Pavlakis.

   INTRODUCTION: Malignant pleural mesothelioma (MPM) has limited treatment options with minimal new therapy approvals for unresectable disease in the past 15 years. However, considerable work has occurred to develop immunotherapies and biomarker driven therapy to improve patient outcomes over this period.
AREAS COVERED: This review examines current standard of care systemic therapy in the first- and second line setting. The last 12 months has seen 2 significant trials (Checkmate 743 and CONFIRM) which establish evidence supporting the role of immunotherapy in the management of MPM. Further trials are underway to assess the role of combination chemoimmunotherapy and personalised therapy. Additionally, a large number of clinical trials are ongoing to assess the efficacy of oncoviral, dendritic cell, anti-mesothelin and chimeric antigen receptor T cell therapy in the treatment of MPM.
EXPERT OPINION: Recent Phase III trial results have established a role for immunotherapy in the management of MPM. The optimal sequencing and combination of chemotherapy and immunotherapy remains to be determined. Novel therapies for MPM are promising however efficacy remains to be determined and issues remain regarding access to and delivery of these therapies.

Keywords:  Chimeric Antigen Receptor (CAR) T cells; Dendritic Cell Therapy; Immune Checkpoint Inhibitors; Immunotherapy; Malignant Pleural Mesothelioma (MPM); Mesothelin; Tumour Treating Fields

DOI:  https://doi.org/10.1080/14728214.2021.1924670