Frontiers in Oncology

Our medical research library holds 149 studies published in Frontiers in Oncology (2011–2026). Each entry links to the study's record on PubMed and, where there is one, to the publisher's page and a free full text. 142 have an abstract, the authors' own summary as PubMed records it: open "Abstract" to read it.

About the journal

• Publisher: Frontiers Research Foundation]
• Published: 2011 to the present, Switzerland
• Language: English
• ISSN: 2234-943X (electronic)
• Its record in the NLM Catalog

2020s

• A case of well-differentiated papillary mesothelial tumor concomitant with primary gastric cancer: case report and literature review. G. Wang, P. Wang, C. Jiao. 2026;16:1796106. Case report PubMed · Publisher · Free full text

  Abstract

  Background: Well-differentiated papillary mesothelial tumor (WDPMT) is a rare neoplasm characterized by low malignant potential. Due to the absence of distinct clinical symptoms, WDPMT is frequently detected incidentally during surgical procedures.

  Case Description: This report describes a patient diagnosed with primary gastric cancer (GC) and concomitant WDPMT. The lesion was identified during laparoscopic radical gastrectomy and subsequently confirmed via histopathological and immunohistochemical analysis. No recurrence or disease progression was observed during a two-year postoperative follow-up period.

  Conclusion: WDPMT remains a relatively rare disease. In addition to histopathological evaluation, immunohistochemistry and, where available, molecular genetic analysis contribute to diagnostic accuracy. However, conclusive evidence from large-scale studies are currently lacking. The overall prognosis of WDPMT is favorable, with surgical excision representing the standard therapeutic approach.

  Copyright © 2026 Wang, Wang and Jiao.

• Analysis on the efficacy and safety of chemotherapy combined with or without bevacizumab after CRS+HIPEC in patients with malignant peritoneal mesothelioma: a single-center retrospective study. Z.R. Yang, X.L. Liang, X.B. Li, et al. 2026;16:1733967. PubMed · Publisher · Free full text

  Abstract

  Objective: To investigate the efficacy and safety of pemetrexed/platinum-based chemotherapy combined with or without bevacizumab after cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of patients with malignant peritoneal mesothelioma (MPM).

  Methods: A retrospective non-randomized study was performed on 205 MPM patients treated with CRS+HIPEC at our institution. A total of 97 eligible patients were analyzed: 58 patients who received postoperative chemotherapy combined with bevacizumab (C&B) and 39 patients who received chemotherapy alone (C) were divided into a study group and a control group, respectively. The patients were also divided into the bevacizumab-exposed subgroup and the bevacizumab-unexposed subgroup based on whether they had a history of bevacizumab infusion. Clinicopathological data and follow-up information were statistically analyzed. Independent prognostic factors were identified via survival analysis, and the safety of combination therapy was assessed via adverse event analysis.

  Results: As of the follow-up cutoff date of July 1, 2025, in both the subgroups with and without a history of bevacizumab infusion, there was no statistically significant difference between the control and study groups in baseline pathological characteristic parameters (p > 0.05). Survival analysis revealed that in the subgroup of patients with a history of bevacizumab infusion, the difference in median overall survival (mOS) between the control and study groups was statistically significant (31.9 months vs. NR; p = 0.031), and the difference in median disease-free survival (mDFS) between the control and study groups was statistically significant (12.5 months vs. NR; p = 0.001); in the subgroup of patients without a history of bevacizumab infusion, the difference in mOS between the control and study groups was also statistically significant (20.5 months vs. NR; p = 0.001), and the difference in mDFS between the control and study groups was statistically significant (13.2 vs. 36.2 months; p = 0.001). The Cox regression model found that postoperative C&B was an independent prognostic factor (p = 0.009, HR = 0.081, 95% CI: 0.012-0.526) in the subgroup with a history of bevacizumab infusion, and the Ki-67 index (p = 0.043, HR = 2.563, 95% CI: 1.029-6.386) and postoperative C&B were independent prognostic factors (p = 0.01, HR = 0.086, 95% CI: 0.032-0.232) in the subgroup with no bevacizumab treatment history. A total of 101 cases of grade 1~2 adverse events in the study group were revealed via adverse event analysis, with common events including nausea/vomiting, fatigue, leukopenia/neutropenia, thrombocytopenia, anemia, abnormal liver function, hypertension, and proteinuria. There were four cases with grade 3 adverse events, mainly leukopenia/neutropenia, hypertension, and proteinuria. In the control group, there were 84 cases of grade 1~2 adverse events, and three cases of grade 3 adverse events were observed.

  Conclusion: Our exploratory findings suggest that bevacizumab combined with pemetrexed/platinum-based chemotherapy may be a therapeutic option for MPM patients after CRS+HIPEC; however, a prospective, randomized controlled clinical study is needed to validate our findings.

  Copyright © 2026 Yang, Liang, Li, Zhang, Wu, Su, Li and An.

• Case Report: Immune checkpoint inhibitor-triggered anti-Ma2 paraneoplastic encephalitis in sarcomatoid pleural mesothelioma: a fatal case. I.N. Okten, T. Baydaş. 2026;16:1739494. Case report PubMed · Publisher · Free full text

  Abstract

  Background: Neurological immune-related adverse events (N-irAEs) represent rare but potentially fatal complications of immune checkpoint inhibitor (ICI) therapy. Among these, encephalitis associated with paraneoplatic neuronal antibodies poses a major diagnostic and therapeutic challenge, as it blurs the distinction between drug-induced toxicity and tumor-driven autoimmunity.

  Case Presentation: We report a 61-year-old male diagnosed with unresectable sarcomatoid pleural mesothelioma who was treated with first-line nivolumab plus ipilimumab. Following the third treatment cycle, the patient developed progressive hyperphagia, central sleep apnea, and autonomic dysfunction. Serum testing revealed strong positivity for anti-Ma2/Ta antibodies, while brain magnetic resonance imaging was unremarkable. Despite discontinuation of immunotherapy and treatment with high-dose corticosteroids and intravenous immunoglobulin, the patient experienced relentless neurological deterioration. Notably, follow-up positron emission tomography demonstrated complete metabolic tumor response. The patient ultimately died from progressive brainstem dysfunction.

  Discussion: Anti-Ma2-associated encephalitis is classically categorized as a paraneoplastic neurological syndrome mediated by cytotoxic T-cell responses against intracellular neuronal antigens. Recent evidence suggests that ICIs can unmask or accelerate latent paraneoplastic autoimmunity by amplifying pre-existing immune responses. In this context, our case is best interpreted as an ICI-triggered paraneoplastic neurological syndrome rather than a primary immune-related adverse event.

  Conclusion: This case highlights a fatal neurological complication occurring in parallel with complete oncologic remission, underscoring the paradox of effective cancer immunotherapy precipitating catastrophic immune-mediated neurotoxicity. Early recognition of prodromal neurological symptoms and heightened awareness of paraneoplastic syndromes in the ICI era are critical to improving patient outcomes.

  Copyright © 2026 Okten and Baydaş.

• Case Report: Iparomlimab and Tuvonralimab-based therapy for epithelioid malignant peritoneal mesothelioma: a three-case series. Z. Xu, L. Zhu, Y. Fang, et al. 2026;16:1914733. PubMed · Publisher · Free full text

  Abstract

  Background: Epithelioid malignant peritoneal mesothelioma (EMPM) is a rare and aggressive malignancy of serosal origin. Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy is generally reserved for carefully selected patients in whom adequate cytoreduction appears feasible, while evidence supporting systemic immunotherapy remains limited for patients with unresectable disease or those unable to tolerate intensive treatment. Iparomlimab and tuvonralimab (QL1706) is a fixed-ratio anti-PD-1/anti-CTLA-4 MabPair formulation that has shown preliminary antitumor activity in several advanced solid tumors, but clinical experience in EMPM remains scarce.

  Case Presentation: We retrospectively describe three patients with EMPM diagnosed through integrated clinicopathologic assessment who received QL1706 either as monotherapy or in combination with an antiangiogenic agent. Treatment response was assessed by the treating team on serial computed tomography (CT) using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as the evaluation framework.

  Results: Case 1 was a 53-year-old woman with a programmed death-ligand 1 (PD-L1) combined positive score (CPS) of 10. Diffuse peritoneal disease persisted after surgery and three sessions of postoperative catheter-based hyperthermic intraperitoneal chemotherapy. QL1706 plus bevacizumab subsequently produced stable disease with symptomatic improvement for approximately 7 months. Case 2 was an 89-year-old man with a PD-L1 CPS of 0 who was considered unsuitable for surgery or intensive chemotherapy. QL1706 plus dose-reduced lenvatinib achieved a partial response that remained ongoing for more than 10 months. Case 3 was a 70-year-old man with a PD-L1 CPS of 55 and pre-existing nephrotic syndrome. QL1706 monotherapy induced a rapid partial response, but treatment was discontinued because of worsening proteinuria and edema; the disease subsequently progressed, with a new intracranial lesion radiologically suspicious for metastasis.

  Conclusion: QL1706-based therapy achieved disease control in all three patients with EMPM who had limited conventional treatment options, including a durable response in an elderly patient with PD-L1-negative disease and rapid tumor regression with QL1706 monotherapy. The contrasting clinical courses suggest that overall benefit depends not only on tumor sensitivity but also on the accompanying treatment strategy and baseline organ function.

  Copyright © 2026 Xu, Zhu, Fang and Jiang.

• Case Report: Tislelizumab combined with bevacizumab in the treatment of primary malignant pericardial mesothelioma. Z. Liu, Y. Yan, C. Jiang. 2026;16:1848097. Case report PubMed · Publisher · Free full text

  Abstract

  Background: Primary malignant pericardial mesothelioma (PMPM) is an exceedingly rare and highly malignant tumor that originates in the serosal layer of the pericardium. Currently, there are no specific guidelines for diagnosis and treatment in China and international countries for this disease, so treatment experiences from previous clinical cases are very important in the management of this disease.

  Case Summary: A case involving grade IV bone marrow suppression following pemetrexed in combination with platinum-based chemotherapy has been documented. Subsequently, the patient underwent treatment with tislelizumab and bevacizumab (an immune checkpoint inhibitor combined with a vascular endothelial growth factor inhibitor). After 29.4 months of this treatment, the patient experienced significant relief from symptoms of chest tightness and breathlessness, while the primary tumor lesion remained stable. Imaging assessments indicated stable disease (SD). Throughout the treatment course, no severe adverse reactions resulting in mortality were observed, with only grade II bone marrow suppression and intermittent dry, scaly, and peeling skin on the feet reported. Symptoms improved following symptomatic and supportive interventions.

  Conclusion: This case report provides suggestive information for the application of tislelizumab combined with bevacizumab in the treatment of pericardial mesothelioma patients, especially those who are unable to tolerate the adverse effects associated with pemetrexed and platinum-based chemotherapy. The limitation is that only one patient is included, the number of cases is small, and there may be uniqueness of individual cases. Consequently, it remains uncertain whether this combination therapy is applicable to all patients with pericardial mesothelioma, nor can we ascertain whether other immune checkpoint inhibitor (ICIs) and vascular endothelial growth factor inhibitors (VEGF inhibitors) exhibit similar efficacy in this context.

  Copyright © 2026 Liu, Yan and Jiang.

• Experimental assessment of computationally nominated small molecules targeting the YAP-TEAD interface in Hippo pathway-altered mesothelioma cell models. G.J. Weiss, J.C. Loftus, D.W. Mallery, et al. 2026;16:1908974. PubMed · Publisher · Free full text

  Abstract

  Aberrant activation of the Hippo-YAP/TAZ-TEAD transcriptional axis is a recurrent feature of multiple solid tumors and contributes to tumor maintenance, lineage plasticity, and therapeutic resistance. Recent medicinal chemistry has shown that TEAD proteins are druggable, but the rate at which in silico screening nominates compounds that prove functionally active in cells remains poorly defined, and negative validation results are rarely reported. Here we describe an experimental assessment of a focused set of computationally nominated candidate compounds, selected from a structure-guided virtual screen of the YAP-TEAD interface across approximately 917,000 library compounds and three predicted binding sites. Candidates were evaluated using long-term (144 hour) CellTiter-Glo proliferation assays in three Hippo-altered malignant pleural mesothelioma cell lines (MSTO-211H, NCI-H2052, NCI-H226), with the validated TEAD inhibitor K-975 and cisplatin as positive controls, and an exploratory TEAD-responsive luciferase reporter in MCF7 cells. K-975 produced dose-dependent antiproliferative activity in MSTO-211H and NCI-H2052, with reduced sensitivity in NCI-H226, while cisplatin reduced viability in all lines. In contrast, the computationally nominated compounds, including AG-690/36549045, AN-655/40856217, and additional library members, did not produce measurable antiproliferative activity at the concentrations tested. In the exploratory reporter, apparent suppression of TEAD activity consistently co-occurred with loss of cell viability, a pattern consistent with cytotoxicity rather than selective transcriptional inhibition; no TEAD-active reference compound was co-tested within the reporter panel, and no direct YAP-TEAD biochemical or target-engagement assay was performed. These results describe a case in which computational nomination at the YAP-TEAD interface showed limited concordance with cell-based activity and provide a transparent account of negative findings to inform expectations for early-stage discovery targeting Hippo-dependent transcriptional programs.

  Copyright © 2026 Weiss, Loftus, Mallery and Tran.

• From biology to therapy: current standards and emerging strategies in pleural mesothelioma. J.H.L.T. van Genugten, C.J. de Gooijer, P. Baas. 2026;16:1778121. Review PubMed · Publisher · Free full text

  Abstract

  Pleural mesothelioma (PM) is an aggressive malignancy with limited therapeutic options and poor long-term prognosis. Platinum-based chemotherapy has been the standard-of-care for most patients for decades. While the decoding of the genomic alterations in PM has triggered renewed interest in mesothelioma biology and targeted therapies, these have yet to reach clinical practice. The recent introduction of dual immune checkpoint blockade (ICB) with nivolumab plus ipilimumab has marked the first major advance in PM treatment for decades, yet, many patients do not respond to these drugs and durable long-term responses remain rare. A range of alternative treatment modalities are currently under clinical investigation in PM, including antibody-drug conjugates, bi-specific antibodies, chimeric antigen receptor T-cells, cancer vaccines, and oncolytic viruses. Here we review recent progress in the understanding of PM biology and evaluate relevant phase I-III clinical trials aimed at improving treatment for this disease. We also highlight ongoing and future clinical trials with promising candidates for PM therapy.

  Copyright © 2026 van Genugten, de Gooijer and Baas.

• Glutathione peroxidase 2 expression in human tumors: a tissue microarray study on 18,555 tumors. V. Chirico, N. Jahn, S. Büyücek, et al. 2026;16:1809848. PubMed · Publisher · Free full text

  Abstract

  Background: Glutathione peroxidase 2 (GPX2) has a pivotal role in removing reactive oxygen species (ROS) from cells. Although the number of studies analyzing GPX2 in cancer is still limited, data suggesting a role of altered GPX2 expression in various cancer types are accumulatin.

  Methods: To better comprehend the role of GPX2 expression in cancer, GPX2 was analyzed by immunohistochemistry on tissue microarrays containing 18,555 samples from 148 different tumor types.

  Results: A total of 95 of 148 tumor categories showed GPX2 expression in at least one case, and 61 tumor categories contained at least one strongly positive case. GPX2 positivity was most seen in colorectal adenocarcinomas (97.9%) and adenomas (100%), non-invasive urothelial carcinomas (88.9-100%), pancreatico-biliary cancers (83.4-94.7%), Brenner tumors of the ovary (89.7%), gastro-esophageal adenocarcinomas (83.1-87.3%), and seminomas (85.6%). Clinically important cancer types with infrequent and often weak GPX2 staining included sarcomas, lymphomas, high-grade serous ovarian carcinomas, prostatic adenocarcinomas, melanomas, mesotheliomas, and renal cell carcinomas. Reduced GPX2 staining was linked to microsatellite instability (MSI, p<0.0001), advanced pT stage (p=0.0044), nodal metastasis (p=0.0093), V1 (p=0.0020) and L1 (p=0.0057) in colorectal adenocarcinoma, invasive growth (p<0.0001), high grade (p=0.0013), nodal metastasis (p=0.0005), V1 (p=0.0004) and L1 (p=0.0001) in urothelial carcinoma, high grade in pancreatic ductal adenocarcinoma (p=0.0233), and MSI in gastric adenocarcinoma (p=0.0325).

  Conclusion: It is concluded, that GPX2 expression is common in cancer and preferably occurs in tumor entities derived from normal cell types with high GPX2 expression. In these tumors, reduced GPX2 expression is often linked to features of aggressive disease.

  Copyright © 2026 Chirico, Jahn, Büyücek, Schraps, Lennartz, Möller, Bady, Hornsteiner, Plage, Hube-Magg, Kluth, Jacobsen, Viehweger, Dum, Hinsch, Fraune, Bernreuther, Lebok, Sauter, Clauditz, Krech, Marx, Simon, Burandt, Gorbokon, Minner and Steurer.

• Isolated primary pericardial sarcomatoid mesothelioma: a case report. P. Nezafati, R. Vilain, T. Singh. 2026;16:1817459. Case report PubMed · Publisher · Free full text

  Abstract

  Background: Primary pericardial mesothelioma is an exceedingly rare malignancy, often diagnosed late due to nonspecific clinical and radiologic findings. We report a case of isolated pericardial mesothelioma progressing from mesothelioma in situ to invasive sarcomatoid disease, presenting with recurrent effusions and constrictive pericarditis.

  Case Presentation: A 58-year-old male with a remote history of Hodgkin's lymphoma (previously treated with chemotherapy and mediastinal radiotherapy) presented with progressive dyspnoea, orthopnoea, and recurrent pericardial and left pleural effusions. Initial diagnostic video-assisted thoracoscopic surgery (VATS) with mini-thoracotomy revealed densely adherent pericardium, intra-pericardial clots, and 1.5L of blood-stained pleural fluid. Histology demonstrated a sparse population of surfcatypical mesothelial proliferation with methylthioadenosine phosphorylase (MTAP) loss and retained BRCA1-associated protein 1 (BAP1). There was no invasive growth and therefore, the appearance for concerning for mesothelioma in situ, at a minimum. Cytology of the pleural fluid was non-malignant. Due to progressive constrictive physiology, a total pericardiectomy via median sternotomy was performed with femoro-femoral cardiopulmonary bypass. Intraoperatively, the pericardium was excised in the standard fashion for total pericardiectomy, and cardiopulmonary bypass was required due to dense epicardial adhesions. Final histopathology confirmed sarcomatoid mesothelioma with high-grade spindle cell morphology, brisk mitotic activity, necrosis, and MTAP loss. Immunohistochemistry was positive for WT1, calretinin, CK5/6, and D2-40. The patient was referred for oncology follow-up and underwent PET-CT staging for systemic therapy planning.

  Conclusion: This case highlights the importance of early diagnostic suspicion in patients with prior mediastinal irradiation who present with recurrent pericardial effusions or evolving constrictive physiology. While pericardiectomy remains the standard of care for constriction regardless of etiology, the diagnosis of mesothelioma-particularly sarcomatoid subtype-warrants timely intervention. Early recognition of pre-invasive histological changes may offer a critical opportunity for curative resection before progression to aggressive disease.

  Copyright © 2026 Nezafati, Vilain and Singh.

• Localized peritoneal epithelioid clear cell subtype mesothelioma: a case report and literature review. B. Huang, H. Liu, H. Zhou. 2026;16:1790964. Case report PubMed · Publisher · Free full text

  Abstract

  Epithelioid mesothelioma with a clear cell morphology is rare and has only been described in a few case reports. The diagnosis of epithelioid clear cell mesothelioma is challenging and often requires extensive immunohistochemical staining. Here, we report a case of epithelioid mesothelioma, clear cell variant, occurring in the peritoneum of a 76-year-old male. Computed Tomography(CT)imaging revealed a localized irregular intra-abdominal mass measuring approximately 6.0×5.0cm. Combined with histomorphology and immunophenotype analysis, the patient was diagnosed with localized epithelioid clear cell mesothelioma. There was no recurrence or metastasis after 24 months of follow-up. This case enriches the clinical and molecular data of localized peritoneal epithelioid clear cell mesothelioma, and provides insights into its diagnosis, differential diagnosis, and treatment.

  Copyright © 2026 Huang, Liu and Zhou.

• Malignant mesothelioma of the tunica vaginalis testis initially misdiagnosed as a benign testicular hydrocele: a case report. C. Zhang, H. Su, L. Guo, et al. 2026;16:1902555. Case report PubMed · Publisher · Free full text

  Abstract

  Objective: To improve the clinical understanding, diagnostic accuracy, and therapeutic management of mesothelioma of the tunica vaginalis testis.

  Methods: We present a case of mesothelioma of the tunica vaginalis in a patient recently admitted to our institution. The clinical characteristics, histopathological features, and therapeutic modalities used are described. FAPI PET/CT was applied as an adjunctive diagnostic tool for preoperative surgical planning. A narrative review of the relevant literature was conducted to discuss current diagnostic approaches, treatment options, and prognostic outcomes.

  Results: Postoperative histopathological examination revealed an epithelioid mesothelioma of the left testis. The tumor infiltrated the visceral tunica vaginalis and extended outward into the subcutaneous fibrous connective tissue of the scrotum. The infiltration also extended through the parietal tunica vaginalis to the tunica albuginea and involved the smooth muscle of the spermatic cord and the pampiniform venous plexus, with formation of a tunica vaginalis cyst. The adjacent testicular parenchyma and epididymis were not involved, and the spermatic cord surgical margin was free of malignancy.

  Conclusion: Mesothelioma of the tunica vaginalis is a rare malignancy with distinctive histopathological features. Because its clinical presentation resembles that of hydrocele, it is readily misdiagnosed. This case underscores the need to maintain a high index of suspicion when evaluating patients who present with hydrocele. The absence of recurrence at the limited 2-month follow-up does not permit any conclusion regarding disease control, cure, or recurrence, and prolonged surveillance is required. The efficacy and necessity of postoperative adjuvant treatment-including chemotherapy, radiotherapy, and targeted therapy-warrant further validation in prospective studies.

  Copyright © 2026 Zhang, Su, Guo, Li, Wang, Chen and Wang.

• Multi-omics integration in malignant pleural mesothelioma: from molecular evolution and immune ecosystems to precision therapy. H. Li, K. Zhou, R. Xu, et al. 2026;16:1883870. Review PubMed · Publisher · Free full text

  Abstract

  Malignant pleural mesothelioma (MPM) exhibits substantial molecular and cell-state heterogeneity, together with marked spatial variation in its immune and stromal microenvironment. Histological classification and individual biomarkers alone cannot adequately explain its evolution or heterogeneous treatment responses. This review critically integrates genomic, epigenomic, transcriptomic, single-cell, and spatial omics evidence along a conceptual continuum encompassing tumor-intrinsic molecular evolution, microenvironmental ecosystem remodeling, candidate stratification, and precision therapy. Current evidence indicates that alterations involving BAP1, CDKN2A/MTAP, and the NF2/Hippo pathway impose evolutionary constraints and create candidate therapeutic vulnerabilities but are insufficient to determine functional phenotypes independently. Epithelioid, uncommitted, and sarcomatoid malignant cell states may coexist within the same genetic clone, while immune and stromal features display pronounced regional heterogeneity. Based on published human MPM cohorts, we further propose four provisional immune-ecosystem archetypes: T-cell-inflamed, B-cell/tertiary lymphoid structure-organized, myeloid-dominant, and immune-desert. Tumor-intrinsic molecular states and stromal-spatial features are treated as interpretive modifiers. This literature-derived framework is intended for hypothesis generation and has not been developed or validated as a clinical classifier. At present, the principal value of multi-omics lies in mechanistic discovery and the design of biomarker-enriched clinical trials. Future studies should employ standardized assays in multicenter cohorts, independent external validation, formal archetype-by-treatment interaction testing within randomized trials, and longitudinal sampling to determine the treatment-predictive value and clinical feasibility of this framework.

  Copyright © 2026 Li, Zhou, Xu, Wang, Song, Zhou, Ren, Wang, Liang, Chen, Poudel, Yu, Lin, Yin, Yang and Zhuang.

• Prognostic associations of PD-L1 expression and BAP1 loss in pleural mesothelioma: a retrospective single-center cohort from Colombia. R. Brugés, C. Carvajal, A. Luna-Meza, et al. 2026;16:1920798. PubMed · Publisher · Free full text

  Abstract

  Background: Evidence on the prognostic associations of programmed death-ligand 1 (PD-L1) and BRCA1-associated protein 1 (BAP1) in pleural mesothelioma (PM) remains inconsistent, and joint data from Latin American cohorts are limited. We evaluated these biomarkers in a Colombian cohort.

  Methods: This retrospective single-center cohort included adults with histologically confirmed PM treated at the Instituto Nacional de Cancerología, Bogotá, from January 2011 through December 2023. PD-L1 was quantified using tumor proportion score (TPS), with ≥1% as the primary threshold; BAP1 was classified as retained or lost by nuclear immunoreactivity. Overall survival (OS) was measured from pathologic diagnosis to death. Event-free survival (EFS) was measured from diagnosis to first documented progression or death; patients without an event were censored at last contact. Kaplan-Meier methods and separate multivariable Cox models were used.

  Results: Sixty-seven patients were included; 60/67 (89.6%) had locally advanced or metastatic disease. PD-L1 TPS ≥1% was present in 26/67 (38.8%), and BAP1 loss in 47/61 evaluable tumors (77.0%). All 67 patients died. Median OS was 9.20 months (95% CI, 6.11-14.13), and median EFS was 6.51 months (95% CI, 5.49-9.13). PD-L1 TPS ≥1% was not clearly associated with OS (adjusted HR, 1.03; 95% CI, 0.57-1.86) or EFS (adjusted HR, 1.11; 95% CI, 0.62-2.00). BAP1 loss also showed no clear adjusted association with OS (HR, 1.57; 95% CI, 0.78-3.16) or EFS (HR, 1.65; 95% CI, 0.82-3.33).

  Conclusions: Neither PD-L1 TPS ≥1% nor BAP1 loss showed a clear adjusted association with survival. These jointly measured estimates extend the evidence from an underrepresented Latin American population but require external validation; the exploratory ≥5% and ≥10% analyses were based on only 14 and 7 patients, respectively.

  Copyright © 2026 Brugés, Carvajal, Luna-Meza, Núñez, Navarrete and Parra-Medina.

• Proliferation of pleural mesothelioma cells is enhanced by the microRNA-197-3p activity. I. Bononi, G. Di Mauro, M.L. Tramarin, et al. 2026;16:1807528. PubMed · Publisher · Free full text

  Abstract

  Human Pleural Mesothelioma (HPM) is an aggressive asbestos-related tumor with limited treatment options and a poor prognosis. MicroRNAs (miRNAs), known to play key roles in the pathogenesis of HPM, have emerged as promising candidates for both diagnostic and therapeutic applications. Among them, miR-197-3p has been previously identified as dysregulated in sera from HPM patients and workers ex-exposed to asbestos fibers. To investigate the functional role of miR-197-3p, loss- and gain-of-function studies were performed in HPM cell lines and human mesothelial cells (HMC) using miR-197-3p-specific antagomiR and mimic. The effects of miR-197-3p modulation on cell proliferation, viability, migration, and apoptosis were evaluated. In addition, bioinformatics analyses were performed to identify potential miR-197-3p target genes, which were subsequently evaluated at both mRNA and protein levels. MiR-197-3p tested significantly upregulated in HPM cells. Its inhibition led to a marked reduction of the HPM cell proliferation, whereas its overexpression in HMC promoted a proliferative phenotype, supporting a potential role in cell growth regulation. Among the predicted targets, TGF-β1 and p120 showed modulation at the mRNA level, although protein-level changes were limited or only partially consistent. These findings suggest that miR-197-3p may contribute to HPM pathogenesis by promoting cell proliferation and influencing critical molecular pathways. However, the underlying molecular mechanisms remain to be fully elucidated, and the interaction with candidate targets, such as TGF-β1 and p120, should be considered putative. Further investigations, including functional and mechanistic validation in more representative experimental models, will be required to clarify the role of miR-197-3p in HPM pathobiology.

  Copyright © 2026 Bononi, Di Mauro, Tramarin, Esposito, Tonnini, Oton-Gonzalez, Dallan, Torreggiani, Martini and Tognon.

• Risk for second primary malignancies in patients with multiple myeloma: a systematic review and meta-analysis. Y. Tian, L. Su, Y. Li, et al. 2026;16:1770120. Systematic review PubMed · Publisher · Free full text

  Abstract

  Background: With improving survival in multiple myeloma (MM), second primary malignancies (SPMs) remain an important issue in long-term care. This study assessed the risk of SPMs among individuals with MM.

  Methods: We systematically searched EMBASE, PubMed, and the Cochrane Library for studies published up to August 15, 2025, and pooled standardized incidence ratios (SIRs) to compare SPM risks in MM patients with those in the general population.

  Results: Of 1602 records screened, 15 studies comprising 279,894 MM patients met the inclusion criteria. The overall risks of SPMs and solid tumors were not significantly higher than those in the general population. In contrast, the risk of hematologic SPMs was markedly increased (SIR = 2.91; 95% CI: 1.57-5.41). Higher risks were identified for several malignancies, including non-Hodgkin lymphoma (NHL), myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), mesothelioma, skin cancer, melanoma, endocrine tumors, and thyroid cancer. Reduced risks were observed for chronic lymphocytic leukemia (CLL), head and neck cancer, tracheal/bronchial/lung cancer, bladder cancer, and breast cancer. Subgroup analyses showed no meaningful variation by diagnostic period, latency, age, or sex.

  Conclusion: These findings demonstrate that MM have a distinct SPM pattern, underscoring the need for tumor-specific surveillance with particular attention to hematologic SPMs and selected solid tumors. The lower incidence of breast cancer is an unexpected and potentially informative signal that could help guide future research. Overall, follow-up strategies should be shaped by site-specific risks rather than applied uniformly across all SPMs.

  Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420251087056.

  Copyright © 2026 Tian, Su, Li, Ye, Zhang, Li, Jiao and Wu.

• The genetics of cancer heterogeneity and mesothelioma. L.R. Chirieac, R. Gill, R. Attanoos. 2026;16:1744382. Review PubMed · Publisher · Free full text

  Abstract

  Diffuse mesothelioma is an invasive cancer that originates from the cells in the smooth tissue lining (serosal membrane) that surrounds various body cavities. While most cases originate in the pleural lining of the thoracic cavity, a subset primarily involves the peritoneum or, rarely, the pericardium or the tunica vaginalis. Advances in molecular biology have established that cancer heterogeneity is common across a wide variety of histogenetically diverse neoplasms and that 'mesothelioma' as a disease is the same. It is increasingly evident that age, sex, and anatomic site-specific variations do exist which are often driven by recognized and recurrent mutations although a high degree of inter- and intra-tumor heterogeneity is present, and this is reviewed. Diverse patterns of disease exist with respect to clinical, radiologic, pathologic findings and these are driven by unique molecular events, the mechanisms and origin of which are increasingly determined to be due to stochastic events. Consequently, mesothelioma has not only considerable radiologic, macroscopic, and microscopic heterogeneity, but includes multiple distinct genetic entities. Most mesotheliomas are characterized by recurrent mutations in tumor suppressor genes and epigenetic regulators, including BAP1, NF2, TP53, SETD2, and other genes. Alterations are identified in multiple pathways in the regulation of cell-cycle, RNA processing, histone regulation, and cell growth. BAP1 is one of the most frequently altered genes and is activated by diverse mechanisms including BAP1 point mutations, copy number loss, inactivating structural rearrangements, and minute chromosomal deletions. Consistent with its histomorphologic heterogeneity, mesothelioma displays an impressive molecular diversity. Subsets of mesothelioma have unusual genetic alterations: genomic near-haploidization in rare pleural mesotheliomas with mutations in TP53 and/or SETDB1; oncogenic EWSR1-ATF1 fusion; ALK rearrangements in rare patients with peritoneal mesothelioma. In addition, germline mutations are present in a subset of patients with mesothelioma and primarily involve genes in the DNA repair and cell cycle regulation and are more common in patients who are young, with family history of mesothelioma, or with peritoneal mesothelioma. In this review, we discuss the considerable heterogeneity of mesothelioma, the diversity of radiologic and gross presentation, various morphologic features with distinctive histologies and ultimately, we individually describe subsets of tumors characterized by uncommon alterations such as germline mutations, genomic near-haploidization, ALK rearrangement, ATF1 rearrangement, or EWSR1::YY1 fusion, as well as the implications of these findings on the diagnostic workup.

  Copyright © 2026 Chirieac, Gill and Attanoos.

• Trop-2 expression is associated with poor survival in pleural mesothelioma. A. Aviles-Salas, N. Hernández-Pedro, E. Caballé-Perez, et al. 2026;16:1841585. PubMed · Publisher · Free full text

  Abstract

  Introduction: Pleural mesothelioma (PM) lacks reliable biomarkers to guide therapy. Trophoblast cell-surface antigen 2 (Trop-2) is targetable in epithelial cancers, but its prevalence and clinical relevance in PM remain unclear.

  Methods: This retrospective cohort study selected patients with PM at the Instituto Nacional de Cancerología of Mexico from 2010 to 2022. Two independent pathologists evaluated Trop-2 positivity in histological tumor samples, defined as specific membranous staining of any intensity in ≥1% of analyzed tumor cells, equivalent to an H-score ranging 1 to 300. Median progression-free survival (mPFS) and overall survival (mOS) stratified by Trop-2 status were estimated by Kaplan-Meier method, and clinicopathologic associations were adjusted by multivariable Cox models.

  Results: Among sixty cases, Trop-2 was positive in 12 cases, associated with lung (p = 0.016) and non-regional lymph nodes (p = 0.002) metastases, shorter mOS (7.9 vs 27.8 months; p = 0.021), and independently predicted of worse PFS (adjusted hazard ratio [aHR] 2.20; p = 0.048) and OS (aHR 3.79; p = 0.009). Poorer OS was also predicted by Sarcomatoid histology (aHR 6.19; p = 0.025) and PLECH score >3 (aHR 2.64; p = 0.025).

  Discussion: Despite this small sample size, Trop-2 was related to adverse clinical outcomes, which may represent a key vulnerability for antibody-drug conjugates in PM, and highlight the need for its prospective standardized evaluation.

  Conclusions: Trop-2 was expressed in 20% of PMs, exclusively in epithelioid histology, associated with advanced disease and poor survival outcomes. These results support the prospective evaluation of Trop-2-targeted therapies in PM.

  Copyright © 2026 Aviles-Salas, Hernández-Pedro, Caballé-Perez, Lucio-Lozada, Castillo-Ruiz, Chanona-Vilchis, Aranda-Gutierrez, Orozco-Morales, Barrios-Bernal, Parra-Medina, Cabrera-Miranda, Cardona and Arrieta.

• Ultrasonic manifestations of diffuse pericardial mesothelioma masquerading as pericardial effusion: a case report. S. Zhu, Y. Zhou. 2026;16:1921935. Case report PubMed · Publisher · Free full text

  Abstract

  Background: Primary pericardial mesothelioma (PPM) is an exceedingly rare, highly invasive cardiac neoplasm with insidious onset and non-specific clinical symptoms. Due to the lack of typical early manifestations and effective routine diagnostic methods, PPM is often misdiagnosed and missed, resulting in delayed treatment and poor prognosis.

  Case Presentation: A 42-year-old male presented with 6 months of recurrent chest tightness and pain, worsening over 2 months, and two prior admissions for unexplained pericardial effusion. On admission, he had tachycardia, distant heart sounds, bilateral lower extremity edema, and a 3×2 cm hard, fixed left supraclavicular lymph node. Imaging confirmed pericardial effusion with abnormal pericardial lesions. Ultrasound-guided pericardiocentesis yielded only a small amount of red jelly-like material, with cytology suggesting epithelioid neoplastic cells. Supraclavicular lymph node biopsy confirmed metastatic malignant mesothelioma. Nivolumab immunotherapy showed no improvement. Pericardial tumor resection revealed diffuse, fish-flesh-like tumor invading the myocardium and great vessels. Final pathology confirmed epithelioid-type PPM.

  Conclusion: Patients with recurrent unexplained pericardial effusion and atypical sonographic features, such as flocculent echoes and irregular pericardial thickening, should raise suspicion for PPM. Early recognition of these signs and timely pathological confirmation are critical to avoid diagnostic delays and may improve outcomes.

  Copyright © 2026 Zhu and Zhou.

• ASPHD1 Is a tumor-suppressive and prognostic marker in glioma. J. Yang, F. Gao, X. Wang, et al. 2025;15:1694116. PubMed · Publisher · Free full text

  Abstract

  Introduction: Glioma is a highly aggressive primary brain tumor. To identify novel prognostic biomolecules and potential therapeutic targets, we investigated Aspartate betahydroxylase domain-containing protein 1 (ASPHD1), encoded by the ASPHD1 gene and predicted to function as a Fe (II)/2-oxoglutarate-dependent dioxygenase involved in peptide amino-acid modification. ASPHD1 has not previously been characterized in glioma.

  Methods: We assessed its expression and prognostic value using transcriptomic data from the Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and Chinese Glioma Genome Atlas (CGGA). Co-expressed gene enrichment and DNA-methylation analyses were performed, and associations between ASPHD1 expression and overall survival (OS) were evaluated. Gene Ontology and KEGG analyses of ASPHD1 coexpressed genes indicated enrichment in synaptic signaling, ion-channel activity, and calcium-signaling pathways, suggesting a link with neuronal and synaptic function.

  Results: ASPHD1 expression showed a pronounced inverse correlation with WHO grade, and higher ASPHD1 expression was associated with prolonged OS; multivariable Cox models identified low ASPHD1 as an independent adverse prognostic factor. Pan-cancer analysis further revealed that higher ASPHD1 expression was associated with longer OS in skin cutaneous melanoma (SKCM), uveal melanoma (UVM), and mesothelioma (MESO). In glioma cell lines, ASPHD1 overexpression suppressed proliferation, migration, and invasion in vitro, and inhibited tumor growth in a subcutaneous U87 xenograft model. ASPHD1 overexpression also upregulated neuronal differentiation-related genes, produced more negative resting membrane potentials on whole-cell patch-clamp recordings, enhanced depolarization-evoked Ca2+ transients on calcium imaging, and increased NeuN protein expression.

  Discussion: Together, these findings identify ASPHD1 as a favorable prognostic biomarker in glioma and suggest that high ASPHD1 expression restrains glioma progression while promoting neuron-like differentiation of glioma cells.

  Copyright © 2026 Yang, Gao, Wang, Zhang and Li.

• Case Report: IL-6 suppression: a potential strategy for mitigating severe immune-related adverse events in nivolumab and ipilimumab therapy for malignant pleural mesothelioma. A. Yanagisawa, T. Fukaya, K. Noda, et al. 2025;15:1671503. Case report PubMed · Publisher · Free full text

  Abstract

  Background: Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer with a poor prognosis, often presenting challenges in treatment. The CheckMate-743 trial demonstrated significant improvements in overall survival with the combination therapy of nivolumab and ipilimumab in advanced MPM. However, the management of immune-related adverse events (irAEs) remains a critical concern.

  Case Presentation: We present a 74-year-old male with a history of polymyalgia rheumatica (PMR), diagnosed two years prior. His PMR was initially treated with corticosteroids, but tapering the dose was difficult. Therefore, tocilizumab was initiated one year before the current presentation, leading to a stable remission. One month before starting cancer therapy, tocilizumab was discontinued while the patient's PMR remained well-controlled. He then developed multiple serious irAEs following the first cycle of nivolumab and ipilimumab for advanced MPM. These included cytokine release syndrome (CRS), immune-related aseptic meningitis, and liver dysfunction. All irAEs were successfully managed with corticosteroids, and the patient's tumor progression remained under control.

  Conclusion: This case suggests that residual IL-6 suppression from prior tocilizumab therapy may attenuate the severity of subsequent irAEs, permitting effective management without compromising anti-tumor efficacy. IL-6 modulation could be a promising strategy to improve the therapeutic index of dual checkpoint inhibition in MPM.

  Copyright © 2025 Yanagisawa, Fukaya, Noda, Kojima and Shimizu.

• Case Report: Malignant peritoneal mesothelioma with TFG-ROS1 fusion responds to crizotinib. W. Ye, P. Li, C. Fu, et al. 2025;15:1617457. Case report PubMed · Publisher · Free full text

  Abstract

  Background: Malignant peritoneal mesothelioma (MPM) is an exceptionally rare tumor type, and its molecular properties are poorly understood. In recent years, gene rearrangement has been found in a subset of MPMs. However, ROS1 rearrangement has not been previously reported in MPM.

  Case Presentation: Here, we present the first case report of MPM with TFG-ROS1 rearrangement in a 56-year-old female with no history of asbestos exposure. The patient did not respond to immunotherapy but exhibited sensitivity to crizotinib with a progression-free survival (PFS) of 6 months. Importantly, we identified ROS1 p.K1991N as a potential acquired drug resistance mutation to crizotinib, suggesting that entrectinib may serve as a targeted therapy to overcome this resistance mechanism.

  Conclusion: ROS1 rearrangement could potentially represent a novel driver mutation in MPM, especially in female adults. This case report illustrates the benefits of molecular detection in MPM and underscores the potential for lessons learned from other solid tumors to inform treatment strategies for rare diseases.

  Copyright © 2025 Ye, Li, Fu and Zhou.

• Clinical application of confocal laser endomicroscopy in the diagnosis of malignant pleural effusion. S. Ye, M. Yuan, C. Song, et al. 2025;15:1666259. PubMed · Publisher · Free full text

  Abstract

  Objective: Probe-based confocal laser endomicroscopy (pCLE) is an innovative in vivo microscopic imaging technique that enables real-time visualization of tissue cytology during endoscopic examinations. This study aimed to evaluate the clinical utility of pCLE in diagnosing MPE.

  Methods: A total of 41 patients with pleural effusion (PE) who underwent pCLE examination were enrolled in this prospective study. The diagnostic performance of pCLE was assessed by calculating sensitivity (SEN), specificity (SPE), positive predictive value (PPV), negative predictive value (NPV), and accuracy (ACC), using histopathological results as the reference standard. Additionally, the safety profile of the pCLE procedure was evaluated.

  Results: Among the 41 patients, histopathological analysis confirmed MPE in 31 patients and benign pleural effusion (BPE) in 10 patients. Of the 31 MPE cases, 26 were lung adenocarcinoma (LUAD), 2 were lung squamous cell carcinoma (LSCC), 1 was large cell lung cancer (LCLC, a subtype of non-small cell lung cancer [NSCLC]), 1 was pleural malignant mesothelioma (PMM), and 1 was pleural metastasis from other tumors. Compared with histopathology, pCLE demonstrated a sensitivity of 96.77%, specificity of 80%, accuracy of 92.68%, PPV of 93.75%, and NPV of 88.89%. There was substantial agreement between pCLE and histopathological findings (kappa = 0.79, p < 0.001). Furthermore, compared to conventional thoracoscopy, pCLE facilitated targeted biopsy sampling and improved detection of malignant lesions. No adverse events related to pCLE were observed, indicating its favorable safety profile.

  Conclusions: Our study demonstrates that pCLE is a valuable tool for enhancing the diagnosis of MPE, with high concordance with histopathological findings (kappa = 0.79, p < 0.001) and significant guidance for thoracoscopic pleural biopsies. The diagnostic sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of pCLE were 96.77%, 80%, 92.68%, 93.75%, and 88.89%, respectively, when compared with histopathology. These results indicate that pCLE can effectively differentiate between benign and malignant pleural effusion in patients with undetermined etiology and serves as a robust complementary method to existing diagnostic approaches. However, the small sample size of this study limits the generalizability of the findings, and further large-scale, multicenter clinical trials are needed to validate these results.

  Copyright © 2026 Ye, Yuan, Song, Yang, Hu and Ni.

• Development and validation of a prognostic nomogram for patients with malignant peritoneal mesothelioma. X. Wang, R. Liu, C. Wang, et al. 2025;15:1480197. PubMed · Publisher · Free full text

  Abstract

  Background: Malignant peritoneal mesothelioma(MPM) is a highly aggressive malignant tumor that originates from peritoneal mesothelial cells. Due to the rarity of MPM, there are few survival prediction models specifically for visualization of malignant peritoneal mesothelioma.

  Objective: This study aimed to develop a nomogram for the overall survival of MPM based on the Surveillance, Epidemiology, and End Results (SEER) database and the data of Cangzhou People's Hospital were used for external verification.

  Methods: Patients screened from the SEER database were divided into a training group and an internal verification group in a 7:3 ratio, with data from Cangzhou People's Hospital used as the external verification group. Cox proportional hazard regression was utilized to identify significant factors, and nomograms for 6-month, 12-month, and 18-month overall survival were developed. The performance of the nomogram was assessed using consistency index, calibration curve, and K-M curve.

  Results: Age, sex, histology, surgery, tumor size, chemotherapy, differentiated and the number of organ metastases were significant risk factors (p<0.05) and were included in the nomogram.The area under the subject worker curve at 6,12,18 months overall survival (AUC) was 0.782,0.784,0.766 for the training group, 0.804,0.791,0.796 for the internal verification group, 0.767,0.749,0.783 for the external verification group. The predicted correction curve was in good agreement with the observed results. The Kaplan-Meier curves of different risk groups showed significant differences.

  Conclusion: This study represents the first visual prognostic model of MPM and the initial incorporation of organ metastasis into MPM prognostic factors. The nomograph serves as a reliable tool for clinicians to personalize overall survival prediction and maximize patient benefits by identifying the most effective treatment.

  Copyright © 2025 Wang, Liu, Wang, Sun and Yang.

• External validation of pathological T adjustments in the ninth edition of the pleural mesothelioma tumor-node-metastasis classification. Z. Liu, J. Cai, Y. Li, et al. 2025;15:1557097. PubMed · Publisher · Free full text

  Abstract

  Introduction: In the ninth edition pleural mesothelioma (PM) pathological (p) T staging, patients with fissural invasion are upgraded from T1 to T2. This study aimed to externally validate this staging modification.

  Methods: Resected pT1/2 PM patients were selected. The Kaplan-Meier method was applied to assess survival differences, and propensity score matching was utilized to balance baseline characteristics. Univariable and multivariable Cox analyses were conducted to determine prognostic factors. Multiple model parameters were used to evaluate the performance of the ninth and eighth edition pT staging in distinguishing between T1 and T2 patients.

  Results: A total of 818 eligible patients were included, among whom 325 initially classified as T1 were reclassified as T2 due to fissural invasion, resulting in 57 patients remaining with pT1 disease. Survival analyses demonstrated that both before and after matching, the ninth edition T staging effectively differentiated between T1 and T2 patients, whereas the eighth edition did not perform as satisfactorily in distinguishing between the groups. Cox regression analyses further confirmed that the ninth edition T staging was a strong prognostic factor, whereas the eighth edition T staging was not prognostic. Lastly, model parameter results indicated that the ninth edition T staging performed better in distinguishing between T1 and T2 patients compared to the eighth edition.

  Discussion: Our study provided validation and endorsement for the revisions implemented in the ninth edition pT staging, specifically the reclassification of patients with fissural invasion from pT1 to pT2. This research contributed to the precise staging of PM patients.

  Copyright © 2025 Liu, Cai, Li and Weng.

• Global, regional, and national burden of head and neck cancer in males and associated risk factors from 1990 to 2021: a systematic analysis for the Global Burden of Disease Study 2021. J. Jiang, Z. Xia, W. Yao. 2025;15:1607890. PubMed · Publisher · Free full text

  Abstract

  Background: Head and neck cancer (HNC) is one of the most prevalent malignant tumors, with higher incidence and mortality rates in men than in women, particularly for lip and oral cavity, nasopharyngeal, laryngeal, and other pharyngeal cancers. This study investigates global trends in the occurrence of these cancers in men from 1990 to 2021 and analyzes their changing trends to guide healthcare policymakers in resource allocation.

  Methods: Using data from the 2021 Global Burden of Disease Study (GBD 2021), this study assesses the global prevalence, incidence, mortality, and disability-adjusted life years (DALYs) for male head and neck cancers. It also evaluates the relationship between cancer burden and economic development using the Socio-Demographic Index (SDI) and analyzes the risk factors for male head and neck cancer mortality and DALYs.

  Results: From 1990 to 2021, the impact of male head and neck cancers increased at varying rates. In 2021, there were 968,573 prevalent cases of lip and oral cavity cancer, 272,917 incident cases, 136,890 deaths, and 3,969,812 DALYs globally. The burden of nasopharyngeal, laryngeal, and other pharyngeal cancers was lower, with 385,913, 939,924, and 258,723 prevalent cases, respectively. The age-standardized incidence rates for all four cancers were positively correlated with the SDI. Key risk factors for male head and neck cancers include smoking and alcohol consumption. Additional risk factors include chewing tobacco for lip and oral cavity cancer deaths, formaldehyde exposure for nasopharyngeal cancer, and occupational exposure to sulfuric acid and asbestos for laryngeal cancer.

  Conclusions: Lip and oral cavity cancer remains the most burdensome, while nasopharyngeal cancer is increasing in East and Southeast Asia. Laryngeal cancer has declined in high-SDI regions, while other pharyngeal cancers are rising. Gender and lifestyle are key risk factors, underscoring the need for early prevention, particularly in resource-limited areas. As the global population ages, targeted prevention and improved healthcare infrastructure are essential.

  Copyright © 2025 Jiang, Xia and Yao.

• Hyperleukocytosis, leukemoid reaction caused by malignant peritoneal mesothelioma: a case report and review of literature. K. Zhu, D. Zhou, K. Liu, et al. 2025;15:1550868. Case report PubMed · Publisher · Free full text

  Abstract

  Paraneoplastic leukemoid reaction (PLR)-induced hyperleukocytosis remains a critical diagnostic challenge. Malignant peritoneal mesothelioma, known for its nonspecific clinical presentation, often evades early detection. We report a 75-year-old male with cirrhosis presenting with fever (38.2°C), progressive ascites, leukocytosis (109.9×109/L), and elevated CRP (247.41 mg/L). Initial diagnosis of spontaneous peritonitis failed to explain the leukocytosis, prompting bone marrow examination, including cytomorphology and genetic analysis, which turned out do not support a diagnosis of leukemia or myeloproliferative neoplasms. Subsequent peritoneal biopsy confirmed diffuse malignant peritoneal mesothelioma. Despite prompt diagnosis, the patient developed progressive multi-organ dysfunction and died on day 14. This case underscores the imperative to consider PLR as a potential cause of hyperleukocytosis in oncological contexts, rather than attributing it solely to hematological malignancies. Moreover, it highlights the importance of considering malignant peritoneal mesothelioma in the differential diagnosis of unexplained ascites and peritoneal thickening. Additionally, we propose the hypothesis that glucocorticoids may hold therapeutic potential in the management of PLR.

  Copyright © 2025 Zhu, Zhou, Liu, Wu, Jin and Luo.

• Malignant mesothelioma in rare sites: two case reports. Q. Du, J. Guo, Z. Zhu, et al. 2025;15:1698949. Case report PubMed · Publisher · Free full text

  Abstract

  Mesothelioma is a rare tumor originating from mesothelial cells in the pleura or other sites. Malignant pleural mesothelioma (MPM) is the most common aggressive type of mesothelioma (accounting for 81%) and carries a poor prognosis (median OS: 1 year). Diagnosing diverse histologic types is challenging. We report two cases: a 72-year-old female with peritoneal mesothelioma demonstrated a remarkable response, with the lesion shrinking from 150×160mm to radiologically undetectable after chemo-immunotherapy, resulting in a sustained complete response. Conversely, a 66-year-old male with MPM exhibited primary platinum resistance, progressing after first-line pemetrexed/lobaplatin and subsequent second-line chemotherapy. Peritoneal mesothelioma responded better to immuno-chemotherapy, while MPM showed platinum resistance. These contrasting disparate outcomes underscore that precise pathology and individualized treatment based on anatomic site are crucial, suggesting that malignant pleural and peritoneal mesothelioma may represent distinct clinical entities.

  Copyright © 2025 Du, Guo, Zhu, Zhang, Cui, Xu, Yang and Liang.

• Mapping three decades of air pollution-lung cancer research: trends, hotspots, and networks (1990-2025). H. Fan, L. Wang, L. Zhai, et al. 2025;15:1698246. Systematic review PubMed · Publisher · Free full text

  Abstract

  Background: The relationship between air pollution and lung cancer has attracted considerable attention from researchers worldwide. To systematically assess the scholarly landscape and pinpoint research fronts, this study employs bibliometric analysis to delineate global trends, collaborative networks, and key publications within this field.

  Methods: Publications from 1990 to 2025 were extracted from Web of Science Core Collection and Scopus databases. Bibliometric tools including VOSViewer, Citespace, and Bibliometrix R were used to examine trends, key contributors, research themes, and prominent journals.

  Results: Among 4,238 publications, citation rates rose significantly. China produced the most publications, with leading institutions such as Harvard University and the Chinese Academy of Sciences. Key researchers included Lan Q, Rothman N, and Vermeulen R. Major journals were Environmental Health Perspectives and Atmospheric Environment. Frequently used keywords like "Lung Cancer" and "Particulate Matter" indicate core themes, while emerging terms such as "Covid-19" and "Machine Learning" reflect evolving interests.

  Conclusion: Fine particulate matter is an established environmental risk factor for lung cancer, and research on polycyclic aromatic hydrocarbons and asbestos remains active. The field has shifted from exposure assessment to mechanistic investigations focusing on oxidative stress, gene expression, and machine learning applications, defining key future research directions.

  Copyright © 2025 Fan, Wang, Zhai, Deng, Li, Niu, Zhao, Gao and Gao.

• Rare comorbidity of colon cancer, hepatic malignant mesothelioma, and abdominal Ewing's sarcoma: a case report. Y. Li, L. Teng, S. Wang, et al. 2025;15:1558347. Case report PubMed · Publisher · Free full text

  Abstract

  We present a rare case of a patient with a history of colon cancer who subsequently developed hepatic mesothelioma and extraosseous Ewing's sarcoma 10 years after surgery. The diagnosis of three completely different types of cancer in the same patient over a decade was confirmed through histopathological and immunohistochemical analysis. This case highlights the importance of clinicians maintaining a heightened awareness and clinical vigilance regarding multiple primary cancers, ensuring patients receive comprehensive diagnosis and treatment for improved prognosis and desired survival outcomes.

  Copyright © 2025 Li, Teng, Wang, Wu and Huang.

• Updating the genomic and clinicopathologic features of thoracic SMARCA4-deficient undifferentiated tumor: a mini-series including a long-term survivor. K. Ofori, C. Pagan, M.C. Smithgall, et al. 2025;15:1601443. PubMed · Publisher · Free full text

  Abstract

  Introduction: Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-dUT) is a recently described type of lung cancer, presenting as a bulky mass variably involving the mediastinum and the lung in patients with smoking history, and exhibits adverse prognosis. The essential diagnostic immunomorphologic features and typical genomic findings have been described. However, there is a continuing need to catalogue the spectrum of genomic changes underlying the disease, the heterogeneity of antigen expression in order to avoid diagnostic pitfalls, and any variability in patient outcomes. We sought to update the literature on the clinicopathologic and genomic characteristics of thoracic SMARCA4- dUT.

  Methods: We searched for cases diagnosed in our institution, reviewed clinical data, performed comprehensive genomic analysis, and evaluated immunomorphologic features.

  Results: Four cases (three males and one female) were identified at a median age of 61.5 years (range, 49-72 years), all with smoking history. The series included a patient with limited disease treated with surgery and adjuvant chemotherapy, who remained disease-free over a year after diagnosis, underscoring the importance of lung cancer screening among smokers and the possibility of a subgroup of thoracic SMARCA4-dUT with less aggressive disease. In addition to the known immunophenotypic features of the disease, we identified the expression of FLI (in three out of three cases) and WT-1 (in one of three cases), which are endothelial and mesothelial markers, and are findings to be cognizant of to avoid misdiagnosis as angiosarcoma or mesothelioma, respectively. While the neuroendocrine markers synaptophysin and CD56 were variably expressed in some cases, the expression of INSM1 was absent in all cases. Genomic analysis demonstrated tobacco-related features, including a high median tumor mutation burden and TP53 variants. In this limited series, mutational signature analysis revealed evidence of SBS87 as the predominant single-base substitution COSMIC signature.

  Conclusion: Our work expands the possible diagnostic antigen expression of thoracic SMARCA4-dUT, contributes to the emerging reports on patients with variant disease presentation, and highlights the need for large-scale genomic studies to determine additional mechanisms of the initiation of carcinogenesis.

  Copyright © 2025 Ofori, Pagan, Smithgall, Jadalla, Upadhyay Baskota, Crapanzano, Hsiao and Mansukhani.

• Volatile organic compounds in exhaled human breath for the diagnosis of malignant pleural mesothelioma: a meta-analysis. T. Zhao, X. Hu, M. Peng, et al. 2025;15:1537767. Systematic review PubMed · Publisher · Free full text

  Abstract

  Objective: Malignant pleural mesothelioma (MPM) is a relatively rare thoracic tumor with a high mortality rate, making early diagnosis and treatment challenging. The present study evaluated the utility of exhaled volatile organic compounds (VOCs) in diagnosing MPM.

  Methods: The Cochrane Library, PubMed, EMBASE, and Web of Science were systematically searched for clinical trials assessing the diagnostic ability of VOCs for MPM through August 30, 2024. Quality was evaluated using the QUADAS-2 tool. A meta-analysis was performed with a bivariate model for sensitivity and specificity using Stata MP 17.0 software.

  Results: Eight trials with 859 subjects were included. VOCs were found to have a pooled sensitivity of 0.86 (95% confidence interval [CI] 0.75-0.93), a pooled specificity of 0.73 (95% CI 0.58-0.84), and an area under the curve (AUC) of 0.88 (95% CI 0.85-0.90) in differentiating MPM patients from healthy controls. In addition VOCs had a pooled sensitivity of 0.89 (95% CI 0.83-0.93), a pooled specificity of 0.79 (95% CI 0.57-0.91), and an AUC of 0.91 (95% CI 0.88-0.93) in differentiating MPM patients from asymptomatic individuals formerly exposed to asbestos (AEx).

  Conclusions: Although the utility of VOCs in diagnosing MPM varied among clinical trials, VOCs in exhaled human breath may have a potential role in the diagnosis of MPM. Large-scale randomized clinical trials are warranted.

  Copyright © 2025 Zhao, Hu, Peng, Wei, Fu, Chen and Chen.

• A case of ovarian mesothelioma with VHL mutation diagnosed by immunohistochemistry and literature review. Y. Yao, H. Yan, J. Xiong, et al. 2024;14:1471978. Review PubMed · Publisher · Free full text

  Abstract

  The malignant mesothelioma mainly develops in the pleura and peritoneum, while primary ovarian mesothelioma is very rare. Here, we report the first case of primary ovarian mesothelioma (clear cell variant) with VHL mutations in the world based on the results of histomorphology, immunohistochemistry, and genetic testing. This is an extremely rare type of tumor that has not been reported so far. Through the literature search, we reviewed primary ovarian mesothelioma, focusing on its differential diagnosis and molecular genetics. The purpose of this paper is to deepen the flexible selection and application of immunohistochemical markers in mesothelioma, so as to reduce missed diagnosis and misdiagnosis.

  Copyright © 2024 Yao, Yan, Xiong and Duan.

• Case report: A case of primary cardiac malignant mesothelioma. A. Wang, B. Liu, S. Dong, et al. 2024;14:1356592. Case report PubMed · Publisher · Free full text

  Abstract

  Primary cardiac malignant tumors are extremely rare, making up about 10% of all primary cardiac tumors. Most of these tumors are primary sarcomas, with primary mesothelioma being even less common. This report details a 53-year-old male patient diagnosed with primary cardiac malignant mesothelioma. The patient had symptoms of chest pain and difficulty breathing. A CT scan showed an enlarged heart, fluid around the heart, and irregular thickening of the pericardium. Diagnosis was confirmed through a surgical biopsy, which showed the presence of malignant mesothelioma. After the procedure, the patient received appropriate cardiac support. Although stable at discharge, the patient unfortunately died three months later due to severe wheezing. There may be a potential link between exposure to radioactive iodine treatment and this outcome. This case highlights the diagnostic and treatment challenges of primary cardiac malignant tumors and reminds physicians to consider this rare disease when evaluating patients with similar symptoms.

  Copyright © 2024 Wang, Liu, Dong and Wang.

• Case report: complete response and long-term survival on third-line immunotherapy in patient with pleural mesothelioma. Ž. Jurić Čuljak, S. Tomić, K. Šitum, et al. 2024;14:1388829. Case report PubMed · Publisher · Free full text

  Abstract

  Introduction: Pleural mesothelioma (PM) is a rare neoplasm with median survival time range from 8 to 14 months from diagnosis, and the 5-year survival rate less than 10%, indicating a poor prognosis. The standard treatment for unresectable PM for a long time has been polychemotherapy with pemetrexed and cisplatin for fit patients. Currently, the combination of the anti PD-1 inhibitor nivolumab and the anti-CTLA4 inhibitor ipilimumab has been recognized as the best possible frontline therapy (especially in the sarcomatoid or biphasic type) due to improved outcomes compared to the standard chemotherapy combination. There are still no established predictive biomarkers for any type of systemic therapy in this disease.

  Case Presentation: Patient who presented with cough and dyspnea has been diagnosed with advanced epithelioid type PM in May 2016. He was treated with three lines of therapy, including an antiangiogenic agent and immunotherapy with pembrolizumab in the third line. Immunotherapy with the PD-1 inhibitor pembrolizumab achieved a complete and prolonged response that transferred to long- term survival. Seven years from diagnosis, the patient is still alive. Histological findings showed an unusually immune-inflamed tumor microenvironment possibly leading to excellent response on immunotherapy.

  Conclusions: The course of the disease in our patient points out that we need better predictive biomarkers to direct the treatment algorithm, as some of the patients, although chemorefractory to the best chemotherapy option, can sustain great benefit of second-line chemotherapy in combination with antiangiogenic agent, and especially immunotherapy, even in late lines of therapy.

  Copyright © 2024 Jurić Čuljak, Tomić, Šitum and Boraska Jelavić.

• Case report: Radiological features of a case of desmoplastic malignant mesothelioma of peritoneum. J. Wang, H. Deng. 2024;14:1502105. Case report PubMed · Publisher · Free full text

  Abstract

  Desmoplastic malignant peritoneal mesothelioma (DMPM) is an extremely rare and aggressive subtype of sarcomatoid malignant mesothelioma, originating from the mesothelial lining of body cavities. It is characterized by significant local invasiveness and poor prognosis. The nonspecific symptoms of DMPM often result in delayed diagnosis. This case report presents the multimodality imaging findings of DMPM in a 58-year-old male, including ultrasound, CT, contrast-enhanced CT, magnetic resonance imaging (MRI), and 18-fluorodeoxy-glucose positron emission tomography combined with CT (18F-FDG PET/CT). These findings aim to enhance radiologists' understanding of the imaging features and differential diagnosis of DMPM. In this case, the tumor was located in the right subdiaphragm and the right anterior and left medial lobes of the liver. Due to the patient's history of alcoholic cirrhosis-a known risk factor for primary liver tumors-the initial diagnostic focus was on identifying a primary liver tumor with potential peritoneal invasion, overlooking other possible etiologies. However, histological results revealed that the liver lesion was secondary to invasion by DMPM. To the best of our knowledge, cases of DMPM invading the liver are exceedingly rare. This report underscores the importance of considering peritoneal tumors in the differential diagnosis when lesions involve both the peritoneum and adjacent organs, despite their rarity.

  Copyright © 2024 Wang and Deng.

• Major response of a peritoneal mesothelioma to nivolumab and ipilimumab: a case report, molecular analysis and review of literature. M.F. Reveneau, J. Masliah-Planchon, M. Fernandez, et al. 2024;14:1410322. Case report PubMed · Publisher · Free full text

  Abstract

  Malignant peritoneal mesothelioma (MPM) is a rare tumor associated with a poor prognosis and a lack of consensus regarding treatment strategies. While the Checkmate 743 trial demonstrated the superiority of first-line nivolumab and ipilimumab over chemotherapy in malignant pleural mesothelioma (MPlM), few studies have assessed the effectiveness of immunotherapy against MPM, due to its rarity. Here, we report a major and sustained 12-month response in a 74-year-old female patient who received the anti-PD-1 nivolumab and the anti-CTLA4 ipilimumab as first-line therapy for diffuse MPM. PD-L1 was expressed and BAP1 expression was lost, as shown by immunohistochemistry, however the BAP1 gene was not mutated. Our findings suggest a role for ICI in non-resectable diffuse MPM exhibiting PD-L1 overexpression and loss of BAP1 expression, and instill new hope in their treatment. To our knowledge, this is the second reported case of dual immunotherapy used as first-line in MPM with a major clinical response. To investigate the clinical outcome, we conducted additional molecular analyses of the MPM tumor and we reviewed the literature on immunotherapy in MPM to discuss the role of PD-L1 and BAP1.

  Copyright © 2024 Reveneau, Masliah-Planchon, Fernandez, Ouikene, Dron, Dadamessi, Dayen, Golmard and Chauffert.

• Multiple aspects of matrix stiffness in cancer progression. A. Mancini, M.T. Gentile, F. Pentimalli, et al. 2024;14:1406644. Review PubMed · Publisher · Free full text

  Abstract

  The biophysical and biomechanical properties of the extracellular matrix (ECM) are crucial in the processes of cell differentiation and proliferation. However, it is unclear to what extent tumor cells are influenced by biomechanical and biophysical changes of the surrounding microenvironment and how this response varies between different tumor forms, and over the course of tumor progression. The entire ensemble of genes encoding the ECM associated proteins is called matrisome. In cancer, the ECM evolves to become highly dysregulated, rigid, and fibrotic, serving both pro-tumorigenic and anti-tumorigenic roles. Tumor desmoplasia is characterized by a dramatic increase of α-smooth muscle actin expressing fibroblast and the deposition of hard ECM containing collagen, fibronectin, proteoglycans, and hyaluronic acid and is common in many solid tumors. In this review, we described the role of inflammation and inflammatory cytokines, in desmoplastic matrix remodeling, tumor state transition driven by microenvironment forces and the signaling pathways in mechanotransduction as potential targeted therapies, focusing on the impact of qualitative and quantitative variations of the ECM on the regulation of tumor development, hypothesizing the presence of matrisome drivers, acting alongside the cell-intrinsic oncogenic drivers, in some stages of neoplastic progression and in some tumor contexts, such as pancreatic carcinoma, breast cancer, lung cancer and mesothelioma.

  Copyright © 2024 Mancini, Gentile, Pentimalli, Cortellino, Grieco and Giordano.

• Pathological complete response in a patient with pleural mesothelioma treated with immunotherapy: a case report. E. Faccioli, F. Grosso, A. Dell'Amore, et al. 2024;14:1378530. Case report PubMed · Publisher · Free full text

  Abstract

  The role of immunotherapy in the multimodal treatment for pleural mesothelioma (PM) is still under investigation, particularly in the preoperative setting. Pathological complete response (pCR) has been previously described after chemotherapy and immunotherapy; however, there is no prior experience reported with immunotherapy alone before surgery. We report the case of a 58-year-old male with biphasic PM treated with immunotherapy, resulting in a major clinical partial response. Following a multidisciplinary evaluation between thoracic surgeons, medical oncologists, pathologists, radiologists and radiation oncologists, the patient underwent surgery with radical intent through a right extended pleurectomy/decortication (eP/D). Histopathological examination of the specimen confirmed a pathological Complete Response (pCR). This case supports the feasibility and potential efficacy of combining preoperative immunotherapy with surgery in the management of advanced PM.

  Copyright © 2024 Faccioli, Grosso, Dell’Amore, Delfanti, Zambello, Cerbone, Canu, De Angelis, Sambataro, Pezzuto, Barbieri, Pasello, Calabrese and Rea.

• Pericardial mesothelioma mimicking mediastinal lymphoma and systemic rheumatic disease: a case report. G. Hirnle, M. Kapałka, M. Krawiec, et al. 2024;14:1481373. Case report PubMed · Publisher · Free full text

  Abstract

  Introduction: Pericardial mesothelioma is an exceedingly rare pericardial neoplasm. It has atypical clinical symptoms and imaging characteristics that often lead to an inconclusive diagnosis. The diagnosis of a rare tumor such as pericardial mesothelioma, which can present with a variety of manifestations, requires a multidisciplinary approach.

  Case Presentation: A 36-year-old Caucasian female patient without significant past medical history was admitted to the hospital with chest pain and a high fever and was diagnosed with acute pericarditis. The following month, the patient was treated for sepsis; during this hospitalization, lab tests for antinuclear antibodies (ANA) turned out to be positive. Concurrently, mediastinal lymphadenopathy was observed. Given the suspicion of mediastinal lymphoma, a mediastinoscopy with lymph node biopsy was performed. Following a negative biopsy result, positron emission tomography combined with computed tomography (PET/CT) and blood immunophenotyping were performed. Both tests ruled out a diagnosis of lymphoma. Concurrently, the patient was hospitalized in the rheumatology department due to positive ANA results. There, in addition to the ANA titer at a level of 1:320, lupus anticoagulant was detected. The patient was diagnosed with systemic lupus erythematosus (SLE) and initiated on chronic steroid therapy. As heart failure progressed, the patient was admitted to the cardiology department. Tissue Doppler echocardiography and cardiac magnetic resonance imaging (MRI) revealed features indicative of constrictive pericarditis. The patient underwent a pericardiectomy with satisfactory results. However, the pathology result of the pericardium remained equivocal. The patient was readmitted 3 months later with severe circulatory failure, and a salvage procedure of pericardiectomy was performed. Histopathological examination of the sections confirmed the diagnosis of pericardial epithelioid mesothelioma. The patient died after 3 weeks of palliative care.

  Conclusions: In the differential diagnosis of relapsing and resultant constrictive pericarditis, neoplastic processes that may mimic systemic rheumatic diseases should also be considered. Pericardial mesothelioma is a very rare diagnosis and may result in increased ANA titers, particularly anti-dense fine speckled 70 (DFS70) antibodies.

  Copyright © 2025 Hirnle, Kapałka, Krawiec and Hrapkowicz.

• Pharmacological inhibition of CDK4/6 impairs diffuse pleural mesothelioma 3D spheroid growth and reduces viability of cisplatin-resistant cells. A. Costa, I.M. Forte, F. Pentimalli, et al. 2024;14:1418951. PubMed · Publisher · Free full text

  Abstract

  Introduction: Diffuse pleural mesothelioma (DPM) of the pleura is a highly aggressive and treatment-resistant cancer linked to asbestos exposure. Despite multimodal treatment, the prognosis for DPM patients remains very poor, with an average survival of 2 years from diagnosis. Cisplatin, a platinum-based chemotherapy drug, is commonly used in the treatment of DPM. However, the development of resistance to cisplatin significantly limits its effectiveness, highlighting the urgent need for alternative therapeutic strategies. New selective inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) have shown promise in various malignancies by inhibiting cell cycle progression and suppressing tumor growth. Recent studies have indicated the potential of abemaciclib for DPM therapy, and a phase II clinical trial has shown preliminary encouraging results.

  Methods: Here, we tested abemaciclib, palbociclib, and ribociclib on a panel of DPM cell lines and non-tumor mesothelial(MET-5A) cells.

  Results: Specifically, we focused on abemaciclib, which was the mosteffective cytotoxic agent on all the DPM cell lines tested. Abemaciclib reduced DPM cell viability, clonogenic potential, and ability to grow as three-dimensional (3D) spheroids. In addition, abemaciclib induced prolonged effects, thereby impairing second-generation sphere formation and inducing G0/G1 arrest and apoptosis/ necrosis. Interestingly, single silencing of RB family members did not impair cell response to abemaciclib, suggesting that they likely complement each other in triggering abemaciclib's cytostatic effect. Interestingly, abemaciclib reduced the phosphorylation of AKT, which is hyperactive in DPM and synergized with the pharmacological AKT inhibitor (AKTi VIII). Abemaciclib also synergized with cisplatin and reduced the viability of DPM cells with acquired resistance to cisplatin.

  Discussion: Overall, our results suggest that CDK4/6 inhibitors alone or in combination with standard of care should be further explored for DPM therapy.

  Copyright © 2024 Costa, Forte, Pentimalli, Iannuzzi, Alfano, Capone, Camerlingo, Calabrese, von Arx, Benot Dominguez, Quintiliani, De Laurentiis, Morrione and Giordano.

• Pleural Rosai-Dorfman disease complicated with renal clear cell carcinoma: a case report and literature review. S. Tang, X. Yang, S. Wang, et al. 2024;14:1476243. Case report PubMed · Publisher · Free full text

  Abstract

  Background: Rosai-Dorfman disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy, is a rare non-malignant disorder characterized by excessive proliferation of histiocytes, the cause of which remains unknown. Although the lymph nodes are the most commonly affected site, some patients may present with extranodal involvement, particularly in the skin, nasal cavity, eyes, and bones. In this report, we aim to present a unique case of RDD with pleural involvement in a 61-year-old patient. To our knowledge, only a few cases of RDD primarily manifesting as pleural disease have been reported thus far.

  Case Summary: A 61-year-old male with left brachial plexus neuropathy was found to have a space-occupying lesion in the left posterior pleura. Initial chest CT showed a 5.7cm × 1.3cm soft tissue density shadow, which grew to 6.8cm × 1.7cm two years later. Given a history of clear cell renal cell carcinoma, pleural metastasis was suspected. The patient declined a needle biopsy but underwent surgical excision. Postoperative pathology and immunohistochemistry confirmed Rosai-Dorfman disease (RDD). After surgery, the patient received anti-infection, phlegm reduction, rehydration, and analgesia treatments and recovered well.

  Conclusion: RDD originating in pleura is rare, its clinical and imaging manifestations lack specificity, and it is easy to be misdiagnosed. It is crucial to consider the possibility of RDD when encountering nodular pleural masses or lamellar soft tissue lesions. Differential diagnosis should include pleural mesothelioma, pleural metastases, solitary fibrous neoplasms, and schwannomas of the pleura. Ultimately, a definitive diagnosis can be achieved through pathology and immunohistochemistry analysis.

  Copyright © 2025 Tang, Yang, Wang and Xiao.

• Transfer learning approach in pre-treatment CT images to predict therapeutic response in advanced malignant pleural mesothelioma. A. Fanizzi, A. Catino, S. Bove, et al. 2024;14:1432188. PubMed · Publisher · Free full text

  Abstract

  Introduction: Malignant pleural mesothelioma (MPM) is a poor-prognosis disease. Owing to the recent availability of new therapeutic options, there is a need to better assess prognosis. The initial clinical response could represent a useful parameter.

  Methods: We proposed a transfer learning approach to predict an initial treatment response starting from baseline CT scans of patients with advanced/unresectable MPM undergoing first-line systemic therapy. The therapeutic response has been assessed according to the mRECIST criteria by CT scan at baseline and after two to three treatment cycles. We used three slices of baseline CT scan as input to the pre-trained convolutional neural network as a radiomic feature extractor. We identified a feature subset through a double feature selection procedure to train a binary SVM classifier to discriminate responders (partial response) from non-responders (stable or disease progression).

  Results: The performance of the prediction classifiers was evaluated with an 80:20 hold-out validation scheme. We have evaluated how the developed model was robust to variations in the slices selected by the radiologist. In our dataset, 25 patients showed an initial partial response, whereas 13 patients showed progressive or stable disease. On the independent test, the proposed model achieved a median AUC and accuracy of 86.67% and 87.50%, respectively.

  Conclusions: The proposed model has shown high performance even by varying the reference slices. Novel tools could help to improve the prognostic assessment of patients with MPM and to better identify subgroups of patients with different therapeutic responsiveness.

  Copyright © 2024 Fanizzi, Catino, Bove, Comes, Montrone, Sicolo, Signorile, Perrotti, Pizzutilo, Galetta and Massafra.

• Unveiling the mystery: a rare case of localized malignant pericardial mesothelioma-case report. Y. Zhang, M. Pang. 2024;14:1342748. Case report PubMed · Publisher · Free full text

  Abstract

  Primary malignant pericardial mesothelioma (PMPM) is a rare pericardial malignant tumor. Most manifestations of PMPM are localized or diffuse masses surrounding the heart. The prognosis of diffuse PMPM is poor due to the difficulty of surgical resection. Although the edge of localized PMPM is clear and can be easily resected, the diagnosis of this disease is difficult. Timely diagnosis and proper treatment are key to a good prognosis. Here, we report a patient with localized PMPM and describe the method for the diagnosis of this disease.

  Copyright © 2024 Zhang and Pang.

• A pan-cancer analysis of ABI3BP: a potential biomarker for prognosis and immunoinfiltration. Y. Feng, F. Tao, H. Qiao, et al. 2023;13:1159725. PubMed · Publisher · Free full text

  Abstract

  Objective: ABI Family Member 3 Binding Protein (ABI3BP) is an extracellular matrix protein that affects the carcinogenesis of lung and esophageal cancer. However, the relevance of ABI3BP in different forms of cancer is uncertain.

  Methods: ABI3BP expression was interpreted using the Cancer Genome Atlas (TCGA) database, the Genotype Tissue Expression Atlas (GTEx) database, the Human Protein Atlas (HPA) database, the Cancer Cell Line Encyclopedia (CCLE) database, and immunohistochemistry. The R programming language was used to analyze the association between ABI3BP expression and patient prognosis and evaluate the relationship between ABI3BP and the immune characteristics of tumors. Using the GDSC and CTRP databases, a drug sensitivity analysis of ABI3BP was conducted.

  Results: ABI3BP mRNA expression was shown by differential analysis to be down-regulated in 16 tumor types relative to normal tissues, corresponding with its protein expression level as determined by immunohistochemistry. Abnormal expression of ABI3BP accurately predicts the prognosis of patients with renal chromophobe carcinoma (KICH), mesothelioma (MESO), and pancreatic adenocarcinoma (PAAD). Meanwhile, aberrant expression of ABI3BP was associated with immune checkpoints, TMB, MSI, tumor purity, HRD, LOH, and drug sensitivity. A correlation between ABI3BP expression and the amount of infiltration of several immune-related cells in pan-cancer was determined by Immune Score, Stromal Score, and Estimated Score.

  Conclusion: Our results show that ABI3BP might be employed as a molecular biomarker to predict prognosis, treatment susceptibility, and immunological response in patients with pan-cancer.

  Copyright © 2023 Feng, Tao, Qiao and Tang.

• Case report: The activity of multi-kinase VEGF inhibitor, Pazopanib, in metastatic undifferentiated round cell sarcomas harboring EWSR1::CREM fusion: clinicopathological series of two cases and literature review. L. Campoverde, F. Camacho, F. Alessandrino, et al. 2023;13:1215003. Case report PubMed · Publisher · Free full text

  Abstract

  Soft tissue sarcomas harboring EWSR1::CREM fusion are rare and challenging to treat. Pazopanib, a multi-tyrosine kinase inhibitor, is FDA-approved for advanced soft tissue sarcomas, but predictive biomarkers for its efficacy remain unidentified. We conducted a study on > 240,000 neoplasms submitted to Caris Life Sciences (Phoenix, AZ) to detect rearrangements using whole transcriptome sequencing. Two sarcoma-experienced, board-certified pathologists performed histological reviews, and treatment/outcome information was collected. Among the identified cases (n = 18), we observed a diverse range of sarcoma and other cancers, including an intracranial myxoid mesenchymal tumor, mesothelioma, hyalinizing clear cell carcinomas of the head and neck, clear cell sarcomas, and undifferentiated round cell sarcomas, as well as histologically malignant tumors with epithelioid morphology. Notably, two undifferentiated, metastatic, abdominal round cell sarcoma cases treated with pazopanib demonstrated significant sustained partial response and clinical benefit. To explore the genetic factors associated with the efficacy of pazopanib in these cases, next-generation sequencing and fluorescence in situ hybridization were analyzed for alterations in the tumors. The genomic analysis provided compelling evidence confirming the presence of EWSR1::CREM fusion in both cases, with no other pathogenic gene variants or copy number alterations detected. These cases demonstrate the potential of Pazopanib as a promising therapeutic option for patients with EWSR1::CREM fusion-positive soft tissue sarcomas, including metastatic undifferentiated round cell sarcomas. The sustained clinical benefit and partial responses observed in these cases warrant further research to validate these findings and explore the wider utility of Pazopanib in this rare and challenging subset of soft tissue sarcomas. Case studies: Case 1: A 49-year-old man presented with abdominal pain, weight loss, and chronic cough. A computed tomography (CT) of the chest, abdomen, and pelvis showed multiple lung nodules and masses and a right rectus mass that was biopsied and revealed an undifferentiated round cell sarcoma with a rare fusion EWSR1-CREM. No additional pathogenic gene variants or copy number alterations were detected. He received neoadjuvant chemotherapy with three cycles of Vincristine, Adriamycin, and Ifosfamide (VAI) and seven cycles of Vincristine/Irinotecan and Temodar (VIT). After cycle 7 of VIT, he had surgical resection of the abdominal mass and received radiation for lung metastasis. He completed 13 cycles of VIT after which he presented with progression of disease and switched to monotherapy with Pazopanib. At the time of this analysis he had stable disease for 28 months. Case 2: A 75-year-old woman presented with pelvic pain and new onset constipation. CT abdomen showed a large pelvic mass and intraperitoneal tumor spread. Exploratory laparotomy revealed a ruptured pelvic mass and a small bowel tumor. Both tumors were proved to be high-grade, poorly differentiated sarcoma. Genomic analysis demonstrated an EWSR1::CREM fusion but no other pathogenic gene variants or copy number alterations. She was treated initially for a primitive neuroectodermal tumor (PNET) with four cycles of Vincristine/Adriamycin/Cytoxan/Olaratumab but declined additional chemotherapy after progression. Two years later, she presented with recurrent abdominal mass and received one cycle of Temodar/Irinotecan, then she began Pozapanib and underwent palliative radiation to the entire pelvis. She has been on Pazopanib for 23 months with stable disease.

  Copyright © 2023 Campoverde, Camacho, Alessandrino, Evans, Elliot, Rosenberg and Trent.

• Coexistence of a novel STRN-ALK, NBEA-ALK double-fusion in an ovarian malignant mesothelioma patient: a case report and review. X. Wu, Q. Wang, X. Xu. 2023;13:1156329. Case report PubMed · Publisher · Free full text

  Abstract

  Primary ovarian mesothelioma (POM) is a rare malignant tumor with poor prognosis. Although anaplastic lymphoma kinase gene (ALK) double-fusion partners have been found in various tumors, it is rarely reported in mesothelioma. In this article, we describe the coexistence of a novel STRN-ALK, neurobeachin (NBEA)-ALK double-fusion in a patient with primary ovarian mesothelioma. A 30-year-old woman was found to have pelvic masses for more than a year. Color Doppler ultrasound showed mixed mass in the left ovary and multiple solid masses in the right ovary. the patient underwent laparoscopic surgery, including total hysterectomy, bilateral salpingo-oopherectomy, pelvic lymph node and abdominal aortic lymph node resection, omentum resection and abdominal focus resection. Pathologic examination revealed bilateral ovarian malignant mesothelioma and no evidence of malignancy in the resected bilateral round/broad ligaments, bilateral parametrial tissues, vaginal stump, bilateral fallopian tubes, pelvic and paraaortic lymph nodes. Immunohistochemistry showed that it was positive for Calretinin, VIM, WT1, PAX8, mesothelin, CK5/6, PCK, CK7, MLH1, PMS2, MSH2, MSH6, weakly positive for BAP1, while being negative for Napsin A, P504S, CEA, D2-40, GATA3. The sequencing analysis identified STRN-ALK (intron3:intron19) and NBEA-ALK (intron1:intron16) double-ALK fusion. To the best of our knowledge, this is the first report that a novel NBEA-ALK and EML4-ALK coexist in one patient with POM. The patient has completed 6 cycles of continuous chemotherapy and is in stable condition. Whether ALK inhibitors can bring promising benefits to POM patients in the future deserves further study.

  Copyright © 2023 Wu, Wang and Xu.

• Commentary: Case report: Mesothelioma and BAP1 tumor predisposition syndrome: implications for public health. C. Sassorossi, M. Chiappetta, M.T. Congedo, et al. 2023;13:1279786. Comment PubMed · Publisher · Free full text

• Diagnostic value of combination of biomarkers for malignant pleural mesothelioma: a systematic review and meta-analysis. M. Zhu, Z. Lu, H. Guo, et al. 2023;13:1136049. Systematic review PubMed · Publisher · Free full text

  Abstract

  Introduction: Early-stage accurate diagnosis of malignant pleural mesothelioma (MPM) has always been a formidable challenge. DNA and protein as biomarkers for the diagnosis of MPM have received considerable attention, and yet the outcomes are inconsistent.

  Methods: In this study, a systematic search employing PubMed, EMBASE, and Cochrane Library to identify relevant studies from the first day of databases to October 2021. Moreover, we adopt the QUADAS-2 to evaluate the quality of eligible studies and Stata 15.0 and Review Manager 5.4 software programs to perform the meta-analysis. Additionally, bioinformatics analysis was performed at GEPIA for the purpose of exploring relationship between related genes and the survival time of MPM patients.

  Results: We included 15 studies at the DNA level and 31studies at the protein level in this meta-analysis. All results demonstrated that the diagnostic accuracy of the combination of MTAP + Fibulin-3 was the highest with the SEN 0.81 (95% CI: 0.67, 0.89) and the SPE 0.95 (95% CI: 0.90, 0.97). And the bioinformatics analysis indicated that the higher MTAP gene expression level was beneficial to enhance the survival time of MPM patients.

  Discussion: Nonetheless, as a result of the limitations of the included samples, it may be necessary to conduct additional research before drawing conclusions.

  Systematic Review Registration: https://inplasy.com/inplasy-2022-10-0043/, identifier INPLASY2022100043.

  Copyright © 2023 Zhu, Lu, Guo, Gu, Wei and Zhang.

• Editorial: Advances in malignant pleural mesothelioma: Diagnosis, treatment, and molecular mechanisms. M.G. Mastromarino, V. Aprile, M. Lucchi. 2023;13:1158416. Editorial PubMed · Publisher · Free full text

• Editorial: Moving beyond the molecular mechanisms of malignant pleural mesothelioma: Cues for novel biomarkers and drug targets. I. Cavallari, F. Cerciello, E. Giovannetti, et al. 2023;13:1163144. Editorial PubMed · Publisher · Free full text

• Geographic variation in malignant cardiac tumors and their outcomes: SEER database analysis. M. Rahouma, S. Khairallah, A. Dabsha, et al. 2023;13:1071770. PubMed · Publisher · Free full text

  Abstract

  Introduction: Primary malignant cardiac tumors (PMCTs) are rare. Geographical distribution has been demonstrated to affect cancer outcomes, making the reduction of geographical inequalities a major priority for cancer control agencies. Geographic survival disparities have not been reported previously for PMCT and the aim of this study is to compare the prevalence and the long-term survival rate with respect to the geographic location of PMCTs using the Surveillance, Epidemiology, and End Results (SEER) research plus data 17 registries between 2000 and 2019.

  Methods: The SEER database was queried to identify geographic variation among PMCTs. We classified the included states into 4 geographical regions (Midwest, Northeast, South and West regions) based on the U.S. Census Bureau-designated regions and divisions. Different demographic and clinical variables were analyzed and compared between the four groups. Kaplan Meier curves and Cox regression were used for survival assessment.

  Results: A total of 563 patients were included in our analysis. The median age was 53 years (inter-quartile range (IQR): 38 - 68 years) and included 26, 90, 101, and 346 patients from the Midwest, Northeast, South, and West regions respectively. Sarcoma represented 65.6% of the cases, followed by hematological tumors (26.2%), while mesothelioma accounted for 2.1%. Treatment analysis showed no significant differences between different regions. Median overall survival was 11, 21, 13, and 11 months for Midwest, Northeast, South and West regions respectively and 5-year overall survival was 22.2%, 25.4%, 14.9%, and 17.6% respectively. On multivariate Cox regression, significant independent predictors of late overall mortality among the entire cohort included age (Hazard Ratio [HR] 1.028), year of diagnosis (HR 0.967), sarcoma (HR 3.36), surgery (HR 0.63) and chemotherapy (HR 0.56).

  Conclusion: Primary malignant cardiac tumors are rare and associated with poor prognosis. Sarcoma is the most common pathological type. Younger age, recent era diagnosis, surgical resection, and chemotherapy were the independent predictors of better survival. While univariate analysis revealed that patients in the South areas had a worse survival trend compared to other areas, geographic disparity in survival was nullified in multivariate analysis.

  Copyright © 2023 Rahouma, Khairallah, Dabsha, Baudo, El-Sayed Ahmed, Gambardella, Lau, Esmail, Mohamed, Girardi, Gaudino, Lorusso and Mick.

• Human intravital microscopy in the study of sarcomas: an early trial of feasibility. E.M. Gabriel, K. Sukniam, K. Popp, et al. 2023;13:1151255. PubMed · Publisher · Free full text

  Abstract

  Unlabelled: Sarcomas comprise a vast and heterogenous group of rare tumors. Because of their diversity, it is challenging to study sarcomas as a whole with regard to their biological and molecular characteristics. This diverse set of tumors may also possess differences related to their tumor-associated vasculature, which in turn may impact the ability to deliver systemic therapies (e.g., chemotherapy, targeted therapies, and immunotherapy). Consequently, response to systemic treatment may also be variable as these depend on the ability of the therapy to reach the tumor target via the tumor-associated vasculature. There is a paucity of data regarding sarcoma-related tumor vessels, likely in part to the rarity and heterogeneity of this cancer as well as the previously limited ability to image tumor-associated vessels in real time. Our group has previously utilized confocal fluorescent imaging technology to observe and characterize tumor-associated vessels in real time during surgical resection of tumors, including cutaneous melanoma and carcinomatosis implants derived from gastrointestinal, gynecological, or primary peritoneal (e.g., mesothelioma) tumors. Our prior studies have demonstrated the feasibility of real-time, human intravital microscopy in the study of these tumor types, leading to early but important new data regarding tumor vessel characteristics and their potential implications on drug delivery and efficacy. In this brief report, we present our latest descriptive findings in a cohort of patients with sarcoma who underwent surgical resection and real-time, intravital microscopy of their tumors. Overall, intravital imaging was feasible during the surgical resection of large sarcomas.

  Clinical Trial Registrations: ClinicalTrials.gov, identifier NCT03517852; ClinicalTrials.gov, identifier NCT03823144.

  Copyright © 2023 Gabriel, Sukniam, Popp and Bagaria.

• Indolyl-chalcone derivatives trigger apoptosis in cisplatin-resistant mesothelioma cells through aberrant tubulin polymerization and deregulation of microtubule-associated proteins. S. Steinlein, F. Essmann, A.F. Ghilardi, et al. 2023;13:1190988. PubMed · Publisher · Free full text

  Abstract

  Introduction: Malignant pleural mesothelioma (MPM) is a neoplasm with dismal prognosis and notorious resistance to the standard therapeutics cisplatin and pemetrexed. Chalcone derivatives are efficacious anti-cancer agents with minimal toxicity and have, therefore, gained pharmaceutical interest. Here, we investigated the efficacy of CIT-026 and CIT-223, two indolyl-chalcones (CITs), to inhibit growth and viability of MPM cells and defined the mechanism by which the compounds induce cell death.

  Methods: The effects of CIT-026 and CIT-223 were analyzed in five MPM cell lines, using viability, immunofluorescence, real-time cell death monitoring, and tubulin polymerization assays, along with siRNA knockdown. Phospho-kinase arrays and immunoblotting were used to identify signaling molecules that contribute to cell death.

  Results: CIT-026 and CIT-223 were toxic in all cell lines at sub-micromolar concentrations, in particular in MPM cells resistant to cisplatin and pemetrexed, while normal fibroblasts were only modestly affected. Both CITs targeted tubulin polymerization via (1) direct interaction with tubulin and (2) phosphorylation of microtubule regulators STMN1, CRMP2 and WNK1. Formation of aberrant tubulin fibers caused abnormal spindle morphology, mitotic arrest and apoptosis. CIT activity was not reduced in CRMP2-negative and STMN1-silenced MPM cells, indicating that direct tubulin targeting is sufficient for toxic effects of CITs.

  Discussion: CIT-026 and CIT-223 are highly effective inducers of tumor cell apoptosis by disrupting microtubule assembly, with only modest effects on non-malignant cells. CITs are potent anti-tumor agents against MPM cells, in particular cells resistant to standard therapeutics, and thus warrant further evaluation as potential small-molecule therapeutics in MPM.

  Copyright © 2023 Steinlein, Essmann, Ghilardi, Horn, Schüler, Hausser, Sun, Ott and Kalla.

• Leptospermum extract (QV0) suppresses pleural mesothelioma tumor growth in vitro and in vivo by mitochondrial dysfunction associated apoptosis. H. Shi, L. Zhang, T.K. Yu, et al. 2023;13:1162027. PubMed · Publisher · Free full text

  Abstract

  Pleural mesothelioma (PM) is a highly aggressive, fast-growing asbestos-induced cancer with limited effective treatments. There has been interest in using naturally occurring anticancer agents derived from plant materials for the treatment of PM. However, it is unclear if an aqueous extract from Leptospermum polygalifolium (QV0) has activity against PM. Here we investigated the anti-cancer properties of QV0 and Defender® (QV0 dietary formula) in vitro and in vivo, respectively. QV0 suppressed the growth of eight PM cell lines in a dose-dependent manner, effective at concentrations as low as 0.02% w/v (equivalent to 0.2 mg/ml). This response was found to be associated with inhibited cell migration, proliferation, and colony formation but without evident cell cycle alteration. We observed mitochondrial dysfunction post-QV0 treatment, as evidenced by significantly decreased basal and maximal oxygen consumption rates. Ten SCID mice were treated with 0.25 mg/g Defender® daily and exhibited reduced tumor size over 30 days, which was associated with an average extension of seven days of mouse life. There was no evidence of liver toxicity or increased blood glucose post-treatment in animals treated with Defender®. Significantly enhanced tumor apoptosis was observed in the Defender®-treated animals, correlating to mitochondrial dysfunction. Lastly, the high levels of polyphenols and antioxidant properties of QV0 and Defender® were detected in HPLC analysis. To the best of our knowledge, this study constitutes the first demonstration of an improved host survival (without adverse effects) response in a QV0-treated PM mouse model, associated with evident inhibition of PM cell growth and mitochondrial dysfunction-related enhancement of tumor apoptosis.

  Copyright © 2023 Shi, Zhang, Yu, Zhuang, Ke, Johnson, Rath, Lee, Klebe, Kao, Qin, Pham, Vuong and Cheng.

• Malignant mediastinal mesothelioma treated with anlotinib: a case report and review of the literature. Y. Zhang, W. He, K. Zhan, et al. 2023;13:1153233. Case report PubMed · Publisher · Free full text

  Abstract

  Malignant mesothelioma that originates from mediastinal (MMM) is a rare form of malignant pleural mesothelioma (MPM). The prognosis of advanced stage MPM was poor, and the traditional treatment was chemotherapy. Here, we present a patient with MMM that was treated with anlotinib, a multitargeted tyrosine kinase inhibitor (TKI) who had a 24-month progression-free survival (PFS). Further review of the literature showed that, despite some explorations of applying small-molecule multitargeted TKIs in the treatment of MPM, until today, no large series had a positive result. Anlotinib had been approved by the China Food and Drug Administration on treating non-small cell lung cancer, soft tissue sarcoma, renal cell carcinoma, and medullary thyroid cancer. We assumed that the ability of anlotinib to target more tyrosine kinase receptors than most of other TKIs could contribute to the long duration of PFS in this case, but further study is needed to further validate the efficacy of anlotinib in treatment of MPM.

  Copyright © 2023 Zhang, He, Zhan, Zhang, Cao and Xu.

• Malignant mesothelioma tumours: molecular pathogenesis, diagnosis, and therapies accompanying clinical studies. R.K. Sahu, S. Ruhi, A.K. Jeppu, et al. 2023;13:1204722. Review PubMed · Publisher · Free full text

  Abstract

  The pathetic malignant mesothelioma (MM) is a extremely uncommon and confrontational tumor that evolves in the mesothelium layer of the pleural cavities (inner lining- visceral pleura and outer lining- parietal pleura), peritoneum, pericardium, and tunica vaginalis and is highly resistant to standard treatments. In mesothelioma, the predominant pattern of lesions is a loss of genes that limit tumour growth. Despite the worldwide ban on the manufacture and supply of asbestos, the prevalence of mesothelioma continues to increase. Mesothelioma presents and behaves in a variety of ways, making diagnosis challenging. Most treatments available today for MM are ineffective, and the median life expectancy is between 10 and 12 months. However, in recent years, considerable progress has already been made in understanding the genetics and molecular pathophysiology of mesothelioma by addressing hippo signaling pathway. The development and progression of MM are related to many important genetic alterations. This is related to NF2 and/or LATS2 mutations that activate the transcriptional coactivator YAP. The X-rays, CT scans, MRIs, and PET scans are used to diagnose the MM. The MM are treated with surgery, chemotherapy, first-line combination chemotherapy, second-line treatment, radiation therapy, adoptive T-cell treatment, targeted therapy, and cancer vaccines. Recent clinical trials investigating the function of surgery have led to the development of innovative approaches to the treatment of associated pleural effusions as well as the introduction of targeted medications. An interdisciplinary collaborative approach is needed for the effective care of persons who have mesothelioma because of the rising intricacy of mesothelioma treatment. This article highlights the key findings in the molecular pathogenesis of mesothelioma, diagnosis with special emphasis on the management of mesothelioma.

  Copyright © 2023 Sahu, Ruhi, Jeppu, Al-Goshae, Syed, Nagdev, Widyowati, Ekasari, Khan, Bhattacharjee, Goyal, Bhattacharya and Jangde.

• Novel combinatorial therapy of oncolytic adenovirus AdV5/3-D24-ICOSL-CD40L with anti PD-1 exhibits enhanced anti-cancer efficacy through promotion of intratumoral T-cell infiltration and modulation of tumour microenvironment in mesothelioma mouse model. M. Garofalo, M. Wieczorek, I. Anders, et al. 2023;13:1259314. PubMed · Publisher · Free full text

  Abstract

  Introduction: Malignant mesothelioma is a rare and aggressive form of cancer. Despite improvements in cancer treatment, there are still no curative treatment modalities for advanced stage of the malignancy. The aim of this study was to evaluate the anti-tumor efficacy of a novel combinatorial therapy combining AdV5/3-D24-ICOSL-CD40L, an oncolytic vector, with an anti-PD-1 monoclonal antibody.

  Methods: The efficacy of the vector was confirmed in vitro in three mesothelioma cell lines - H226, Mero-82, and MSTO-211H, and subsequently the antineoplastic properties in combination with anti-PD-1 was evaluated in xenograft H226 mesothelioma BALB/c and humanized NSG mouse models.

  Results And Discussion: Anticancer efficacy was attributed to reduced tumour volume and increased infiltration of tumour infiltrating lymphocytes, including activated cytotoxic T-cells (GrB+CD8+). Additionally, a correlation between tumour volume and activated CD8+ tumour infiltrating lymphocytes was observed. These findings were confirmed by transcriptomic analysis carried out on resected human tumour tissue, which also revealed upregulation of CD83 and CRTAM, as well as several chemokines (CXCL3, CXCL9, CXCL11) in the tumour microenvironment. Furthermore, according to observations, the combinatorial therapy had the strongest effect on reducing mesothelin and MUC16 levels. Gene set enrichment analysis suggested that the combinatorial therapy induced changes to the expression of genes belonging to the "adaptive immune response" gene ontology category. Combinatorial therapy with oncolytic adenovirus with checkpoint inhibitors may improve anticancer efficacy and survival by targeted cancer cell destruction and triggering of immunogenic cell death. Obtained results support further assessment of the AdV5/3-D24-ICOSL-CD40L in combination with checkpoint inhibitors as a novel therapeutic perspective for mesothelioma treatment.

  Copyright © 2023 Garofalo, Wieczorek, Anders, Staniszewska, Lazniewski, Prygiel, Zasada, Szczepińska, Plewczynski, Salmaso, Caliceti, Cerullo, Alemany, Rinner, Pancer and Kuryk.

• PD-L1 expression complements CALGB prognostic scoring system in malignant pleural mesothelioma. A. Avilés-Salas, L. Cabrera-Miranda, N. Hernández-Pedro, et al. 2023;13:1269029. PubMed · Publisher · Free full text

  Abstract

  Background: Programmed death ligand-1 (PD-L1) expression is a predictive biomarker in patients with lung cancer, but its role in malignant pleural mesothelioma (MPM) remains unclear. Evidence suggests that higher PD-L1 expression is correlated with worse survival. CALGB is the main scoring system used to predict the benefit of chemotherapy treatment. This study aimed to determine the prognostic value of PD-L1 expression and its addition to CALGB scoring system in patients with MPM.

  Methods: In this retrospective analysis, we evaluated samples with confirmed locally advanced or metastatic MPM. PD-L1 Tumor Proportional Score (TPS) was determined by immunohistochemistry at diagnosis.

  Results: 73 patients were included in this study. A cutoff value of 15 was set for a high or low PD-L1 TPS. In total, 71.2% (n=52) and 28.8% (n=21) of individuals harbored low or high PD-L1 expression, respectively. PD-L1High was associated with worse median progression-free Survival (mPFS) [4.9 vs. 10.8 months; HR 2.724, 95% CI (1.44-5.14); p = 0.002] and Overall Survival (OS) [6.0 vs. 20.9 months; HR 6.87, 95% CI (3.4-8.7); p<0.001] compared to patients with PD-L1Low. Multivariate analysis confirmed that PD-L1 expression was an independent factor for PFS and OS in patients with MPM and CALGB score of 5-6.

  Conclusion: PD-L1 addition to CALGB scale improves its prognostic estimation of MPM survival and should be considered in future research.

  Copyright © 2023 Avilés-Salas, Cabrera-Miranda, Hernández-Pedro, Vargas-Lías, Samtani, Muñoz-Montaño, Motola-Kuba, Corrales-Rodríguez, Martín, Cardona, Palomares-Palomares and Arrieta.

• Primary ectopic meningioma in the thoracic cavity: A rare case report and review of the literature. X. Liu, J. Liu, T. Nai, et al. 2023;13:1149627. Case report PubMed · Publisher · Free full text

  Abstract

  Background: Meningioma is a common type of intracranial tumor in adults. It rarely arises in the chest, with only a few case reports in the English literature. Here, we report the case of a patient with a primary ectopic meningioma (PEM) located in the thoracic cavity.

  Case Presentation: A 55-year-old woman presented with exercise-induced asthma, chest tightness, intermittent dry cough and fatigue for several months. Computed tomography revealed the presence of a huge mass in the thoracic cavity, with no connection to the spinal canal. Lung cancer and mesothelioma were suspected, and surgery was performed. Grossly, the mass was a grayish-white solid 9.5 cm × 8.4 cm × 5.3 cm in size. The microscopic morphology of the lesion was consistent with that of typical central nervous system meningioma. The pathological subtype was transitional meningioma. The tumor cells were arranged in a fascicular, whorled, storiform and meningithelial pattern, with occasional intranuclear pseudo-inclusions and psammoma bodies. In focal areas tumor cells were considerably dense, and the cells were round or irregular in shape, with less cytoplasm, uniform nuclear chromatin, and visible nucleoli and mitoses (2/10 HPF). By immunohistochemistry, the neoplastic cells showed strong and diffuse staining with vimentin, epithelial membrane antigen and SSTR2 with variable expression of PR, ALK and S100 protein. However, the cells were negative for GFAP, SOX-10, inhibin, CD34, STAT6, smooth muscle actin, desmin, CKpan, D2-40, WT-1, CK5/6 and CD45. The highest proliferation index by Ki-67 was 15%. The abnormal expression of ALK led to the initial misdiagnosis of an inflammatory myofibroblastic tumor. After 12 months of follow-up, no disease progression was observed.

  Conclusion: The presence of primary ectopic meningiomas in the thoracic cavity is extremely rare, and this tumor is easily misdiagnosed clinically. Imaging is suggested to determine the location and possible differential diagnosis, while the final diagnosis should be via pathological examination. Immunohistochemistry is crucial for disease diagnosis. Owing to our limited knowledge of PEM, its pathogenesis and tissue of origin remain unclear. Clinicians should pay close attention to such potential patients. The present case report may provide insights into the diagnosis and therapy of patients with this tumor.

  Copyright © 2023 Liu, Liu, Nai, Yang and Hu.

• Radiographic response to neoadjuvant therapy in pleural mesothelioma should serve as a guide for patient selection for cytoreductive operations. N. Deboever, N. Zhou, D.J. McGrail, et al. 2023;13:1216999. PubMed · Publisher · Free full text

  Abstract

  Background: Malignant pleural mesothelioma (MPM) is associated with poor prognosis despite advances in multimodal therapeutic strategies. While patients with resectable disease may benefit from added survival with oncologic resection, patient selection for mesothelioma operations often relies on both objective and subjective evaluation metrics. We sought to evaluate factors associated with improved overall survival (OS) in patients with mesothelioma who underwent macroscopic complete resection (MCR).

  Methods: Patients with MPM who received neoadjuvant therapy and underwent MCR were identified in a prospectively maintained departmental database. Clinicopathologic, blood-based, and radiographic variables were collected and included in a Cox regression analysis (CRA). Response to neoadjuvant therapy was characterized by a change in tumor thickness from pretherapy to preoperative scans using the modified RECIST criteria.

  Results: In this study, 99 patients met the inclusion criteria. The median age of the included patients was 64.7 years, who were predominantly men, had smoking and asbestos exposure, and who received neoadjuvant therapy. The median change in tumor thickness following neoadjuvant therapy was -16.5% (interquartile range of -49.7% to +14.2%). CRA demonstrated reduced OS associated with non-epithelioid histology [hazard ratio (HR): 3.06, 95% confidence interval (CI): 1.62-5.78, p < 0.001] and a response to neoadjuvant therapy inferior to the median (HR: 2.70, CI: 1.55-4.72, p < 0.001). Patients who responded poorly (below median) to neoadjuvant therapy had lower median survival (15.8 months compared to 38.2 months, p < 0.001).

  Conclusion: Poor response to neoadjuvant therapy in patients with MPM is associated with poor outcomes even following maximum surgical cytoreduction and should warrant a patient-centered discussion regarding goals of care and may therefore help guide further therapeutic decisions.

  Copyright © 2023 Deboever, Zhou, McGrail, Tomczak, Oliva, Feldman, Parra, Zhang, Lee, Antonoff, Hofstetter, Mehran, Rajaram, Rice, Roth, Swisher, Vaporciyan, Altan, Weissferdt, Tsao, Haymaker and Sepesi.

• The incidence of malignancies in asbestosis with chrysotile exposure: a large Chinese prospective cohort study. J. Wang, X. Huang, R. Ma, et al. 2023;13:1172496. PubMed · Publisher · Free full text

  Abstract

  Background: Asbestos exposure is closely related to the occurrence and development of various malignancies. This prospective cohort study aimed to evaluate the incidence rate and potential risk factors in a cohort of asbestosis patients in China.

  Methods: The incidence of malignancies was determined in patients who had been exposed to chrysotile asbestos and diagnosed with asbestosis sequentially at Beijing Chaoyang Hospital from 1 January 2007 to 31 December 2019. Cox regression analyses were used to analyze the correlations between clinical variables and asbestosis combined with malignancies.

  Results: A total of 618 patients with asbestosis were identified, of whom 544 were eligible for analysis. Among them, 89 (16.36%) were diagnosed with various malignancies. The standardized incidence ratios (SIRs) of patients with asbestosis combined with malignancies were 16.61, 175, 5.23, and 8.77 for lung cancer, mesothelioma, breast cancer, and endometrial carcinoma, respectively. The risks of all malignancies and lung cancer increased with initial exposure before 17 years old, longer asbestos exposure, and smoking.

  Conclusions: The SIRs of patients with asbestosis-related malignancies were significantly increased in lung cancer, mesothelioma, breast cancer, and endometrial carcinoma in a hospital-based Chinese cohort. Smoking and the duration of asbestos exposure increased the risk of lung cancer.

  Copyright © 2023 Wang, Huang, Ma, Zhang, Wu, Du and Ye.

• 3-Dimensional mesothelioma spheroids provide closer to natural pathophysiological tumor microenvironment for drug response studies. H. Shi, E.M. Rath, R.C.Y. Lin, et al. 2022;12:973576. PubMed · Publisher · Free full text

  Abstract

  Traditional studies using cancer cell lines are often performed on a two-dimensional (2D) cell culture model with a low success rate of translating to Phase I or Phase II clinical studies. In comparison, with the advent of developments three-dimensional (3D) cell culture has been championed as the latest cellular model system that better mimics in vivo conditions and pathological conditions such as cancer. In comparison to biospecimens taken from in vivo tissue, the details of gene expression of 3D culture models are largely undefined, especially in mesothelioma - an aggressive cancer with very limited effective treatment options. In this study, we examined the veracity of the 3D mesothelioma cell culture model to study cell-to-cell interaction, gene expression and drug response from 3D cell culture, and compared them to 2D cell and tumor samples. We confirmed via SEM analysis that 3D cells grown using the spheroid methods expressed highly interconnected cell-to-cell junctions. The 3D spheroids were revealed to be an improved mini-tumor model as indicated by the TEM visualization of cell junctions and microvilli, features not seen in the 2D models. Growing 3D cell models using decellularized lung scaffold provided a platform for cell growth and infiltration for all cell types including primary cell lines. The most time-effective method was growing cells in spheroids using low-adhesive U-bottom plates. However, not every cell type grew into a 3D model using the the other methods of hanging drop or poly-HEMA. Cells grown in 3D showed more resistance to chemotherapeutic drugs, exhibiting reduced apoptosis. 3D cells stained with H&E showed cell-to-cell interactions and internal architecture that better represent that of in vivo patient tumors when compared to 2D cells. IHC staining revealed increased protein expression in 3D spheroids compared to 2D culture. Lastly, cells grown in 3D showed very different microRNA expression when compared to that of 2D counterparts. In conclusion, 3D cell models, regardless of which method is used. Showed a more realistic tumor microenvironment for architecture, gene expression and drug response, when compared to 2D cell models, and thus are superior preclinical cancer models.

  Copyright © 2022 Shi, Rath, Lin, Sarun, Clarke, McCaughan, Ke, Linton, Lee, Klebe, Maitz, Song, Wang, Kao and Cheng.

• A Community-Driven, Openly Accessible Molecular Pathway Integrating Knowledge on Malignant Pleural Mesothelioma. M. Martens, F. Kreidl, F. Ehrhart, et al. 2022;12:849640. PubMed · Publisher · Free full text

  Abstract

  Malignant pleural mesothelioma (MPM) is a highly aggressive malignancy mainly triggered by exposure to asbestos and characterized by complex biology. A significant body of knowledge has been generated over the decades by the research community which has improved our understanding of the disease toward prevention, diagnostic opportunities and new treatments. Omics technologies are opening for additional levels of information and hypotheses. Given the growing complexity and technological spread of biological knowledge in MPM, there is an increasing need for an integrating tool that may allow scientists to access the information and analyze data in a simple and interactive way. We envisioned that a platform to capture this widespread and fast-growing body of knowledge in a machine-readable and simple visual format together with tools for automated large-scale data analysis could be an important support for the work of the general scientist in MPM and for the community to share, critically discuss, distribute and eventually advance scientific results. Toward this goal, with the support of experts in the field and informed by existing literature, we have developed the first version of a molecular pathway model of MPM in the biological pathway database WikiPathways. This provides a visual and interactive overview of interactions and connections between the most central genes, proteins and molecular pathways known to be involved or altered in MPM. Currently, 455 unique genes and 247 interactions are included, derived after stringent manual curation of an initial 39 literature references. The pathway model provides a directly employable research tool with links to common databases and repositories for the exploration and the analysis of omics data. The resource is publicly available in the WikiPathways database (Wikipathways : WP5087) and continues to be under development and curation by the community, enabling the scientists in MPM to actively participate in the prioritization of shared biological knowledge.

  Copyright © 2022 Martens, Kreidl, Ehrhart, Jean, Mei, Mortensen, Nash, Nymark, Evelo and Cerciello.

• Case report: Mesothelioma and BAP1 tumor predisposition syndrome: Implications for public health. L. Vimercati, D. Cavone, F. Fortarezza, et al. 2022;12:966063. Case report PubMed · Publisher · Free full text

  Abstract

  BRCA-1 associated protein 1 (BAP1) tumour predisposition syndrome (TPDS) is a hereditary condition characterised by germline mutation of the tumour suppressor BAP1. This disorder is associated with the development of various benign and malignant tumours, mainly involving the skin, eyes, kidneys, and mesothelium. In this article, we report the case of a man recruited through the Apulia (Southern Italy) Mesothelioma Regional Operational Centre of the National Register of Mesotheliomas, who suffered from uveal melanoma, renal cancer, and mesothelioma, and a familial cluster of BAP1 germline mutations demonstrated by molecular analyses. The family members of the proband developed multiple malignancies. As tumours arising in this context have specific peculiarities in terms of clinical behaviour, identification of this condition through appropriate genetic counselling should be considered for adequate primary, secondary, and tertiary prevention measures for offspring.

  Copyright © 2022 Vimercati, Cavone, Fortarezza, Delfino, Ficarella, Gentile, De Palma, Marulli, De Maria, Caporusso, Marzullo, d’Amati, Romano, Caputi, Sponselli, Serio and Pezzuto.

• Case report: Rare intrapulmonary malignant mesothelioma complicated with myositis. D. Gong, J. Yu, X. Jiang. 2022;12:1074821. Case report PubMed · Publisher · Free full text

  Abstract

  Malignant pleural mesothelioma is an uncommon aggressive tumor. Its incidence is even lower when the lung parenchyma is the primary site. Myositis is a common paraneoplastic syndrome, but it rarely presents with malignant pleural mesothelioma. This report presents a rare intrapulmonary malignant mesothelioma complicated by cancer-associated myositis. The patient presented with limb muscle weakness as the first symptom and was diagnosed with intrapulmonary malignant mesothelioma complicated by cancer-associated myositis on the basis of clinical, histological, immunohistochemical, and radiological findings. The patient responded poorly to conventional hormone therapy and died of respiratory failure within 2 months after the first presence of limb muscle weakness.

  Copyright © 2022 Gong, Yu and Jiang.

• Challenging Diagnostic Process for a Malignant Peritoneal Mesothelioma Patient With Ascites and Pleural Effusion: A Case Report and Review of the Literature. X. Zeng, K. Xu, L. Zhang, et al. 2022;12:784064. Case report PubMed · Publisher · Free full text

  Abstract

  Malignant peritoneal mesothelioma (MPM) is a sporadic and fatal disease of the peritoneal lining. Its diagnosis has been known to be challenging, time-consuming, and money-consuming. In this paper, we report an MPM case of a 58-year-old man with severe abdominal distension. After he had received all kinds of auxiliary examination, including computed tomography scans of the chest and whole abdomen, examinations of peripheral and pleural fluid, positron emission tomography, and twice fine-needle peritoneal biopsies, his disease still could not be confirmed. Eventually, the patient was diagnosed with MPM through laparoscopic biopsy and IHC. From this case, we concluded that clinicians can gradually discover and diagnose the disease through 1) high platelet and CA125 levels and CT imaging results, 2) cytologic examinations of ascites and pleural fluid, 3) peritoneal biopsies (fine-needle biopsy, laparoscopy biopsy), and 4) histopathological examinations and immunohistochemistry findings. The diagnostic process involving this patient can be an example to demonstrate the effectiveness of various auxiliary examination methods in MPM diagnosis.

  Copyright © 2022 Zeng, Xu, Zhang and Huang.

• Complete Pathological Response After Neoadjuvant Chemo-Immunotherapy in Malignant Pleural Mesothelioma. F.T. Tostes, M. Zugman, V.R. Paes, et al. 2022;12:836751. PubMed · Publisher · Free full text

• Current State of Pleural-Directed Adjuncts Against Malignant Pleural Mesothelioma. A.Y. Choi, A. Singh, D. Wang, et al. 2022;12:886430. Review PubMed · Publisher · Free full text

  Abstract

  Multimodality therapy including surgical resection is the current paradigm in treating malignant pleural mesothelioma (MPM), a thoracic surface cancer without cure. The main limitation of all surgical approaches is the lack of long-term durability because macroscopic complete resection (R1 resection) commonly predisposes to locoregional relapse. Over the years, there have been many studies that describe various intrapleural strategies that aim to extend the effect of surgical resection. The majority of these approaches are intraoperative adjuvants. Broadly, there are three therapeutic classes that employ diverse agents. The most common, widely used group of adjuvants are comprised of direct therapeutics such as intracavitary chemotherapy (± hyperthermia). By comparison, the least commonly employed intrathoracic adjuvant is the class comprised of drug-device combinations like photodynamic therapy (PDT). But the most rapidly evolving (new) class with much potential for improved efficacy are therapeutics delivered by specialized drug vehicles such as a fibrin gel containing cisplatin. This review provides an updated perspective on pleural-directed adjuncts in the management of MPM as well as highlighting the most promising near-term technology breakthroughs.

  Copyright © 2022 Choi, Singh, Wang, Pittala and Hoang.

• Efficacy and Adverse Events of Apatinib Salvage Treatment for Refractory Diffuse Malignant Peritoneal Mesothelioma: A Pilot Study. Z.R. Yang, Y.D. Su, R. Ma, et al. 2022;12:811800. PubMed · Publisher · Free full text

  Abstract

  Objective: To investigate the clinical efficacy and adverse events (AEs) of apatinib salvage treatment for diffuse malignant peritoneal mesothelioma (DMPM) that has failed to respond to the recommended treatments.

  Methods: 27 patients with refractory DMPM were treated with apatinib at our center from April 2014 to October 2020, at the initial dose of 250 mg/d. The dose was reduced to 125 mg/d when serious adverse events (SAEs) occurred. 28-day was set as a treatment cycle. The frequency of follow up was once every 28 days. The efficacy evaluation was conducted according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria and the serum tumor markers before and after apatinib treatment. The safety assessment was performed with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The primary endpoints were objective response rate (ORR) and disease control rate (DCR), and the secondary endpoints were AEs.

  Results: The 27 patients completed a median treatment-cycle of 15.0, ranging from 5.1 to 39.4 cycles. At the median follow-up of 14.3 (4.8-51.8) months, median overall survival (OS) was 59.4 months, median apatinib-treatment-related survival (ATRS) was 14.0 (4.8-36.8) months. Complete response (CR) was observed in 0 case (0.0%), partial response (PR) in 4 cases (14.8%), stable disease (SD) in 12 cases (44.4%), and progression disease (PD) in 11 cases (40.7%). The ORR was 14.8%, and DCR was 59.3%. The median serum CA125 values before and after apatinib treatment were 32.9 (7.0-4592.4) U/mL and 29.7 (6.1-4327.4) U/mL, respectively (P=0.009). The common AEs were hypertension (6/27; 22.2%), hand-foot syndrome (5/27; 18.5%), albuminuria (4/27; 14.8%), anemia (4/27; 14.8%), leukopenia (4/27; 14.8%), rash (2/27; 7.4%), fatigue (2/27; 7.4%), oral ulcers (2/27; 7.4%), hoarseness (2/27; 7.4%), nausea/vomiting (2/27; 7.4%), diarrhea (2/27; 7.4%), headache (1/27; 3.7%), and fever (1/27; 3.7%). The incidence rate of grade III/IV AEs was 16.2%.

  Conclusions: Apatinib is effective in treating refractory DMPM, with promising efficacy and acceptable safety.

  Copyright © 2022 Yang, Su, Ma, Wu and Li.

• Establishment of predictive nomogram and web-based survival risk calculator for malignant pleural mesothelioma: A SEER database analysis. S. Chen, W. Yu, S. Shao, et al. 2022;12:1027149. PubMed · Publisher · Free full text

  Abstract

  Background: Malignant pleural mesothelioma (MPM) is an uncommon condition with limited available therapies and dismal prognoses. The purpose of this work was to create a multivariate clinical prognostic nomogram and a web-based survival risk calculator to forecast patients' prognoses.

  Methods: Using a randomization process, training and validation groups were created for a retrospective cohort study that examined the Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2015 for individuals diagnosed with MPM (7:3 ratio). Overall survival (OS) and cancer-specific survival (CSS) were the primary endpoints. Clinical traits linked to OS and CSS were identified using Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression analysis, which was also utilized to develop nomogram survival models and online survival risk calculators. By charting the receiver operating characteristic (ROC), consistency index (C-index), calibration curve, and decision curve analysis (DCA), the model's performance was assessed. The nomogram was used to classify patients into various risk categories, and the Kaplan-Meier method was used to examine each risk group's survival rate.

  Results: The prognostic model comprised a total of 1978 patients. For the total group, the median OS and CSS were 10 (9.4-10.5) and 11 (9.4-12.6) months, respectively. As independent factors for OS and CSS, age, gender, insurance, histology, T stage, M stage, surgery, and chemotherapy were chosen. The calibration graphs demonstrated good concordance. In the training and validation groups, the C-indices for OS and CSS were 0.729, 0.717, 0.711, and 0.721, respectively. Our nomogram produced a greater clinical net benefit than the AJCC 7th edition, according to DCA and ROC analysis. According to the cut-off values of 171 for OS and 189 for CSS of the total scores from our nomogram, patients were classified into two risk groups. The P-value < 0.001 on the Kaplan-Meier plot revealed a significant difference in survival between the two patient groups.

  Conclusions: Patient survival in MPM was correctly predicted by the risk evaluation model. This will support clinicians in the practice of individualized medicine.

  Copyright © 2022 Chen, Yu, Shao, Xiao, Bai, Pu and Li.

• Expert guidance on prophylaxis and treatment of dermatologic adverse events with Tumor Treating Fields (TTFields) therapy in the thoracic region. M.J. Anadkat, M. Lacouture, A. Friedman, et al. 2022;12:975473. Review PubMed · Publisher · Free full text

  Abstract

  Tumor Treating Fields (TTFields) are electric fields, delivered via wearable arrays placed on or near the tumor site, that exert physical forces to disrupt cellular processes critical for cancer cell viability and tumor progression. As a first-in-class treatment, TTFields therapy is approved for use in newly diagnosed glioblastoma, recurrent glioblastoma, and pleural mesothelioma. Additionally, TTFields therapy is being investigated in non-small cell lung cancer (NSCLC), brain metastases from NSCLC, pancreatic cancer, ovarian cancer, hepatocellular carcinoma, and gastric adenocarcinoma. Because TTFields therapy is well tolerated and delivery is locoregional, there is low risk of additive systemic adverse events (AEs) when used with other cancer treatment modalities. The most common AE associated with TTFields therapy is mild-to-moderate skin events, which can be treated with topical agents and may be managed without significant treatment interruptions. Currently, there are no guidelines for oncologists regarding the management of TTFields therapy-related skin AEs in the thoracic region, applicable for patients with pleural mesothelioma or NSCLC. This publication aims to provide guidance on preventing, minimizing, and managing dermatologic AEs in the thoracic region to help improve patient quality of life and reduce treatment interruptions that may impact outcomes with TTFields therapy.

  Copyright © 2023 Anadkat, Lacouture, Friedman, Horne, Jung, Kaffenberger, Kalmadi, Ovington, Kotecha, Abdullah and Grosso.

• Genomics of Tumor Origin and Characteristics for Adenocarcinoma and Malignant Pleural Mesothelioma: A Case Report. K. Usuda, Y. Niida, M. Ishikawa, et al. 2022;12:858094. Case report PubMed · Publisher · Free full text

  Abstract

  A female underwent a right middle lobectomy for a pulmonary adenocarcinoma (AD). She eventually died of a right malignant pleural mesothelioma (MPM; sarcomatoid type) 4 years and 7 months after the removal of the AD even though she did not have any history of asbestos exposure, smoking, or radiation exposure. Her chest CT revealed multiple pulmonary nodules and bilateral pleural effusion with a right pleural tumor directly invading into the abdominal cavity. The genomics of tumor origin and characteristics were examined for the AD and the MPM. As a result, 50 somatic variants were detected in the AD, and 29 somatic variants were detected in the MPM. The variants which were common in both the AD and the MPM were not present, which suggested that the AD and the MPM had occurred independently in different origins. The MPM had two driver oncogenes of TP53 and EP300, but the AD did not. Two driver oncogenes of TP53 and EP300 were hypothesized to make the MPM aggressive. The speed at which the MPM progressed without the patient having a history of asbestos exposure, smoking, or radiation exposure was alarming.

  Copyright © 2022 Usuda, Niida, Ishikawa, Iwai, Yamagata, Iijima, Motono, Yamada and Uramoto.

• Headspace Volatile Organic Compound Profiling of Pleural Mesothelioma and Lung Cancer Cell Lines as Translational Bridge for Breath Research. E. Janssens, Z. Mol, L. Vandermeersch, et al. 2022;12:851785. PubMed · Publisher · Free full text

  Abstract

  Introduction: Malignant pleural mesothelioma (MPM) is a lethal cancer for which early-stage diagnosis remains a major challenge. Volatile organic compounds (VOCs) in breath proved to be potential biomarkers for MPM diagnosis, but translational studies are needed to elucidate which VOCs originate from the tumor itself and thus are specifically related to MPM cell metabolism.

  Methods: An in vitro model was set-up to characterize the headspace VOC profiles of six MPM and two lung cancer cell lines using thermal desorption-gas chromatography-mass spectrometry. A comparative analysis was carried out to identify VOCs that could discriminate between MPM and lung cancer, as well as between the histological subtypes within MPM (epithelioid, sarcomatoid and biphasic).

  Results: VOC profiles were identified capable of distinguishing MPM (subtypes) and lung cancer cells with high accuracy. Alkanes, aldehydes, ketones and alcohols represented many of the discriminating VOCs. Discrepancies with clinical findings were observed, supporting the need for studies examining breath and tumor cells of the same patients and studying metabolization and kinetics of in vitro discovered VOCs in a clinical setting.

  Conclusion: While the relationship between in vitro and in vivo VOCs is yet to be established, both could complement each other in generating a clinically useful breath model for MPM.

  Copyright © 2022 Janssens, Mol, Vandermeersch, Lagniau, Vermaelen, van Meerbeeck, Walgraeve, Marcq and Lamote.

• Immune marker expression of irradiated mesothelioma cell lines. F. Chang, S. Keam, T.S. Hoang, et al. 2022;12:1020493. PubMed · Publisher · Free full text

  Abstract

  Background: Though immune checkpoint inhibition has recently shown encouraging clinical efficacy in mesothelioma, most patients do not respond. Combining immune checkpoint inhibition with radiotherapy presents an attractive option for improving treatment responses owing to the various immunomodulatory effects of radiation on tumors. However, the ideal dosing and scheduling of combined treatment remains elusive, as it is poorly studied in mesothelioma. The present study characterizes the dose- and time-dependent changes to expression of various immune markers and cytokines important to antitumor responses following irradiation of mesothelioma cell lines.

  Methods: Two murine (AB1, AE17) and two human (BYE, JU77) mesothelioma cell lines were treated with titrated gamma-radiation doses (1-8 Gy) and the expression of MHC class-I, MHC class-II and PD-L1 was measured over a series of post-irradiation timepoints (1-72 hours) by flow cytometry. Levels of cytokines IL-1α, IL-1β, IL-6, IL-10, IL-12p70, IL-17A, IL-23, IL-27, MCP-1, IFN-β, IFN-γ, TNF-α, and GM-CSF were measured by multiplex immunoassay in murine cell lines following 8 Gy radiation.

  Results: Following irradiation, a dose-dependent upregulation of MHC-I and PD-L1 was observed on three of the four cell lines studied to varying extents. For all cell lines, the increase in marker expression was most pronounced 72 hours after radiation. At this timepoint, increases in levels of cytokines IFN-β, MCP-1 and IL-6 were observed following irradiation with 8 Gy in AB1 but not AE17, reflecting patterns in marker expression.

  Conclusions: Overall, this study establishes the dose- and time-dependent changes in immune marker expression of commonly studied mesothelioma cell lines following radiation and will inform future study into optimal dosing and scheduling of combined radiotherapy and immune checkpoint inhibition for mesothelioma.

  Copyright © 2022 Chang, Keam, Hoang, Creaney, Gill, Nowak, Ebert and Cook.

• Lack of Cardiotoxicity Endpoints in Prospective Trials Involving Chest Radiation Therapy: A Review of Registered, Latter-Phase Studies. R.N. Prasad, E.D. Miller, D. Addison, et al. 2022;12:808531. PubMed · Publisher · Free full text

  Abstract

  Background: Chest radiation therapy (RT) has been associated with increased cardiac morbidity and mortality in numerous studies including the landmark Darby study published in 2013 demonstrating a linear increase in cardiac mortality with increasing mean heart radiation dose. However, the extent to which cardiotoxicity has been incorporated as an endpoint in prospective RT studies remains unknown.

  Methods: We queried clincaltrials.gov to identify phase II/III trials in lung, esophageal, lymphoma, mesothelioma, thymoma, or breast cancer from 1/1/2006-2/1/2021 enrolling greater than 100 patients wherein chest RT was delivered in at least one treatment arm. The primary endpoint was the rate of inclusion of cardiotoxicity as a specific primary or secondary endpoint in the pre- (enrollment started prior to 1/1/2014) versus post-Darby era using the Chi-square test (p<0.05 considered significant). We also analyzed clinical trial factors associated with the inclusion of cardiotoxicity as an endpoint using logistic regression analysis.

  Results: In total, 1,822 trials were identified, of which 256 merited inclusion. 32% were for esophageal, 31% lung, 28% breast, and 7% lymphoma/thymoma/mesothelioma cancers, respectively. 5% (N=13) included cardiotoxicity as an endpoint: 6 breast cancer, 3 lung cancer, 3 esophageal cancer, and 1 lymphoma study. There was no difference in the inclusion of cardiotoxicity endpoints in the pre-Darby versus post-Darby era (3.9% vs. 5.9%, P=0.46). The greatest absolute increase in inclusion of cardiotoxicity as an endpoint was seen for lung cancer (0% vs. 6%, p=0.17) and breast cancer (5.7% vs. 10.8%, p=0.43) studies, though these increases remained statistically non-significant. We found no clinical trial factors associated with the inclusion of cardiotoxicity as an endpoint.

  Conclusions: Among prospective trials involving chest RT, cardiotoxicity remains an uncommon endpoint despite its prevalence as a primary source of toxicity following treatment. In order to better characterize cardiac toxicities, future prospective studies involving chest RT should include cardiotoxicity endpoints.

  Copyright © 2022 Prasad, Miller, Addison and Bazan.

• Molecular Pathways in Peritoneal Mesothelioma: A Minireview of New Insights. F. Fortarezza, F. Pezzuto, A. Marzullo, et al. 2022;12:823839. Review PubMed · Publisher · Free full text

  Abstract

  Mesothelioma is a rare malignant neoplasm with poor survival. It mainly affects the pleura (90%) but can arise in all serous cavities: peritoneum (5-10%), pericardium and tunica vaginalis testis (<1%). The onset of pleural mesothelioma is strictly related to asbestos exposure with a long latency time. The causal link with asbestos has also been suggested for peritoneal mesothelioma, while the importance of exposure in the onset of pericardial and tunica vaginalis testis mesotheliomas is not well known. Mesothelioma remains an aggressive and fatal disease with a five-year mortality rate higher than 95%. However, new therapeutic approaches based on molecular-targeted and immunomodulatory therapies are being explored but have conflicting results. In this context, the identification of critical targets appears mandatory. Awareness of the molecular and physiological changes leading to the neoplastic degeneration of mesothelial cells and the identification of gene mutations, epigenetic alterations, gene expression profiles and altered pathways could be helpful for selecting targetable mechanisms and molecules. In this review, we aimed to report recent research in the last 20 years focusing on the molecular pathways and prognostic factors in peritoneal mesothelioma and their possible diagnostic and therapeutic implications.

  Copyright © 2022 Fortarezza, Pezzuto, Marzullo, Cavone, Romano, d’Amati, Serio and Vimercati.

• Mortality due to respiratory system disease and lung cancer among female workers exposed to chrysotile in Eastern China: A cross-sectional study. Z. Jiang, J. Chen, J. Chen, et al. 2022;12:928839. PubMed · Publisher · Free full text

  Abstract

  Female workers in the asbestos processing industry of Eastern China are at high risk of developing multiple types of cancer, and more data are urgently needed to better understand and address this issue. Death certificate data were selected from an asbestos processing city in China from 2005 to 2006. Information was investigated using the relatives of those individuals who had died as sources of information. Individuals were classified into one of three asbestos exposure levels. Standardized mortality ratio and 95% confidence interval were calculated. A total of 2,964 individual deaths were identified from 2005 to 2006; of these, 21.4% were occupationally exposed to asbestos. The main cause of death was circulatory system diseases (21.2%). The proportion of individuals with respiratory system diseases increased by age among each exposure subgroup (P trend < 0.01). Among females, a significant trend was observed between increased asbestos exposure and mortality due to respiratory system diseases and lung cancer. Our study indicated that asbestos exposure was associated with excess mortality from lung cancer and respiratory diseases, particularly among female workers in an asbestos processing area in Eastern China.

  Copyright © 2022 Jiang, Chen, Chen, Feng, Jin, Zhong, Ju, Zhu, Xiao, Jia, Xu, Yu, Zhang and Lou.

• MSLN Correlates With Immune Infiltration and Chemoresistance as a Prognostic Biomarker in Ovarian Cancer. Y. Li, W. Tian, H. Zhang, et al. 2022;12:830570. PubMed · Publisher · Free full text

  Abstract

  Mesothelin (MSLN) is a glycoprotein with various expression degrees in different tumors including mesothelioma, ovarian cancer, pancreatic cancer, etc. MSLN is considered to play an important role in cell survival, proliferation, and tumor progression. Although the expression of MSLN in tumors makes it a potential therapeutic target, its mechanism of action is still unclear, especially its correlation with immune cells infiltration in the tumor microenvironment has not been investigated. In this study, we detected the overexpression of MSLN in ovarian cancer using database analysis and tissue-array staining. We further evaluated the diagnostic value of MSLN and found it was associated with poor overall survival in ovarian cancer. In addition, the high expression of MSLN was significantly related to the immune-related genes and chemoresistant genes. We confirmed the overexpression of MSLN in the chemoresistant ovarian cancer cell lines. Our research suggests that MSLN participates in a variety of pathways related to the suppression of immune activation and promotion of chemoresistance, leading to a poor prognosis in ovarian cancer.

  Copyright © 2022 Li, Tian, Zhang, Zhang, Zhao, Chang, Lei and Zhang.

• Novel Insights Into Mesothelioma Therapy: Emerging Avenues and Future Prospects. L. Kuryk, G. Rodella, M. Staniszewska, et al. 2022;12:916839. Review PubMed · Publisher · Free full text

  Abstract

  Malignant mesothelioma is a rare and aggressive cancer that develops in the thin layer surrounding the mesothelium and is mainly caused by asbestos exposure. Despite improvements in patient prognosis with conventional cancer treatments, such as surgery, chemotherapy, and radiotherapy, there are still no curative treatment modalities for advanced disease. In recent years, new therapeutic avenues have been explored. Improved understanding of the mechanisms underlying the dynamic tumor interaction with the immune system has led to the development of immunotherapeutic approaches. Numerous recent clinical trials have shown a desire to develop more effective treatments that can be used to fight against the disease. Immune checkpoint inhibitors, oncolytic adenoviruses, and their combination represent a promising strategy that can be used to synergistically overcome immunosuppression in the mesothelioma tumor microenvironment. This review provides a synthesized overview of the current state of knowledge on new therapeutic options for mesothelioma with a focus on the results of clinical trials conducted in the field.

  Copyright © 2022 Kuryk, Rodella, Staniszewska, Pancer, Wieczorek, Salmaso, Caliceti and Garofalo.

• Prognostic Role of Tumor Immune Microenvironment in Pleural Epithelioid Mesothelioma. H. Ollila, M.I. Mäyränpää, L. Paavolainen, et al. 2022;12:870352. PubMed · Publisher · Free full text

  Abstract

  Background: Pleural mesothelioma (MPM) is an aggressive malignancy with an average patient survival of only 10 months. Interestingly, about 5%-10% of the patients survive remarkably longer. Prior studies have suggested that the tumor immune microenvironment (TIME) has potential prognostic value in MPM. We hypothesized that high-resolution single-cell spatial profiling of the TIME would make it possible to identify subpopulations of patients with long survival and identify immunophenotypes for the development of novel treatment strategies.

  Methods: We used multiplexed fluorescence immunohistochemistry (mfIHC) and cell-based image analysis to define spatial TIME immunophenotypes in 69 patients with epithelioid MPM (20 patients surviving ≥ 36 months). Five mfIHC panels (altogether 21 antibodies) were used to classify tumor-associated stromal cells and different immune cell populations. Prognostic associations were evaluated using univariate and multivariable Cox regression, as well as combination risk models with area under receiver operating characteristic curve (AUROC) analyses.

  Results: We observed that type M2 pro-tumorigenic macrophages (CD163+pSTAT1-HLA-DRA1-) were independently associated with shorter survival, whereas granzyme B+ cells and CD11c+ cells were independently associated with longer survival. CD11c+ cells were the only immunophenotype increasing the AUROC (from 0.67 to 0.84) when added to clinical factors (age, gender, clinical stage, and grade).

  Conclusion: High-resolution, deep profiling of TIME in MPM defined subgroups associated with both poor (M2 macrophages) and favorable (granzyme B/CD11c positivity) patient survival. CD11c positivity stood out as the most potential prognostic cell subtype adding prediction power to the clinical factors. These findings help to understand the critical determinants of TIME for risk and therapeutic stratification purposes in MPM.

  Copyright © 2022 Ollila, Mäyränpää, Paavolainen, Paajanen, Välimäki, Sutinen, Wolff, Räsänen, Kallioniemi, Myllärniemi, Ilonen and Pellinen.

• Structure-based discovery of a novel small-molecule inhibitor of TEAD palmitoylation with anticancer activity. A. Gridnev, S. Maity, J.R. Misra. 2022;12:1021823. PubMed · Publisher · Free full text

  Abstract

  The paralogous oncogenic transcriptional coactivators YAP and TAZ are the distal effectors of the Hippo signaling pathway, which plays a critical role in cell proliferation, survival and cell fate specification. They are frequently deregulated in most human cancers, where they contribute to multiple aspects of tumorigenesis including growth, metabolism, metastasis and chemo/immunotherapy resistance. Thus, they provide a critical point for therapeutic intervention. However, due to their intrinsically disordered structure, they are challenging to target directly. Since YAP/TAZ exerts oncogenic activity by associating with the TEAD1-4 transcription factors, to regulate target gene expression, YAP activity can be controlled indirectly by regulating TEAD1-4. Interestingly, TEADs undergo autopalmitoylation, which is essential for their stability and function, and small-molecule inhibitors that prevent this posttranslational modification can render them unstable. In this article we report discovery of a novel small molecule inhibitor of YAP activity. We combined structure-based virtual ligand screening with biochemical and cell biological studies and identified JM7, which inhibits YAP transcriptional reporter activity with an IC50 of 972 nMoles/Ltr. Further, it inhibits YAP target gene expression, without affecting YAP/TEAD localization. Mechanistically, JM7 inhibits TEAD palmitoylation and renders them unstable. Cellular thermal shift assay revealed that JM7 directly binds to TEAD1-4 in cells. Consistent with the inhibitory effect of JM7 on YAP activity, it significantly impairs proliferation, colony-formation and migration of mesothelioma (NCI-H226), breast (MDA-MB-231) and ovarian (OVCAR-8) cancer cells that exhibit increased YAP activity. Collectively, these results establish JM7 as a novel lead compound for development of more potent inhibitors of TEAD palmitoylation for treating cancer.

  Copyright © 2022 Gridnev, Maity and Misra.

• Survival analysis and development of a prognostic nomogram for patients with malignant mesothelioma in different anatomic sites. S. Shao, L. Sun, K. Qin, et al. 2022;12:950371. PubMed · Publisher · Free full text

  Abstract

  Background: Malignant mesothelioma (MMe) is a rare and fatal cancer with a poor prognosis. Our study aimed to compare the overall survival (OS) of MMe patients across various sites and develop a prognostic model to provide a foundation for individualized management of MMe patients.

  Methods: From the Surveillance, Epidemiology, and End Results (SEER) database, 1,772 individuals with malignant mesothelioma (MMe) were identified. The X-tile software was used to identify the optimal cut-off point for continuous variables. The Kaplan-Meier method was employed to compare the survival of MMe across different sites. The Cox proportional hazards model was applied to identify the independent risk factors of overall survival (OS) and a nomogram was constructed.

  Results: In the survival analysis, MMe originating from the reproductive organs and hollow organs showed a relatively better prognosis than those originating from soft tissue, solid organs, and pleura. Age, gender, location, histological type, grade of differentiation, extent of disease, lymph node status, lymph node ratio (LNR), and chemotherapy were all found to be independent risk variables for the prognosis of MMe patients (P<0.05) in a multivariate Cox analysis and were included in the construction of nomogram. In the training and testing sets, the C-index of the nomogram was 0.701 and 0.665, respectively, and the area under the ROC curve (AUROC) of the 1-, 3-, and 5-year overall survival rate was 0.749, 0.797, 0.833 and 0.730, 0.800, 0.832, respectively. The calibration curve shows that the nomogram is well-calibrated.

  Conclusions: This is the first research to examine the prognosis of MMe patients based on the location. However, previous studies often focused on malignant pleural mesothelioma or malignant peritoneal mesothelioma with high incidence. Furthermore, a nomograph with good prediction efficiency was established according to the variables that influence patient survival outcomes, which provides us with a reference for clinical decision-making.

  Copyright © 2022 Shao, Sun, Qin, Jin, Yi, Liu and Wang.

• The extracellular matrix protein fibulin-3/EFEMP1 promotes pleural mesothelioma growth by activation of PI3K/Akt signaling. A. Roshini, C. Goparaju, S. Kundu, et al. 2022;12:1014749. PubMed · Publisher · Free full text

  Abstract

  Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis and limited therapeutic options. The extracellular matrix protein fibulin-3/EFEMP1 accumulates in the pleural effusions of MPM patients and has been proposed as a prognostic biomarker of these tumors. However, it is entirely unknown whether fibulin-3 plays a functional role on MPM growth and progression. Here, we demonstrate that fibulin-3 is upregulated in MPM tissue, promotes the malignant behavior of MPM cells, and can be targeted to reduce tumor progression. Overexpression of fibulin-3 increased the viability, clonogenic capacity and invasion of mesothelial cells, whereas fibulin-3 knockdown decreased these phenotypic traits as well as chemoresistance in MPM cells. At the molecular level, fibulin-3 activated PI3K/Akt signaling and increased the expression of a PI3K-dependent gene signature associated with cell adhesion, motility, and invasion. These pro-tumoral effects of fibulin-3 on MPM cells were disrupted by PI3K inhibition as well as by a novel, function-blocking, anti-fibulin-3 chimeric antibody. Anti-fibulin-3 antibody therapy tested in two orthotopic models of MPM inhibited fibulin-3 signaling, resulting in decreased tumor cell proliferation, reduced tumor growth, and extended animal survival. Taken together, these results demonstrate for the first time that fibulin-3 is not only a prognostic factor of MPM but also a relevant molecular target in these tumors. Further development of anti-fibulin-3 approaches are proposed to increase early detection and therapeutic impact against MPM.

  Copyright © 2022 Roshini, Goparaju, Kundu, Nandhu, Longo, Longo, Chou, Middleton, Pass and Viapiano.

• The role of TGR5 as an onco-immunological biomarker in tumor staging and prognosis by encompassing the tumor microenvironment. Z. Guan, L. Luo, S. Liu, et al. 2022;12:953091. PubMed · Publisher · Free full text

  Abstract

  The relationship between G protein-coupled bile acid receptor 1 (TGR5, GPBAR1) and, specifically, cancer has been studied in in vivo and in vitro experiments, but there is still a lack of pan-cancer analysis to understand the prognostic significance and functioning mechanism of TGR5 in different cancer-driving oncogenic processes. Here, we used Gene Expression Integration, Human Protein Atlas, and The Cancer Genome Atlas (TCGA) to perform a pan-cancer analysis of the role of TGR5 in all 33 tumors. In all TCGA tumors, the TGR5 gene expression has been assessed, and we found that the high TGR5 gene expression in most cancers is associated with poor prognosis of overall survival for cancers such as glioblastoma multiforme (p = 0.0048), kidney renal papillary cell carcinoma (p = 0.033), lower grade glioma (p = 0.0028), thymoma (p = 0.048), and uveal melanoma (p = 0.004), and then the lower expression of TGR5 was linked with poor prognosis in cervical squamous cell carcinoma and endocervical adenocarcinoma (p = 0.014), malignant mesothelioma (MESO) (p = 0.048), sarcoma (p = 0.018), and skin cutaneous melanoma (p = 0.0085). The TGR5 expression was linked with the immune infiltration level of the macrophage M2_TIDE and was also associated with DNA methylation in ovarian and breast cancers. The regulation of hormone secretion, Rap1 pathway, osteoclast differentiation, and bile acid pathway was involved in the functional mechanism of TGR5. Besides, gene expressions were different in different tumors detected by RT-PCR, and cell activity experiments have also found that TGR5 can increase the activity of renal cell carcinoma and reduce the activity of skin cancer and osteosarcoma cells. In this investigation, the aim was to assess the comprehensive overview of the oncogenic roles of TGR5 in all TCGA tumors using pan-analysis.

  Copyright © 2022 Guan, Luo, Liu, Guan, Zhang, Wu and Tao.

• Unraveling tumor microenvironment heterogeneity in malignant pleural mesothelioma identifies biologically distinct immune subtypes enabling prognosis determination. K. Yang, T. Yang, T. Yang, et al. 2022;12:995651. PubMed · Publisher · Free full text

  Abstract

  Background: Malignant pleural mesothelioma (MPM) is a rare and intractable disease exhibiting a remarkable intratumoral heterogeneity and dismal prognosis. Although immunotherapy has reshaped the therapeutic strategies for MPM, patients react with discrepant responsiveness.

  Methods: Herein, we recruited 333 MPM patients from 5 various cohorts and developed an in-silico classification system using unsupervised Non-negative Matrix Factorization and Nearest Template Prediction algorithms. The genomic alterations, immune signatures, and patient outcomes were systemically analyzed across the external TCGA-MESO samples. Machine learning-based integrated methodology was applied to identify a gene classifier for clinical application.

  Results: The gene expression profiling-based classification algorithm identified immune-related subtypes for MPMs. In comparison with the non-immune subtype, we validated the existence of abundant immunocytes in the immune subtype. Immune-suppressed MPMs were enriched with stroma fraction, myeloid components, and immunosuppressive tumor-associated macrophages (TAMs) as well exhibited increased TGF-β signature that informs worse clinical outcomes and reduced efficacy of anti-PD-1 treatment. The immune-activated MPMs harbored the highest lymphocyte infiltration, growing TCR and BCR diversity, and presented the pan-cancer immune phenotype of IFN-γ dominant, which confers these tumors with better drug response when undergoing immune checkpoint inhibitor (ICI) treatment. Genetically, BAP1 mutation was most commonly found in patients of immune-activated MPMs and was associated with a favorable outcome in a subtype-specific pattern. Finally, a robust 12-gene classifier was generated to classify MPMs with high accuracy, holding promise value in predicting patient survival.

  Conclusions: We demonstrate that the novel classification system can be exploited to guide the identification of diverse immune subtypes, providing critical biological insights into the mechanisms driving tumor heterogeneity and responsible for cancer-related patient prognoses.

  Copyright © 2022 Yang, Yang, Yang, Yuan and Li.

• A Pan-Cancer Analysis of the Oncogenic Role of Twinfilin Actin Binding Protein 1 in Human Tumors. G. Huo, Y. Wang, J. Chen, et al. 2021;11:692136. PubMed · Publisher · Free full text

  Abstract

  Background: Understanding common and unique mechanisms driving oncogenic processes in human tumors is indispensable to develop efficient therapies. Recent studies have proposed Twinfilin Actin Binding Protein 1 (TWF1) as a putative driver gene in lung cancer, pancreatic cancer and breast cancer, however a systematic pan-cancer analysis has not been carried out.

  Methods: Here, we set out to explore the role of TWF1 in 33 tumor types using TCGA (The Cancer Genome Atlas), GEO (Gene Expression Omnibus) dataset, Human Protein Atlas (HPA), and several bioinformatic tools.

  Results: As part of our analysis, we have assessed TWF1 expression across tumors. We found that over-expression of TWF1 generally predicted poor OS for patients with tumors with high TWF1 expression, such as mesothelioma, lung adenocarcinoma, cervical cancer and pancreatic adenocarcinoma. We also assessed the mutation burden of TWF1 in cancer and the TWF1-associated survival of cancer patients, compared the phosphorylation of TWF1 between normal and primary tumor tissues and explored putative functional mechanisms in TWF1-mediated oncogenesis.

  Conclusions: Our pan-cancer analysis provides a comprehensive overview of the oncogenic roles of TWF1 in multiple human cancers.

  Copyright © 2021 Huo, Wang, Chen, Song, Zhang, Guo, Zuo, Zhu, Cui, Chen, Chen and Chen.

• A3 Adenosine and P2X7 Purinergic Receptors as New Targets for an Innovative Pharmacological Therapy of Malignant Pleural Mesothelioma. F. Vincenzi, J.C. Rotondo, S. Pasquini, et al. 2021;11:679285. PubMed · Publisher · Free full text

  Abstract

  Human malignant pleural mesothelioma (MPM) is a rare, but aggressive tumor of the serosal cavities whose 5-year survival rate is 15%. At present, there are no effective therapies for MPM. Although recent findings suggest that A3 adenosine (A3AR) and P2X7 (P2X7R) receptors can be employed as antitumoral pharmacological targets in MPM, their potential role in a combined therapy is currently unknown. The A3AR agonist Cl-IB-MECA and the P2X7 receptor antagonist AZ10606120, as a single compound or in combination, were investigated in vitro for their anti-tumor activities. Assays were carried out in MPM cell lines IST-Mes2 and MPP89 and in primary human normal mesothelial cells (HMCs), as control. Single treatment with Cl-IB-MECA reduced cell proliferation and favored a pro-apoptotic effect in both MPP89 and IST-Mes2 cell lines, whereas AZ10606120 inhibited cell proliferation and induced apoptosis in IST-Mes2, only. The combined treatment with Cl-IB-MECA and AZ10606120 reduced cell proliferation and favored apoptosis in MPP89 and IST-Mes2 cell lines, whereas no synergistic effect was detected. These data cumulatively suggest the absence of a synergistic effect in combined targeting of A3 adenosine and P2X7 receptors of MPM cell lines. This study may stimulate further investigations aimed at determining new combinations of antitumor compounds and more effective therapeutic strategies against MPM.

  Copyright © 2021 Vincenzi, Rotondo, Pasquini, Di Virgilio, Varani and Tognon.

• An EBC/Plasma miRNA Signature Discriminates Lung Adenocarcinomas From Pleural Mesothelioma and Healthy Controls. A. Faversani, C. Favero, L. Dioni, et al. 2021;11:643280. PubMed · Publisher · Free full text

  Abstract

  Background: Despite significant improvement in screening programs for cancers of the respiratory district, especially in at-risk subjects, early disease detection is still a major issue. In this scenario, new molecular and non-invasive biomarkers are needed to improve early disease diagnosis.

  Methods: We profiled the miRNome in exhaled breath condensate (EBC) and plasma samples from fourteen patients affected by lung AdCa, nine healthy subjects. miRNA signatures were then analyzed in another neoplasia of the respiratory district, i.e. pleural mesothelioma (n = 23) and subjects previously exposed to asbestos were used as controls for this cohort (n = 19). Selected miRNAs were analyzed in purified pulmonary neoplastic or normal epithelial and stromal cell subpopulation from AdCa patients. Finally, the plasmatic miRNA signature was analyzed in a publicly available cohort of NSCLC patients for data validation and in silico analysis was performed with predicted miRNA targets using the multiMiR tool and STRING database.

  Results: miR-597-5p and miR-1260a are significantly over-expressed in EBC from lung AdCa and are associated with AdCa. Similarly, miR-1260a is also up-regulated in the plasma of AdCa patients together with miR-518f-3p and correlates with presence of lung cancer, whereas let-7f-5p is under-expressed. Analysis of these circulating miRNAs in pleural mesothelioma cases confirmed that up-regulation of miR-518f-3p, -597-5p and -1260a, is specific for lung AdCa. Lastly, quantification of the miRNAs in laser-assisted microdissected lung tissues revealed that miR-518f-3p, 597-5p and miR-1260a are predominantly expressed in tumor epithelial cells. Validation analysis confirmed miR-518f-3p as a possible circulating biomarker of NSCLC. In silico analysis of the potentially modulated biological processes by these three miRNAs, shows that tumor bioenergetics are the most affected pathways.

  Conclusions: Overall, our data suggest a 3-miRNAs signature as a non-invasive and accurate biomarker of lung AdCa. This approach could supplement the current screening approaches for early lung cancer diagnosis.

  Copyright © 2021 Faversani, Favero, Dioni, Pesatori, Bollati, Montoli, Musso, Terrasi, Fusco, Nosotti, Vaira and Palleschi.

• Aurora Kinase A as a Diagnostic and Prognostic Marker of Malignant Mesothelioma. Z. Guo, L. Shen, N. Li, et al. 2021;11:789244. PubMed · Publisher · Free full text

  Abstract

  Background: Malignant mesothelioma (MM) is a highly aggressive cancer with a poor prognosis. Despite the use of several well-known markers, the diagnosis of MM is still challenging in some cases. we applied bioinformatics to identify key genes and screen for diagnostic and prognostic markers of MM.

  Methods: The expression profiles of GSE2549 and GSE112154 microarray datasets from the Gene Expression Omnibus database contained 87 cases of MM tissue and 8 cases of normal mesothelial tissue in total. The GEO2R tool was used to detect differentially expressed genes (DEGs). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of DEGs were performed using DAVID Bioinformatics Resources. The DEGs protein-protein interaction networks were constructed from the STRING database. Cytoscape was used to identify significant modules and hub genes. The GEPIA database was used to explore relationships between hub genes and prognosis of MM. Immunohistochemistry was used to analyze protein expression in tissue microarrays with 47 Chinese MM tissues. Statistical analyses diagnostic and prognostic values.

  Results: 346 DEGs were identified: 111 genes upregulated, and 235 downregulated. GO analysis showed that the primary biological processes of these DEGs were cell adhesion, leukocyte migration, and angiogenesis. The main cellular components included the extracellular space, extracellular exosome, and extracellular region. The molecular functions were integrin binding, heparin binding, and calcium ion binding. KEGG pathway analysis showed that DEGs are primarily involved in PPAR signaling pathway, extracellular matrix-receptor interactions, and regulation of lipolysis in adipocytes. Survival analysis showed that seven genes-AURKA, GAPDH, TOP2A, PPARG, SCD, FABP4, and CEBPA-may be potential prognostic markers for MM. Immunohistochemical studies showed that Aurora kinase A (AURKA gene encode, Aurora-A) and GAPDH were highly expressed in MM tissue in comparison with normal mesothelial tissue. Kaplan-Meier analysis confirmed a correlation between Aurora-A protein expression and overall survival but did not confirm a correlation with GAPDH. The receiver operating characteristic curves of Aurora-A protein expression suggested acceptable accuracy (AUC = 0.827; 95% CI [0.6686 to 0.9535]; p = 0.04). The sensitivity and specificity of Aurora-A were 83.33% and 77.78%, respectively.

  Conclusion: Aurora-A could be an optimal diagnostic biomarker and a potential prognostic marker for MM.

  Copyright © 2021 Guo, Shen, Li, Wu, Wang, Gu, Chen, Liu, Mao and Han.

• BAP1-Altered Malignant Pleural Mesothelioma: Outcomes With Chemotherapy, Immune Check-Point Inhibitors and Poly(ADP-Ribose) Polymerase Inhibitors. E. Dudnik, J. Bar, A. Moore, et al. 2021;11:603223. PubMed · Publisher · Free full text

  Abstract

  Objectives: Little is known regarding the outcomes of systemic treatments in BAP1-altered malignant pleural mesothelioma (MPM).

  Materials And Methods: Forty five patients with MPM [group A: eight MPM patients with BAP1 inactivating mutation/copy number loss (FoundationOne® CDx/TEMPUSxT), selected from the electronic databases of four Israeli cancer centers (ICC); group B: 37 consecutive (years 2016-2018) MPM patients selected from the electronic databases of two ICC-of those six patients without a BAP1 alteration (group B1) and 31 patients not tested for BAP1 (group B2)] were analyzed for ORR, PFS (mRECIST), and OS with 1st-line platinum/pemetrexed+/-antiangiogenic drug (CT, n-28), immune check-point inhibitors (ICPi, n-16) and poly (ADP-ribose) polymerase inhibitors (PARPi, n-4). OS since diagnosis (OSDx) was assessed.

  Results: There were no differences in ORR or mPFS with CT between the groups: ORR-50% vs. 47% vs. 50% vs. 47% (p>0.9), mPFS-9.1mo (95% CI, 1.2-16.1) vs. 9.2mo (95% CI, 2.9-13.3) vs. 7.2mo (95% CI, 2.3-NR) vs. 10.9mo (95% CI, 2.9-20.3) (p>0.8) in groups A, B, B1, and B2, respectively. There were no differences in ORR or mPFS with ICPi between the groups: ORR-0% vs. 27% vs. 33% vs. 25% (p>0.2), mPFS-2.5mo (95% CI, 1.4-3.7) vs. 3.0mo (95% CI, 1.3-10.5) vs. 2.0mo (95% CI, 1.9-NR) vs. 4.5mo (95% CI, 0.3-10.5) (p>0.3) in groups A, B, B1, and B2, respectively. In group A, no responses were seen with PARPi; mPFS with PARPi was 1.8mo (95% CI, 1.8-NR). OSDx was 98.3mo (95% CI, 9.7-98.3) vs. 19.4mo (95% CI, 9.7-47.3) vs. 18.8mo (95% CI, 8.5-NR) vs. 19.5mo (95% CI, 8.3-82.2) in groups A, B, B1, and B2, respectively (p>0.3).

  Conclusions: BAP1-altered MPM, as compared to non-selected MPM, is characterized by similar efficacy of CT and ICPi. Numerically longer OS in BAP1-altered MPM may reflect favorable tumor biology. No responses were observed with PARPi.

  Copyright © 2021 Dudnik, Bar, Moore, Gottfried, Moskovitz, Dudnik, Shochat, Allen, Zer, Rotem, Peled and Urban.

• Biological Pathways Associated With the Development of Pulmonary Toxicities in Mesothelioma Patients Treated With Radical Hemithoracic Radiation Therapy: A Preliminary Study. S. Crovella, A. Revelant, E. Muraro, et al. 2021;11:784081. PubMed · Publisher · Free full text

  Abstract

  Radical hemithoracic radiotherapy (RHR), after lung-sparing surgery, has recently become a concrete therapeutic option for malignant pleural mesothelioma (MPM), an asbestos-related, highly aggressive tumor with increasing incidence and poor prognosis. Although the toxicity associated to this treatment has been reduced, it is still not negligible and must be considered when treating patients. Genetic factors appear to play a role determining radiotherapy toxicity. The aim of this study is the identification of biological pathways, retrieved through whole exome sequencing (WES), possibly associated to the development of lung adverse effects in MPM patients treated with RHR. The study included individuals with MPM, treated with lung-sparing surgery and chemotherapy, followed by RHR with curative intent, and followed up prospectively for development of pulmonary toxicity. Due to the strong impact of grade 3 pulmonary toxicities on the quality of life, compared with less serious adverse events, for genetic analyses, patients were divided into a none or tolerable pulmonary toxicity (NoSTox) group (grade ≤2) and a severe pulmonary toxicity (STox) group (grade = 3). Variant enrichment analysis allowed us to identify different pathway signatures characterizing NoSTox and Stox patients, allowing to formulate hypotheses on the protection from side effects derived from radiotherapy as well as factors predisposing to a worst response to the treatment. Our findings, being aware of the small number of patients analyzed, could be considered a starting point for the definition of a panel of pathways, possibly helpful in the management of MPM patients.

  Copyright © 2021 Crovella, Revelant, Muraro, Moura, Brandão, Trovò, Steffan, Zacchi, Zabucchi, Minatel and Borelli.

• Carbon Nanotubes: A Summary of Beneficial and Dangerous Aspects of an Increasingly Popular Group of Nanomaterials. C. Zhang, L. Wu, M. de Perrot, et al. 2021;11:693814. Review PubMed · Publisher · Free full text

  Abstract

  Carbon nanotubes (CNTs) are nanomaterials with broad applications that are produced on a large scale. Animal experiments have shown that exposure to CNTs, especially one type of multi-walled carbon nanotube, MWCNT-7, can lead to malignant transformation. CNTs have characteristics similar to asbestos (size, shape, and biopersistence) and use the same molecular mechanisms and signaling pathways as those involved in asbestos tumorigenesis. Here, a comprehensive review of the characteristics of carbon nanotubes is provided, as well as insights that may assist in the design and production of safer nanomaterials to limit the hazards of currently used CNTs.

  Copyright © 2021 Zhang, Wu, de Perrot and Zhao.

• CDKN2A Determines Mesothelioma Cell Fate to EZH2 Inhibition. G. Pinton, Z. Wang, C. Balzano, et al. 2021;11:678447. PubMed · Publisher · Free full text

  Abstract

  Malignant pleural mesothelioma is an aggressive cancer, heterogeneous in its presentation and behaviour. Despite an increasing knowledge about molecular markers and their diagnostic and prognostic value, they are not used as much as they might be for treatment allocation. It has been recently reported that mesothelioma cells that lack BAP1 (BRCA1 Associated Protein) are sensitive to inhibition of the EZH2 (Enhancer of Zeste Homolog 2) histone methyltransferase. Since we observed strong H3K27me3 (histone H3 lysine 27 trimetylation) immunoreactivity in BAP1 wild-type mesothelioma biopsies, we decided to characterize in vitro the response/resistance of BAP1 wild-type mesothelioma cells to the EZH2 selective inhibitor, EPZ-6438. Here we demonstrate that BAP1 wild-type mesothelioma cells were rendered sensitive to EPZ-6438 upon SIRT1 (Sirtuin 1) silencing/inhibition or when cultured as multicellular spheroids, in which SIRT1 expression was lower compared to cells grown in monolayers. Notably, treatment of spheroids with EPZ-6438 abolished H3K27me3 and induced the expression of CDKN2A (Cyclin-Dependent Kinase Inhibitor 2A), causing cell growth arrest. EPZ-6438 treatment also resulted in a rapid and sustained induction of the genes encoding HIF2α (Hypoxia Inducible Factor 2α), TG2 (Transglutaminase 2) and IL-6 (Interleukin 6). Loss of CDKN2 is a common event in mesothelioma. CDKN2A silencing in combination with EPZ-6438 treatment induced apoptotic death in mesothelioma spheroids. In a CDKN2A wild-type setting apoptosis was induced by combining EPZ-6438 with 1-155, a TG2 selective and irreversible inhibitor. In conclusion, our data suggests that the expression of CDKN2A predicts cell fate in response to EZH2 inhibition and could potentially stratify tumors likely to undergo apoptosis.

  Copyright © 2021 Pinton, Wang, Balzano, Missaglia, Tavian, Boldorini, Fennell, Griffin and Moro.

• Combined Analysis of RNA Sequence and Microarray Data Reveals a Competing Endogenous RNA Network as Novel Prognostic Markers in Malignant Pleural Mesothelioma. W. Duan, K. Wang, Y. Duan, et al. 2021;11:615234. PubMed · Publisher · Free full text

  Abstract

  Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with short survival time. Unbalanced competing endogenous RNAs (ceRNAs) have been shown to participate in the tumor pathogenesis and served as biomarkers for the clinical prognosis. However, the comprehensive analyses of the ceRNA network in the prognosis of MPM are still rarely reported. In this study, we obtained the transcriptome data of the MPM and the normal samples from TCGA, EGA, and GEO databases and identified the differentially expressed (DE) mRNAs, lncRNAs, and miRNAs. The functions of the prognostic genes and the overlapped DEmRNAs were further annotated by the multiple enrichment analyses. Then, the targeting relationships among lncRNA-miRNA and miRNA-mRNA were predicted and calculated, and a prognostic ceRNA regulatory network was established. We included the prognostic 73 mRNAs and 13 miRNAs and 26 lncRNAs into the ceRNA network. Moreover, 33 mRNAs, three miRNAs, and seven lncRNAs were finally associated with prognosis, and a model including seven mRNAs, two lincRNAs, and some clinical factors was finally established and validated by two independent cohorts, where CDK6 and SGMS1-AS1 were significant to be independent prognostic factors. In addition, the identified co-expressed modules associated with the prognosis were overrepresented in the ceRNA network. Multiple enrichment analyses showed the important roles of the extracellular matrix components and cell division dysfunction in the invasion of MPM potentially. In summary, the prognostic ceRNA network of MPM was established and analyzed for the first time and these findings shed light on the function of ceRNAs and revealed the potential prognostic and therapeutic biomarkers of MPM.

  Copyright © 2021 Duan, Wang, Duan, Chen, Chu, Hu and Xiong.

• Editorial: Epigenetic Modifications in Mesothelioma. Y.Y. Cheng, M.L. Yuen, H. Jin. 2021;11:650136. Editorial PubMed · Publisher · Free full text

• Efficacy of Intraoperative Hypertonic Glucose Solution Administration on Persistent Air Leak After Extended Pleurectomy/Decortication for Malignant Pleural Mesothelioma: A Retrospective Case-Control Study. A. Testori, G. Perroni, M. Alloisio, et al. 2021;11:767791. PubMed · Publisher · Free full text

  Abstract

  Background: Persistent air leak is a common complication occurring from 6% to 23% of cases after extended pleurectomy/decortication for malignant pleural mesothelioma. Treatment options for this complication after major lung resection are well documented in literature; nevertheless, lines of evidence in extended pleurectomy/decortication for malignant pleural mesothelioma are absent. The aim of the study is to evaluate the efficacy of intraoperative administration of 50% hypertonic glucose solution in reducing duration of air leak following extended pleurectomy/decortication for malignant pleural mesothelioma.

  Materials And Methods: In this retrospective case-control study, we analyzed our electronic health record and selected those patients with a histological diagnosis of malignant pleural mesothelioma who underwent extended pleurectomy/decortication in the period 2013-2021. From 2018, we introduced a lavage with 500 ml of glucose solution at 50% concentration into the chest cavity at the end of the surgical procedure. Patients operated before 2018 were used as the control group. Postoperative glycemia was measured, and patients were followed after hospital discharge until the air leak resolved and the chest tube was removed. Statistical analysis was performed using R software.

  Results: A total of 71 patients met our criteria. Treatment and control groups were similar for age, sex, smoking status, number of comorbidities, tumor histotype, and side of disease. Use of hypertonic glucose solution resulted in shorter chest tube maintenance after hospital discharge (p = 0.0028). A statistically significant difference (p = 0.02) was also found in postoperative glycemia between the treatment (103 g/dl ± 8.9) and control group (98.8 g/dl ± 8.6). Days of hospitalization and chest tube maintenance during hospitalization did not significantly differ between the groups.

  Interpretation: Intraoperative administration of 50% hypertonic glucose solution reduced the duration of air leak after hospital discharge. An increase in postoperative glycemia was found in the treatment group, but with no clinical effect. Hypertonic glucose solution is an effective and safe method to manage persistent air leak after extended pleurectomy/decortication for malignant pleural mesothelioma.

  Copyright © 2021 Testori, Perroni, Alloisio, Voulaz, Giudici, Cariboni and Bottoni.

• Efficacy, Safety, and Cost-Minimization Analysis of Continuous Infusion of Low-Dose Gemcitabine Plus Cisplatin in Patients With Unresectable Malignant Pleural Mesothelioma. O. Arrieta, W. Muñoz-Montaño, S. Muñiz-Hernández, et al. 2021;11:641975. PubMed · Publisher · Free full text

  Abstract

  Background: Malignant pleural mesothelioma (MPM) is rare and aggressive neoplasia, with a poor prognosis; furthermore, the monetary cost of its treatment represents a major challenge for many patients. The economic burden this malignancy imposes is underscored by the fact that asbestos exposure, which is the most frequent risk factor, is much more prevalent in the lower socioeconomic population of developing countries. The aims of the present study were to evaluate the efficacy, safety, and cost of continuous infusion of low-dose Gemcitabine plus Cisplatin (CIGC) as a treatment strategy for patients with unresectable MPM.

  Methods: We performed a prospective cohort study to determine efficacy and safety of continuous infusion gemcitabine at a dose of 250 mg/m2 in a 6-h continuous infusion plus cisplatin 35 mg/m2 on days 1 and 8 of a 21-day cycle in patients with unresectable MPM. We also performed a cost-minimization analysis to determine if this chemotherapy regimen is less expensive than other currently used regimens.

  Results: The median number of chemotherapy cycles was six (range 1-11 cycles); objective response rate was documented in 46.2%, and disease control rate was seen in 81.2%. Median PFS was 8.05 months (CI 95% 6.97-9.13); median OS was 16.16 months (CI 95% 12.5-19.9). The cost minimization analysis revealed savings of 66.4, 61.9, and 97.7% comparing CIGC with short-infusion gemcitabine plus cisplatin (SIGC), cisplatin plus pemetrexed (CP), and cisplatin plus pemetrexed and bevacizumab (CPB), respectively. Furthermore, this chemotherapy regimen proved to be safe at the administered dosage.

  Conclusion: CIGC is an effective and safe treatment option for patients with unresectable MPM; besides, this combination is a cost-saving option when compared with other frequently used chemotherapy schemes. Therefore, this treatment scheme should be strongly considered for patients with unresectable MPM and limited economic resources.

  Copyright © 2021 Arrieta, Muñoz-Montaño, Muñiz-Hernández, Campos, Catalán, Soto-Molina, Guzmán Vázquez, Díaz-Álvarez, Martínez-Pacheco, Turcott, Ramos-Ramírez, Cabrera-Miranda, Barrón and Cardona.

• Germline BAP1 Mutation in a Family With Multi-Generational Meningioma With Rhabdoid Features: A Case Series and Literature Review. R.N. Prasad, U.G. Gardner, A. Yaney, et al. 2021;11:721712. PubMed · Publisher · Free full text

  Abstract

  Meningioma is the most common primary brain tumor, and recurrence risk increases with increasing WHO Grade from I to III. Rhabdoid meningiomas are a subset of WHO Grade III tumors with rhabdoid cells, a high proliferation index, and other malignant features that follow an aggressive clinical course. Some meningiomas with rhabdoid features either only focally or without other malignant features are classified as lower grade yet still recur early. Recently, inactivating mutations in the tumor suppressor gene BAP1 have been associated with poorer prognosis in rhabdoid meningioma and meningioma with rhabdoid features, and germline mutations have been linked to a hereditary tumor predisposition syndrome (TPDS) predisposing patients primarily to melanoma and mesothelioma. We present the first report of a familial BAP1 inactivating mutation identified after multiple generations of a family presented with meningiomas with rhabdoid features instead of with previously described BAP1 loss-associated malignancies. A 24-year-old female presented with a Grade II meningioma with rhabdoid and papillary features treated with subtotal resection, adjuvant external beam radiation therapy, and salvage gamma knife radiosurgery six years later. Around that time, her mother presented with a meningioma with rhabdoid and papillary features managed with resection and adjuvant radiation therapy. Germline testing was positive for a pathogenic BAP1 mutation in both patients. Sequencing of both tumors demonstrated biallelic BAP1 inactivation via the combination of germline BAP1 mutation and either loss of heterozygosity or somatic mutation. No additional mutations implicated in oncogenesis were noted from either patient's germline or tumor sequencing, suggesting that the inactivation of BAP1 was responsible for pathogenesis. These cases demonstrate the importance of routine BAP1 tumor testing in meningioma with rhabdoid features regardless of grade, germline testing for patients with BAP1 inactivated tumors, and tailored cancer screening in this population.

  Copyright © 2021 Prasad, Gardner, Yaney, Prevedello, Koboldt, Thomas, Mardis and Palmer.

• Homozygous Co-Deletion of Type I Interferons and CDKN2A Genes in Thoracic Cancers: Potential Consequences for Therapy. M. Grard, C. Chatelain, T. Delaunay, et al. 2021;11:695770. Review PubMed · Publisher · Free full text

  Abstract

  Homozygous deletion (HD) of the tumor suppressor gene CDKN2A is the most frequent genetic alteration in malignant pleural mesothelioma and is also frequent in non-small cell lung cancers. This HD is often accompanied by the HD of the type I interferons (IFN I) genes that are located closed to the CDKN2A gene on the p21.3 region of chromosome 9. IFN I genes encode sixteen cytokines (IFN-α, IFN-β…) that are implicated in cellular antiviral and antitumor defense and in the induction of the immune response. In this review, we discuss the potential influence of IFN I genes HD on thoracic cancers therapy and speak in favor of better taking these HD into account in patients monitoring.

  Copyright © 2021 Grard, Chatelain, Delaunay, Pons-Tostivint, Bennouna and Fonteneau.

• How to Better Understand the Influence of Host Genetics on Developing an Effective Immune Response to Thoracic Cancers. K. Behrouzfar, K. Burton, S.E. Mutsaers, et al. 2021;11:679609. Review PubMed · Publisher · Free full text

  Abstract

  Thoracic cancers pose a significant global health burden. Immune checkpoint blockade therapies have improved treatment outcomes, but durable responses remain limited. Understanding how the host immune system interacts with a developing tumor is essential for the rational development of improved treatments for thoracic malignancies. Recent technical advances have improved our understanding of the mutational burden of cancer cells and changes in cancer-specific gene expression, providing a detailed understanding of the complex biology underpinning tumor-host interactions. While there has been much focus on the genetic alterations associated with cancer cells and how they may impact treatment outcomes, how host genetics affects cancer development is also critical and will greatly determine treatment response. Genome-wide association studies (GWAS) have identified genetic variants associated with cancer predisposition. This approach has successfully identified host genetic risk factors associated with common thoracic cancers like lung cancer, but is less effective for rare cancers like malignant mesothelioma. To assess how host genetics impacts rare thoracic cancers, we used the Collaborative Cross (CC); a powerful murine genetic resource designed to maximize genetic diversity and rapidly identify genes associated with any biological trait. We are using the CC in conjunction with our asbestos-induced MexTAg mouse model, to identify host genes associated with mesothelioma development. Once genes that moderate tumor development and progression are known, human homologues can be identified and human datasets interrogated to validate their association with disease outcome. Furthermore, our CC-MexTAg animal model enables in-depth study of the tumor microenvironment, allowing the correlation of immune cell infiltration and gene expression signatures with disease development. This strategy provides a detailed picture of the underlying biological pathways associated with mesothelioma susceptibility and progression; knowledge that is crucial for the rational development of new diagnostic and therapeutic strategies. Here we discuss the influence of host genetics on developing an effective immune response to thoracic cancers. We highlight current knowledge gaps, and with a focus on mesothelioma, describe the development and application of the CC-MexTAg to overcome limitations and illustrate how the knowledge gained from this unique study will inform the rational design of future treatments of mesothelioma.

  Copyright © 2021 Behrouzfar, Burton, Mutsaers, Morahan, Lake and Fisher.

• Immune Microenvironment and Genetics in Malignant Pleural Mesothelioma. B. Wadowski, R. Bueno, A. De Rienzo. 2021;11:684025. Review PubMed · Publisher · Free full text

  Abstract

  Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy with limited therapeutic options beyond surgery and cytotoxic chemotherapy. The success of immune checkpoint inhibition has been found to correlate with expression of immune-related genes such as CD274 (PD-L1) in lung and other solid cancers. However, only a small subset of MPM patients respond to checkpoint inhibition, and this response has been varied and unpredictable across several clinical trials. Recent advances in next-generation sequencing (NGS) technology have improved our understanding of the molecular features of MPM, also with respect to its genetic signature and how this impacts the immune microenvironment. This article will review current evidence surrounding the interplay between MPM genetics, including epigenetics and transcriptomics, and the immune response.

  Copyright © 2021 Wadowski, Bueno and De Rienzo.

• Insulin-Like Growth Factor 2 mRNA Binding Protein 3 Promotes Cell Proliferation of Malignant Mesothelioma Cells by Downregulating p27Kip1. I. Endo, V.J. Amatya, K. Kushitani, et al. 2021;11:795467. PubMed · Publisher · Free full text

  Abstract

  Malignant mesothelioma is a tumor with a poor prognosis, mainly caused by asbestos exposure and with no adequate treatment yet. To develop future therapeutic targets, we analyzed the microarray dataset GSE 29370 of malignant mesothelioma and reactive mesothelial hyperplasia, downloaded from the Gene Expression Omnibus (GEO) database. We identified insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) as one of the significantly upregulated genes in malignant mesothelioma. IGF2BP3 functions as an oncoprotein in many human cancers; however, to our knowledge, this is the first study on the biological function of IGF2BP3 in malignant mesothelioma cells. The knockdown of IGF2BP3 in malignant mesothelioma cells resulted in the suppression of cell proliferation with an increase in the proportion of cells in the G1 phase of the cell cycle. Furthermore, knockdown of IGF2BP3 inhibited cell migration and invasion. We focused on the cell cycle assay to investigate the role of IGF2BP3 in cell proliferation in malignant mesothelioma. Among the various proteins involved in cell cycle regulation, the expression of p27 Kip1 (p27) increased significantly upon IGF2BP3 knockdown. Next, p27 siRNA was added to suppress the increased expression of p27. The results showed that p27 knockdown attenuated the effects of IGF2BP3 knockdown on cell proliferation and G1 phase arrest. In conclusion, we found that IGF2BP3 promotes cell proliferation, a critical step in tumorigenesis, by suppressing the expression of p27 in malignant mesothelioma.

  Copyright © 2022 Endo, Amatya, Kushitani, Kambara, Nakagiri, Fujii and Takeshima.

• Lurbinectedin in Refractory Diffuse Malignant Peritoneal Mesothelioma: Report of Two Cases. L. Gros, P. Szturz, A. Diciolla, et al. 2021;11:704295. PubMed · Publisher · Free full text

  Abstract

  Mesothelioma is a malignancy of serosal membranes. Parietal pleura is the most common site, with peritoneum being the second most frequent location. Malignant peritoneal mesothelioma (MPM) is a rare and aggressive disease. The prognosis is often very poor with median overall survival ranging from 6 to 18 months in patients who are not candidates for cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) due to non-resectable disease or comorbid conditions. For patients with resectable disease, CRS and HIPEC have become the standard of care. However, for patients with unresectable malignant mesothelioma there is unfortunately no effective systemic treatment beyond the first line. Based on the results of a recent phase II trial, lurbinectedin has clinical activity and acceptable toxicity in the second- and third-line treatment of malignant pleural mesothelioma. However, until present, no data have been available for patients with MPM and for patients who become refractory after multiple treatment lines. We report on two patients with metastatic MPM who achieved durable disease control of 10+ and 8 months with lurbinectedin in the fourth and fifth treatment line, respectively.

  Copyright © 2021 Gros, Szturz, Diciolla, Kirchner, Peters, Schaefer, Hubner and Digklia.

• P14/ARF-Positive Malignant Pleural Mesothelioma: A Phenotype With Distinct Immune Microenvironment. F. Pezzuto, F. Lunardi, L. Vedovelli, et al. 2021;11:653497. PubMed · Publisher · Free full text

  Abstract

  Introduction: The CDKN2A gene plays a central role in the pathogenesis of malignant pleural mesothelioma (MPM). The gene encodes for two tumor suppressor proteins, p16/INK4A and p14/ARF, frequently lost in MPM tumors. The exact role of p14/ARF in MPM and overall its correlation with the immune microenvironment is unknown. We aimed to determine whether there is a relationship between p14/ARF expression, tumor morphological features, and the inflammatory tumor microenvironment.

  Methods: Diagnostic biopsies from 76 chemo-naive MPMs were evaluated. Pathological assessments of histotype, necrosis, inflammation, grading, and mitosis were performed. We evaluated p14/ARF, PD-L1 (tumor proportion score, TPS), and Ki-67 (percentage) by immunohistochemistry. Inflammatory cell components (CD3+, CD4+, CD8+ T lymphocytes; CD20+ B-lymphocytes; CD68+ and CD163+ macrophages) were quantified as percentages of positive cells, distinguishing between intratumoral and peritumoral areas. The expression of p14/ARF was associated with several clinical and pathological characteristics. A random forest-based machine-learning algorithm (Boruta) was implemented to identify which variables were associated with p14/ARF expression.

  Results: p14/ARF was evaluated in 68 patients who had a sufficient number of tumor cells. Strong positivity was detected in 14 patients (21%) (11 epithelioid and 3 biphasic MPMs). At univariate analysis, p14/ARF-positive epithelioid mesotheliomas showed higher nuclear grade (G3) (p = 0.023) and higher PD-L1 expression (≥50%) (p = 0.042). The percentages of CD4 and CD163 in peritumoral areas were respectively higher and lower in p14/ARF positive tumors but did not reach statistical significance with our sample size (both p = 0.066). The Boruta algorithm confirmed the predictive value of PD-L1 percentage for p14/ARF expression in all histotypes.

  Conclusions: p14/ARF-positive epithelioid mesotheliomas may mark a more aggressive pathological phenotype (higher nuclear grade and PD-L1 expression). Considering the results regarding the tumor immune microenvironment, p14/ARF-negative tumors seem to have an immune microenvironment less sensitive to immune checkpoint inhibitors, being associated with low PD-L1 and CD4 expression, and high CD163 percentage. The association between p14/ARF-positive MPMs and PD-L1 expression suggests a possible interaction of the two pathways. Confirmation of our preliminary results could be important for patient selection and recruitment in future clinical trials with anticancer immunotherapy.

  Copyright © 2021 Pezzuto, Lunardi, Vedovelli, Fortarezza, Urso, Grosso, Ceresoli, Kern, Vlacic, Faccioli, Schiavon, Gregori, Rea, Pasello and Calabrese.

• Pleural Fluid Has Pro-Growth Biological Properties Which Enable Cancer Cell Proliferation. R. Asciak, N.I. Kanellakis, X. Yao, et al. 2021;11:658395. PubMed · Publisher · Free full text

  Abstract

  Objectives: Patients with malignant pleural mesothelioma (MPM) or pleural metastases often present with malignant pleural effusion (MPE). This study aimed to analyze the effect of pleural fluid on cancer cells.

  Materials And Methods: Established patient-derived cancer cell cultures derived from MPE (MPM, breast carcinoma, lung adenocarcinoma) were seeded in 100% pleural fluid (exudate MPM MPE, transudate MPE, non-MPE transudate fluid) and proliferation was monitored. In addition, the establishment of new MPM cell cultures, derived from MPE specimens, was attempted by seeding the cells in 100% MPE fluid.

  Results: All established cancer cell cultures proliferated with similar growth rates in the different types of pleural fluid. Primary MPM cell culture success was similar with MPE fluid as with full culture medium.

  Conclusions: Pleural fluid alone is adequate for cancer cell proliferation in vitro, regardless of the source of pleural fluid. These results support the hypothesis that pleural fluid has important pro-growth biological properties, but the mechanisms for this effect are unclear and likely not malignant effusion specific.

  Copyright © 2021 Asciak, Kanellakis, Yao, Abd Hamid, Mercer, Hassan, Bedawi, Dobson, Fsadni, Montefort, Dong, Rahman and Psallidas.

• Preclinical Models and Resources to Facilitate Basic Science Research on Malignant Mesothelioma - A Review. B.W. Johnson, K. Takahashi, Y.Y. Cheng. 2021;11:748444. Review PubMed · Publisher · Free full text

  Abstract

  Malignant mesothelioma is an aggressive cancer with poor prognosis, predominantly caused by human occupational exposure to asbestos. The global incidence of mesothelioma is predicted to increase as a consequence of continued exposure to asbestos from a variety of sources, including construction material produced in the past in developed countries, as well as those currently being produced in developing countries. Mesothelioma typically develops after a long latency period and consequently it is often diagnosed in the clinic at an advanced stage, at which point standard care of treatment, such as chemo- and radio-therapy, are largely ineffective. Much of our current understanding of mesothelioma biology, particularly in relation to disease pathogenesis, diagnosis and treatment, can be attributed to decades of preclinical basic science research. Given the postulated rising incidence in mesothelioma cases and the limitations of current diagnostic and treatment options, continued preclinical research into mesothelioma is urgently needed. The ever-evolving landscape of preclinical models and laboratory technology available to researchers have made it possible to study human disease with greater precision and at an accelerated rate. In this review article we provide an overview of the various resources that can be exploited to facilitate an enhanced understanding of mesothelioma biology and their applications to research aimed to improve the diagnosis and treatment of mesothelioma. These resources include cell lines, animal models, mesothelioma-specific biobanks and modern laboratory techniques/technologies. Given that different preclinical models and laboratory technologies have varying limitations and applications, they must be selected carefully with respect to the intended objectives of the experiments. This review therefore aims to provide a comprehensive overview of the various preclinical models and technologies with respect to their advantages and limitations. Finally, we will detail about a highly valuable preclinical laboratory resource to curate high quality mesothelioma biospecimens for research; the biobank. Collectively, these resources are essential to the continued advancement of precision medicine to curtail the increasing health burden caused by malignant mesothelioma.

  Copyright © 2021 Johnson, Takahashi and Cheng.

• SPRY4-AS1, A Novel Enhancer RNA, Is a Potential Novel Prognostic Biomarker and Therapeutic Target for Hepatocellular Carcinoma. M. Ye, S. Wang, J.B. Qie, et al. 2021;11:765484. PubMed · Publisher · Free full text

  Abstract

  A growing number of evidence have demonstrated the involvement of enhancer RNAs (eRNAs) in tumor progression. However, the possible functions of eRNAs in hepatocellular carcinoma (HCC) remain largely unclear. Our present research aimed to screen critical eRNAs and to further delve into the clinical significance of eRNAs in HCC patients. In this study, we identified 124 prognosis-related eRNAs by analyzing The Cancer Genome Atlas (TCGA) datasets. Among them, SPRY4 antisense RNA 1 (SPRY4-AS1) may be a key eRNA involved in HCC progression. SPRY4 was a regulatory target of SPRY4-AS1. High SPRY4-AS1 expression was associated with poor prognosis of HCC patients. Kyoto Encyclopedia of Genes and Genomes (KEGG) assays revealed that the mainly enriched biological process included Human papillomavirus infection, Hippo signaling pathway, and Proteoglycans in cancer. Besides, RT-PCR and immunohistochemical staining confirmed SPRY4-AS1 as an overexpressed eRNA in HCC specimens. The pan-cancer assays revealed that SPRY4-AS1 was associated with glioblastoma multiforme (GBM), adrenocortical carcinoma (ACC), brain lower grade glioma (LGG) and mesothelioma(MESO). Positive associations were observed between SPRY4-AS1 and SPRY4 (its target gene) in 16 tumor types. Collectively, our findings reveal a novel eRNA SPRY4-AS1 for HCC progression and suggest that SPRY4-AS1 may be a potential biomarker and therapeutic target for HCC.

  Copyright © 2021 Ye, Wang, Qie and Sun.

• Tumor Immune Microenvironment and Genetic Alterations in Mesothelioma. S. Hiltbrunner, L. Mannarino, M.B. Kirschner, et al. 2021;11:660039. Review PubMed · Publisher · Free full text

  Abstract

  Malignant pleural mesothelioma (MPM) is a rare and fatal disease of the pleural lining. Up to 80% of the MPM cases are linked to asbestos exposure. Even though its use has been banned in the industrialized countries, the cases continue to increase. MPM is a lethal cancer, with very little survival improvements in the last years, mirroring very limited therapeutic advances. Platinum-based chemotherapy in combination with pemetrexed and surgery are the standard of care, but prognosis is still unacceptably poor with median overall survival of approximately 12 months. The genomic landscape of MPM has been widely characterized showing a low mutational burden and the impairment of tumor suppressor genes. Among them, BAP1 and BLM are present as a germline inactivation in a small subset of patients and increases predisposition to tumorigenesis. Other studies have demonstrated a high frequency of mutations in DNA repair genes. Many therapy approaches targeting these alterations have emerged and are under evaluation in the clinic. High-throughput technologies have allowed the detection of more complex molecular events, like chromotripsis and revealed different transcriptional programs for each histological subtype. Transcriptional analysis has also paved the way to the study of tumor-infiltrating cells, thus shedding lights on the crosstalk between tumor cells and the microenvironment. The tumor microenvironment of MPM is indeed crucial for the pathogenesis and outcome of this disease; it is characterized by an inflammatory response to asbestos exposure, involving a variety of chemokines and suppressive immune cells such as M2-like macrophages and regulatory T cells. Another important feature of MPM is the dysregulation of microRNA expression, being frequently linked to cancer development and drug resistance. This review will give a detailed overview of all the above mentioned features of MPM in order to improve the understanding of this disease and the development of new therapeutic strategies.

  Copyright © 2021 Hiltbrunner, Mannarino, Kirschner, Opitz, Rigutto, Laure, Lia, Nozza, Maconi, Marchini, D’Incalci, Curioni-Fontecedro and Grosso.

• A Randomized Controlled Trial of a Non-pharmacological Intervention for Cancer-Related Dyspnea. P. Yates, J. Hardy, A. Clavarino, et al. 2020;10:591610. PubMed · Publisher · Free full text

  Abstract

  Objectives: To evaluate the efficacy of a brief tailored non-pharmacological intervention comprising breathing retraining and psychosocial support for managing dyspnea in cancer patients. Design: Multicenter, single blinded, parallel group, randomized controlled trial. Setting: Four major public hospitals, Brisbane, Australia. Participants: One hundred and forty four cancer patients, including 81 who received an 8-week tailored intervention and 63 who received standard care. Inclusion Criteria: Diagnosis of small or non-small cell lung cancer, mesothelioma or lung metastases; completed first line therapy for the disease; average dyspnea rating >2 on (0-10) rating scale in past week; anticipated life expectancy ≥3 months. Outcomes: The primary outcome measure was change in "worst" dyspnea at 8 weeks compared to baseline. Secondary outcomes were change in: dyspnea "at best" and "on average"; distress; perceived control over dyspnea; functional status, psychological distress; and use of non-pharmacological interventions to manage dyspnea at 8 weeks relative to baseline. Results: The mean age of participants was 67.9 (SD = 9.6) years. Compared to the control group, the intervention group demonstrated a statistically significant: (i) improvement in average dyspnea from T1(M = 4.5, SE = 0.22) to T3 (M = 3.6, SE = 0.24) vs. (M = 3.8, SE = 0.24) to (M = 4.1, SE = 0.26); (ii) greater control over dyspnea from T1 (M = 5.7, SE = 0.28) to T3 (M = 7.5, SE = 0.31) vs. (M = 6.8, SE = 0.32) to (M = 6.6, SE = 0.33); and (iii) greater reduction in anxiety from T1 (M = 5.4, SE = 0.43) to T3 (M = 4.5, SE = 0.45) vs. (M = 4.2, SE = 0.49) to (M = 4.6, SE = 0.50). This study found no intervention effect for best and worst dyspnea, distress from breathlessness, functional status, and depression over time. Conclusions: This study demonstrates efficacy of tailored non-pharmacological interventions in improving dyspnea on average, control over dyspnea, and anxiety for cancer patients. Clinical Trial Registration: The trial is registered at the Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au). The registration number is ACTRN12607000087459.

  Copyright © 2020 Yates, Hardy, Clavarino, Fong, Mitchell, Skerman, Brunelli and Zhao.

• Antiangiogeneic Strategies in Mesothelioma. A.K. Nowak, S. Brosseau, A. Cook, et al. 2020;10:126. Review PubMed · Publisher · Free full text

  Abstract

  There is a strong rationale for inhibiting angiogenesis in mesothelioma. Vascular endothelial growth factor (VEGF) is an autocrine growth factor in mesothelioma and a potent mitogen for mesothelial cells. Further, the abnormal tumor vasculature promotes raised interstitial pressure and hypoxia, which may be detrimental to both penetration and efficacy of anticancer agents. Antiangiogenic agents have been trialed in mesothelioma for close to two decades, with early phase clinical trials testing vascular targeting agents, the VEGF-A targeting monoclonal antibody bevacizumab, and numerous tyrosine kinase inhibitors, many with multiple targets. None of these have shown efficacy which has warranted further development as single agents in any line of therapy. Whilst a randomized phase II trial combining the multitargeted tyrosine kinase inhibitor nintedanib with platinum/pemetrexed chemotherapy was positive, these results were not confirmed in a subsequent phase III study. The combination of cisplatin and pemetrexed with bevacizumab, in appropriately selected patients, remains the only anti-angiogenic combination showing efficacy in mesothelioma. Extensive efforts to identify biomarkers of response have not yet been successful.

  Copyright © 2020 Nowak, Brosseau, Cook and Zalcman.

• Apatinib Mesylate Inhibits the Proliferation and Metastasis of Epithelioid Malignant Peritoneal Mesothelioma In Vitro and In Vivo. Z.R. Yang, Z.G. Chen, X.M. Du, et al. 2020;10:585079. PubMed · Publisher · Free full text

  Abstract

  Objective: Malignant peritoneal mesothelioma (MPM) is a rare malignancy with few effective molecular therapies. In this study, we evaluated the anti-tumor activity and safety of apatinib, a vascular endothelial growth factor receptor 2 inhibitor, in MPM in vitro and in vivo.

  Methods: We established several patient-derived xenograft (PDX) models and primary cell lines of MPM. The cell lines were used to study the effects of apatinib on proliferation, cell cycle, migration, and apoptosis by CCK8, flow cytometry, wound-healing, Transwell, DAPI staining, and caspase-3 assays, respectively. For in vivo study, apatinib was delivered by gastric gavage into PDX models, and then efficacy and toxicity were determined by experimental peritoneal cancer index (ePCI) score and pathological examinations.

  Results: Our results showed that apatinib significantly inhibited the proliferation and migration of MPM cells in vitro and induced cell cycle arrest. Studies on PDX models concurred that apatinib effectively suppressed subphrenic and liver invasions of nude mice. Moreover, histopathological analysis found that lymphocyte infiltration, coagulation necrosis and eosinophilic cell fragments were detected in tumor tissues after apatinib treatment. Apatinib showed no obvious effects on body mass of models and did not affect function of important organs, except for occasional focal lymphoid infiltration of liver (16.7%) and cardiac muscle (16.7%).

  Conclusions: We successfully established MPM PDX models and primary cell lines, and confirmed that apatinib effectively inhibited proliferation and metastasis of MPM in vitro and in vivo study.

  Copyright © 2020 Yang, Chen, Du and Li.

• CDKN2A and MTAP Are Useful Biomarkers Detectable by Droplet Digital PCR in Malignant Pleural Mesothelioma: A Potential Alternative Method in Diagnosis Compared to Fluorescence In Situ Hybridisation. Y.Y. Cheng, M.L. Yuen, E.M. Rath, et al. 2020;10:579327. PubMed · Publisher · Free full text

  Abstract

  Background: The diagnosis of malignant pleural mesothelioma (MPM) can be difficult, in part due to the difficulty in distinguishing between MPM and reactive mesothelial hyperplasia (RMH). The tumor suppressor gene, CDKN2A, is frequently silenced by epigenetic mechanisms in many cancers; in the case of MPM it is mostly silenced via genomic deletion. Co-deletion of the CDKN2A and methylthioadenosine phosphorylase (MTAP) genes has been researched extensively and discovered to be a highly specific characteristic of MPM. Most studies have used FISH to detect the deletion of CDKN2A and IHC for MTAP as a surrogate for this. In this study, we aim to investigate and validate droplet digital PCR (ddPCR) as an emerging alternative and efficient testing method in diagnosing MPM, by particularly emphasizing on the loss of MTAP and CDKN2A.

  Methods: This study included 75 formalin fixed paraffin embedded (FFPE) MPM tissue, and 12 normal pleural tissue and 10 RMH as control. Additionally, primary MPM cell lines and normal pleural samples were used as biomarker detection controls, as established in our previous publication. All FFPE specimens were processed to isolate the DNA, that was subsequently used for ddPCR detection of CDKN2A and MTAP. FFPE samples were also analyzed by fluorescence in situ hybridization (FISH) for CDKN2A and MTAP deletion, and for MTAP IHC expression. Concordance of IHC and ddPCR with FISH were studied in these samples.

  Results: 95% and 82% of cases showed co-deletion of both MTAP and CDKN2A when determined by FISH and ddPCR respectively. ddPCR has a sensitivity of 72% and specificity of 100% in detecting CDKN2A homozygous loss in MPM. ddPCR also has a concordance rate of 92% with FISH in detecting homozygous loss of CDKN2A. MTAP IHC was 68% sensitive and 100% specific for detecting CDKN2A homozygous loss in MPM when these losses were determined by ddPCR.

  Conclusion: Our study confirms that MTAP is often co-deleted with CDKN2A in MPM. Our in-house designed ddPCR assays for MTAP and CDKN2A are useful in differentiating MPM from RMH, and is highly concordant with FISH that is currently used in diagnosing MPM. ddPCR detection of these genetic losses can potentially be utilized as an alternative method in the diagnosis of MPM and for the future development of a less-invasive MPM-specific detection technique on MPM tumor tissue DNA.

  Copyright © 2020 Cheng, Yuen, Rath, Johnson, Zhuang, Yu, Aleksova, Linton, Kao, Clarke, McCaughan, Takahashi and Lee.

• Cellular Immunotherapy and Locoregional Administration of CAR T-Cells in Malignant Pleural Mesothelioma. R.A. Belderbos, H. Vroman, J.G.J.V. Aerts. 2020;10:777. Review PubMed · Publisher · Free full text

  Abstract

  Malignant pleural mesothelioma (MPM) is a treatment recalcitrant tumor with a poor overall survival (OS). Current approved treatment consists of first line chemotherapy that only modestly increases OS, illustrating the desperate need for other treatment options in MPM. Unfortunately, clinical studies that investigate the effectivity of checkpoint inhibitor (CI) treatment failed to improve clinical outcome over current applied therapies. In general, MPM is characterized as an immunological cold tumor with low T-cell infiltration, which could explain the disappointing results of clinical trials investigating CI treatment in MPM. Currently, many other therapeutic approaches, such as cellular therapies and cancer vaccines are investigated that could induce a tumor-specific immune response and increase of the number of tumor-infiltrating lymphocytes. In this review we will discuss these novel treatment approaches for MPM.

  Copyright © 2020 Belderbos, Vroman and Aerts.

• Circulating Epigenetic Biomarkers in Malignant Pleural Mesothelioma: State of the Art and critical Evaluation. L. Ferrari, M. Carugno, C. Mensi, et al. 2020;10:445. Review PubMed · Publisher · Free full text

  Abstract

  Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer, which originates from the mesothelial cells of the pleura and is associated with asbestos exposure. In light of its aggressive nature, late diagnosis and dismal prognosis, there is an urgent need for identification of biomarkers in easily accessible samples (such as blood) for early diagnosis of MPM. In the last 10 years, epigenetic markers, such as DNA methylation and microRNAs (miRNAs), have gained popularity as possible early diagnostic and prognostic biomarkers in cancer research. The aim of this review is to provide a critical analysis of the current evidences on circulating epigenetic biomarkers for MPM and on their translational potential to the clinical practice for early diagnosis and for prognosis.

  Copyright © 2020 Ferrari, Carugno, Mensi and Pesatori.

• Editorial: Emerging Therapies for Malignant Mesothelioma. N. van Zandwijk, G. Reid, P. Baas. 2020;10:939. Editorial PubMed · Publisher · Free full text

• Emerging Treatments for Malignant Pleural Mesothelioma: Where Are We Heading?. L. Cantini, R. Hassan, D.H. Sterman, et al. 2020;10:343. Review PubMed · Publisher · Free full text

  Abstract

  Malignant pleural mesothelioma (MPM) is an uncommon but aggressive and treatment resistant neoplasm with low survival rates. In the last years we assisted to an exponential growth in the appreciation of mesothelioma pathobiology, leading several new treatments to be investigated both in the early stage of the disease and in the advanced setting. In particular, expectations are now high that immunotherapy will have a leading role in the next years. However, caution is required as results from phase II studies in MPM were often not replicated in larger, randomized, phase III trials. In this review, we describe the most promising emerging therapies for the treatment of MPM, discussing the biological rationale underlying their development as well as the issues surrounding clinical trial design and proper selection of patients for every treatment.

  Copyright © 2020 Cantini, Hassan, Sterman and Aerts.

• Epigenetic Alterations and Biomarkers for Immune Checkpoint Inhibitors-Current Standards and Future Perspectives in Malignant Pleural Mesothelioma Treatment. Y. Yoshikawa, K. Kuribayashi, T. Minami, et al. 2020;10:554570. Review PubMed · Publisher · Free full text

  Abstract

  Malignant pleural mesothelioma (MPM) is strongly associated with occupational or environmental asbestos exposure and arises from neoplastic transformation of mesothelial cells in the pleural cavity. The only standard initial treatment for unresectable MPM is combination chemotherapy with cisplatin (CDDP) and pemetrexed (PEM). Further, CDDP/PEM is the only approved regimen with evidence of prolonged overall survival (OS), although the median OS for patients treated with this regimen is only 12 months after diagnosis. Thus, the development of new therapeutic strategies has been investigated for approximately 20 years. In contrast to recent advances in personalized lung cancer therapies, diagnostic and prognostic biomarker research has just started in mesothelioma. Epigenetic alterations include DNA methylation, histone modifications, and other chromatin-remodeling events. These processes are involved in numerous cellular processes including differentiation, development, and tumorigenesis. Epigenetic modifications play an important role in gene expression and regulation related to malignant MPM phenotypes and histological subtypes. An immune checkpoint PD-1 inhibitor, nivolumab, was approved as second-line therapy for patients who had failed initial chemotherapy, based on the results of the MERIT study. Various clinical immunotherapy trials are ongoing in patients with advanced MPM. In this review, we describe recent knowledge on epigenetic alterations, which might identify candidate therapeutic targets and immunotherapeutic regimens under development for MPM.

  Copyright © 2020 Yoshikawa, Kuribayashi, Minami, Ohmuraya and Kijima.

• gC1qR/HABP1/p32 Is a Potential New Therapeutic Target Against Mesothelioma. E. Peerschke, K. Stier, X. Li, et al. 2020;10:1413. PubMed · Publisher · Free full text

  Abstract

  Mesothelioma is an aggressive cancer of the serous membranes with poor prognosis despite combination therapy consisting of surgery, radiotherapy, and platinum-based chemotherapy. Targeted therapies, including immunotherapies, have reported limited success, suggesting the need for additional therapeutic targets. This study investigates a potential new therapeutic target, gC1qR/HABP1/p32 (gC1qR), which is overexpressed in all morphologic subtypes of mesothelioma. gC1qR is a complement receptor that is associated with several cellular functions, including cell proliferation and angiogenesis. In vitro and in vivo experiments were conducted to test the hypothesis that targeting gC1qR with a specific gC1qR monoclonal antibody 60.11 reduces mesothelioma tumor growth, using the biphasic mesothelioma cell line MSTO-211H (MSTO). In vitro studies demonstrate cell surface and extracellular gC1qR expression by MSTO cells, and a modest 25.3 ± 1.8% (n = 4) reduction in cell proliferation by the gC1qR blocking 60.11 antibody. This inhibition was specific for targeting the C1q binding domain of gC1qR at aa 76-93, as a separate monoclonal antibody 74.5.2, directed against amino acids 204-218, had no discernable effect. In vivo studies, using a murine orthotopic xenotransplant model, demonstrated an even greater reduction in MSTO tumor growth (50% inhibition) in mice treated with the 60.11 antibody compared to controls. Immunohistochemical studies of resected tumors revealed increased cellular apoptosis by caspase 3 and TUNEL staining, in 60.11 treated tumors compared to controls, as well as impaired angiogenesis by decreased CD31 staining. Taken together, these data identify gC1qR as a potential new therapeutic target against mesothelioma with both antiproliferative and antiangiogenic properties.

  Copyright © 2020 Peerschke, Stier, Li, Kandov, de Stanchina, Chang, Xiong, Manova-Todorova, Fan, Barlas, Ghebrehiwet and Adusumilli.

• Immunotherapy in Malignant Pleural Mesothelioma. C.J. de Gooijer, F.J. Borm, A. Scherpereel, et al. 2020;10:187. Review PubMed · Publisher · Free full text

  Abstract

  The only registered systemic treatment for malignant pleural mesothelioma (MPM) is platinum based chemotherapy combined with pemetrexed, with or without bevacizumab. Immunotherapy did seem active in small phase II trials. In this review, we will highlight the most important immunotherapy-based research performed and put a focus on the future of MPM. PD-(L)1 inhibitors show response rates between 10 and 29% in phase II trials, with a wide range in progression free (PFS) and overall survival (OS). However, single agent pembrolizumab was not superior to chemotherapy (gemcitabine or vinorelbine) in the recent published PROMISE-Meso trial in pre-treated patients. In small studies with CTLA-4 inhibitors there is evidence for response in some patients, but it fails to show a better PFS and OS compared to best supportive care in a randomized study. A combination of PD-(L)1 inhibitor with CTLA-4 inhibitor seem to have a similar response as PD-(L)1 monotherapy. The first results of combining durvalumab (PD-L1 blocking) with cisplatin-pemetrexed in the first line are promising. Another immune treatment is Dendritic Cell (DC) immunotherapy, which is recently tested in mesothelioma, shows remarkable anti-tumor activity in three clinical studies. The value of single agent checkpoint inhibitors is limited in MPM. There is an urgent need for biomarkers to select the optimal candidates for immunotherapy among MPM patients in terms of efficacy and tolerance. Results of combination checkpoint inhibitors with chemotherapy are awaiting.

  Copyright © 2020 de Gooijer, Borm, Scherpereel and Baas.

• Manipulating microRNAs for the Treatment of Malignant Pleural Mesothelioma: Past, Present and Future. G. Reid, T.G. Johnson, N. van Zandwijk. 2020;10:105. Review PubMed · Publisher · Free full text

  Abstract

  microRNAs (miRNAs) are an important class of non-coding RNA that post-transcriptionally regulate the expression of most protein-coding genes. Their aberrant expression in tumors contributes to each of the hallmarks of cancer. In malignant pleural mesothelioma (MPM), in common with other tumor types, changes in miRNA expression are characterized by a global downregulation, although elevated levels of some miRNAs are also found. While an increasing number of miRNAs exhibit altered expression in MPM, relatively few have been functionally characterized. Of a growing number with tumor suppressor activity in vitro, miR-16, miR-193a, and miR-215 were also shown to have tumor suppressor activity in vivo. In the case of miR-16, the significant inhibitory effects on tumor growth following targeted delivery of miR-16-based mimics in a xenograft model was the basis for a successful phase I clinical trial. More recently overexpressed miRNAs with oncogenic activity have been described. Many of these changes in miRNA expression are related to the characteristic loss of tumor suppressor pathways in MPM tumors. In this review we will highlight the studies providing evidence for therapeutic effects of modulating microRNA levels in MPM, and discuss these results in the context of emerging approaches to miRNA-based therapy.

  Copyright © 2020 Reid, Johnson and van Zandwijk.

• Preclinical Models of Malignant Mesothelioma. J.R. Testa, A. Berns. 2020;10:101. Review PubMed · Publisher · Free full text

  Abstract

  Rodent models of malignant mesothelioma help facilitate the understanding of the biology of this highly lethal cancer and to develop and test new interventions. Introducing the same genetic lesions as found in human mesothelioma in mice results in tumors that show close resemblance with the human disease counterpart. This includes the extensive inflammatory responses that characterize human malignant mesothelioma. The relatively fast development of mesothelioma in mice when the appropriate combination of lesions is introduced, with or without exposure to asbestos, make the autochthonous models particularly useful for testing new treatment strategies in an immunocompetent setting, whereas Patient-Derived Xenograft models are particularly useful to assess effects of inter- and intra-tumor heterogeneity and human-specific features of mesothelioma. It is to be expected that new insights obtained by studying these experimental systems will lead to new more effective treatments for this devastating disease.

  Copyright © 2020 Testa and Berns.

• Prevention and Management of Dermatologic Adverse Events Associated With Tumor Treating Fields in Patients With Glioblastoma. M.E. Lacouture, M.J. Anadkat, M.T. Ballo, et al. 2020;10:1045. Review PubMed · Publisher · Free full text

  Abstract

  Importance: Tumor Treating Fields (TTFields) are an anti-mitotic treatment approved for treating newly diagnosed and recurrent glioblastoma, and mesothelioma. TTFields in glioblastoma comprise alternating electric fields (200 kHz) delivered continuously, ideally for ≥18 h/day, to the tumor bed via transducer arrays placed on the shaved scalp. When applied locoregionally to the tumor bed and combined with systemic temozolomide chemotherapy, TTFields improved overall survival vs. temozolomide alone in patients with newly diagnosed glioblastoma. Improved efficacy outcomes with TTFields were demonstrated, while maintaining a well-tolerated and manageable safety profile. The most commonly-reported TTFields-associated adverse events (AEs) are beneath-array dermatologic events. Since survival benefit from TTFields increases with duration-of-use, prevention and management of skin AEs are critical to maximize adherence. This paper describes TTFields-associated dermatological AEs and recommends prevention and management strategies based on clinical trial evidence and real-world clinical experience. Observations: TTFields-associated skin reactions include contact dermatitis (irritant/allergic), hyperhidrosis, xerosis or pruritus, and more rarely, skin erosions/ulcers and infections. Skin AEs may be prevented through skin-care and shifting (~2 cm) of array position during changes. TTFields-related skin AE management should be based on clinical phenotype and severity. Depending on diagnosis, recommended treatments include antibiotics, skin barrier films, moisturizers, topical corticosteroids, and antiperspirants. Water-based lotions, soaps, foams, and solutions with minimal impact on electrical impedance are preferred with TTFields use over petroleum-based ointments, which increase impedance. Conclusions: Early identification, prophylactic measures, and symptomatic skin AE management help patients maximize TTFields usage, while maintaining quality-of-life and optimizing therapeutic benefit. Implications for practice: TTFields confer a survival benefit in patients with glioblastoma that correlates positively with duration of daily use. Skin events (rash) are the primary treatment-related AE that can limit duration of use. The recommendations described here will help healthcare professionals to recognize, prevent, and manage dermatologic AEs associated with TTFields treatment. These recommendations may improve cutaneous health and support adherence to therapy, both of which would maximize treatment outcomes.

  Copyright © 2020 Lacouture, Anadkat, Ballo, Iwamoto, Jeyapalan, La Rocca, Schwartz, Serventi and Glas.

• Prognostic Implications of Pan-Cancer CMTM6 Expression and Its Relationship with the Immune Microenvironment. Y. Zhao, M. Zhang, H. Pu, et al. 2020;10:585961. PubMed · Publisher · Free full text

  Abstract

  CKLF-like MARVEL transmembrane domain-containing 6 (CMTM6) reportedly stabilizes programmed death-ligand 1 (PD-L1) and enhances the efficacy of immunotherapy. However, correlations between CMTM6 expression and the immune microenvironment and its prognostic value remain unknown in a variety of tumors. CMTM6 expression data were obtained from The Cancer Genome Atlas (TCGA) for 33 cancer types classified into high and low expression subgroups according to the median CMTM6 expression value. Pan-cancer analysis of CMTM6 protein expression in 20 tumor types was performed using a cohort from the Human Protein Atlas (HPA). PD-L1 protein expression data were obtained from The Cancer Proteome Atlas (TCPA) for 32 cancer types. Frequencies of CMTM6 copy number alterations and mutations were analyzed using cBioPortal. MANTIS was employed to estimate microsatellite instability in the TCGA cohort. CIBERSORT and the ESTIMATE algorithm were applied to estimate the relative fractions of infiltrating immune cell types and immune scores, respectively. Kaplan-Meier survival curve analysis was performed to assess the pan-cancer prognostic value of CMTM6.CMTM6 is heterogeneously expressed in diverse cancers. Further, the results revealed low CMTM6 mutation frequencies in multiple cancers. Among them, CMTM6 mutation frequency was the highest in uterine cancer. Additionally, CMTM6 expression was related to PD-L1 protein expression in breast invasive carcinoma, cervical squamous cell carcinoma and endocervical adenocarcinoma, cholangiocarcinoma, glioblastoma multiforme (GBM), head and neck squamous cell carcinoma, kidney renal papillary cell carcinoma, sarcoma (SARC), stomach adenocarcinoma, and uterine carcinosarcoma. Increased CMTM6 expression may be associated with increased infiltration of neutrophils in some types of cancer. Finally, pan-cancer analysis indicated that CMTM6 expression was closely related to overall survival in adrenocortical carcinoma, GBM, acute myeloid leukemia, liver hepatocellular carcinoma, mesothelioma, SARC, thymoma, and uveal melanoma. Taken together, these findings highlight that CMTM6 plays an important role in the tumor immune microenvironment, and CMTM6 has been identified to have prognostic value in some types of cancers. Thus, CMTM6 is a potential target for cancer immunotherapy and effective prognostic biomarker.

  Copyright © 2021 Zhao, Zhang, Pu, Guo, Zhang and Wang.

• Surgery for Mesothelioma After Radiation Therapy (SMART); A Single Institution Experience. W.G. Breen, Y.I. Garces, K.R. Olivier, et al. 2020;10:392. PubMed · Publisher · Free full text

  Abstract

  Background: The optimal treatment sequence for localized malignant pleural mesothelioma (MPM) is controversial. We aimed to assess outcomes and toxicities of treating localized MPM with neoadjuvant radiation therapy (RT) followed by extrapleural pneumonectomy (EPP). Methods: Patients were enrolled on an institutional protocol of surgery for mesothelioma after radiation therapy (SMART) between June 2016 and May 2017. Eligible patients were adults with MPM localized to the ipsilateral pleura. Patients underwent staging with PET/CT, pleuroscopy, bronchoscopy/EBUS, mediastinoscopy, and laparoscopy. Five fractions of RT were delivered using intensity modulated radiation therapy (IMRT), with 30 Gy delivered to gross disease and 25 Gy to the entire pleura. EPP was performed 4-10 days following completion of RT. Results: Five patients were treated on protocol. Median age was 62 years (range 36-66). Histology was epithelioid on initial biopsy in all patients, but one was found to have biphasic histology after surgery. Three patients had surgeon-assessed gross total resection, and two had gross residual disease. While all patients were clinically node negative by pretreatment staging, three had positive nodal disease at surgery. Patients were hospitalized for a median 24 days (range 5-69) following surgery. Two patients developed empyema, one of whom developed respiratory failure and subsequently renal failure requiring dialysis, while the other required multiple surgical debridements. Two patients developed atrial fibrillation with rapid ventricular response after surgery, one of whom developed acute respiratory distress requiring intubation and tracheostomy. At last follow-up, one patient died at 1.4 years after local and distant progression, two were alive with local and distant progression, and the remaining two were alive without evidence of disease at 0.1 and 2.7 years. Median time to progression was 9 months. Three patients received salvage chemotherapy. Conclusions: SMART provided promising oncologic outcomes at the cost of significant treatment related morbidity. Due to the significant treatment associated morbidity and favorable treatment alternatives, we have not broadly adopted SMART at our institution.

  Copyright © 2020 Breen, Garces, Olivier, Park, Merrell, Nichols, Peikert, Molina, Mansfield, Roden, Blackmon and Wigle.

• The Biology of Malignant Mesothelioma and the Relevance of Preclinical Models. C. Blanquart, M.C. Jaurand, D. Jean. 2020;10:388. Review PubMed · Publisher · Free full text

  Abstract

  Malignant mesothelioma (MM), especially its more frequent form, malignant pleural mesothelioma (MPM), is a devastating thoracic cancer with limited therapeutic options. Recently, clinical trials that used immunotherapy strategies have yielded promising results, but the benefits are restricted to a limited number of patients. To develop new therapeutic strategies and define predictors of treatment response to existing therapy, better knowledge of the cellular and molecular mechanisms of MM tumors and sound preclinical models are needed. This review aims to provide an overview of our present knowledge and issues on both subjects. MM shows a complex pattern of molecular changes, including genetic, chromosomic, and epigenetic alterations. MM is also a heterogeneous cancer. The recently described molecular classifications for MPM could better consider inter-tumor heterogeneity, while histo-molecular gradients are an interesting way to consider both intra- and inter-tumor heterogeneities. Classical preclinical models are based on use of MM cell lines in culture or implanted in rodents, i.e., xenografts in immunosuppressed mice or isografts in syngeneic rodents to assess the anti-tumor immune response. Recent developments are tumoroids, patient-derived xenografts (PDX), xenografts in humanized mice, and genetically modified mice (GEM) that carry mutations identified in human MM tumor cells. Multicellular tumor spheroids are an interesting in vitro model to reduce animal experimentation; they are more accessible than tumoroids. They could be relevant, especially if they are co-cultured with stromal and immune cells to partially reproduce the human microenvironment. Even if preclinical models have allowed for major advances, they show several limitations: (i) the anatomical and biological tumor microenvironments are incompletely reproduced; (ii) the intra-tumor heterogeneity and immunological contexts are not fully reconstructed; and (iii) the inter-tumor heterogeneity is insufficiently considered. Given that these limitations vary according to the models, preclinical models must be carefully selected depending on the objectives of the experiments. New approaches, such as organ-on-a-chip technologies or in silico biological systems, should be explored in MM research. More pertinent cell models, based on our knowledge on mesothelial carcinogenesis and considering MM heterogeneity, need to be developed. These endeavors are mandatory to implement efficient precision medicine for MM.

  Copyright © 2020 Blanquart, Jaurand and Jean.

• The Impact on Outcome by Adding Bevacizumab to Standard Induction Chemotherapy Prior to Mesothelioma Surgery: A Retrospective Single Center Analysis. O. Lauk, K. Bruestle, T. Neuer, et al. 2020;10:588563. PubMed · Publisher · Free full text

  Abstract

  Objectives: Adding bevacizumab, an anti-Vascular Endothelial Growth Factor (VEGF), to platinum-based chemotherapy/pemetrexed in 1st line treatment of advanced malignant pleural mesothelioma (MPM), significantly improved overall survival. However, increased high grade bleeding after operation was reported in patients with colorectal cancer who previously received bevacizumab. In the present analysis, we assessed for the first time the impact of adding bevacizumab to induction chemotherapy prior to surgery for mesothelioma patients.

  Methods: Two hundred twenty-seven MPM patients, intended to be treated with induction chemotherapy followed by surgery at the University Hospital of Zurich between 2002 and December 2018, were included in the present analysis. After propensity score matching for gender, histology and age (1:3 ratio), data from 88 patients were analyzed. Sixty-six patients underwent induction chemotherapy (with cis-/carboplatin and pemetrexed: control group) alone and 22 patients underwent induction chemotherapy with the addition of bevacizumab (bevacizumab group) prior macroscopic complete resection (MCR). Perioperative and long-term outcome variables were analyzed.

  Results: Patients undergoing combination treatment with bevacizumab had a significantly better response than with chemotherapy alone as assessed by modified RECIST (p=0.046). Intraoperative complications in the bevacizumab group (one patient), or in the control group (three patients) were not related to intraoperative bleeding. Postoperative transfusion of blood products occurred in a larger amount in the control group than in the bevacizumab group (p=0.047). Overall survival was not statistically different between both groups.

  Conclusion: These initial data demonstrate that MCR can be performed safely after triple induction chemotherapy with bevacizumab without increased intra- and postoperative bleeding complications. Response rates were significantly improved by the addition of bevacizumab.

  Copyright © 2020 Lauk, Bruestle, Neuer, Battilana, Nguyen, Frauenfelder, Stahel, Weder, Curioni-Fontecedro and Opitz.

• The Use of Immunohistochemistry, Fluorescence in situ Hybridization, and Emerging Epigenetic Markers in the Diagnosis of Malignant Pleural Mesothelioma (MPM): A Review. E. Rozitis, B. Johnson, Y.Y. Cheng, et al. 2020;10:1742. Review PubMed · Publisher · Free full text

  Abstract

  Malignant pleural mesothelioma (MPM) is an aggressive asbestos related disease that is generally considered to be difficult to diagnose, stage and treat. The diagnostic process is continuing to evolve and requires highly skilled pathology input, and generally an extensive list of biomarkers for definitive diagnosis. Diagnosis of MPM requires histological evidence of invasion by malignant mesothelial cells often confirmed by various immunohistochemical biomarkers in order to separate it from pleural metastatic carcinoma. Often when invasion of neoplastic mesothelial cells into adjacent tissue is not apparent, further immunohistochemical testing - namely BAP1 and MTAP, as well as FISH testing for loss of p16 (CDKN2A) are used to separate reactive mesothelial proliferation due to benign processes, from MPM. Various combinations of these markers, such as BAP1 and/or MTAP immunohistochemistry alongside FISH testing for loss of p16, have shown excellent sensitivity and specificity in the diagnosis of MPM. Additionally, over the recent years, research into epigenetic marker use in the diagnosis of MPM has gained momentum. Although still in their research stages, various markers in DNA methylation, long non-coding RNA, micro RNA, circular RNA, and histone modifications have all been found to support diagnosis of MPM with generally good sensitivity and specificity. Many of these studies are however, limited by small sample sizes or other study limitations and further research into the area would be beneficial. Epigenetic markers show promise for use in the future to facilitate the diagnosis of MPM.

  Copyright © 2020 Rozitis, Johnson, Cheng and Lee.

• Therapeutic Landscape of Malignant Pleural Mesothelioma: Collateral Vulnerabilities and Evolutionary Dependencies in the Spotlight. D. Xu, H. Yang, R.A. Schmid, et al. 2020;10:579464. Review PubMed · Publisher · Free full text

  Abstract

  Malignant pleural mesothelioma (MPM) is the epitome of a recalcitrant cancer driven by pharmacologically intractable tumor suppressor proteins. A significant but largely unmet challenge in the field is the translation of genetic information on alterations in tumor suppressor genes (TSGs) into effective cancer-specific therapies. The notion that abnormal tumor genome subverts physiological cellular processes, which creates collateral vulnerabilities contextually related to specific genetic alterations, offers a promising strategy to target TSG-driven MPM. Moreover, emerging evidence has increasingly appreciated the therapeutic potential of genetic and pharmacological dependencies acquired en route to cancer development and drug resistance. Here, we review the most recent progress on vulnerabilities co-selected by functional loss of major TSGs and dependencies evolving out of cancer development and resistance to cisplatin based chemotherapy, the only first-line regimen approved by the US Food and Drug Administration (FDA). Finally, we highlight CRISPR-based functional genomics that has emerged as a powerful platform for cancer drug discovery in MPM. The repertoire of MPM-specific "Achilles heel" rises on the horizon, which holds the promise to elucidate therapeutic landscape and may promote precision oncology for MPM.

  Copyright © 2020 Xu, Yang, Schmid and Peng.

• Tumor Microenvironment-Associated Immune-Related Genes for the Prognosis of Malignant Pleural Mesothelioma. X. Xu, L. Cheng, Y. Fan, et al. 2020;10:544789. PubMed · Publisher · Free full text

  Abstract

  Malignant pleural mesothelioma (MPM) is a rare but highly aggressive thoracic malignancy. ESTIMATE algorithm-derived immune scores are commonly used to quantify the immune and stromal components in tumors. Thus, this algorithm may help determine the tumor microenvironment (TME)-related gene expression profile associated with tumor immunity. This study aimed at mining public databases to determine a potential correlation between differentially expressed genes (DEGs) and survival in patients with MPM. We categorized patients from the Gene Expression Omnibus database according to their immune/stromal scores into high- and low-score groups. Functional enrichment analysis and the construction of protein-protein interaction networks showed that the DEGs identified were primarily involved in the TME. Furthermore, we validated these genes in an independent cohort of patients with MPM from The Cancer Genome Atlas database. DEG analysis showed that 29 DEGs were cancer driver genes. Subsequently, 14 TME-related genes, which have been previously neglected, were shown to exhibit significant prognostic potential in MPM. In conclusion, immune/stromal scores are novel predictors of a poor prognosis in patients with MPM. We identified DEGs that are involved in immunity against MPM and may contribute to patient survival. Owing to their potential as prognostic factors for MPM, these 14 TME-related genes need to be studied in detail in the future.

  Copyright © 2020 Xu, Cheng, Fan and Mao.

2010s

• Association Between Simian Virus 40 and Human Tumors. J.C. Rotondo, E. Mazzoni, I. Bononi, et al. 2019;9:670. Review PubMed · Publisher · Free full text

  Abstract

  Simian virus 40 (SV40) is a small DNA tumor virus of monkey origin. This polyomavirus was administered to human populations mainly through contaminated polio vaccines, which were produced in naturally infected SV40 monkey cells. Previous molecular biology and recent immunological assays have indicated that SV40 is spreading in human populations, independently from earlier SV40-contaminated vaccines. SV40 DNA sequences have been detected at a higher prevalence in specific human cancer specimens, such as the brain and bone tumors, malignant pleural mesotheliomas, and lymphoproliferative disorders, compared to the corresponding normal tissues/specimens. However, other investigations, which reported negative data, did not confirm an association between SV40 and human tumors. To circumvent the controversies, which have arisen because of these molecular biology studies, immunological researches with newly developed indirect ELISA tests were carried out in serum samples from patients affected by the same kind of tumors as mentioned above. These innovative indirect ELISAs employ synthetic peptides as mimotopes/specific SV40 antigens. SV40 mimotopes do not cross-react with the homologous human polyomaviruses, BKPyV, and JCPyV. Immunological data obtained from indirect ELISAs, using SV40 mimotopes, employed to analyze serum samples from oncological patients, have indicated that these sera had a higher prevalence of antibodies against SV40 compared to healthy subjects. The main data on (i) the biology and genetics of SV40; (ii) the epidemiology of SV40 in the general population, (iii) the mechanisms of SV40 transformation; (iv) the putative role of SV40 in the onset/progression of specific human tumors, and (v) its association with other human diseases are reported in this review.

• Development and Validation of a Prognostic Signature for Malignant Pleural Mesothelioma. J.G. Zhou, H. Zhong, J. Zhang, et al. 2019;9:78. PubMed · Publisher · Free full text

  Abstract

  Introduction: Dysregulated genes play a critical role in the development and progression of cancer, suggesting their potential as novel independent biomarkers for cancer diagnosis and prognosis. Prognostic model-based gene expression profiles are not widely utilized in clinical medicine. We investigated the prognostic significance of an expression profile-based gene signature for outcome prediction in patients with malignant pleural mesothelioma (MPM). Methods: The gene expression profiles of a large cohort of patients with MPM were obtained and analyzed by repurposing publicly available microarray data. A gene-based risk score model was developed with the training dataset and then validated with the TCGA-MESO (mesothelioma) dataset. The time-dependent receiver operating characteristic (ROC) curve was used to evaluate the prognostic performance of survival prediction. The biological function of the prognostic genes was predicted using bioinformatics analysis. Results: Three genes in the training dataset (GSE2549) were identified as significantly associated with the overall survival (OS) of patients with MPM and were combined to develop a three-gene prognostic signature to stratify patients into low-risk and high-risk groups. The MPM patients of the training dataset in the low-risk group exhibited longer OS than those in the high-risk group (HR = 0.25, 95% CI = 0.11-0.56, P < 0.001). Similar prognostic values for the three-gene signature were observed in the validated TCGA-MESO cohort (HR = 0.53 95% CI = 0.33-0.85, P = 0.008). ROC analysis also demonstrated the good performance in predicting 3-year OS in the GEO and TCGA cohorts (KM-AUC for GEO = 0.989, KM-AUC for TCGA = 0.618). The C-statistic for the 3-gene model was 0.761. Validation with TCGA-MESO confirmed the model's ability to discriminate between risk groups in an alternative data set with fair performance (C-statistic: 0.68). Functional enrichment analysis suggested that these three genes may be involved in genetic and epigenetic events with known links to MPM. Conclusions: This study has identified and validated a novel 3-gene model to reliably discriminate patients at high and low risk of death in unselected populations of patients with MPM. Further larger, prospective multi-institutional cohort studies are necessary to validate this model.

• Epigenetic Regulation of miRNA Expression in Malignant Mesothelioma: miRNAs as Biomarkers of Early Diagnosis and Therapy. M. Tomasetti, S. Gaetani, F. Monaco, et al. 2019;9:1293. Review PubMed · Publisher · Free full text

  Abstract

  Asbestos exposure leads to epigenetic and epigenomic modifications that, in association with ROS-induced DNA damage, contribute to cancer onset. Few miRNAs epigenetically regulated in MM have been described in literature; miR-126, however, is one of them, and its expression is regulated by epigenetic mechanisms. Asbestos exposure induces early changes in the miRNAs, which are reversibly expressed as protective species, and their inability to reverse reflects the inability of the cells to restore the physiological miRNA levels despite the cessation of carcinogen exposure. Changes in miRNA expression, which results from genetic/epigenetic changes during tumor formation and evolution, can be detected in fluids and used as cancer biomarkers. This article has reviewed the epigenetic mechanisms involved in miRNA expression in MM, focusing on their role as biomarkers of early diagnosis and therapeutic effects.

  Copyright © 2019 Tomasetti, Gaetani, Monaco, Neuzil and Santarelli.

• Globular C1q Receptor (gC1qR/p32/HABP1) Is Overexpressed in Malignant Pleural Mesothelioma and Is Associated With Increased Survival in Surgical Patients Treated With Chemotherapy. X. Li, T. Eguchi, R.G. Aly, et al. 2019;9:1042. PubMed · Publisher · Free full text

  Abstract

  Introduction: Globular C1q receptor (gC1qR/p32/HABP1) is overexpressed in a variety of cancers, particularly adenocarcinomas. This study investigated gC1qR expression in malignant pleural mesothelioma (MPM) and its pathophysiologic correlates in a surgical patient cohort. Methods: Tissue microarrays comprising 6 tumoral and 3 stromal cores from 265 patients with MPM (216 epithelioid, 26 biphasic, and 23 sarcomatoid; 1989-2010) were investigated by immunohistochemistry for gC1qR expression (intensity and distribution by H-score, range 0-300), and immune cell infiltration. Overall survival (OS) was analyzed by the Kaplan-Meier method (high vs. low gC1qR expression delineated by median score) in the whole cohort and by neoadjuvant chemotherapy (NAC) status. Multivariable Cox analysis included stage, chemotherapy, and immune cell infiltration. Results: gC1qR was overexpressed in all histological types of MPMs (263/265, 99.2%) compared to normal pleura. In epithelioid MPM, high gC1qR expression was associated with better OS (median 25 vs. 11 months; p = 0.020) among NAC patients, and among patients without NAC (No-NAC) but who received post-operative chemotherapy (median OS 38 vs. 19 months; p = 0.0007). In multivariable analysis, high gC1qR expression was an independent factor for improved OS in patients treated with NAC. In the No-NAC cohort, high gC1qR expression correlated with lower tumor stage. Moreover, the influence of Ki67 and CD4 T-cell infiltration on OS were more pronounced among patients with high gC1qR expression. Conclusion: This is the first description of gC1qR expression in MPM. The data identify gC1qR as a potential new prognostic factor in patients treated with surgery and chemotherapy.

  Copyright © 2019 Li, Eguchi, Aly, Chintala, Tan, Zauderer, Dembitzer, Beasley, Ghebrehiwet, Adusumilli and Peerschke.

• Liquid Biopsy in Malignant Pleural Mesothelioma: State of the Art, Pitfalls, and Perspectives. I. Cavallari, L. Urso, E. Sharova, et al. 2019;9:740. Review PubMed · Publisher · Free full text

  Abstract

  Malignant pleural mesothelioma (MPM) is an aggressive tumor linked to asbestos exposure. Although the risk factors for MPM are well-known, the majority of MPM patients are diagnosed at an advanced stage and have a very poor prognosis. Circulating biomarkers for early diagnosis remain to be identified, and the current standard for MPM diagnosis relies on pleural biopsies. Robust non-invasive tests for the screening of asbestos-exposed subjects are therefore an important unmet clinical need. This review provides a critical summary of recent liquid biopsy-based studies aimed at discovering novel blood-based circulating biomarkers for the early diagnosis and prognostic stratification of MPM patients.

• Malignant Pleural Mesothelioma: State-of-the-Art on Current Therapies and Promises for the Future. F. Nicolini, M. Bocchini, G. Bronte, et al. 2019;9:1519. Review PubMed · Publisher · Free full text

  Abstract

  Malignant pleural mesothelioma (MPM) is a rare, aggressive cancer of the pleural surface associated with asbestos exposure. The median survival of MPM patients is a mere 8-14 months, and there are few biomarkers and no cure available. It is hoped that, eventually, the incidence of MPM will drop and remain low and constant, given that most nations have banned the use of asbestos, but in the meantime, the incidence in Europe is still growing. The exact molecular mechanisms that explain the carcinogenicity of asbestos are not known. Standard therapeutic strategies for MPM include surgery, often coupled with chemotherapy and/or radiotherapy, in a small percentage of eligible patients and chemotherapy in tumors considered unresectable with or without adjuvant radiotherapy. In recent years, several new therapeutic avenues are being explored. These include angiogenesis inhibitors, synthetic lethal treatment, miRNA replacement, oncoviral therapies, and the fast-growing field of immunotherapy alone or in combination with chemotherapy. Of particular promise are the multiple options offered by immunotherapy: immune checkpoint inhibitors, tumor vaccines, and therapies taking advantage of tumor-specific antigens, such as specific therapeutic antibodies or advanced cell-based therapies exemplified by the CAR-T cells. This review comprehensively presents both old and new therapeutic options in MPM, focusing on the results of the numerous recent and on-going clinical trials in the field, including the latest data presented at international meetings (AACR, ASCO, and ESMO) this year, and concludes that more work has to be done in the framework of tailored therapies to identify reliable targets and novel biomarkers to impact MPM management.

  Copyright © 2020 Nicolini, Bocchini, Bronte, Delmonte, Guidoboni, Crinò and Mazza.

• Mesothelioma Driver Genes, Ferroptosis, and Therapy. E. Felley-Bosco, S.G. Gray. 2019;9:1318. PubMed · Publisher · Free full text

• Multi-antigen Vaccination With Simultaneous Engagement of the OX40 Receptor Delays Malignant Mesothelioma Growth and Increases Survival in Animal Models. P.R. Hoffmann, F.W. Hoffmann, T.A. Premeaux, et al. 2019;9:720. PubMed · Publisher · Free full text

  Abstract

  Malignant Mesothelioma (MM) is a rare and highly aggressive cancer that develops from mesothelial cells lining the pleura and other internal cavities, and is often associated with asbestos exposure. To date, no effective treatments have been made available for this pathology. Herein, we propose a novel immunotherapeutic approach based on a unique vaccine targeting a series of antigens that we found expressed in different MM tumors, but largely undetectable in normal tissues. This vaccine, that we term p-Tvax, is comprised of a series of immunogenic peptides presented by both MHC-I and -II to generate robust immune responses. The peptides were designed using in silico algorithms that discriminate between highly immunogenic T cell epitopes and other harmful epitopes, such as suppressive regulatory T cell epitopes and autoimmune epitopes. Vaccination of mice with p-Tvax led to antigen-specific immune responses that involved both CD8+ and CD4+ T cells, which exhibited cytolytic activity against MM cells in vitro. In mice carrying MM tumors, p-Tvax increased tumor infiltration of CD4+ T cells. Moreover, combining p-Tvax with an OX40 agonist led to decreased tumor growth and increased survival. Mice treated with this combination immunotherapy displayed higher numbers of tumor-infiltrating CD8+ and CD4+ T cells and reduced T regulatory cells in tumors. Collectively, these data suggest that the combination of p-Tvax with an OX40 agonist could be an effective strategy for MM treatment.

• Sirtuin Family Members Selectively Regulate Autophagy in Osteosarcoma and Mesothelioma Cells in Response to Cellular Stress. R. Garva, C. Thepmalee, U. Yasamut, et al. 2019;9:949. PubMed · Publisher · Free full text

  Abstract

  The class III NAD+ dependent deacetylases-sirtuins (SIRTs) link transcriptional regulation to DNA damage response and reactive oxygen species generation thereby modulating a wide range of cellular signaling pathways. Here, the contribution of SIRT1, SIRT3, and SIRT5 in the regulation of cellular fate through autophagy was investigated under diverse types of stress. The effects of sirtuins' silencing on cell survival and autophagy was followed in human osteosarcoma and mesothelioma cells exposed to DNA damage and oxidative stress. Our results suggest that the mitochondrial sirtuins SIRT3 and 5 are pro-proliferative under certain cellular stress conditions and this effect correlates with their role as positive regulators of autophagy. SIRT1 has more complex role which is cell type specific and can affect autophagy in both positive and negative ways. The mitochondrial sirtuins (SIRT3 and SIRT5) affect both early and late stages of autophagy, whereas SIRT1 acts mostly at later stages of the autophagic process. Investigation of potential crosstalk between SIRT1, SIRT3, and SIRT5 revealed several feedback loops and a significant role of SIRT5 in regulating SIRT3 and SIRT1. Results presented here support the notion that sirtuin family members play important as well as differential roles in the regulation of autophagy in osteosarcoma vs. mesothelioma cells exposed to DNA damage and oxidative stress, and this can be exploited in increasing the response of cancer cells to chemotherapy.

  Copyright © 2019 Garva, Thepmalee, Yasamut, Sudsaward, Guazzelli, Rajendran, Tongmuang, Khunchai, Meysami, Limjindaporn, Yenchitsomanus, Mutti, Krstic-Demonacos and Demonacos.

• Stereotactic Body Radiation Therapy (SBRT) as Salvage Therapy for Oligorecurrent Pleural Mesothelioma After Multi-Modality Therapy. C. Schröder, I. Opitz, M. Guckenberger, et al. 2019;9:961. PubMed · Publisher · Free full text

  Abstract

  Introduction: Therapy options for patients with oligoprogressive malignant pleural mesothelioma (MPM) are limited. Stereotactic Body Radiotherapy (SBRT) may be a promising therapeutic option, as it delivers a localized ablative dose of radiation and therefore balances efficacy and treatment related toxicities. The intent of this retrospective analysis was to evaluate the feasibility of SBRT for limited pleural recurrences. Methods and Materials: This retrospective single-institution study is based on the 21 consecutive patients treated with hypofractionated radiotherapy for oligoprogressive MPM. Clinical and radiological data was collected at regular follow-up visits including toxicity, local control and survival. Results: At primary diagnosis, 57% of the patients presented with stage III disease. Initial treatment of MPM consisted of induction chemotherapy (n = 12) prior to a macroscopic complete resection (n = 18). Three patients received additional intracavitary chemotherapy and another three patients were treated with chemotherapy alone without another treatment at the time of first diagnosis. A total of 50 lesions in recurrent MPM were treated with SBRT. The median number of radiotherapy fractions was 5 (range 3-20) with a median dose per fraction of 5 Gy (range 2.5-12.5 Gy). The median total treatment dose was 30 Gy (20-50 Gy) with a median prescription isodose line (IDL) of 65% (65-100%). Median follow-up of all patients from diagnosis was 28 months (range 7-152 months). Analyzing all lesions separately, the 12-months-local control from SBRT was 73.5%. The median progression free survival (PFS) after SBRT was 6 months (range 0-21 months) and the median OS from first first SBRT was 29 months (range 0-61 months). Only one patients experienced above Grade 3 toxicities. Conclusion: This analysis demonstrates the feasibility of a SBRT approach for oligorecurrent MPM. SBRT was well-tolerated even after multiple repetitions and local control was high with a promising median OS.

  Copyright © 2019 Schröder, Opitz, Guckenberger, Stahel, Weder, Förster, Andratschke and Lauk.

• The Immune Microenvironment in Mesothelioma: Mechanisms of Resistance to Immunotherapy. G.J. Chu, N. van Zandwijk, J.E.J. Rasko. 2019;9:1366. Review PubMed · Publisher · Free full text

  Abstract

  Although mesothelioma is the consequence of a protracted immune response to asbestos fibers and characterized by a clear immune infiltrate, novel immunotherapy approaches show less convincing results as compared to those seen in melanoma and non-small cell lung cancer. The immune suppressive microenvironment in mesothelioma is likely contributing to this therapy resistance. Therefore, it is important to explore the characteristics of the tumor microenvironment for explanations for this recalcitrant behavior. This review describes the stromal, cytokine, metabolic, and cellular milieu of mesothelioma, and attempts to make connection with the outcome of immunotherapy trials.

  Copyright © 2019 Chu, van Zandwijk and Rasko.

• The Oncolytic Virus dl922-947 Triggers Immunogenic Cell Death in Mesothelioma and Reduces Xenograft Growth. S. Di Somma, C.A. Iannuzzi, C. Passaro, et al. 2019;9:564. PubMed · Publisher · Free full text

  Abstract

  Background: Malignant pleural mesothelioma (MPM) is an aggressive cancer associated with asbestos exposure that urgently requires effective therapeutic strategies. Current treatments are unable to increase significantly patient survival, which is often limited to <1 year from diagnosis. Virotherapy, based on the use of oncolytic viruses that exert anti-cancer effects by direct cell lysis and through the induction of anti-tumor immune response, represents an alternative therapeutic option for rare tumors with limited life expectancy. In this study, we propose the use of the adenovirus dl922-947, engineered to allow selective replication in cancer cells, to counteract MPM. Methods: We performed a thorough preclinical assessment of dl922-947 effects in a set of MPM cell lines and xenografts. Cytotoxicity of dl922-947 alone and in combination assays was evaluated by sulforhodamine B assay. Cell cycle, calreticulin expression, and high mobility group box protein 1 (HMGB1) secretion were determined by flow cytometry, whereas ATP content was determined by a luminescence-based bioassay. The modulation of angiogenic factors in MPM-infected cells was evaluated through ELISA. Results: We found that dl922-947 infection exhibits cytotoxic effects in MPM cell lines, affecting cell viability, cell cycle progression, and regulating main hallmarks of immunogenic cell death inducing calreticulin surface exposure, HMGB1 and ATP release. Our results also suggest that dl922-947 may affect angiogenic signals by regulation of VEGF-A and IL-8 secretion. Furthermore, dl922-947 shows anti-tumor efficacy in murine xenograft models reducing tumor growth and enhancing survival. Finally, the combination with cisplatin potentiated the cytotoxic effect of dl922-947. Conclusions: Overall our data identify virotherapy, based on the use of dl922-947, as a new possible therapeutic strategy against MPM, which could be used alone, in combination with standard chemotherapy drugs, as shown here, or other approaches also aimed at enhancing the antitumoral immune response elicited by the virus.

• Live-Cell Mesothelioma Biobank to Explore Mechanisms of Tumor Progression. K. Oehl, J. Kresoja-Rakic, I. Opitz, et al. 2018;8:40. PubMed · Publisher · Free full text

  Abstract

  Experimental models closely representing in vivo conditions allow investigating mechanisms of resistance. Our aims were to establish a live-cell biobank of malignant pleural mesothelioma (MPM) samples and to obtain proof of principle that primary culture chemoresistant models, mimicking tumor progression observed in patients, can be obtained in vitro, providing a useful tool to investigate underlying mechanisms. Primary mesothelioma cultures were established from 235 samples between 2007 and 2014. Of two MPM patients, primary cultures obtained at different time points: at initial diagnosis, after neoadjuvant treatment at surgery and/or after tumor recurrence, were deeply investigated. Cells and corresponding tumor tissue were characterized by mesothelial protein and gene expression analysis. In addition, primary cultures from chemo naive patients were exposed to increasing doses of cisplatin/pemetrexed during three months and compared with non-treated cells in a cytotoxicity assay, and by selected profiling of senescence markers. In vitro chemoresistance in the primary mesothelioma cell cultures was associated with increased Thy1 (CD90) expression. Thy1 expression in MPM samples was significantly associated with poor overall survival in the TCGA MPM cohort. Our results illustrate that the establishment of a large live-cell MPM biobank contributes to a better understanding of therapy resistance observed in vivo, which eventually may lead to a more logical approach for developing new treatment strategies.

• MicroRNAs for the Diagnosis and Management of Malignant Pleural Mesothelioma: A Literature Review. G. Lo Russo, A. Tessari, M. Capece, et al. 2018;8:650. Review PubMed · Publisher · Free full text

  Abstract

  Malignant pleural mesothelioma (MPM) is a rare and aggressive tumor with a variable incidence among different countries. Occupational asbestos exposure is the most important etiological factor and a very long latency period is widely reported. In the early phase of the disease, clinical signs are absent or not specific. For this reason, the diagnosis is frequently achieved only in the advanced stages. The histopathological diagnosis per se is also very complex, and no known factor can predict the prognosis with certainty. Nonetheless, current survival rates remain very low, despite the use of standard treatments, which include surgery, chemotherapy and radiotherapy. The identification of new prognostic and/or diagnostic biomarkers, and the discovery of therapeutic targets is a priority and could lead to a real significant impact on the management of malignant pleural mesothelioma. In this scenario, the role of microRNAs is becoming increasingly relevant, with the promise of a quick translation in the current clinical practice. Despite the relative novelty of this field, the number of works and candidate microRNAs that are present in literature is striking. Unfortunately, to date the microRNAs with the most clinical relevance for MPM are still matter of debate, probably due to the variety of approaches, techniques, and collected samples. Although specific microRNAs (e.g., let-7, miR-15 and miR-16, miR-21, miR-34a, and the miR-200 family) have been reported several times from different groups, the heterogeneity of published data reinforces the need of more comprehensive and unified studies on this topic. In this review we collect and discuss the studies focused on the involvement of microRNAs in different aspects of MPM, from their biological role in tumorigenesis and progression, to their possible application as diagnostic, prognostic and predictive biomarkers. Lastly, we examine their potential value as for the design of therapeutic approaches that could benefit MPM patients.

• miR-182 and miR-183 Promote Cell Proliferation and Invasion by Targeting FOXO1 in Mesothelioma. R. Suzuki, V.J. Amatya, K. Kushitani, et al. 2018;8:446. PubMed · Publisher · Free full text

  Abstract

  Dysregulation of miR-182 and miR-183 has been implicated in the progression of several human cancers. Our previous study showed that miR-182 and miR-183 are upregulated in malignant mesothelioma. However, their biological functions remain unclear. We performed in-situ hybridization to analyze the expression of miR-182 and miR-183 in human tissues. Functional analysis was performed by treatment of two mesothelioma cell lines (ACC-MESO1 and CRL-5915) with miR-182 and miR-183 inhibitors. RT-PCR and western blot analysis were conducted to analyze the expression of FOXO1, a known target of both miR-182 and miR-183. Mesothelioma cells treated with FOXO1 siRNA and miR-182/183 inhibitors were also analyzed by evaluating cell proliferation and invasion, as well as expression of FOXO1 and its downstream targets. We confirmed miR-182 expression in 25/29 cases and miR-183 expression in 29/29 cases of human mesothelioma tissue by in-situ hybridization. Notably, inhibition of miR-182 or miR-183 reduced cell proliferation, invasion, migration, and adhesion abilities of mesothelioma cells. Surprisingly, transfection with both miR-182 and miR-183 inhibitors showed even more effects on cell progression. Furthermore, FOXO1 was identified as a target of miR-182 and miR-183 in mesothelioma cells. Inhibition of miR-182 and miR-183 reduced cell proliferation ability via upregulation of FOXO1 and its downstream targets, namely, p27. Moreover, inhibition of miR-182 and miR-183 reduced the cell invasion properties of mesothelioma cells. Our findings indicated that miR-182 and miR-183 promote mesothelioma cell progression via downregulation of FOXO1 and p27. Targeting the miR-182/183-FOXO1 axis could serve as a novel treatment against malignant mesothelioma.

• New Perspectives on Diagnosis and Therapy of Malignant Pleural Mesothelioma. M. Rossini, P. Rizzo, I. Bononi, et al. 2018;8:91. Review PubMed · Publisher · Free full text

  Abstract

  Malignant pleural mesothelioma (MPM) is a rare, but severe form of cancer, with an incidence that varies significantly within and among different countries around the world. It develops in about one to two persons per million of the general population, leading to thousands of deaths every year worldwide. To date, the MPM is mostly associated with occupational asbestos exposure. Asbestos represents the predominant etiological factor, with approximately 70% of cases of MPM with well-documented occupational exposure to asbestos, with the exposure time, on average greater than 40 years. Environmental exposure to asbestos is increasingly becoming recognized as a cause of mesothelioma, together with gene mutations. The possible roles of other cofactors, such as viral infection and radiation exposure, are still debated. MPM is a fatal tumor. This cancer arises during its early phase without clinical signs. Consequently, its diagnosis occurs at advanced stages. Standard clinical therapeutic approaches include surgery, chemo- and radiotherapies. Preclinical and clinical researches are making great strides in the field of this deadly disease, identifying new biomarkers and innovative therapeutic approaches. Among the newly identified markers and potential therapeutic targets, circulating microRNAs and the Notch pathway represent promising avenues that could result in the early detection of the tumor and novel therapeutic approaches.

• Oncolytic Viral Therapy for Mesothelioma. D.F. Pease, R.A. Kratzke. 2017;7:179. Review PubMed · Publisher · Free full text

  Abstract

  The limited effectiveness of conventional therapy for malignant pleural mesothelioma demands innovative approaches to this difficult disease. Even with aggressive multimodality treatment of surgery, radiation, and/or chemotherapy, the median survival is only 1-2 years depending on stage and histology. Oncolytic viral therapy has emerged in the last several decades as a rapidly advancing field of immunotherapy studied in a wide spectrum of malignancies. Mesothelioma makes an ideal candidate for studying oncolysis given the frequently localized pattern of growth and pleural location providing access to direct intratumoral injection of virus. Therefore, despite being a relatively uncommon disease, the multitude of viral studies for mesothelioma can provide insight for applying such therapy to other malignancies. This article will begin with a review of the general principles of oncolytic therapy focusing on antitumor efficacy, tumor selectivity, and immune system activation. The second half of this review will detail results of preclinical models and human studies for oncolytic virotherapy in mesothelioma.

• Microenvironment-Dependent Phenotypic Changes in a SCID Mouse Model for Malignant Mesothelioma. E. Darai-Ramqvist, G. Nilsonne, C. Flores-Staino, et al. 2013;3:203. PubMed · Publisher · Free full text

  Abstract

  Background And Aims: Malignant mesothelioma is an aggressive, therapy-resistant tumor. Mesothelioma cells may assume an epithelioid or a sarcomatoid phenotype, and presence of sarcomatoid cells predicts poor prognosis. In this study, we investigated differentiation of mesothelioma cells in a xenograft model, where mesothelioma cells of both phenotypes were induced to form tumors in severe combined immunodeficiency mice.

  Methods: Xenografts were established and thoroughly characterized using a comprehensive immunohistochemical panel, array comparative genomic hybridization (aCGH) of chromosome 3, fluorescent in situ hybridization, and electron microscopy.

  Results: Epithelioid and sarcomatoid cells gave rise to xenografts of similar epithelioid morphology. While sarcomatoid-derived xenografts had higher growth rates, the morphology and expression of differentiation-related markers was similar between xenografts derived from both phenotypes. aCGH showed a convergent genotype for both xenografts, resembling the original aggressive sarcomatoid cell sub-line.

  Conclusion: Human mesothelioma xenografts from sarcomatoid and epithelioid phenotypes converged to a similar differentiation state, and genetic analyses suggested that clonal selection in the mouse microenvironment was a major contributing factor. This thoroughly characterized animal model can be used for further studies of molecular events underlying tumor cell differentiation.

• The role of syndecan-1 in cellular signaling and its effects on heparan sulfate biosynthesis in mesenchymal tumors. T. Szatmári, K. Dobra. 2013;3:310. Review PubMed · Publisher · Free full text

  Abstract

  Proteoglycans (PGs) and in particular the syndecans are involved in the differentiation process across the epithelial-mesenchymal axis, principally through their ability to bind growth factors and modulate their downstream signaling. Malignant tumors have individual proteoglycan profiles, which are closely associated with their differentiation and biological behavior, mesenchymal tumors showing a different profile from that of epithelial tumors. Syndecan-1 is the main syndecan of epithelial malignancies, whereas in sarcomas its expression level is generally low, in accordance with their mesenchymal phenotype and highly malignant behavior. This proteoglycan is often overexpressed in adenocarcinoma cells, whereas mesothelioma and fibrosarcoma cells express syndecan-2 and syndecan-4 more abundantly. Increased expression of syndecan-1 in mesenchymal tumors changes the tumor cell morphology to an epithelioid direction whereas downregulation results in a change in shape from polygonal to spindle-like morphology. Although syndecan-1 plays major roles on the cell-surface, there are also intracellular functions, which are not very well studied. On the functional level, syndecan-1 affects mesenchymal tumor cell proliferation, adhesion, migration and motility, and the effect varies with the different domains of the core protein. Syndecan-1 may exert stimulatory or inhibitory effects, depending on the concentration of various mitogens, enzymes, and signaling molecules, the ratio between the shed and membrane-associated syndecan-1 and histological grade of the tumour. Growth factor signaling seems to be delicately controlled by regulatory loops involving the syndecan expression levels and their sulfation patterns. Overexpression of syndecan-1 modulates the biosynthesis and sulfation of heparan sulfate and it also affects the expression of other PGs. On transcriptomic level, syndecan-1 modulation results in profound effects on genes involved in regulation of cell growth.

• Investigational approaches for mesothelioma. V.F. Surmont, E.R. van Thiel, K. Vermaelen, et al. 2011;1:22. PubMed · Publisher · Free full text

  Abstract

  Malignant pleural mesothelioma (MPM) is a rare, aggressive tumor with a poor prognosis. In view of the poor survival benefit from first-line chemotherapy and the lack of subsequent effective treatment options, there is a strong need for the development of more effective treatment approaches for patients with MPM. This review will provide a comprehensive state of the art of new investigational approaches for mesothelioma. In an introductory section, the etiology, epidemiology, natural history, and standard of care treatment for MPM will be discussed. This review provide an update of the major clinical trials that impact mesothelioma treatment, discuss the impact of novel therapeutics, and provide perspective on where the clinical research in mesothelioma is moving. The evidence was collected by a systematic analysis of the literature (2000-2011) using the databases Medline (National Library of Medicine, USA), Embase (Elsevier, Netherlands), Cochrane Library (Great Britain), National Guideline Clearinghouse (USA), HTA Database (International Network of Agencies for Health Technology Assessment - INAHTA), NIH database (USA), International Pleural Mesothelioma Program - WHOLIS (WHO Database), with the following keywords and filters: mesothelioma, guidelines, treatment, surgery, chemotherapy, radiotherapy, review, investigational, drugs. Currently different targeted therapies and biologicals are under investigation for MPM. It is important that the molecular biologic research should first focus on mesothelioma-specific pathways and biomarkers in order to have more effective treatment options for this disease. The use of array technology will be certainly an implicit gain in the identification of new potential prognostic or biomarkers or important pathways in the MPM pathogenesis. Probably a central mesothelioma virtual tissue bank may contribute to the ultimate goal to identify druggable targets and to develop personalized treatment for the MPM patients.

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