Translational Lung Cancer Research

About the journal

Publisher: Pioneer Bioscience Publishing Company
Published: 2012 to the present, China
Language: English
ISSN: 2226-4477 (electronic), 2218-6751 (print)
Its record in the NLM Catalog

2020s

Convex-probe endobronchial ultrasound-guided cryobiopsy for pleural tumors: three case reports. T. Nakai, Y. Furukawa, H. Nagamine, et al. 2026;15(2):43. Case report PubMed · Publisher · Free full text

Abstract

Background: Endobronchial ultrasound-guided cryobiopsy (EBUS-cryo) is an emerging minimally invasive technique that enables acquisition of high-quality tissue specimens, particularly from mediastinal lymphadenopathy. Here, we describe three cases in which its application to pleural tumors helped establish a definitive diagnosis.

Case Description: Case 1 involved a 74-year-old man with multiple pleural lesions detected via computed tomography (CT), the largest of which was encased by major vessels. EBUS-cryo sampling of the largest lesion, performed through the left lower bronchus, led to the diagnosis of epithelioid pleural mesothelioma. Case 2 involved a 69-year-old man with multiple pleural masses encircling the mediastinal aspect of the right lung without associated pleural effusion. EBUS-cryo sampling of a pleural lesion located along the right dorsal side of the trachea led to the diagnosis of biphasic pleural mesothelioma. Case 3 involved an 82-year-old man with multiple pleural lesions and consolidation in the left upper lobe. Semi-rigid pleuroscopy could not establish a definitive diagnosis; however, EBUS-cryo performed on a mediastinal pleural tumor through the left posterior trachea established a diagnosis of B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT) type.

Conclusions: EBUS-guided cryobiopsy of pleural tumors may represent a generally safe minimally invasive option for obtaining diagnostic tissue in selected patients.

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Feasibility of multimodality treatment, including pleurectomy decortication, in carefully selected patients with sarcomatoid mesothelioma. M. Lapidot, E. Mazzola, R. Bueno. 2026;15(1):11. PubMed · Publisher · Free full text

Abstract

Background: Pleural mesothelioma (PM) represents an uncommon and exceptionally lethal malignancy. The sarcomatoid subtype constitutes the rarest histological variant, traditionally linked to the worst prognosis, while the advantages of operative intervention remain inadequately established. In this study, we present findings from a cohort of 34 sequential cases with sarcomatoid mesothelioma managed at a specialized high-volume center employing pleurectomy decortication (PD) within a comprehensive therapeutic strategy. We aim to identify patients in this cohort who may benefit from a multimodality approach.

Methods: All patients diagnosed with sarcomatoid mesothelioma between 2007 and 2019 who received PD at our facility were enrolled, and relevant medical, histopathological, and operative data collected. Survival curves generated through Kaplan-Meier methodology alongside log-rank testing enabled comparison of longevity outcomes, while Cox proportional hazards modeling facilitated examination of predictive variables.

Results: The cohort included 31 male subjects (91.2%), 24 procedures performed on the right side (70.6%), with a median patient age of 71.5 years (range, 51-85 years). Preoperative treatment was administered to 8 individuals (24.2%), while 23 participants (67.7%) underwent intraoperative heated chemotherapy (IOHC). Macroscopic complete resection (MCR) was accomplished in 22 cases (64.7%). Mortality at 30 and 90 days post-surgery stood at 2.9% and 14.7%, respectively. The median overall survival for the entire cohort reached 7.4 months, extending to 20.1 months among those with forced expiratory volume in 1 second (FEV1) at or above 80% predicted. In multivariate analysis, preoperative FEV1 ≥80% was associated with prolonged overall survival [P=0.01; hazard ratio (HR) =0.54].

Conclusions: As expected, the median survival for most patients with sarcomatoid histology who undergo surgery is under one year. However, a small subset of patients with FEV1 ≥80% do quite well using the multimodality approach.

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MET amplification in diffuse pleural mesothelioma and response to savolitinib: a case report. Y. Chen, M. Shen, J. Lv, et al. 2026;15(3):66. Case report PubMed · Publisher · Free full text

Abstract

Background: Pleural mesothelioma (PM) is a rare malignancy globally, most frequently associated with alterations in tumor suppressor genes such as NF2, BAP1 and CDKN2A. In contrast, mutations or amplifications of the MET gene are seldomly reported in PM.

Case Description: Here, we report the case of a 60-year-old East Asian male without asbestos exposure, never-smoker, diagnosed with advanced PM. The disease proved refractory to multiple lines of therapy, including platinum-based chemotherapy, immunotherapy, intrathoracic instillation and a subsequent individualized regimen comprising intraperitoneal cisplatin plus sintilimab for local disease control and potential immunomodulation synergized with oral anlotinib. Following disease progression accompanied by rapidly accumulating seroperitoneum and pelvic effusion, next-generation sequencing (NGS) of ascitic fluid revealed MET gene amplification, and the subsequent switch to savolitinib controlled the malignant ascites. Unfortunately, the patient died of sudden cardiac and respiratory arrest in December 2023.

Conclusions: This case underscores the critical importance of comprehensive genetic testing in guiding the treatment of advanced PM, particularly after the failure of standard therapies. It illustrates that rare but actionable genomic alterations, such as MET amplification, can be identified through liquid or tissue biopsy and can inform successful targeted treatment strategies, even in a tumor type where such alterations are uncommon. Histological classification combined with molecular profiling remains pivotal for personalized oncology.

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Prognostic value of SUVpeak and prognostic nutritional index in patients with pleural mesothelioma treated with platinum-based chemotherapy. Y. Kato, K. Hashimoto, H. Imai, et al. 2026;15(8):243. PubMed · Publisher · Free full text

Abstract

Background: Pleural mesothelioma (PM) is an aggressive malignancy with poor prognosis, and reliable prognostic biomarkers are needed to better inform clinical management. We retrospectively investigated the prognostic value of the Glasgow prognostic score (GPS), prognostic nutritional index (PNI), neutrophil-to-lymphocyte ratio (NLR), body mass index (BMI), and tumor glucose metabolism measured by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET).

Methods: We retrospectively reviewed patients with PM treated with first-line platinum-pemetrexed chemotherapy at our institution (April 2007-December 2023; data cutoff, December 2024) and evaluated the prognostic value of these markers and baseline FDG-PET parameters.

Results: Among 79 patients diagnosed with PM, 51 who received first-line platinum-based chemotherapy with pemetrexed were analyzed. The median age was 69 (range, 42-81) years, 78% were male, and 67% had epithelioid histology. The objective response rate (ORR) was 27.5% [95% confidence interval (CI), 17.1-40.9%], and the disease control rate (DCR) was 72.5% (95% CI, 59.1-82.9%). The median progression-free survival (PFS) and overall survival (OS) were 5.8 (95% CI, 3.4-7.8) and 21.8 (95% CI, 13.4-33.5) months, respectively. Low PNI (≤45) was significantly associated with shorter OS than high PNI (>45) (18.8 vs. 28.5 months; P=0.04) and remained an independent prognostic factor in multivariable analysis (P=0.04). For 35 patients who underwent pretreatment 18F-FDG-PET, high peak standardized uptake value (SUVpeak) (>7.73) was significantly associated with worse OS than low SUVpeak (9.1 vs. 33.6 months; P<0.001) and remained an independent predictor in the multivariable analysis (P<0.001). None of the evaluated biomarkers significantly predicted PFS. GPS, NLR, and BMI showed no significant association with survival outcomes in the univariate analysis and were therefore not included in the multivariable models.

Conclusions: Low PNI and high SUVpeak significantly predicted poor OS in patients with PM treated with platinum-based chemotherapy. These factors may serve as practical prognostic indicators in this population.

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Using an artificial intelligence tool to improve the recognition of pseudoprogression in pleural mesothelioma patients treated with immunotherapy: a case series. I. Smesseim, K. Chupetlovska, V. Pugliese, et al. 2026;15(8):254. Case report PubMed · Publisher · Free full text

Abstract

Background: Pseudoprogression, defined as initial radiological tumor growth followed by treatment response, can complicate treatment response assessment in patients receiving immunotherapy. In pleural mesothelioma (PM) patients treated with immunotherapy reliable identification of pseudoprogression remains challenging with the modified Response Evaluation Criteria in Solid Tumors (mRECIST) v1.1 criteria. Automated volumetric assessment using an artificial intelligence (AI) tool (ARTIMES) may provide additional insight into tumor response patterns. We aim to describe cases of pseudoprogression identified using the ARTIMES criteria in PM patients treated with immunotherapy.

Case Description: We performed a retrospective observational study of adult PM patients treated with immunotherapy at a tertiary center between January 1, 2013 and July 1, 2022. Tumor volumes were automatically segmented and quantified using the ARTIMES model. Patients demonstrating disease progression according to ARTIMES criteria followed by subsequent tumor volume decrease were evaluated for pseudoprogression. The results were presented in graphs depicting tumor volume, treatment duration, and the start and stop dates of immunotherapy. Among 368 PM patients treated with immunotherapy, 8 patients met inclusion criteria for confirmed pseudoprogression. All patients were male, with a median age of 67.5 years. Most patients had epithelioid histology (75.0%). All patients showed initial volumetric progression on early follow-up imaging, followed by objective tumor volume reduction either during continued immunotherapy or after treatment discontinuation. Volumetric tumor tracking enabled visualization of delayed responses that would have been difficult to interpret using standard imaging comparisons alone.

Conclusions: Pseudoprogression occurs in a subset of PM patients treated with immunotherapy. Automated volumetric tumor assessment can help identify pseudoprogression patterns. Integrating volumetric analysis with clinical evaluation may reduce premature discontinuation of potentially effective immunotherapy.

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Circulating stem-like exhausted CD8 T cells point to better outcomes in lung cancer: a brief report. L. Ye, I. Dick, T. Firth, et al. 2025;14(11):5074-5081. PubMed · Publisher · Free full text

Abstract

Anti-cancer T cells exhibit a spectrum of functional abilities and exhaustion levels and can be broadly categorized as stem-like exhausted T cells (Texstem) that retain cancer-killing capacity, and terminally exhausted T cells (Texterm) with limited function. Previously, we identified CD8 Texstem and Texterm cells in malignant pleural effusions (PEs) of non-small cell lung cancer (NSCLC) and mesothelioma patients. In both cancers, increased frequency of Texstem cells was associated with improved overall survival (OS). However, not all cancer patients develop PE, and sampling of PE is invasive, with associated risks. In this study we sought to determine if Texstem and Texterm cells in the blood of patients with NSCLC also associated with survival. Using flow cytometry, we quantified Texstem and Texterm in blood samples from 30 patients with advanced NSCLC and assessed their correlation with OS. In half of these cases, we also analyzed matched PE samples for comparison. Compared to PE, peripheral blood had a lower frequency of Texstem (3.8% vs. 9.4% of CD8 T cells, P=0.006) and Texterm (0.3% vs. 1.1%, P=0.002). However, both subsets were significantly correlated between the two sites (Texstem r=0.82, P<0.001; Texterm r=0.63, P=0.01). Higher Texstem cell frequency in the blood was associated with improved survival after adjusting for potentially prognostic patient and tumor related factors. When stratified into high and low groups based on the median, higher Texstem cells levels correlated with better OS [hazard ratio (HR) 0.16, 95% confidence interval (CI): 0.03-0.10, P=0.048]. As shown previously in PE, Texterm cells in the blood did not correlate with OS. Our results further support the importance of Texstem in the anti-cancer immune response and provide useful evidence for the utility of peripheral blood sampling for future studies examining exhausted T cells (Tex).

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Liquid biopsy perspectives in pleomorphic carcinoma of the lung: case report. T. Rossi, M. Cortesi, M. Zanoni, et al. 2025;14(6):2324-2336. Case report PubMed · Publisher · Free full text

Abstract

Background: Liquid biopsy has recently made it possible to use minimally invasive testing to examine tumor-derived material released into peripheral blood, including circulating tumor cells (CTCs), extracellular vesicles (EVs), and circulating tumor deoxyribonucleic acid (ctDNA). Lung pleomorphic carcinoma (PC) is an extremely rare and severe form of cancer. Although resection tissues are the basis for PC diagnosis in everyday practice, tiny biopsies and cytologic specimens might potentially raise suspicions. Because PC may show varied expression of conventional carcinoma markers, it can be particularly challenging to differentiate sarcomatoid (i.e., spindle cell or giant cell) components from other tumor forms, such as sarcomatoid mesothelioma and other sarcomas. We think that defining a more specific context to better understand patient prognosis may be aided by the discovery of blood molecular markers in PC.

Cases Description: We present two cases of patients underwent major lung resection at our center with a diagnosis of PC of the lung; specifically, according with 8th TNM edition, case 1 showed a final pathological stage pathological tumor-node-metastasis (pTNM): pT1cN0G3LV0R0, and case 2 showed a stage pTNM: pT3N0G3LV0R0. Patients were both discharged after surgery with no postoperative complications. Oncologists suggested a 5-year clinical and radiological follow-up, however case 1 patient is free from recurrence at the moment, while case 2 patient died for brain recurrence 10 months after surgery. Immediately after surgical resection, patient's specimens were sent to the pathology unit. The pathologist, without affecting the accuracy of histological diagnosis, selected representative tissue samples and sent them at 4 ℃ in specific media, to Bioscience Laboratory, IRCCS IRST "Dino Amadori" for tissue analysis. Additionally, blood samples collected before surgery were sent for the characterization of CTCs and EVs.

Conclusions: To better characterize the potential relationship between the presence of CTCs, EVs and high grade of malignancy and any subsequent connection to death and/or recurrence, we think that liquid biopsy, which involves the identification and characterization of tumor-derived elements, may serve as future approach and tool not only in NSCLC but also in each specific histotype as for lung PC.

Copyright © 2025 AME Publishing Company. All rights reserved.
Neoadjuvant systemic therapy for pleural mesothelioma patients: a systematic review. I. Smesseim, J. Raskin, J.A. Burgers. 2025;14(10):4618-4627. Review PubMed · Publisher · Free full text

Abstract

Background: Pleural mesothelioma is an aggressive malignancy with a poor prognosis. The role of surgery in its management remains controversial, with ongoing debate regarding the definition of resectable disease. Neoadjuvant therapy aims to reduce tumor burden. This systematic review evaluates prospective neoadjuvant trials in pleural mesothelioma to identify subgroups that may benefit from this approach.

Methods: A systematic search was conducted from inception to July 01, 2024, for phase II/III prospective trials evaluating neoadjuvant systemic therapy followed by surgery in adult patients with histologically confirmed pleural mesothelioma. Data were extracted on patient characteristics, treatment regimens, surgical outcomes, survival, and adverse events.

Results: Sixteen trials were found: 861/1,184 patients (72.7%) were male, median age ranged between 57-69 years. Neoadjuvant chemotherapy was used in 15 trials and immunotherapy in one trial. Surgery was performed in 61.8% of patients, with extrapleural pneumonectomy (EPP) being the predominant approach. Median overall survival in single-arm trials was 17.4 months [95% confidence interval (CI): 15.8-19.0], n=523 for the intention-to-treat population and 21.4 months (95% CI: 19.2-23.7), n=345 for the surgery population. The phase III trial (MARS-2) comparing neoadjuvant chemotherapy plus extended pleurectomy decortication versus chemotherapy alone found a shorter median survival in the surgery and chemotherapy group {19.3 months [interquartile range (IQR), 10.0-33.7 months] vs. 24.8 months (IQR, 12.6-37.4 months), P=0.01}.

Conclusions: This review shows that the predominant neoadjuvant approach consists of platinum doublet chemotherapy, but the role of immunotherapy is being explored. Additional randomized trials are needed to determine the optimal neoadjuvant strategy and patient subgroups most likely to benefit.

Copyright © 2025 AME Publishing Company. All rights reserved.
PD-L1 expression as a prognostic factor for postoperative outcomes in pleural mesothelioma. M. Kanayama, T. Manabe, K. Yoshimatsu, et al. 2025;14(9):3913-3923. PubMed · Publisher · Free full text

Abstract

Background: Pleural mesothelioma (PM) is an uncommon malignancy with a poor prognosis, even after surgical resection. Programmed death-ligand 1 (PD-L1) expression is a potential prognostic biomarker in various cancers, yet its role in PM patients undergoing pleurectomy/decortication (P/D) is unclear. This study aimed to evaluate the prognostic significance of PD-L1 expression in patients with PM who underwent P/D.

Methods: This retrospective study included patients with PM who underwent P/D from 2012 to 2022. PD-L1 expression in tumor cells was evaluated by immunohistochemistry, categorizing patients by tumor proportion score (TPS): 0%, 1-49%, and ≥50%. Survival outcomes were assessed using Kaplan-Meier curves and Cox proportional hazards regression models.

Results: A total of 58 patients were enrolled in the study. The median overall survival (OS) was 77.0 months for TPS 0%, 41.0 months for TPS 1-49%, and 25.3 months for TPS ≥50%. The corresponding relapse-free survival (RFS) was 34.3, 13.2, and 6.7 months, respectively. Lower PD-L1 expression was significantly associated with improved outcomes (OS: P=0.041, RFS: P=0.002). In multivariable analysis, PD-L1 TPS 0% (vs. ≥1%) emerged as an independent prognostic factor for RFS (hazard ratio, 0.37; 95% confidence interval: 0.18-0.76; P=0.007), but not OS.

Conclusions: Our findings suggest that PD-L1 expression levels in tumor cells may influence postoperative prognosis and relapse risk in patients with PM undergoing P/D. Lower PD-L1 expression correlates with improved survival outcomes, positioning PD-L1 as a potential biomarker to inform therapeutic strategies in this population. Further studies are warranted to explore the implications of PD-L1 in treatment decisions.

Copyright © 2025 AME Publishing Company. All rights reserved.
Pleural mesothelioma patients and ex-exposed asbestos workers are immunologically poor responders to oncogenic Merkel cell polyomavirus. C. Mazziotta, C. Lanzillotti, C.F. Cervellera, et al. 2025;14(7):2611-2625. PubMed · Publisher · Free full text

Abstract

Background: Pleural mesothelioma (PM) is an aggressive tumor of the serous cavities primarily caused by the inhalation of asbestos, a carcinogenic and immunomodulatory mineral. Other factors, such as oncogenic viruses, might be involved in PM onset. Merkel cell polyomavirus (MCPyV) is a ubiquitous oncogenic DNA virus whose increased activity has been documented in conditions of immunosuppression. In this study, we aimed to investigate the immunological response to MCPyV in PM patients and workers ex-exposed to asbestos (WEA).

Methods: MCPyV serology was investigated herein in sera from 108 PM patients, 102 WEA, and 110 healthy subjects (HS). Total serum immunoglobulin G (IgG) levels were evaluated. The presence of MCPyV DNA and viral protein (VP)1 and large T (LT) messenger RNAs (mRNAs) was evaluated by droplet-digital polymerase chain reaction (ddPCR)/quantitative polymerase chain reaction (qPCR) in 50 tumor specimens from PM patients unrelated to PM serum donors.

Results: Reduced serum anti-MCPyV IgG rates and optical densities (ODs) were detected in PM (26.9% and 0.08-0.09) and WEA (27.5% and 0.08-0.09) compared to HS (60.9% and 0.16-0.33) (P<0.001), while the mean total IgG concentrations were similar among groups (4.3-5.7 mg/mL) (P>0.05). Biphasic PM histotype exhibited the lowest MCPyV IgG levels. WEAs with the highest asbestos exposure had the lowest rate and ODs of serum anti-MCPyV IgGs (5.6% and 0.074-0.083) in contrast to WEA (44.4% and 0.083-0.096) with lower exposure. Spearman analyses revealed an inverse correlation between ODs and both cumulative asbestos exposure and years of asbestos exposure (P<0.05), while a direct correlation was detected between years since last exposure and ODs (P=0.02). MCPyV DNA was detected in 32% of PM specimens with a mean viral DNA load of 0.39±0.2 copy/cell. VP1 mRNA was detected in all MCPyV DNA-positive PMs, while 69% of these specimens tested LT mRNA-positive.

Conclusions: Our study provides the first evidence that PM and WEA may experience a specific impairment of their immune response to MCPyV. This might possibly depend on the immunomodulatory effect of asbestos, a well-known immunosuppressive mineral.

Copyright © 2025 AME Publishing Company. All rights reserved.
Potential utility of miRNAs derived from pleural fluid extracellular vesicles to differentiate between benign and malignant pleural effusions. T.M. Chee, C.J. Zahra, K.M. Fong, et al. 2025;14(1):124-138. PubMed · Publisher · Free full text

Abstract

Background: Cytological examination is of suboptimal sensitivity but high specificity for the diagnosis of malignant pleural effusions (MPEs). Pleural fluid extracellular vesicles (PFEVs) are enriched with disease-specific microRNAs (miRNAs) which may improve the diagnostic yield for MPE. Our previous study demonstrated the feasibility of isolating miRNAs from PFEVs and profiling PFEV miRNAs by Nanostring nCounter® Human v3 miRNA expression assay. Here, we interrogated in a small cohort to evaluate the diagnostic potential of PFEV miRNAs to differentiate between benign pleural effusion and MPE.

Methods: Extracellular vesicles (EVs) from pleural fluids were isolated by two sequential ultracentrifugation steps. PFEVs were extracted and characterised by western blotting analysis, particle analysis by tunable resistive pulse sensing (TRPS) technology, and transmission electron microscopy (TEM). Total RNAs (including miRNAs) were extracted from PFEVs and profiled by the Nanostring nCounter® 827 probe miRNA expression assay. Differential expression analysis of the miRNA expression assays on PFEV samples was performed using the Bioconductor DESeq2 package.

Results: EVs from pleural fluids were evident by staining of positive EV-associated protein markers, particle size distribution within the expected parameters, and the cup-shaped morphology by TEM. Employing Nanostring nCounter® Human v3 miRNA expression assay, this proof-of-principle study demonstrated PFEV miRNAs were differentially expressed between benign effusions and malignant effusions [malignant pleural mesothelioma (MPM) or lung adenocarcinoma metastatic to pleura (metLUAD)]. The expression of six miRNAs (hsa-miR-1246, hsa-miR-136-5p, hsa-miR-141-3p, hsa-miR-145-5p, hsa-miR-200c-3p, and hsa-miR-9-5p) significantly differed between benign and malignant effusions, or between MPM and metLUAD, at adjusted P<0.05 and log2fold change ≥1.0.

Conclusions: The miRNAs identified from this study could be interrogated further for their utility as a single biomarker candidate or to be tested simultaneously in a panel to complement pleural effusion diagnostics. PFEV miRNAs represent a novel bioresource with potential to aid in the diagnosis of pleural effusions. Larger prospective studies are needed to confirm their diagnostic utility.

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Real-world outcomes of first-line immunotherapy and subsequent systemic therapies in pleural mesothelioma: a multicenter study in China. B. Tian, B. Sun, Z. Zhou, et al. 2025;14(12):5465-5478. PubMed · Publisher · Free full text

Abstract

Background: Pleural mesothelioma (PM) has a poor prognosis, and immune checkpoint inhibitors (ICIs) have reshaped first-line therapy. However, real-world data comparing first-line immunotherapy with chemotherapy ± targeted therapy and defining optimal second-line strategies in Chinese patients remain limited. This multicenter retrospective real-world study aimed to compare survival outcomes between first-line immunotherapy and chemotherapy-based regimens and to evaluate the effectiveness of different subsequent systemic therapies in patients with PM.

Methods: This multicenter retrospective real-world cohort included patients with pathologically confirmed PM who received at least one line of systemic therapy at tertiary hospitals in China between January 2015 and January 2025. Patients were grouped by first-line regimen (immunotherapy vs. chemotherapy ± targeted therapy). The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety. Generalized propensity scores with overlap weighting (OW) were used to balance baseline covariates, followed by weighted Kaplan-Meier and Cox regression analyses. For post-first-line analyses, chemo-start and immuno-start cohorts were used to compare OS across second-line chemotherapy, chemo-immunotherapy, and dual immunotherapy. Hazard ratio (HR), 95% confidence interval (CI), and Eastern Cooperative Oncology Group (ECOG) performance status (PS) were reported.

Results: Seventy-eight patients were included (chemotherapy ± targeted, n=50; immunotherapy, n=28; median follow-up, 35.7 months). After weighting, first-line immunotherapy improved OS vs. chemotherapy ± targeted therapy (weighted HR, 0.47; 95% CI: 0.23-0.95) and showed a trend toward longer PFS (weighted HR, 0.64; 95% CI: 0.34-1.17). OS benefit was greater in patients with ECOG PS 0-1 (HR, 0.44; 95% CI: 0.21-0.93), non-epithelioid histology (HR, 0.30; 95% CI: 0.10-0.97), or no prior radiotherapy (HR, 0.29; 95% CI: 0.12-0.68). In multivariate models, first-line immunotherapy (HR, 0.34; 95% CI: 0.13-0.90) and prior radiotherapy (HR, 0.35; 95% CI: 0.14-0.86) were independent protective factors for OS. ORR and DCR were similar between groups, and immune-related adverse events occurred in 14/28 (50.0%) immunotherapy patients, mostly grade 1-2, with no immune-related deaths. In the chemo-start cohort, second-line dual immunotherapy improved OS vs. chemo-immunotherapy (HR, 0.13; 95% CI: 0.03-0.62) but not vs. chemotherapy alone (HR, 0.43; 95% CI: 0.17-1.11), and chemo-immunotherapy did not differ from chemotherapy (HR, 2.08; 95% CI: 0.94-4.57). In the smaller immuno-start cohort, no significant OS differences were seen between second-line strategies (weighted Cox P=0.31).

Conclusions: In this multicenter real-world Chinese cohort, first-line immunotherapy was associated with a clinically meaningful OS improvement in PM, particularly among patients with good PS, non-epithelioid histology, or no prior radiotherapy. Dual immunotherapy may be a promising second-line option after chemotherapy, warranting confirmation in larger prospective studies.

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Differential expression of DMD transcripts as a novel prognostic biomarker in histologically diverse mesotheliomas. N. Alnassar, J.M.J. Derry, G.L. Banna, et al. 2024;13(4):733-748. PubMed · Publisher · Free full text

Abstract

Background: The identification of prognostic biomarkers is crucial for guiding treatment strategies in mesothelioma patients. The Duchenne muscular dystrophy (DMD) gene and its specific transcripts have been associated with patient survival in various tumours. In this study, we aimed to investigate the prognostic potential of DMD gene expression and its transcripts in mesothelioma patients.

Methods: We analysed The Cancer Genome Atlas (TCGA) mesothelioma RNAseq, mutation, and clinical data to assess the association between DMD gene expression and its transcripts (Dp427, Dp71 splice variants) and mesothelioma survival. We also evaluated the specific Dp71 transcript as a unique prognostic biomarker across mesothelioma subtypes. Additionally, we performed differential gene expression analysis between high and low DMD gene/transcript expression groups.

Results: The analysis included 57 epithelioid, 23 biphasic, two sarcomatoid, and five not otherwise specified (NOS) histological subtypes of mesothelioma samples. Univariate analysis revealed that high expression of the DMD gene and its Dp71 transcript was significantly associated with shorter survival in mesothelioma patients (P=0.003 and P<0.001, respectively). In a multivariate analysis, the association between Dp71 expression and survival remained significant [hazard ratio (HR) 2.29, 95% confidence interval (CI): 1.24-4.23, P=0.008] across all mesothelioma patients, and also among patients with mesotheliomas without deep CDKN2A deletions (HR 3.58, 95% CI: 1.31-9.80, P=0.01). Pathway analysis revealed enrichment of cell cycle (P=3.01×10-4) and homologous recombination (P=0.01) pathways in differentially expressed genes (DEGs) between high and low Dp71 groups. Furthermore, there were correlations between Dp71 transcript expression and tumour microenvironment (TME) cells, including a weak positive correlation with macrophages (R=0.32, P=0.002) specifically M2 macrophages (R=0.34, P=0.001).

Conclusions: Our findings indicate that the differential expression of specific DMD transcripts is associated with poor survival in mesothelioma patients. The specific Dp71 transcript can serve as a potential biomarker for predicting patient survival in diverse histological subtypes of mesothelioma. Further studies are needed to understand the role of specific dystrophin transcripts in cancer and TME cells, and their implications in the pathogenesis and progression of mesothelioma. Identifying patients at risk of poor survival based on DMD transcript expression can guide treatment strategies in mesothelioma, informing decisions regarding treatment intensity, follow-up schedules, eligibility for clinical trials, and ultimately, end-of-life care planning.

2024 Translational Lung Cancer Research. All rights reserved.
Double immune checkpoint inhibitor therapy for unresectable pleural mesothelioma rarely induces hyperprogressive disease: a case report. G. Naulleau, I. Monnet, G. Rousseau-Bussac, et al. 2024;13(9):2448-2452. Case report PubMed · Publisher · Free full text

Abstract

Background: Use of immune checkpoint inhibitors (ICIs) is associated with new response types, such as hyperprogressive disease (HPD), whose definition is still being discussed. Some authors use dynamic indexes to define HPD. However, since the Checkmate-743 study, ICIs have been a first-line therapy for pleural mesothelioma (PM), thereby making use of dynamic indexes less appropriate. The aim of this study is to describe two cases of HPD and then discuss its definitions and implications.

Case Description: Herein, we report two cases of PM HPD on first-line ICI therapy. A 67-year-old man with right unresectable epithelioid PM, without BAP1 or CDKN2A losses, high neutrophil/lymphocyte ratio and rapid-onset pulmonary and mediastinal HPD after two ICI cycles, died of respiratory failure 1 month after starting treatment. A 40-year-old woman with left unresectable epithelioid PM had HPD at first assessment after 4 ICI infusions with jugular thrombosis, liver metastases and more dismal biological parameters. There are multiple different ways to describe HPD, some not applicable to PM. Suspected mechanisms include macrophage reprogramming to M2 cells. There are no known predictive factors of HPD, and future works should focus on identifying them.

Conclusions: HPD is a mode of progression for ICI-treated PM patients. Further investigation is needed to better define and anticipate HPD in these patients.

2024 AME Publishing Company. All rights reserved.
Major pathological response obtained after neoadjuvant chemotherapy combined with dual immunotherapy for malignant pleural mesothelioma: a case report. Y. Zhang, G. Zhao, C. Xu, et al. 2024;13(6):1420-1425. Case report PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is a rare thoracic malignancy with high morbidity and mortality. A combination of systemic therapy and surgery may be a promising modality for the treatment of MPM, but evidence-based medicine is still lacking.

Case Description: Here we report a case of MPM. The patient presented to hospital with cough and sputum. After ineffective symptomatic treatment, computed tomography (CT) examination suggested a malignant tumor of pleural origin. Positron emission tomography/computed tomography (PET/CT) examination suggested no lymph node metastasis or distant metastasis. The pathologic diagnosis of MPM was confirmed after CT-guided puncture biopsy. Next, she underwent 3 courses of neoadjuvant chemotherapy combined with dual immunotherapy (carboplatin and pemetrexed combined with anti-CTLA4 and anti-PD-1), resulting in significant tumor shrinkage. After obtaining the patient's consent and completing a preoperative evaluation, we modified the extrapleural pneumonectomy (EPP) and pleurectomy/decortication (P/D) by performing a lower lobe resection and partial pleurectomy of the left lung. Intraoperative rapid frozen pathology suggested that the margins of the tumor were negative and complete resection was achieved. The postoperative pathology report showed 10% residual viable tumor, so the major pathological response (MPR) was achieved after treatment.

Conclusions: MPM might respond well to neoadjuvant chemotherapy and dual immunotherapy, improving the probability of complete surgical resection and attaining an encouraging pathologic response.

2024 Translational Lung Cancer Research. All rights reserved.
Prolonged survival and novel prognostic factors in women with pleural mesothelioma treated with extended pleurectomy decortication. M. Lapidot, E. Mazzola, R. Bueno. 2024;13(4):811-820. PubMed · Publisher · Free full text

Abstract

Background: Pleural mesothelioma (PM) is an uncommon and extremely aggressive malignancy associated with past exposure to asbestos. The low representation of women among PM patients is likely due to differences in occupational asbestos exposure. Due to the controversial role of female sex as a prognostic factor in PM, the study aims to evaluate the survival of females treated with lung-sparing surgery. We present a cohort of 114 consecutive female patients with PM who underwent intended extended pleurectomy decortication (ePD) over 11 years in a high-volume single institution.

Methods: All women from 2007-2017 who underwent intended ePD were enrolled in the study. Data on clinical, operative, and outcome were collected. Kaplan-Meier estimators and log-rank tests were employed to assess the overall survival, and Cox regression models were utilized to analyze prognostic factors.

Results: During the study period, 454 patients underwent thoracotomy with intended ePD in a single institution. There were 114 females (25%), and macroscopic complete resection (MCR) was achieved in 97 (85.1%). The median age was 65 years, histology was epithelioid in 81 (71.0%), biphasic in 31 (27.2%), and sarcomatoid in 2 (1.8%). The 30- and 90-day mortality were 3.5% and 6.1%, respectively. Median survival in females was 38 months, and 5-year survival was 28.2%. The median survival and 5-year survival rate for patients with epithelioid histology and MCR were 44.4 months and 36.4%, respectively. In a univariate analysis, several factors were found to be associated with patient overall survival including MCR [hazard ratio (HR): 0.3, P<0.001], early T status (HR: 1.6, P=0.03), adjuvant therapy (HR: 0.5, P=0.006), intraoperative heated chemotherapy (IOHC) (HR: 0.8, P=0.03), age (HR: 1.02, P=0.03) and epithelioid histology (HR: 0.5, P=0.009).

Conclusions: For women with epithelioid PM undergoing intended ePD within a multimodal setting, prolonged survival is anticipated.

2024 Translational Lung Cancer Research. All rights reserved.
Stem-like exhausted CD8 T cells in pleural effusions predict improved survival in non-small cell lung cancer (NSCLC) and mesothelioma. L. Ye, H. Ryu, D. Granadier, et al. 2024;13(9):2352-2372. PubMed · Publisher · Free full text

Abstract

Background: Anti-tumor CD8 T cells are important for immunity but can become 'exhausted' and hence ineffective. Tumor-infiltrating exhausted CD8+ T cells include less differentiated stem-like exhausted T (Texstem) cells and terminally exhausted T (Texterm) cells. Both subsets have been proposed as prognostic biomarkers in cancer patients. In this study, we retrospectively investigated their prognostic significance in patients with metastatic non-small cell lung cancer (NSCLC) and validated our findings in a mesothelioma cohort.

Methods: Pre-treatment malignant pleural effusions (PEs) from 43 NSCLC (41 non-squamous, 2 squamous) patients were analyzed by flow cytometry. The percentages of Texstem and Texterm CD8 T cells were correlated with overall survival (OS) after adjusting for clinicopathological variables. Findings were validated using a mesothelioma cohort (n=49). Mass cytometry was performed on 16 pre-treatment PE samples from 5 mesothelioma and 3 NSCLC patients for T-cell phenotyping. Single-cell multi-omics analysis was performed on 4 pre-treatment PE samples from 2 NSCLC patients and 2 mesothelioma patients for analysis of the transcriptomic profiles, surface markers and T cell receptor (TCR) repertoire.

Results: Higher frequency of Texstem was associated with significantly increased OS [median 9.9 vs. 3.4 months, hazard ratio (HR) 0.36, 95% CI: 0.16-0.79, P=0.01]. The frequency of Texterm was not associated with OS. These findings were validated in the mesothelioma cohort (high vs. low Texstem, median OS 32.1 vs. 19.8 months, HR 0.31, 95% CI: 0.10-0.96, P=0.04). Detailed single-cell sequencing and mass cytometry profiling revealed that exhausted T cells from NSCLC expressed greater stem-likeness and less inhibitory markers than those from mesothelioma and that Texstem cells also contained 'bystander' virus-specific T cells.

Conclusions: This study demonstrates that PE CD8 Texstem cell abundance is associated with better survival outcomes, and thus may be a useful prognostic biomarker.

2024 AME Publishing Company. All rights reserved.
Do we still need to debate the merits of pleurectomy/decortication vs. extrapleural pneumonectomy for malignant pleural mesothelioma?. A. Nakamura, K. Kuribayashi. 2023;12(2):193-196. Editorial · Comment PubMed · Publisher · Free full text
Does hyperthermic povidone-iodine lavage increase the apoptotic rate of residual cancer cell in patients with malignant pleural mesothelioma?-a prospective pilot study. A. Bille, H. Jhala, L. Ashrafian, et al. 2023;12(7):1384-1390. PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is an incurable, late presenting primary cancer, conferring a survival of 8-14 months. Different intrapleural treatments have been tested as part of a multimodality approach to treat a select group of patients with limited disease, increasing survival. Recently, povidone-iodine has been shown to induce apoptosis in microscopic tumour cells in vitro, with no reported complications. This is the first in vivo study assessing the apoptotic rate caused by intraoperative hyperthermic betadine lavage using routine immunohistochemistry combined with transmission electron microscopy (TEM).

Methods: We included surgically fit patients aged >18, undergoing minimally invasive video-assisted thoracoscopic surgery (VATS) pleural biopsy between December 2016 and February 2018, for confirmed or presumed pleural malignancy. Parietal pleural biopsies were obtained at 7.5, 15 and 30 minutes after hyperthermic betadine lavage, and compared to pre-lavage biopsy samples, for apoptotic changes. Viable tumour samples underwent histological, immunohistochemical and ultrastructural analysis as well as TEM for features of apoptosis.

Results: N=6. Median age was 76 years. Median overall survival was 26.7 months. There was no statistical impact on survival of side of disease (left vs. right). There was no significant difference in expressions of markers of apoptotic index pre and post betadine treatment upon immunohistochemical analysis. There was no discernible effect on morphological features of apoptosis seen with betadine treatment, on TEM analysis. No side effects were identified post betadine lavage.

Conclusions: Although hyperthermic betadine lavage is a safe antiseptic solution with no toxicity when performed intraoperatively, it confers no effect on apoptotic rate or necrosis. It is therefore unlikely that hyperthermic betadine lavage will have an impact on reducing the microscopic residual disease after pleurectomy decortication and enhancing survival.

2023 Translational Lung Cancer Research. All rights reserved.
Pleurectomy decortication is the preferred surgical procedure in pleural mesothelioma. M. Lapidot, R. Bueno. 2023;12(2):190-192. Editorial · Comment PubMed · Publisher · Free full text
Some like it hot: the potential role of hyperthermic intrathoracic chemotherapy in the multimodality treatment of pleural mesothelioma. K. Branch, P.S. Adusumilli, M.G. Zauderer. 2023;12(2):187-189. Editorial · Comment PubMed · Publisher · Free full text
Spare the lung: surgical treatment approach for malignant pleural mesothelioma. N. Fujimoto. 2023;12(2):197-199. Editorial · Comment PubMed · Publisher · Free full text
Surgical series in mesothelioma: navigating between biases. J. Raskin, P.E. Van Schil, J.P.V. Meerbeeck. 2023;12(2):184-186. Editorial · Comment PubMed · Publisher · Free full text
Malignant pleural mesothelioma nodules remodel their surroundings to vascularize and grow. I. Kovacs, E. Bugyik, K. Dezso, et al. 2022;11(6):991-1008. PubMed · Publisher · Free full text

Abstract

Background: The microanatomical steps of malignant pleural mesothelioma (MPM) vascularization and the resistance mechanisms to anti-angiogenic drugs in MPM are unclear.

Methods: We investigated the vascularization of intrapleurally implanted human P31 and SPC111 MPM cells. We also assessed MPM cell's motility, invasion and interaction with endothelial cells in vitro.

Results: P31 cells exhibited significantly higher two-dimensional (2D) motility and three-dimensional (3D) invasion than SPC111 cells in vitro. In co-cultures of MPM and endothelial cells, P31 spheroids permitted endothelial sprouting (ES) with minimal spatial distortion, whereas SPC111 spheroids repealed endothelial sprouts. Both MPM lines induced the early onset of submesothelial microvascular plexuses covering large pleural areas including regions distant from tumor colonies. The development of these microvascular networks occurred due to both intussusceptive angiogenesis (IA) and ES and was accelerated by vascular endothelial growth factor A (VEGF-A)-overexpression. Notably, SPC111 colonies showed different behavior to P31 cells. P31 nodules incorporated tumor-induced capillary plexuses from the earliest stages of tumor formation. P31 cells deposited a collagenous matrix of human origin which provided "space" for further intratumoral angiogenesis. In contrast, SPC111 colonies pushed the capillary plexuses away and thus remained avascular for weeks. The key event in SPC111 vascularization was the development of a desmoplastic matrix of mouse origin. Continuously invaded by SPC111 cells, this matrix transformed into intratumoral connective tissue trunks, providing a route for ES from the diaphragm.

Conclusions: Here, we report two distinct growth patterns of orthotopically implanted human MPM xenografts. In the invasive pattern, MPM cells invade and thus co-opt peritumoral capillary plexuses. In the pushing/desmoplastic pattern, MPM cells induce a desmoplastic response within the underlying tissue which allows the ingrowth of a nutritive vasculature from the pleura.

2022 Translational Lung Cancer Research. All rights reserved.
Multimodal therapy of epithelioid pleural mesothelioma: improved survival by changing the surgical treatment approach. L.V. Klotz, H. Hoffmann, R. Shah, et al. 2022;11(11):2230-2242. PubMed · Publisher · Free full text

Abstract

Background: The exact role and type of surgery for malignant pleural mesothelioma (MPM) remains controversial. This study aimed at analyzing a 20-year single center perioperative experience in MPM surgery at our high-volume thoracic surgery center and comparing the overall survival after trimodal extrapleural pneumonectomy (EPP) and extended pleurectomy and decortication combined with hyperthermic intrathoracic chemoperfusion (EPD/HITOC) and adjuvant chemotherapy with that after chemotherapy (CTx) alone.

Methods: Patients with epithelioid MPM treated with neoadjuvant chemotherapy, EPP and adjuvant radiotherapy within a trimodal concept or EPD/HITOC in combination with adjuvant chemotherapy between 2001 and 2018 were included in this retrospective analysis. Surgical cohorts were compared to patients treated with standard chemotherapy.

Results: Overall, 182 patients (69 EPP, 57 EPD/HITOC, 56 CTx) were analyzed. Due to occupational exposure to asbestos for most of the patients, 154 patients (84.6%) were male. The patients in the surgical cohorts were significantly younger than those in the CTx cohort. There was no significant difference between the proportion of patient age and side. The median overall survival of the EPD/HITOC cohort with 38.1 months was significantly longer than that of the EPP and CTx cohorts (24.0 and 15.8 months). Better survival was significantly associated with an ECOG 0 performance status, age below 70 years, and negative lymph node status. In the multivariate analysis, EPD/HITOC was significantly associated with improved overall survival. Perioperative morbidity was lower in the EPD/HITOC group than in the EPP cohort.

Conclusions: EPD/HITOC is feasible and safe for localized epithelioid pleural mesothelioma. Changing the surgical approach to a less radical lung-sparing technique may improve overall survival compared to trimodal EPP.

2022 Translational Lung Cancer Research. All rights reserved.
Picropodophyllin inhibits the growth of pemetrexed-resistant malignant pleural mesothelioma via microtubule inhibition and IGF-1R-, caspase-independent pathways. R. Sun, R. Tanino, X. Tong, et al. 2022;11(4):543-559. PubMed · Publisher · Free full text

Abstract

Background: Acquired pemetrexed resistance leads to treatment interruption in patients with malignant pleural mesothelioma (MPM). Insulin-like growth factor-I receptor (IGF-1R) inhibitor is a candidate for treating pemetrexed-naïve MPM. However, the efficacy of cytotoxic and targeted drugs in acquired-pemetrexed resistant MPM is unclear. We explored anticancer drugs, including the IGF-1R inhibitor picropodophyllin, against acquired pemetrexed-resistant MPMs.

Methods: Acquired pemetrexed-resistant human MPM cell lines, named as H2452/PEM and 211H/PEM after their parental lines H2452 and 211H, respectively, were established by exposure to pemetrexed in vitro. Picropodophyllin and siRNA for IGF-1R knockdown were used to evaluate the efficacy of IGF-1R inhibition. Immunofluorescence was used to evaluate microtubule localization. The efficacy of picropodophyllin was evaluated in 3-dimensional MPM models.

Results: The acquired pemetrexed-resistant MPM lines retained their resistance after the removal of culture treatment. IGF-1R levels in H2452/PEM cells were higher than those in H2452 cells but not in 211H/PEM cells compared to the respective parental line. Picropodophyllin induced sub-G1 arrest in H2452/PEM cells but induced G2/M phase arrest in 211H/PEM cells, leading to caspase-independent cell death in the two acquired pemetrexed-resistant MPM lines. Although picropodophyllin inhibited phosphorylation of IGF-1R, specific inhibition of IGF-1R by RNA interference did not reduce the viability of pemetrexed-resistant MPM lines. Additionally, picropodophyllin reduced the viability of both IGF-1R knockdown pemetrexed-resistant MPM cells. Picropodophyllin was cytotoxic in acquired-pemetrexed-resistant MPM lines because of inhibition of microtubule formation and induction of aberrant mitosis. Moreover, combination treatment with picropodophyllin and vinorelbine synergistically affected the pemetrexed-resistant MPM lines but not the parental lines. Furthermore, we observed a similar efficacy of picropodophyllin in 3-dimensional pemetrexed-resistant MPM models.

Conclusions: Picropodophyllin may offer novel therapeutic properties for treating acquired pemetrexed-resistant MPM. Targeting tubulin may be an important strategy in the treatment of MPM after the discontinuation of pemetrexed.

2022 Translational Lung Cancer Research. All rights reserved.
The epidemic of malignant mesothelioma in China: a prediction of incidence during 2016-2030. Y. Zhai, Z. Hui, W. Chen, et al. 2022;11(12):2403-2411. PubMed · Publisher · Free full text

Abstract

Background: Malignant mesothelioma is an invasive cancer with a poor prognosis. The crude incidence rate of malignant mesothelioma in China increased throughout 2000 to 2013, which attracted attention. In order to predict the incidence trend of malignant mesothelioma in China, a Bayesian age-period-cohort (APC) prediction model was constructed using publicly available data from the National Cancer Registration Network.

Methods: Based on the annual reports of the national cancer registration from 2005 to 2015, the incidence trend of malignant mesothelioma from 2016 to 2030 in China was forecast using the APC Modeling and Prediction package from the Institute of Biomedical Engineering, London.

Results: The crude incidence rates of malignant mesothelioma decreased from 2.2 per one million person-years in 2005 to 1.6 per one million person-years in 2015. The incidence rates remained stable over the 11-year time period after age standardization. Aging was found to have a dominant effect on the trends. The Bayesian APC model showed that the crude incidence rates would increase from 1.4 per one million person-years in 2016 to 1.9 per one million person-years in 2030, and the estimated number of new incident cases would increase to 2,775 in 2030. The age-standardized incidence rate (ASR) remained steady.

Conclusions: In the future decade, the incidence of malignant mesothelioma may increase, but the ASR will remain stable. Considering its high degree of malignancy, malignant mesothelioma still needs to be taken seriously.

2022 Translational Lung Cancer Research. All rights reserved.
Controversies in the role of radiotherapy in pleural mesothelioma. G.G. Hanna, T. John, D.L. Ball. 2021;10(4):2079-2087. Review PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma is an uncommon thoracic cancer with a relatively poor outcome, which has only seen modest improvements when compared to non-small cell lung cancer. The mainstays of treatment have been surgery and systemic therapy, with radiation reserved for palliation or as an adjunct. However, there is re-emergent interest in the use of radiotherapy in the treatment of mesothelioma, given recent technical advances in radiotherapy delivery which permit increased treatment accuracy. This overview article reviews the radiobiology of the mesothelioma and whether or not mesothelioma is an inherently radioresistant cancer and the potential impact that hypofractionation may have on different histological subtypes in mesothelioma. This overview also considers the role of radiation in palliation, as adjunct to surgical resection and as adjunct to pleural tract procedures. In particular we review the growing evidence that pleural tract or port site adjuvant radiotherapy provides no clinical benefit. This overview will also consider potential emerging therapeutic strategies such as pre-operative short course hypofractionated radiotherapy. The role of novel radiotherapy techniques such as stereotactic ablative radiotherapy, image guided radiotherapy, proton therapy and the potential role of radiotherapy as an immune stimulating agent in combination of immunotherapy, will also be discussed. Finally, given the many unanswered questions, this review discusses some of the emerging and ongoing clinical trials of radiotherapy in the treatment of mesothelioma.

2021 Translational Lung Cancer Research. All rights reserved.
Immunotherapy in malignant pleural mesothelioma: a review of literature data. J. Menis, G. Pasello, J. Remon. 2021;10(6):2988-3000. Review PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a rare, aggressive cancer of the pleural surface, associated with asbestos exposure, whose incidence is still growing in some areas of the world. MPM is still considered a rare and an orphan disease with an unchanged median overall survival (OS) ranging from 8 to 14 months and no treatment advances in the last 15 years both in local and advanced disease. In the recent years, chronic inflammation of the mesothelium together with local tumor suppression plays a major role in the malignant transformation. Also, significant heterogeneity in both tumor and the microenvironment is at the basis of MPM biology. Preclinical data have demonstrated the immunogenicity and the lack of an effective antitumor response by the immune system in MPM thus paving the way to the development of immune therapeutics in this disease. Still there is no clear evidence of any predictive biomarker so that, given the close interaction between the immune infiltrate and mesothelial cells, a number of trials are ongoing to investigate the role and prognostic value of the immune microenvironment. In this review we summarize the rationale for immune therapeutics development in MPM, as well as, the relevant literature and ongoing trials of immune checkpoint inhibitors (ICIs) and vaccines used as both first-line treatment and beyond.

2021 Translational Lung Cancer Research. All rights reserved.
Mitogen signal-associated pathways, energy metabolism regulation, and mediation of tumor immunogenicity play essential roles in the cellular response of malignant pleural mesotheliomas to platinum-based treatment: a retrospective study. A. Mathilakathu, S. Borchert, M. Wessolly, et al. 2021;10(7):3030-3042. PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is a rare malignant tumor associated with asbestos exposure, with infaust prognosis and overall survival below 20 months in treated patients. Platinum is still the backbone of the chemotherapy protocols, and the reasons for the rather poor efficacy of platinum compounds in MPM remain largely unknown. Therefore, we aimed to analyze differences in key signaling pathways and biological mechanisms in therapy-naïve samples and samples after chemotherapy in order to evaluate the effect of platinum-based chemotherapy.

Methods: The study cohort comprised 24 MPM tumor specimens, 12 from therapy-naïve and 12 from patients after platinum-based therapy. Tumor samples were screened using the NanoString nCounter platform for digital gene expression analysis with an appurtenant custom-designed panel comprising a total of 366 mRNAs covering the most important tumor signaling pathways. Significant pathway associations were identified by gene set enrichment analysis using the WEB-based GEne SeT AnaLysis Toolkit (WebGestalt).

Results: We have found reduced activity of TNF (normalized enrichment score: 2.03), IL-17 (normalized enrichment score: 1.93), MAPK (normalized enrichment score: 1.51), and relaxin signaling pathways (normalized enrichment score: 1.42) in the samples obtained after platinum-based therapy. In contrast, AMPK (normalized enrichment score: -1.58), mTOR (normalized enrichment score: -1.50), Wnt (normalized enrichment score: -1.38), and longevity regulating pathway (normalized enrichment score: -1.31) showed significantly elevated expression in the same samples.

Conclusions: We could identify deregulated signaling pathways due to a directed cellular response to platinum-induced cell stress. Our results are paving the ground for a better understanding of cellular responses and escape mechanisms, carrying a high potential for improved clinical management of patients with MPM.

2021 Translational Lung Cancer Research. All rights reserved.
Novel patterns of progression upon immunotherapy in other thoracic malignancies and uncommon populations. R. Ferrara, D. Signorelli, C. Proto, et al. 2021;10(6):2955-2969. Review PubMed · Publisher · Free full text

Abstract

In the immunotherapy era, considering the prolonged survival benefit and responses observed with immunecheckpoint inhibitors (ICI) in many cancer types, the identification of patients with rapid progression (PD) and deaths upon ICI has found some skepticism and resistance among the scientific community. Nevertheless, an acceleration of tumour during ICI, defined as hyperprogressive disease (HPD), has been recognized across different cancer types and evidence regarding rapid PDs and deaths are emerging in patients with malignant pleural mesothelioma (MPM), small cell lung cancer (SCLC) and thymic malignancies and in uncommon non-small cell lung cancer (NSCLC) populations. Of note, PD and early deaths (ED) rates upon single agent ICI were up to 60% and 30% in MPM and 70% and 38% in SCLC patients, respectively. Similarly, rapid PDs and deaths were observed in clinical trials and retrospective studies including patients with poor performance status (PS), HIV infection and rare NSCLC histologies. Atypical patterns of response, such as pseudoprogression (PsPD) may also occur in other thoracic malignancies (MPM) and in some uncommon populations (i.e., HIV patients), however probably at lower rate compared to HPD. The characterizations of HPD and PsPD mechanisms and the identification of common definition criteria are the next future challenges in this area of cancer research.

2021 Translational Lung Cancer Research. All rights reserved.
Pembrolizumab-induced myocarditis in a patient with malignant mesothelioma: plasma exchange as a successful emerging therapy-case report. S.R.I. Schiopu, L. Käsmann, U. Schönermarck, et al. 2021;10(2):1039-1046. Case report PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma is an aggressive cancer associated with prior exposure to asbestos and dismal prognosis. Immune checkpoint inhibitor therapy is currently approved by the Food and Drug Administration for pre-treated malignant pleural mesothelioma. We describe a 75-year-old patient with disseminated, progressive malignant mesothelioma receiving 2 cycles of pembrolizumab who presented with generalized muscle weakness, shortness of breath, double vision and ptosis. There was no previous history of cardiovascular disease. The clinical picture, supported by the detection of anti-titin autoantibodies suggested myasthenia gravis (MG). Also, cardiac biomarkers were elevated. Echocardiography showed new severely reduced ejection fraction. A 12-lead resting electrocardiogram (ECG) revealed ST segment elevation in the posterior leads with polymorphic ventricular extrasystoles. Because cardiac catheterization revealed no relevant coronary lesions, immune checkpoint inhibitor-associated myocarditis and MG were suspected. Management and Outcome: The patient was started on steroids. Within a few days of presentation respiratory failure set in and the patient was intubated. Recurrent arrhythmias followed, which were treated by repeated emergency electrical cardioversion. In order to relieve myasthenic symptoms, plasma exchange was initiated and 10 cycles were carried out. This consequently also led to an improvement of myocarditis. Upon discharge, the ejection fraction recovered. The patient recovered and was alive at 1-year follow-up, without relevant limitations to his quality of life. Discussion and Conclusion: The article further discusses the use of plasma exchange for immune checkpoint inhibitor-associated myocarditis based on a review of literature. We conclude that patients showing no improvement after steroid therapy for immune checkpoint inhibitor-related myocarditis should be evaluated for plasma exchange, which appears to be an effective treatment option.

2021 Translational Lung Cancer Research. All rights reserved.
Prognostic impact of PD-1 and PD-L1 expression in malignant pleural mesothelioma: an international multicenter study. L. Brcic, T. Klikovits, Z. Megyesfalvi, et al. 2021;10(4):1594-1607. PubMed · Publisher · Free full text

Abstract

Background: Programmed cell death 1/programmed death ligand 1 (PD-1/PD-L1) immune-checkpoint blockade is a promising new therapeutic strategy in cancer. However, expression patterns and prognostic significance of PD-L1 and PD-1 are still controversial in human malignant pleural mesothelioma (MPM).

Methods: Formalin-fixed paraffin-embedded (FFPE) tumor samples from 203 MPM patients receiving standard treatment without immunotherapy were collected from 5 European centers. PD-L1 and PD-1 expression of tumor cells (TCs) and tumor-infiltrating lymphocytes (TILs) were measured by immunohistochemistry and correlated with clinical parameters and long-term outcome.

Results: High (>10%) PD-L1 TC and PD-1 TILs expressions were found in 18 (8%) and 39 (24%) patients, respectively. PD-L1 was rarely expressed by TILs [≥1%, n=13 (8%); >10%, n=1]. No significant associations were found between the PD-L1 or PD-1 expression of TCs or TILs and clinicopathological parameters such as stage or histological subtype. Notably, patients with high (>10%) TC-specific PD-L1 expression exhibited significantly worse median overall survival (OS) (6.3 vs. 15.1 months of those with low TC PD-L1 expression; HR: 2.51, P<0.001). In multivariate cox regression analysis adjusted for clinical parameters, high TC PD-L1 expression (>10%) proved to be an independent negative prognostic factor for OS (HR: 2.486, P=0.005). There was no significant correlation between PD-L1 or PD-1 expression of TILs and OS.

Conclusions: In this multicenter cohort study, we demonstrate that high (>10%) PD-L1 expression of TCs independently predicts worse OS in MPM. Further studies are warranted to investigate the value of PD-L1/PD-1 expression as a marker for treatment response in MPM patients receiving immunotherapy.

2021 Translational Lung Cancer Research. All rights reserved.
Real-time autOmatically updated data warehOuse in healThcare (ROOT): an innovative and automated data collection system. H.A. Jung, O. Jeong, D.K. Chang, et al. 2021;10(10):3865-3874. PubMed · Publisher · Free full text

Abstract

Background: The American Society for Clinical Oncology recently launched the minimal common oncology data elements project to facilitate cancer data interoperability. However, clinical data are often unrecorded in an organized way, and converting them into a structured format can be time-consuming. Clinical Data Warehouse (CDW) is a database that consolidates data from different clinical sources. However, the clinical data extracted from this database include not only structured data but also natural language generated during clinical practice. Therefore, applying these data to a clinical study is challenging because they are unstructured, and unformatted to allow essential content to be found. This study determined how best to organize a huge amount of clinical data to evaluate the upper aerodigestive tract cancers' clinical features and outcomes, including cancer of the head and neck, esophagus, lung, thymus, and mesothelioma.

Methods: The Real-time autOmatically updated data warehOuse in healThcare (ROOT) uses six main regions to describe the journey of cancer patients. This study, developed an algorithm optimized for each disease category using natural language processing of unstructured data and data capture of structured data. Data from patients diagnosed at the Samsung Medical Center from 2008-2020 were used.

Results: Comprehensive clinical data for 67,617 patients across six tumor types: 28,954 with non-small-cell lung cancer, 2,540 with small-cell lung cancer, 30,035 with head and neck cancer, 4,950 with esophageal cancer, 966 with thymic cancer, and 172 with mesothelioma were collected. Additionally, the results of a longitudinal molecular study, including epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) tests, and next-generation sequencing (NGS), were included. Scattered information was integrated and automatically built up to match the cohort, allowing users to capture the most updated test results and treatment outcomes.

Conclusions: This landmark study documented the successful construction of a real-time updating system for medical big data, based on the CDW program.

2021 Translational Lung Cancer Research. All rights reserved.
Application of immunohistochemistry in diagnosis and management of malignant mesothelioma. D.B. Chapel, J.J. Schulte, A.N. Husain, et al. 2020;9(Suppl 1):S3-S27. Review PubMed · Publisher · Free full text

Abstract

Immunohistochemistry plays an indispensable role in accurate diagnosis of malignant mesothelioma, particularly in morphologically challenging cases and in biopsy and cytology specimens, where tumor architecture is difficult or impossible to evaluate. Application of a targeted panel of mesothelial- and epithelial-specific markers permits correct identification of tumor lineage in the vast majority of cases. An immunopanel including two mesothelial markers (calretinin, CK5/6, WT-1, or D2-40) and two epithelial markers (MOC-31 and claudin-4) offers good sensitivity and specificity, with adjustments as appropriate for the differential diagnosis. Once mesothelial lineage is established, malignancy-specific studies can help verify a diagnosis of malignant mesothelioma. BAP1 loss, CDKN2A homozygous deletion, and MTAP loss are highly specific markers of malignancy in a mesothelial lesion, and they attain acceptable diagnostic sensitivity when applied as a diagnostic panel. Novel markers of malignancy, such as 5-hmC loss and increased EZH2 expression, are promising, but have not yet achieved widespread clinical adoption. Some diagnostic markers also have prognostic significance, and PD-L1 immunohistochemistry may predict tumor response to immunotherapy. Application and interpretation of these immnuomarkers should always be guided by clinical history, radiographic findings, and above all histomorphology.

2020 Translational Lung Cancer Research. All rights reserved.
Chemotherapy options versus "novel" therapies: how should we treat patients with malignant pleural mesothelioma. M.J. Disselhorst, P. Baas. 2020;9(Suppl 1):S77-S85. Review PubMed · Publisher · Free full text

Abstract

Today there are several options for the treatment of patients with malignant pleural mesothelioma (MPM). The therapeutic arsenal has expanded from only chemotherapy with or without surgery in selected cases to a variety of new compounds that target the malignant cell or its micro-environment. Immunotherapy has been the latest achievement and now single arm and randomized studies are being presented. A renewed interest has occurred in the combination of surgery, chemotherapy and radiation therapy. In this review we present the available data on previous and running studies and try to give a recommendation how to select the best patient for the most optimal therapy.

2020 Translational Lung Cancer Research. All rights reserved.
Chromosomal rearrangements and their neoantigenic potential in mesothelioma. A.S. Mansfield, T. Peikert, G. Vasmatzis. 2020;9(Suppl 1):S92-S99. Review PubMed · Publisher · Free full text

Abstract

Chromosomal rearrangements are a defining molecular feature of mesothelioma that are not readily detected by standard DNA sequencing approaches but could be detected by whole genome sequencing methods such as mate-pair sequencing. These chromosomal rearrangements result in novel, unique gene junctions that can be expressed and potentially result in the presentation of several neoantigens. These predicted neoantigens can be presented by tumors on major histocompatibility complex (MHC) proteins and are correlated with clonal expansion of tumor infiltrating T cells. T cells responsive to these neoantigens have been identified in the circulation of a patient. The predictive values of next generation sequencing-based tumor mutation burden measurements may be significantly enhanced by the addition of techniques such as mate-pair sequencing that can detect chromosomal rearrangements. Furthermore, rearrangement associated neo-antigens may also represent valuable targets for future anti-tumor vaccine strategies. Finally, chromosomal rearrangements are now recognized as a mutation signature in cancer and these events are likely to be important in the oncogenesis and immune recognition of not only in mesothelioma but multiple malignancies including non-small cell lung cancer.

2020 Translational Lung Cancer Research. All rights reserved.
Clinical significance of histologic subtyping of malignant pleural mesothelioma. L. Brcic, I. Kern. 2020;9(3):924-933. Review PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma (MM) is uncommon, but very aggressive tumor arising from the mesothelial cells of pleura, pericardium, peritoneum, and tunica vaginalis. Despite multimodality treatments 5-year survival is only 5% after the diagnosis. Histology and TNM staging system are still the best prognostic factors. Furthermore, histologic subtype of MM determines the clinical management of the patients. According to the 2015 WHO classification, MM is divided into diffuse, localized and well differentiated papillary mesothelioma. Major histologic subtypes of diffuse MM, namely epithelioid, biphasic and sarcomatoid, have different prognosis. However, in the last decade it has become evident that more detailed subclassification and histologic/cytological characterization of MM have prognostic and perhaps predictive implications. In this review, major histologic subtypes and cytological features of MM are presented and their relation with prognosis and predictive biomarkers is discussed.

2020 Translational Lung Cancer Research. All rights reserved.
Comment on "EURACAN/IASLC proposals for updating the histologic classification of pleural mesothelioma: towards a more multidisciplinary approach". W.T. Vigneswaran, M. Kittaneh. 2020;9(6):2508-2510. Editorial · Comment PubMed · Publisher · Free full text
Comparison between closed pleural biopsy and medical thoracoscopy for the diagnosis of undiagnosed exudative pleural effusions: a systematic review and meta-analysis. Y. Wei, K. Shen, T. Lv, et al. 2020;9(3):446-458. PubMed · Publisher · Free full text

Abstract

Background: Exudative pleural effusion (EPE) is a common diagnostic challenge. The utility of medical thoracoscopy (MT) and closed pleural biopsy (CPB) to aid in the diagnosis of EPE has been reported in many published studies. Herein, we perform a systematic review and meta-analysis to compare the diagnostic yield and safety of CPB and MT in EPE.

Methods: Four databases were searched for studies reporting the diagnostic yield of CPB and MT for EPE. The quality of the included studies was evaluated according to the quality assessment of diagnostic accuracy studies (QUADAS) tool. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and complication risks were compared between the two groups.

Results: Ten studies dealing with CPB and twenty-three studies dealing with MT for the diagnosis of EPE were included in this meta-analysis. Pooled sensitivity, specificity, PLR, NLR and DOR of CPB group was 77%, 99%, 32.55, 0.22, 165.71, respectively, while pooled sensitivity, specificity, PLR, NLR and DOR of MT group was 93%, 100%, 10.82, 0.08, 162.81, respectively. The area under the summary receiver operating characteristic (SROC) curve of CPB and MT were both 0.97. The ability of CPB to diagnose non-malignant diseases was like MT (69% vs. 68%), while the ability was lower than that of MT to diagnose malignant diseases (72% vs. 92%). The pooled diagnostic accuracy of CPB and MT for mesothelioma was 26% (95% CI, 14-38%) and 42% (95% CI, 22-62%) (P<0.001), respectively. The rate of complications with CBP was lower than that reported for MT.

Conclusions: CBP is a relatively accurate tool with a lower complication rate compared to MT in the diagnosis of EPE, especially in diagnosing non-malignant diseases. We confirm the utility of MT in the diagnostic workup of malignancy (especially mesothelioma); however, in selected cases, CPB could be used as the first diagnostic approach with a favorable safety profile.

2020 Translational Lung Cancer Research. All rights reserved.
Does size matter? -a population-based analysis of malignant pleural mesothelioma. J. He, S. Xu, H. Pan, et al. 2020;9(4):1041-1052. PubMed · Publisher · Free full text

Abstract

Background: The 8th edition staging system for malignant pleural mesothelioma (MPM) has been proposed. The size of tumor is not taken into consideration. We intend to elucidate the prognostic value of the size of MPM and evaluate the current staging system via the data of SEER database.

Methods: All cases of primary MPM were identified and extracted from the SEER database during the period of 2004-2016. The endpoints were overall survival (OS) and cancer-specific survival (CSS) which were analyzed using Kaplan-Meier method. Log-rank test and Cox regression were utilized to identify the prognostic factors.

Results: A total of 2,138 patients were included in the primary cohort. The 1-, 3- and 5-year survival rates of MPM were 39.4%, 11.8% and 3.8%. Older, male and advanced stage patients accounted for larger proportion of the cohort. Besides tumor extension, lymph node involvement and metastatic status, tumor size, pathological type and differentiation grade were significant prognostic factors. In the stratified analysis of tumor extension, size is a significant prognostic factor in T2 patients and indicates inferior survival outcomes. Surgery, chemotherapy and radiation can increase both OS and CSS in MPM patients. Triple combination treatments showed a superiority to other treatments.

Conclusions: Tumor size matters in the prognosis of MPM especially in the early stage of MPM patients. The adjusted TNM staging system incorporating tumor size has better accuracy than the 8th edition IMIG system. However, some stages had not been fully identified. More cases of early stages are warranted for essential revision.

2020 Translational Lung Cancer Research. All rights reserved.
Epidemiology of mesothelioma in the 21st century in Europe and the United States, 40 years after restricted/banned asbestos use. N. Alpert, M. van Gerwen, E. Taioli. 2020;9(Suppl 1):S28-S38. Review PubMed · Publisher · Free full text

Abstract

Research has established a strong association between asbestos exposure and malignant mesothelioma, a deadly form of cancer. Since the early 1980's many countries have restricted or banned the production of asbestos, leading to a decline of occupational asbestos exposure in many industrialized countries. However, some countries continue to use asbestos, and worldwide rates of mesothelioma are still increasing. Because of the long latency between exposure and mesothelioma occurrence and the persistence of environmental exposure, incidence rates (IR) may decrease very slowly for several years ahead. In this review, we examine estimates of asbestos consumption before widespread asbestos regulations and the trends in incidence and mortality rates, as well as changes over time for the United States and Europe. In some countries with earlier asbestos restrictions, mesothelioma incidence has been in a modest decline over time. However, asbestos exposure is still a burden worldwide and legislative action is needed to obtain a full ban. The pattern of mesothelioma is shifting from a mostly male disease to a disease that affects females as well in substantial numbers. Studies on unknown sources of asbestos exposure, of other sources of natural exposure to asbestos and asbestos-like fibers, as well as of individual genetic susceptibility to asbestos fibers are needed.

2020 Translational Lung Cancer Research. All rights reserved.
How asbestos and other fibers cause mesothelioma. G. Gaudino, J. Xue, H. Yang. 2020;9(Suppl 1):S39-S46. Review PubMed · Publisher · Free full text

Abstract

Mesothelioma has long been associated with the exposure to asbestos, which was largely used in manufacturing activities. Toxicology studies in vitro and in vivo demonstrated that asbestos fibers were carcinogenic, and epidemiology studies revealed that asbestos exposure was paralleled by the increase in the incidence of mesothelioma and related mortality rates. More recently, the role of chronic inflammation and the molecular mechanisms involved in carcinogenesis by mineral fibers were elucidated following the discovery of the roles of HMGB1 and inflammasome. A change of paradigm was the discovery of a prevalence of mesotheliomas attributable to inherited mutations of cancer susceptibility genes. The discovery of BAP1 as a predisposition gene for the development of familial mesothelioma and other cancers implemented genome studies in patients with mesothelioma and routine clinical surveys in individuals at risk to identify germline mutations associated with cancers included in the BAP1 syndrome. A further progress in the approach to asbestos-related malignancy was the adoption of combined genetics and environmental analyses according to the model of gene-environment (GxE) interactions. This review aims at updating on the most recently discovered mechanisms of tumorigenesis and the pivotal role of GxE interactions.

2020 Translational Lung Cancer Research. All rights reserved.
Immunotherapy for mesothelioma: a critical review of current clinical trials and future perspectives. S.G. Gray, L. Mutti. 2020;9(Suppl 1):S100-S119. Review PubMed · Publisher · Free full text

Abstract

At the clinical level the role of immunotherapy in cancer is currently at a pivotal point. Therapies such as checkpoint inhibitors are being approved at many levels in cancers such as non-small cell lung cancer (NSCLC). Mesothelioma is a rare orphan disease associated with prior exposure to asbestos, with a dismal prognosis. Various clinical trials for checkpoint inhibitors have been conducted in this rare disease, and suggest that such therapies may play a role as a treatment option for a proportion of patients with this cancer. Most recently approved as a salvage therapy in mesothelioma was granted in Japan, regulatory approval for their use in the clinic elsewhere lags. In this article we review the current pertinent clinical trials of immunotherapies in malignant mesothelioma, discuss the current issues that may affect the clinical outcomes of such therapies and further evaluate potential candidate new avenues that may become future targets for immunotherapy in this cancer.

2020 Translational Lung Cancer Research. All rights reserved.
Integrative approach to cytologic and molecular diagnosis of malignant pleural mesothelioma. A. Hjerpe, S. Abd Own, K. Dobra. 2020;9(3):934-943. Review PubMed · Publisher · Free full text

Abstract

The global incidence of malignant mesothelioma (MM) causes considerable disease burden, suffering and health care costs. Beside preventive measures and ban the use of asbestos, early diagnosis would largely improve the chance of curative treatment. Current histologic criteria, however, requiring presence of invasion in the surrounding fatty tissue fail to identify MM in sufficiently early stage. Unilateral accumulation of pleural effusion is one of the earliest clinical manifestations of MM that occurs in approximately 90% of the patients. Therapeutic thoracocenthesis is necessary to remove the fluid and to relieve patients' symptoms. This effusion is easily accessible and offers early and minimally invasive diagnosis by combining cytology with immunologic, molecular- and biomarker analyses. Typically, the fluid is rich in malignant cells and cell groups, but incipient stages of the disease may be difficult to recognize as the malignant cells can be masked by presence of inflammatory or reactive mesothelial cells. Recurrent, hemorrhagic and cell rich effusion should always be suspicious for MM and adequately prepared and analyzed to provide necessary information for subsequent therapy. Importantly, early detection of MM by integrating cytology and molecular approaches has high sensitivity and positive predictive value and has a major impact on patient survival. Thus, a conclusive positive MM cytology should lead to treatment without delay. This review summarizes molecular and diagnostic criteria of MM diagnosis.

2020 Translational Lung Cancer Research. All rights reserved.
Mesothelioma developing in carriers of inherited genetic mutations. Y. Yoshikawa, M. Emi, T. Nakano, et al. 2020;9(Suppl 1):S67-S76. Review PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma is associated with the exposure to asbestos fibers. Recent discovery of the BAP1 cancer syndrome, a Mendelian disorder with high-penetrance autosomal dominant inheritance fostered the genotyping for nucleotide-level or larger structural alteration of germline DNA. Inherited heterozygous mutations of the BAP1 gene increase the susceptibility to carcinogenic fibers, leading to a concept of gene x environment interaction (GxE) as a pathogenetic mechanism of mesothelioma. Several studies on cohorts of unselected patients with mesothelioma or on familial/early-onset cohorts of mesothelioma cases converged on BAP1 as the more frequent germline mutated gene, followed by other genes involved in DNA repair and homologous recombination. Evidence has been emerging that patients with mesothelioma carrying germline mutations of BAP1 and of other genes, such as those involved in DNA repair and tumor suppressor genes, have better prognosis and higher chemosensitivity when compared with patients with germline wildtype Bap1. We report here a germline genomic analysis targeted 22 genes in a cohort of 101 Japanese patients irrespective of asbestos exposure, age at diagnosis, or personal or family history of cancer. By comparing the results with the Human Genetic Variation Database (HGVD) and the Genome Aggregation Database (gnomAD) we selected rare germline variants with a Combined Annotation Dependent Depletion (CADD) >20. We show here that 31 of 101 subjects were carrying 25 rare variants in 14 genes, neither reported in the HGVD nor in the gnomAD database for 14/25 variants. Besides pathogenic variants of BAP1, rare missense variants were found in genes encoding lysine-specific histone methyltransferase SETD2 and SETDB1 and genes encoding subunits of the mSWI/SNF chromatin remodeling complex. The complete scenario of the genetic background consisting of pathogenic germline variants required for the predisposition and GxE for pathogenesis of mesothelioma appears complex, and further large-scale studies are warranted.

2020 Translational Lung Cancer Research. All rights reserved.
Nivolumab in pre-treated malignant pleural mesothelioma: real-world data from the Dutch expanded access program. L. Cantini, R.A. Belderbos, C.J. Gooijer, et al. 2020;9(4):1169-1179. PubMed · Publisher · Free full text

Abstract

Background: Randomized phase III trials are ongoing to investigate the efficacy of nivolumab in malignant pleural mesothelioma (MPM), but real-world data are still scarce. In this real-world study, we investigated the clinical outcomes of nivolumab treatment in pre-treated MPM patients.

Methods: Data from 107 nivolumab treated MPM patients within the Dutch expanded access program were retrospectively analyzed. Treatment was independent of programmed death ligand 1 (PD-L1) expression on tumor samples. Univariable and multivariable analyses were performed to evaluate the relationship between clinically important factors, baseline peripheral blood parameters and survival. The landmark method was used to compare the outcome of patients according to their radiological response.

Results: In the full cohort, the median progression-free survival (mPFS) was 2.3 months (95% CI: 1.6-2.9) and the median overall survival (mOS) was 6.7 months (95% CI: 6.2-10.0). After 12 weeks, the disease control rate (DCR) was 37% and the objective response rate (ORR) was 10%. PD-L1 status was determined in 33 patients (30%) and PD-L1 positivity (≥1%) was associated with an improved ORR (36% vs. 9%, P value 0.05), but not with PFS or OS. Low albumin was associated with worse OS (P value 0.002). Median OS was significantly longer for patients who had partial response to treatment (P value 0.0002).

Conclusions: In this real-world analysis, ORR and mOS were lower compared to those obtained in phase II trials. However, exceptional survival rates were observed in patients who had a radiological response. Although we cannot determine whether prognostic or predictive, PD-L1 expression and albumin were associated with greater response rate and may represent useful biomarkers for nivolumab treatment in MPM.

2020 Translational Lung Cancer Research. All rights reserved.
Nivolumab resulting in persistently elevated troponin levels despite clinical remission of myocarditis and myositis in a patient with malignant pleural mesothelioma: case report. G. Lie, A. Weickhardt, L. Kearney, et al. 2020;9(2):360-365. Case report PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) remains a deadly disease with limited therapeutic options beyond platinum/pemetrexed chemotherapy. Immune checkpoint inhibitors have demonstrated modest benefit in the second to later-line settings. An MPM patient from our institute developed myocarditis and myositis after 2 cycles of second-line nivolumab. Despite immunosuppression with corticosteroids and mycophenolate mofetil, there was ongoing rise in troponin levels which remained elevated for months. The patient developed an impressive but brief response following cessation of nivolumab. Myocarditis and myositis are rare complications of immune checkpoint inhibitors. Clinicians should be aware of these possible complications as myocarditis can result in mortality.

2020 Translational Lung Cancer Research. All rights reserved.
Peritoneal mesothelioma. A. Greenbaum, H.R. Alexander. 2020;9(Suppl 1):S120-S132. Review PubMed · Publisher · Free full text

Abstract

Malignant peritoneal mesothelioma (MPM) is a rare and lethal disease of the peritoneal lining, with high variability in biologic aggressiveness. Morbidity and mortality of the disease are related to progressive locoregional effects within the abdominal cavity, such as distention, pain, early satiety, and decreased oral intake that can ultimately lead to bowel obstruction and cachexia. The standard of care for patients with resectable disease remains cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC), with potential survival outcomes greater than 5 years in appropriately selected patients. Patients with inoperable MPM can be offered systemic treatment, although the disease is usually refractory to standard chemotherapic regimens. Patients with MPM should be treated at high volume centers with strong consideration for inclusion in tumor registries and clinical trials. In 2020, research will continue to explore promising genetic and immunologic targets and focus on refinement of surgical methods to optimize CRS-HIPEC approaches.

2020 Translational Lung Cancer Research. All rights reserved.
Preliminary study highlights the potential of immune checkpoint inhibitors in sarcomatoid mesothelioma. N.K. Brockwell, M. Alamgeer, B. Kumar, et al. 2020;9(3):639-645. PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is well known as an aggressive disease with poor survival. This has sparked trials of alternate immune-based therapies in MPM. While up to a quarter of MPM patients respond to immune checkpoint inhibitors (ICIs), predicting response remains challenging and PD-L1 expression alone has been deemed insufficient. Additionally, patients with sarcomatoid MPM are often excluded from trials utilizing ICIs due to their rapid progression. Here, we analyze the association of T lymphocytes with response to ICI-based immunotherapy to uncover predictive immune markers across subtypes.

Methods: Retrospective analysis of immunotherapy treated mesothelioma patient cohorts from two sites were pooled. Patient characteristics, including age, sex, subtype and previous treatment were captured. Multiplex immunohistochemistry was used to assess proportions of CD4, CD8, CD45RO and FOXP3 positive infiltrates in MPM and their association with progression free (PFS) and overall (OS) survival post immunotherapy.

Results: Samples derived from 22 patients were analyzed; 13 (59%) had epithelioid MPM, 6 (27%) sarcomatoid and 3 (14%) biphasic. The overall ICI response rate was 40%, with a median PFS (mPFS) and OS (mOS) of 3.8 and 11.17 months, respectively. Of the subtypes, sarcomatoid patients displayed the greatest median PFS and OS (>28 months) post ICI compared to the epithelioid subtype (3 and 11 months respectively), which correlated with higher proportions of infiltrating CD8+, CD45RO+ and CD8+CD45RO+ cells. Patients who received ICIs as first-line therapy had greater PFS than those who received it as second or third line post-chemotherapy.

Conclusions: High proportions of T lymphocytes and CD45RO+ cells were associated with prolonged mPFS and mOS in sarcomatoid patients treated with ICI immunotherapy. These data support the expansion of trials utilizing single and combination ICIs as first-line therapy in sarcomatoid MPM and warrants further studies testing the impact or detriment of chemotherapy pre-ICI.

2020 Translational Lung Cancer Research. All rights reserved.
Rethought histologic classification of pleural mesothelioma to better treat: go forward from looking back. P. Astoul. 2020;9(4):1613-1616. Editorial · Comment PubMed · Publisher · Free full text
SMO mutations confer poor prognosis in malignant pleural mesothelioma. D. Signorelli, C. Proto, L. Botta, et al. 2020;9(5):1940-1951. PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is an aggressive tumor but approximately 12% of patients survive more than 3 years. The biological differences underlying better outcomes are not known. Several targeted agents and immunotherapy have been ineffective. Hedgehog (Hh) is one emerging pathway. We compared the biological profiles of patients with different survival, investigating the most frequently altered genes, including the Hh pathway.

Methods: We analyzed 56 MPM. A 36-month overall survival (OS) cut-off divided patients into 32 normo (NS) and 24 long (LS) survivors. We used next generation sequencing to test 21 genes, immunohistochemistry to evaluate SMO expression. Mutation differences between NS and LS and their associations with clinical features were analysed by Fisher's test, OS with the Kaplan-Meier method and its association with mutations by univariate and multivariate Cox proportional hazard models.

Results: Clinical features were similar in both groups. Eighteen out of 56 patients (32%) were wild-type for the genes analysed. At least five had mutations in BAP1, NF2, TP53, SMO and PTCH1 with no significant differences between the groups except for SMO. SMO, a member of the Hh pathway, was mutated only in NS (15.6%) and only SMO mutations were significantly associated with poor prognosis at univariate (HR =4.36, 95% CI: 2.32-8.18, P<0.0001) and multivariate (HR =9.2, 95% CI: 3.0-28.4, P=0.0001) analysis. All SMO mutated patients expressed high protein levels.

Conclusions: SMO mutations were clearly associated with worse prognosis. SMO may be a therapeutic target but this needs to be confirmed in a prospective trial.

2020 Translational Lung Cancer Research. All rights reserved.
Surgery for pleural mesothelioma, when it is indicated and why: arguments against surgery for malignant pleural mesothelioma. G.A. Woodard, D.M. Jablons. 2020;9(Suppl 1):S86-S91. Review PubMed · Publisher · Free full text

Abstract

Extrapleural pneumonectomy (EPP) and pleurectomy decortication (PD) are radical operations for malignant pleural mesothelioma (MPM) that remain controversial among thoracic surgeons. There is a lack of randomized evidence to support a survival benefit when major surgical resection is included in multi-modality treatment regimens. Current data from retrospective single institution reviews and prospective trials such as the Surgery for Mesothelioma After Radiation Therapy (SMART) trial are limited by biased patient selection to include only the healthiest patients with most limited disease burden. This patient population predictably has relatively longer survival times than patients with inoperable advanced disease. The only randomized trial to date that has objectively evaluated the true benefit of surgical resection was the Mesothelioma and Radical Surgery (MARS) trial which actually showed shorter survival times among patients who underwent EPP compared with those treated medically. Critics of the MARS trial cite a high perioperative mortality rate for driving these results, however a similar trial has never been repeated to refute the MARS trial results. Finally, it is relevant to consider the high mortality and morbidity rates associated with major operations when recommending these interventions to MPM patients. There is a growing body of literature that identifies patients who clearly obtain no benefit from surgery including those with sarcomatoid or biphasic histology, nodal disease, elevated CRP, elevated platelets and advanced age. Surgery in MPM has risks and is of questionable benefit with outcomes data biased by patient selection of those who will have longer overall survival times regardless of treatment.

2020 Translational Lung Cancer Research. All rights reserved.
SV40 and human mesothelioma. M. Carbone, A. Gazdar, J.S. Butel. 2020;9(Suppl 1):S47-S59. Review PubMed · Publisher · Free full text

Abstract

Simian virus 40 (SV40) is a DNA tumor virus capable of infecting and transforming human mesothelial (HM) cells in vitro. Hamsters injected intracardially to expose most tissue types to SV40 preferentially develop mesotheliomas. In humans, asbestos is the main cause of mesothelioma, and asbestos and SV40 are co-carcinogens in transforming HM cells in tissue culture and in causing mesothelioma in hamsters. Laser microdissection experiments conducted in the laboratory of Adi Gazdar demonstrated that SV40 was present specifically in the malignant mesothelioma cells and not in nearby stromal cells. Further experiments demonstrated that SV40 remains episomal in HM cells and astrocytes because of the production of a long antisense RNA that represses viral capsid protein production. Thus, the potent SV40 oncoprotein, T-antigen (Tag), is expressed, but because the capsid proteins are not produced, the cells are not lysed and, instead, become transformed. Together this evidence suggests that SV40 may contribute to the development of mesotheliomas in humans. However, epidemiological evidence to support this hypothesis is lacking. This chapter also summarizes the introduction of SV40, a monkey virus, into the human population as an unrecognized contaminant of early poliovaccines. In addition to mesotheliomas, SV40 now is linked with brain cancers, osteosarcomas, and lymphomas in humans. Explanations are provided for the apparent geographic variations in SV40 prevalence and for controversies about the role of SV40 in human cancer.

2020 Translational Lung Cancer Research. All rights reserved.
This special volume of mesothelioma is dedicated to my friend Adi Gazdar. M. Carbone. 2020;9(Suppl 1):S1-S2. Editorial PubMed · Publisher · Free full text
Update on the pathologic diagnosis of malignant mesothelioma. J.J. Schulte, A.N. Husain. 2020;9(3):917-923. Review PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma is an uncommon tumor that may be difficult to diagnose. The International Mesothelioma Interest Group has been writing guidelines for pathological diagnosis that are periodically updated. The guidelines are being updated based on published literature in the last 3 years, and experience of more than 20 leading international pathologists in the field who will be co-authors. Updates were discussed by attendees of the Pulmonary Pathology Society Biennial Meeting (Dubrovnik, Croatia, June 2019). Areas with significant advancements/changes include utilization of immunohistochemistry (establishing mesothelial lineage and benign versus malignant), prognosis and nuclear grading, biphasic malignant mesothelioma, transitional pattern, malignant mesothelioma in situ, and therapeutic/molecular targets.

2020 Translational Lung Cancer Research. All rights reserved.

2010s

Breath analysis as a diagnostic and screening tool for malignant pleural mesothelioma: a systematic review. L. Brusselmans, L. Arnouts, C. Millevert, et al. 2018;7(5):520-536. Review PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a tumour related to a historical exposure to asbestos fibres. Currently, the definite diagnosis is made only by the histological examination of a biopsy obtained through an invasive thoracoscopy. However, diagnosis is made too late for curative treatment because of non-specific symptoms mainly appearing at advanced stage disease. Hence, due to its biologic aggressiveness and the late diagnosis, survival rate is low and the patients' outcome poor. In addition, radiological imaging, like computed tomographic scans, and blood biomarkers are found not to be sensitive enough to be used as an early diagnostic tool. Detection in an early stage is assumed to improve the patients' outcome but is hampered due to non-specific and late symptomology. Hence, there is a need for a new screening and diagnostic test which could improve the patients' outcome. Despite extensive research has focused on blood biomarkers, not a single has been shown clinically useful, and therefore research recently shifted to "breathomics" techniques to recognize specific volatile organic compounds (VOCs) in the breath of the patient as potential non-invasive biomarkers for disease. In this review, we summarize the acquired knowledge about using breath analysis for diagnosing and monitoring MPM and asbestos-related disorders (ARD). Gas chromatography-mass spectrometry (GC-MS), the gold standard of breath analysis, appears to be the method with the highest accuracy (97%) to differentiate MPM patients from at risk asbestos-exposed subjects. There have already been found some interesting biomarkers that are significantly elevated in asbestosis (NO, 8-isoprostane, leukotriene B4, α-Pinene…) and MPM (cyclohexane) patients. Regrettably, the different techniques and the plethora of studies suffer some limitations. Most studies are pilot studies with the inclusion of a limited number of patients. Nevertheless, given the promising results and easy sampling methods, we can conclude that breath analysis may become a useful tool in the future to screen for MPM, but further research is warranted.
Hotspots of malignant pleural mesothelioma in Western Europe. V. Nuyts, T. Nawrot, B. Nemery, et al. 2018;7(5):516-519. Review PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma, a highly invasive tumour, has been epidemiologically linked to an occupational or environmental exposure to asbestos. Although asbestos has been widely used in diverse industrial applications and in construction, some industrial sectors have been affected much more than others. The objective of this review was to describe the existence of clusters of malignant pleural mesothelioma in Western European countries, based on epidemiological studies published between 2000 and 2015. MEDLINE (PubMed) and Embase were searched for relevant studies on spatial clustering of mesothelioma in Western European countries. Eventually, 16 different studies published between 2000 and 2015 were selected for a comprehensive analysis. Relevant studies on spatial clustering of mesothelioma were found for Belgium, the Netherlands, the United Kingdom, Germany, France, Spain, Italy and Denmark. Clustering of pleural mesothelioma was found mainly around shipyards (16 studies) and asbestos cement industries (10 studies). Although malignant pleural mesothelioma may be found throughout Western Europe, the present study indicates specific areas with higher past and also probable future incidence.
Malignant peritoneal mesothelioma: a review. G. Broeckx, P. Pauwels. 2018;7(5):537-542. Review PubMed · Publisher · Free full text

Abstract

Malignant peritoneal mesothelioma (MPM) is a very rare malignancy of the peritoneum and has a poor prognosis. Of all mesotheliomas, pleural mesothelioma is more common than MPM. In comparison to pleural mesothelioma, the link with asbestos exposure is weaker (33-50% vs. >80%), but it is still the best-defined risk factor. MPM spreads predominantly expansive rather than infiltrative and symptoms are related to tumor spread within the abdominal cavity. Often, MPM is encountered incidentally by diagnostic imaging or by surgery. Computed tomography scan is widely accepted as a first line modality in diagnostic imaging. In diagnostic histopathology, MPM presents some challenges. Firstly, adequate clinical information is of utmost importance to consider the possibility of the diagnosis of MPM. Furthermore, a few morphological subtypes and variants exist. The most sensitive immunohistochemical markers are calretinin (100%), WT1 (94%) and CK5/6 (89%). The malignant character of immunohistochemically demonstrated mesothelial cells is not always obvious. This paradigm somewhat changed with the advent of immunohistochemical demonstration of BAP1 (BRCA-1 associated protein 1). Loss of BAP1 expression supports a diagnosis of malignancy. The gold standard in treatment remains cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC). Targetable molecular pathways in MPM are being identified. An exciting finding was the demonstration of ALK rearrangements in a small subset of patients with MPM and it is hoped for that at least this small subgroup of patients could benefit from treatment with ALK inhibitors. First-generation tyrosine kinase inhibitors against epidermal growth factor receptor (EGFR) did not show any significant activity in MPM. In contrast, nintedanib, an angiokinase inhibitor, improved progression-free survival and bevacizumab, a humanized anti-VEGF antibody increased overall survival in patients with MPM, when administered in combination with cisplatin and pemetrexed. Ongoing immunotherapy trials will offer a possible new treatment.
Response to "An innovative mesothelioma treatment based on mir-16 mimic loaded EGFR targeted minicells (TargomiRs)". N. van Zandwijk, J. McDiarmid, H. Brahmbhatt, et al. 2018;7(Suppl 1):S60-S61. PubMed · Publisher · Free full text

Summary

In this letter, the authors replied to comments by Drs. Viteri and Rosell on their first-in-man, phase 1, open-label, dose-escalation study of microRNA-loaded minicells (TargomiRs) in patients with recurrent malignant pleural mesothelioma, published in Lancet Oncology in October 2017. The commentators had raised two questions: the precise mechanism of action of the treatment, and how it fits among current treatments for mesothelioma. The authors said that a major difficulty was the rapid disappearance of TargomiRs from the circulation after infusion. In preclinical studies in mice and dogs, the minicells accumulated in xenograft tumours 2 hours after administration and were cleared from all sites within 24 hours. The microRNA mimics could not be detected in tumours with existing RT-qPCR platforms. Because biopsies were not planned in the trial, the authors could only theorize that disease control and tumour pain resulted from uptake of the minicells by tumours. They agreed that pre- and post-treatment biopsies will be key. They could not exclude immune reactions to the minicells' LPS-containing surface as an explanation for anti-tumour activity. However, they noted that no responses were seen with cytostatic-loaded minicells, and that inactive controls had no activity in preclinical models. They also accepted that the EGFR-targeting antibody might contribute. They concluded that combination therapy seemed a logical next step and called for carefully designed trials with attention to biomarkers.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.
Diagnostic and prognostic biomarkers for malignant mesothelioma: an update. Z. Chen, G. Gaudino, H.I. Pass, et al. 2017;6(3):259-269. Review PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma (MM) is an aggressive and lethal cancer, mostly related to inhalation of asbestos and erionite fibers. MM is associated with poor prognosis, because of its resistance to current therapies, even if higher survival occurs in patients diagnosed and treated when at stage I of the disease. However, these do not exceed 5% of the total number of cases, due to the inadequacy of the existing biomarkers for early and accurate diagnosis. Therefore, new effective biomarkers are needed for MM detection at earlier stages and to develop tailored therapies. Here we review the most promising biomarkers in MM to date: mesothelin, soluble mesothelin-related peptides (SMRPs), megakaryocyte potentiating factor (MPF), Osteopontin (OPN), Fibulin-3, high mobility group B1 (HMGB1), microRNAs (miRNAs), multiplex protein signatures. The validation of these biomarkers will allow their use, alone or in combination, for monitoring individuals from cohorts at risk of MM and attaining early detection of MM that is instrumental in improving patient survival.
In vitro experimental models of mesothelioma revisited. A. Singh, N. Pruett, C.D. Hoang. 2017;6(3):248-258. Review PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a biologically unusual, highly aggressive cancer that defies current multimodality treatments. Epidemiologic data suggest that this malignancy has not abated despite increasingly strict environmental regulations on asbestos, the putative causative agent for sporadic cases. An incomplete understanding of all the factors mechanistically driving mesothelioma is largely responsible for the current lack of curative treatments. Many approaches have been employed to ascertain the step-by-step molecular events involved in mesothelioma oncogenesis including in vitro, small animal in vivo, and human experimental models; though clearly defined, druggable mechanisms still are elusive. Importantly, the foundation of the latest accepted model of tumor initiation is derived from in vitro systems. A thorough review of in vitro mesothelioma oncogenesis models may suggest further opportunities for discovery.

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Translational Lung Cancer Research

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