bims-mesote 2022-05-08 papers

bims-mesote

Biomed News

on Mesothelioma

Issue of 2022‒05‒08
twelve papers selected by
Laura Mannarino
Humanitas Research

The Role of Real-World Evidence to Support Treatment Choices in Malignant Pleural Mesothelioma.
Mesothelioma in situ with regressive malignant pleural effusion and an unexpected evolution: A case report.
Mesothelioma.
The Predictive and Prognostic Nature of Programmed Death-Ligand 1 in Malignant Pleural Mesothelioma: A Systematic Literature Review.
Lymphocyte predominance in blood, pleural fluid, and tumour stroma; a prognostic marker in pleural mesothelioma.
BAP1 loss by immunohistochemistry predicts improved survival to first line platinum/pemetrexed chemotherapy for pleural mesothelioma patients: A validation study.
Outcomes of pleurectomy decortication in patients with biphasic mesothelioma.
Downregulation of FTL decreases proliferation of malignant mesothelioma cells by inducing G1 cell cycle arrest.
Dissecting and Reconstructing Matrix in Malignant Mesothelioma Through Histocell-Histochemistry Gradients for Clinical Applications.
DNA repair and damage pathways in mesothelioma development and therapy.
Advances in Drug Treatments for Mesothelioma.
Expression of PD-L1 in Patients With Malignant Peritoneal Mesothelioma: A Pilot Study.

JTO Clin Res Rep. 2022 Apr;3(4): 100300

The Role of Real-World Evidence to Support Treatment Choices in Malignant Pleural Mesothelioma.

Paul Wheatley-Price, Sara Moore, Christopher W Lee.

DOI: https://doi.org/10.1016/j.jtocrr.2022.100300
Am J Ind Med. 2022 May 06.

Mesothelioma in situ with regressive malignant pleural effusion and an unexpected evolution: A case report.

Gustavo C de Almeida, Ubiratan de P Santos, Yuri de D M Parente, Philippe de F B Colares, Rafael F Mizutani, Fabíola Del C Bernardi, Ricardo M Terra, Mario Terra-Filho.

  Malignant pleural mesothelioma (MPM) is an aggressive neoplasm that originates from hyperplasia and metaplasia of the mesothelial cells that cover the pleural cavity. Previous exposure to asbestos is the main risk factor. Since MPM is often diagnosed at an advanced stage with rapid evolution and resistance to treatment, it is associated with an unfavorable outcome. Mesothelioma in situ (MIS) has been postulated as a preinvasive phase of MPM; however, its diagnostic criteria have been defined only recently. Diagnosis of MIS may represent an opportunity for early therapies with better results, but the optimal approach has not been defined thus far. Here, we report on a case of a 74-year-old man with right-sided pleural effusion and a previous history of occupational exposure to asbestos for 9 years who was diagnosed with MIS after a latency of 36 years. During follow-up, spontaneous disease regression was observed 5 months after the initial diagnosis; however, it recurred in the form of invasive epithelioid MPM. There is a paucity of literature on MIS and its evolution; however, our case provides relevant knowledge of this unusual behavior, which is important to define follow-up and therapeutic strategies for future cases.

Keywords:  asbestos; mesothelioma; mesothelioma in situ; occupational cancer; pleural effusion

DOI:  https://doi.org/10.1002/ajim.23358
Cytojournal. 2022 ;19 10

Mesothelioma.

Nagarjun Rao, Shuanzeng Wei.

  Mesothelioma arises from the surface serosal cells lining the pleural, peritoneal, and pericardial cavities. It has three variants including: epithelioid, sarcomatous/desmoplastic, and biphasic types. Mesothelioma cells, predominantly of the epithelioid type, can shed into effusions as sheets, clusters/ morulae, papillae, or single cells. The challenges to cytologic diagnosis of mesothelioma are two-fold: 1. distinguishing mesothelial cells from metastatic malignant (most commonly carcinoma) cells; 2. distinguishing reactive mesothelial from mesothelioma cells. Immunocytochemistry is a helpful aid to cytologic evaluation for the former. The distinction of reactive mesothelial cells from mesothelioma can be more difficult, as there is considerable overlap in their appearances in effusion specimens. Recently developed ancillary molecular and genetic tests are proving to be useful in confirming the diagnosis of malignant mesothelioma in cytology specimens.

Keywords:  Cell-block; Cytomorphology; Immunocytochemistry; Mesothelioma; Molecular and genetic tests

DOI:  https://doi.org/10.25259/CMAS_02_08_2021
JTO Clin Res Rep. 2022 May;3(5): 100315

The Predictive and Prognostic Nature of Programmed Death-Ligand 1 in Malignant Pleural Mesothelioma: A Systematic Literature Review.

Aaron S Mansfield, Rebecca J Brown, Cormac Sammon, Melinda J Daumont, Mike McKenna, Jenine K Sanzari, Patrick M Forde.

  Introduction: Given the emergence of combination of programmed cell death protein-1 and CTLA4 pathway blockade as effective treatment options in malignant pleural mesothelioma (MPM), there is interest in the extent to which programmed death-ligand 1 (PD-L1) expression may be prognostic of clinical outcomes and predictive of response to anti-programmed death (ligand) 1 (PD-[L]1) therapies.Methods: MEDLINE and EMBASE electronic databases were searched until November 4, 2020. English-language randomized trials and observational studies that reported clinical outcomes and PD-L1 expression in adult patients (>18 or >20 y) with MPM were included. Forest plots were used to descriptively summarize clinical outcome data across studies.
Results: A total of 29 publications were identified providing data on the research question. Among the studies in which anti-PD-(L)1 therapies were not specified to have been used, 63% (10 of 16) found patients with tumors expressing PD-L1 (typically >1%) to have poorer survival than those with tumors expressing lower levels of PD-L1. Among the studies in which anti-PD-(L)1 therapies were used, 83% (five of six) did not reveal an association between survival and PD-L1 tumor expression. The single study directly comparing outcomes between those treated and untreated with anti-PD-(L)1 therapies across different PD-L1 cutoffs did not identify any differences between the groups.
Conclusions: The quality and consistency of the existing evidence base are currently insufficient to draw conclusions regarding a prognostic or predictive role of PD-L1 in MPM. Furthermore, high-quality studies on this topic are required to support the use of PD-L1 as a biomarker in MPM.

Keywords:  Biomarker; Mesothelioma; PD-L1; Predictive; Prognostic

DOI:  https://doi.org/10.1016/j.jtocrr.2022.100315
BMC Pulm Med. 2022 Apr 30. 22(1): 173

Lymphocyte predominance in blood, pleural fluid, and tumour stroma; a prognostic marker in pleural mesothelioma.

Duneesha De Fonseka, David T Arnold, Anna J Morley, Mary Brett, Nidhi Bhatt, Anthony Edey, Richard Daly, Anna C Bibby, Nick A Maskell.

  BACKGROUND: As promising novel treatments develop for malignant pleural mesothelioma (MPM), early prognostication has become increasingly important. Circulating and local inflammatory cells are known to play a significant role in other tumour types. We assessed the proportion of lymphocyte populations within blood, pleural fluid and tumour stroma to prognosticate patients with MPM at diagnosis.METHODS: Consecutive patients diagnosed with biopsy-proven MPM were prospectively recruited to an observational cohort study and followed up for a minimum of 7.5 years. Blood and pleural fluid results at presentation were extracted from the medical records. Biopsy specimens were independently reviewed by 2 pathologists who scored the degree of lymphocytic and neutrophilic infiltration.
RESULTS: Baseline results were available for 184 patients. The predominant pleural fluid cell type was calculable for 84 patients and 118 patients had biopsy specimens available for review. A low blood neutrophil/lymphocyte ratio (NLR < 4) inferred a better prognosis with a median survival of 420 days versus 301 days (p < 0.01). Survival was better for patients with a lymphocyte-predominant pleural effusion (430 vs 306 days, p < 0.01). Lymphocyte infiltration of tumour stroma was also associated with improved survival (n = 92, survival 430 days) compared with neutrophilic or acellular samples (n = 26, survival 342 days p < 0.01). In multivariable modelling lymphocyte predominance in blood, pleural fluid and tumour stroma were all associated with a better prognosis.
CONCLUSIONS: Lymphocyte predominance within tumour stroma, pleural fluid or blood infers a better prognosis in patients with MPM.

Keywords:  Lymphocytes; Mesothelioma; NLR; Neutrophils; Pleural fluid

DOI:  https://doi.org/10.1186/s12890-022-01968-2
J Thorac Oncol. 2022 Apr 27. pii: S1556-0864(22)00210-6. [Epub ahead of print]

BAP1 loss by immunohistochemistry predicts improved survival to first line platinum/pemetrexed chemotherapy for pleural mesothelioma patients: A validation study.

Amber Louw, Vasiliki Panou, Weronika Maria Szejniuk, Christos Meristoudis, Siaw Ming Chai, Chris van Vliet, Y C Gary Lee, Ian M Dick, Tina Firth, Louise Andersen Lynggaard, Azadeh Birbaneh Asghari, Mogens Vyberg, Johnni Hansen, Jenette Creaney, Oluf Dimitri Røe.

  INTRODUCTION: Pleural mesothelioma (PM) is an aggressive malignancy with no identified predictive biomarkers. We assessed whether tumour BRCA associated protein 1 (BAP1) status is a predictive biomarker for survival in patients receiving first-line combination platinum/pemetrexed therapy.introduction METHODS: PM cases (n=114) from Aalborg, Denmark were stained for BAP1 on tissue microarrays. Demographic, clinical and survival data were extracted from registries and medical records. Surgical cases were excluded. BAP1 status was associated with overall survival (OS) by Cox regression and Kaplan-Meier methods. Results were validated in an independent cohort from Perth, Australia (n=234).RESULTS: BAP1 loss was demonstrated in 62% and 60.3% of all Danish and Australian samples respectively. BAP1 loss was an independent predictor of OS in multivariate analyses corrected for histology, performance status, age, sex and treatment (HR = 2.49, p < 0.001 and 1.48, p = 0.01, respectively). First-line platinum/pemetrexed treated patients with BAP1 loss had significantly longer median survival than those with retained BAP1 in both the Danish (20.1 vs 7.3 months, p < 0.001) and Australian cohorts (19.6 vs 11.1 months, p < 0.01). Survival in patients with BAP1 retained and treated with platinum/pemetrexed was similar as in those with best supportive care (BSC). There was a higher OS in BSC patients with BAP1 loss, but significant only in the Australian cohort (16.8 vs 8.3 months, p < 0.01).results CONCLUSION: BAP1 is a predictive biomarker for survival following first-line combination platinum/pemetrexed chemotherapy and a potential prognostic marker in PM. BAP1 in tumour is a promising clinical tool for treatment stratification.
CONCLUSION:

Keywords:  BAP1; chemotherapy; pemetrexed; pleural mesothelioma; predictive biomarkers

DOI:  https://doi.org/10.1016/j.jtho.2022.04.008
J Thorac Cardiovasc Surg. 2022 Mar 30. pii: S0022-5223(22)00359-2. [Epub ahead of print]

Outcomes of pleurectomy decortication in patients with biphasic mesothelioma.

Moshe Lapidot, Emanuele Mazzola, Raphael Bueno.

  OBJECTIVE: There are limited small, single-institution observational studies on the role of surgery in patients with biphasic mesothelioma. Herein we report a series of 147 consecutive patients with biphasic mesothelioma treated over 11 years in a high-volume single institution with intended pleurectomy decortication (PDC).METHODS: All patients with biphasic mesothelioma from 2007 to 2017 who underwent PDC in our institution were included and clinical, pathologic, and surgical information was retrieved. Kaplan-Meier estimators and log rank test were used to compare the overall survival, and Cox regression models were used to analyzed prognostic factors.
RESULTS: There were 117 men (80%), 99 right-sided operations (67%), and median age was 70 (range, 36-86) years. Neoadjuvant therapy was given to 36 (24.5%) and 108 (73.5%) received intraoperative heated chemotherapy. Macroscopic complete resection was achieved in 126 (86%). Tumors were assigned to stages IA (23; 18.8%), IB (60; 47.5%) II (15; 11.5%), IIIA (17; 13.1%), and IIIB (11; 9%) according to the eighth edition of the tumor-node-metastasis classification of malignant tumors. The 30- and 90-day mortality were 1.3% and 6.1%, respectively. The median overall survival in the macroscopic complete resection group was 16.7 months and 24 months in patients younger than 70 years. In a univariate analysis, factors that were associated with patient overall survival included age (P = .001), preoperative percentage forced expiratory volume in 1 second (P = .019), and adjuvant therapy (P < .001). No correlation was found between sex, neoadjuvant therapy, and nodal status to overall survival.
CONCLUSIONS: In selected patients with biphasic mesothelioma and good prognostic factors prolonged survival after PDC is expected.

Keywords:  biphasic mesothelioma; macroscopic complete resection; malignant pleural mesothelioma; pleurectomy decortication

DOI:  https://doi.org/10.1016/j.jtcvs.2022.01.054
Oncol Lett. 2022 Jun;23(6): 174

Downregulation of FTL decreases proliferation of malignant mesothelioma cells by inducing G1 cell cycle arrest.

Takahiro Kambara, Vishwa Jeet Amatya, Kei Kushitani, Yutaro Fujii, Ihiro Endo, Yukio Takeshima.

  Pleural malignant mesothelioma is a malignant tumor with a poor prognosis that is strongly associated with asbestos exposure during its development. Because there is no adequate treatment for malignant mesothelioma, investigation of its molecular mechanism is important. The ferritin light chain (FTL) is a subunit of ferritin, and its high expression in malignant tumors, including malignant mesothelioma, has recently been reported; however, its role in malignant mesothelioma is unclear. The purpose of the present study was to clarify the function of FTL in malignant mesothelioma. The expression levels of FTL in malignant mesothelioma were examined using the Cancer Cell Line Encyclopedia database and our previous data. The short interfering (si)RNA against FTL was transfected into two mesothelioma cell lines, ACC-MESO-1 and CRL-5915, and functional analysis was performed. Expression of p21, p27, cyclin-dependent kinase 2 (CDK2) and phosphorylated retinoblastoma protein (pRb) associated with the cell cycle were examined as candidate genes associated with FTL. The expression levels of the FTL mRNA were higher in malignant mesothelioma compared with other tumors in the Cancer Cell Line Encyclopedia database, and among other genes in our previous study. Reverse transcription-quantitative PCR and western blotting demonstrated suppression of FTL expression in two cell lines transfected with FTL siRNA compared with cells transfected with negative control (NC) siRNA. In the two cell lines transfected with FTL siRNA, proliferation was significantly suppressed, and cell cycle arrest was observed in the G1 phase. The levels of p21 and p27 were increased, while those of CDK2 and pRb were decreased compared with NC. However, no significant differences in invasion and migration ability were revealed between FTL siRNA-transfected cells and NC. In conclusion, FTL may increase the proliferative capacity of malignant mesothelioma cells by affecting p21, p27, CDK2 and pRb, and promoting the cell cycle at the G1 phase.

Keywords:  G1 arrest; cyclin-dependent kinase 2; ferritin light chain; malignant mesothelioma; p21; p27

DOI:  https://doi.org/10.3892/ol.2022.13294
Front Med (Lausanne). 2022 ;9 871202

Dissecting and Reconstructing Matrix in Malignant Mesothelioma Through Histocell-Histochemistry Gradients for Clinical Applications.

Marcelo Luiz Balancin, Camila Machado Baldavira, Tabatha Gutierrez Prieto, Juliana Machado-Rugolo, Cecília Farhat, Aline Kawassaki Assato, Ana Paula Pereira Velosa, Walcy Rosolia Teodoro, Alexandre Muxfeldt Ab'Saber, Teresa Yae Takagaki, Vera Luiza Capelozzi.

  Background: Malignant pleural mesotheliomas (MM) are known for their heterogenous histology and clinical behavior. MM histology reveals three major tumor cell populations: epithelioid, sarcomatoid, and biphasic. Using a dissecting approach, we showed that histochemical gradients help us better understand tumor heterogeneity and reconsider its histologic classifications. We also showed that this method to characterize MM tumor cell populations provides a better understanding of the underlying mechanisms for invasion and disease progression.Methods: In a cohort of 87 patients with surgically excised MM, we used hematoxylin and eosin to characterize tumor cell populations and Movat's pentachrome staining to dissect the ECM matrisome. Next, we developed a computerized semi-assisted protocol to quantify and reconstruct the ECM in 3D and examined the clinical association between the matricellular factors and patient outcome.
Results: Epithelioid cells had a higher matrix composition of elastin and fibrin, whereas, in the sarcomatoid type, hyaluronic acid and total collagen were most prevalent. The 3D reconstruction exposed the collagen I and III that form channels surrounding the neoplastic cell blocks. The estimated volume of the two collagen fractions was 14% of the total volume, consistent with the median estimated area of total collagen (12.05 mm2) for epithelioid MM.
Conclusion: Differential patterns in matricellular phenotypes in MM could be used in translational studies to improve patient outcome. More importantly, our data raise the possibility that cancer cells can use the matrisome for disease expansion and could be effectively targeted by anti-collagen, anti-elastin, and/or anti-hyaluronic acid therapies.

Keywords:  Movat's pentachrome stain; Picrosirius; immunohistochemistry; malignant mesothelioma; prognosis

DOI:  https://doi.org/10.3389/fmed.2022.871202
Cancer Cell Int. 2022 May 02. 22(1): 176

DNA repair and damage pathways in mesothelioma development and therapy.

Faezeh Malakoti, Niloufar Targhazeh, Erfan Abadifard, Reza Zarezadeh, Sahar Samemaleki, Zatollah Asemi, Simin Younesi, Reza Mohammadnejad, Seyed Hadi Hossini, Ansar Karimian, Forough Alemi, Bahman Yousefi.

  Malignant mesothelioma (MMe) is an aggressive neoplasm that occurs through the transformation of mesothelial cells. Asbestos exposure is the main risk factor for MMe carcinogenesis. Other important etiologies for MMe development include DNA damage, over-activation of survival signaling pathways, and failure of DNA damage response (DDR). In this review article, first, we will describe the most important signaling pathways that contribute to MMe development and their interaction with DDR. Then, the contribution of DDR failure in MMe progression will be discussed. Finally, we will review the latest MMe therapeutic strategies that target the DDR pathway.

Keywords:  BAP1; BRCA1 associated protein 1; DNA damage repair; Malignant mesothelioma; Malignant peritoneal mesothelioma; Signaling pathways

DOI:  https://doi.org/10.1186/s12935-022-02597-9
Expert Opin Pharmacother. 2022 May 04.

Advances in Drug Treatments for Mesothelioma.

Paolo Andrea Zucali, Fabio De Vincenzo, Matteo Perrino, Nunzio Digiacomo, Nadia Cordua, Federica D'Antonio, Federica Borea, Roberta Fazio, Angelo Pirozzi, Armando Santoro.

  INTRODUCTION: The paucity of the therapeutic armamentarium currently available for patients with malignant mesothelioma clearly represents a huge unmet need. Over the last years, based on new advances in understanding the biology of mesothelioma, new therapeutic approaches have been investigated.AREAS COVERED: In this manuscript, the literature data regarding the advances in drug treatment for patients with mesothelioma are critically reviewed, focusing particularly on immunotherapy and targeted therapy.
EXPERT OPINION: The latest findings on immunotherapy and targeted therapy are changing the therapeutic armamentarium for mesothelioma. However, mesothelioma comprises of genomically different subtypes and the phenotypic diversity combined with the rarity of this disease represents a major criticality in developing new effective therapies. Although the first clinical data are encouraging, the treatment's stratification by molecular characteristics for mesothelioma is only at the beginning. Luckily, the rapid improvement of understanding the biology of mesothelioma is producing new opportunities in discovering new therapeutic targets to test in pre-clinical settings and to transfer in the clinical setting. In this evolving scenario, the future perspectives for mesothelioma patients seem really promising.

Keywords:  immunotherapy; malignant mesothelioma; new drugs; targeted therapy

DOI:  https://doi.org/10.1080/14656566.2022.2072211
J Surg Res. 2022 Apr 27. pii: S0022-4804(22)00187-1. [Epub ahead of print]277 131-137

Expression of PD-L1 in Patients With Malignant Peritoneal Mesothelioma: A Pilot Study.

Victor P Gazivoda, Aaron W Kangas-Dick, Alissa A Greenbaum, Joshua Roshal, Chunxia Chen, Dirk F Moore, Russell C Langan, Timothy J Kennedy, Christine Minerowicz, H Richard Alexander.

  INTRODUCTION: Frequency of PD-L1 expression and the role of immunotherapy in malignant peritoneal mesothelioma (MPM) have not been well characterized. The purpose of this study was to determine PD-L1 expression in patients with MPM and perform an exploratory analysis for associations between PD-L1 and its biological behavior in MPM.METHODS: Tumor samples were collected from patients undergoing surgical interventions between January 2018 and June 2020. Specimens were stained with anti-PD-L1 antibodies (Dako 22c3) and positivity was determined by tumor proportion score (TPS) or combined positive score (CPS) being ≥1%.
RESULTS: Twenty one samples were obtained from 21 patients. Sixteen of 21 (76%) samples were CPS positive and 9 of 21 (43%) were TPS positive. Three samples had more aggressive biphasic/sarcomatoid histology and a high CPS and TPS (CPS: 3, 75, 95%; TPS: 2, 60, 90%). On an exploratory analysis, as the CPS or TPS threshold increased, there was a trend towards worse survival.
CONCLUSIONS: MPM has a high frequency of PD-L1 expression, which may be associated with more aggressive tumor biology. These data provide the foundation for continued evaluation of checkpoint inhibition in patients with MPM.

Keywords:  CRS-HIPEC; Immunotherapy; Malignant peritoneal mesothelioma; PD-L1

DOI:  https://doi.org/10.1016/j.jss.2022.04.005