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Archives of Pathology & Laboratory... May 2024Molecular testing has increasingly been utilized in the evaluation of mesothelioma. Diffuse mesothelioma comprises multiple distinct genetic subgroups. While most... (Review)
Review
CONTEXT.—
Molecular testing has increasingly been utilized in the evaluation of mesothelioma. Diffuse mesothelioma comprises multiple distinct genetic subgroups. While most diffuse mesotheliomas lack oncogenic kinase mutations and instead harbor alterations involving tumor suppressors and chromatin regulators, a minor subset of tumors is characterized by uncommon alterations such as germline mutations, genomic near-haploidization, ALK rearrangement, ATF1 rearrangement, or EWSR1::YY1 fusion.
OBJECTIVE.—
To provide updates on the salient molecular features of diffuse mesothelioma, mesothelioma in situ, and other mesothelial lesions: well-differentiated papillary mesothelial tumor, adenomatoid tumor, peritoneal inclusion cyst, and others. We consider the diagnostic, prognostic, and predictive utility of molecular testing in mesothelial lesions.
DATA SOURCES.—
We performed a literature review of recently described genetic features, molecular approaches, and immunohistochemical tools, including BAP1, MTAP, and merlin in mesothelioma and other mesothelial lesions.
CONCLUSIONS.—
Our evolving understanding of the molecular diversity of diffuse mesothelioma and other mesothelial lesions has led to considerable changes in pathology diagnostic practice, including the application of immunohistochemical markers such as BAP1, MTAP, and merlin (NF2), which are surrogates of mutation status. In young patients and/or those without significant asbestos exposure, unusual mesothelioma genetics such as germline mutations, ALK rearrangement, and ATF1 rearrangement should be considered.
Topics: Humans; Mesothelioma; Immunohistochemistry; Biomarkers, Tumor; Neoplasms, Mesothelial; Mesothelioma, Malignant; Mutation; Tumor Suppressor Proteins; Ubiquitin Thiolesterase
PubMed: 38190277
DOI: 10.5858/arpa.2023-0213-RA -
British Journal of Cancer Aug 2023Mutational inactivation of the SETDB1 histone methyltransferase is found in a subset of mesothelioma, particularly in cases with near-haploidy and TP53 mutations....
BACKGROUND
Mutational inactivation of the SETDB1 histone methyltransferase is found in a subset of mesothelioma, particularly in cases with near-haploidy and TP53 mutations. However, the tumourigenic consequences of SETDB1 inactivation are poorly understood.
METHODS
In this study, we investigated SETDB1 tumour suppressor functions in mesothelioma and explored biologic relationships between SETDB1 and TP53.
RESULTS
Immunoblotting of early passage cultures showed that SETDB1 was undetectable in 7 of 8 near-haploid mesotheliomas whereas SETDB1 expression was retained in each of 13 near-diploid mesotheliomas. TP53 aberrations were present in 5 of 8 near-haploid mesotheliomas compared to 2 of 13 near-diploid mesotheliomas, and BAP1 inactivation was demonstrated only in near-diploid mesotheliomas, indicating that near-haploid and near-diploid mesothelioma have distinct molecular and biologic profiles. Lentiviral SETDB1 restoration in near-haploid mesotheliomas (MESO257 and MESO542) reduced cell viability, colony formation, reactive oxygen species levels, proliferative marker cyclin A expression, and inhibited growth of MESO542 xenografts. The combination of SETDB1 restoration with pemetrexed and/or cisplatin treatment additively inhibited tumour growth in vitro and in vivo. Furthermore, SETDB1 restoration upregulated TP53 expression in MESO542 and MESO257, whereas SETDB1 knockdown inhibited mutant TP53 expression in JMN1B near-haploid mesothelioma cells. Likewise, TP53 knockdown inhibited SETDB1 expression. Similarly, immunoblotting evaluations of ten near-diploid mesothelioma biopsies and analysis of TCGA expression profiles showed that SETDB1 expression levels paralleled TP53 expression.
CONCLUSION
These findings demonstrate that SETDB1 inactivation in near-haploid mesothelioma is generally associated with complete loss of SETDB1 protein expression and dysregulates TP53 expression. Targeting SETDB1 pathways could be an effective therapeutic strategy in these often untreatable tumours.
Topics: Humans; Haploidy; Mesothelioma, Malignant; Mesothelioma; Genes, Tumor Suppressor; Chromosome Aberrations; Biological Products; Tumor Suppressor Protein p53; Histone-Lysine N-Methyltransferase
PubMed: 37369845
DOI: 10.1038/s41416-023-02330-x -
American Journal of Industrial Medicine Jan 2024Asbestos is a known human carcinogen and is causally associated with malignant mesothelioma, lung, larynx and ovarian cancers.
BACKGROUND
Asbestos is a known human carcinogen and is causally associated with malignant mesothelioma, lung, larynx and ovarian cancers.
METHODS
Cancer risk was studied among a pool of formerly asbestos-exposed workers in Italy. Fifty-two Italian asbestos cohorts (asbestos-cement, rolling-stock, shipbuilding, and other) were pooled and their mortality follow-up was updated to 2018. Standardized mortality ratios (SMRs) were computed for major causes of death considering duration of exposure and time since first exposure (TSFE), using reference rates by region, age and calendar period.
RESULTS
The study included 63,502 subjects (57,156 men and 6346 women): 40% who were alive, 58% who died (cause known for 92%), and 2% lost to follow-up. Mortality was increased for all causes (SMR: men = 1.04, 95% confidence interval [CI] 1.03-1.05; women = 1.15, 95% CI 1.11-1.18), all malignancies (SMR: men = 1.21, 95% CI 1.18-1.23; women = 1.29, 95% CI 1.22-1.37), pleural and peritoneal malignancies (men: SMR = 10.46, 95% CI 9.86-11.09 and 4.29, 95% CI 3.66-5.00; women: SMR = 27.13, 95% CI 23.29-31.42 and 7.51, 95% CI 5.52-9.98), lung (SMR: men = 1.28, 95% CI 1.24-1.32; women = 1.26, 95% CI 1.02-1.53), and ovarian cancer (SMR = 1.42, 95% CI 1.08-1.84). Pleural cancer mortality increased during the first 40 years of TSFE (latency), reaching a plateau thereafter.
CONCLUSIONS
Analyses by time-dependent variables showed that the risk for pleural neoplasms increased with latency and no longer increases at long TSFE, consistent with with asbestos clearance from the lungs. Peritoneal neoplasm risk increased over all observation time.
Topics: Male; Humans; Female; Cause of Death; Mesothelioma; Cohort Studies; Occupational Exposure; Occupational Diseases; Construction Materials; Asbestos; Pleural Neoplasms; Peritoneal Neoplasms; Ovarian Neoplasms; Italy; Lung Neoplasms
PubMed: 37855384
DOI: 10.1002/ajim.23546 -
The Lancet. Oncology Nov 2023The combination of pembrolizumab, an anti-PD-1 antibody, and lenvatinib, an antiangiogenic multikinase inhibitor, shows synergistic activity in preclinical and clinical...
BACKGROUND
The combination of pembrolizumab, an anti-PD-1 antibody, and lenvatinib, an antiangiogenic multikinase inhibitor, shows synergistic activity in preclinical and clinical studies in solid tumours. We assessed the clinical activity of this combination therapy in patients with pleural mesothelioma who progressed after platinum-pemetrexed chemotherapy.
METHODS
In this single-arm, single-centre, phase 2 study, done at the Netherlands Cancer Institute in Amsterdam, The Netherlands, eligible patients (aged ≥18 years) with pleural mesothelioma with an Eastern Cooperative Oncology Group performance status of 0-1, progression after chemotherapy (no previous immunotherapy), and measurable disease according to the modified Response Evaluation Criteria In Solid Tumours (mRECIST) for mesothelioma version 1.1. Patients received 200 mg intravenous pembrolizumab once every 3 weeks plus 20 mg oral lenvatinib once per day for up to 2 years or until disease progression, development of unacceptable toxicity, or withdrawal of consent. The primary endpoint was objective response rate identified by a local investigator according to mRECIST version 1.1. This trial is registered with ClinicalTrials.gov, NCT04287829, and is recruiting for the second cohort.
FINDINGS
Between March 5, 2021, and Jan 31, 2022, 42 patients were screened, of whom 38 were included in the primary endpoint and safety analyses (median age 71 years [IQR 65-75], 33 [87%] male and five [13%] female) . At data cutoff (Jan 31, 2023), with a median follow-up of 17·7 months (IQR 13·8-19·4), 22 (58%; 95% CI 41-74) of 38 patients had an objective response. The independent review showed an objective response in 17 (45%; 95% CI 29-62) of 38 patients. Serious treatment-related adverse events occurred in ten (26%) patients, including one treatment-related death due to myocardial infarction. The most common treatment-related grade 3 or worse adverse events were hypertension (eight patients [21%]) and anorexia and lymphopenia (both four patients [11%]). In 29 (76%) of 38 patients, at least one dose reduction or discontinuation of lenvatinib was required.
INTERPRETATION
Pembrolizumab plus lenvatinib showed promising anti-tumour activity in patients with pleural mesothelioma with considerable toxicity, similar to that in previous studies. Available evidence from the literature suggests a high starting dose of lenvatinib for optimal anti-tumour activity. This, however, demands a high standard of supportive care. The combination therapy of pembrolizumab and lenvatinib warrants further investigation in pleural mesothelioma.
FUNDING
Merck Sharp & Dohme.
Topics: Humans; Male; Female; Adolescent; Adult; Aged; Antineoplastic Agents, Immunological; Mesothelioma, Malignant; Mesothelioma; Pleural Neoplasms; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37844598
DOI: 10.1016/S1470-2045(23)00446-1 -
Radiology and Oncology Sep 2023Tumor Treating Fields (TTFields) is a non-invasive modality for cancer treatment that utilizes a specific sinusoidal electric field ranging from 100 kHz to 300 kHz, with... (Review)
Review
BACKGROUND
Tumor Treating Fields (TTFields) is a non-invasive modality for cancer treatment that utilizes a specific sinusoidal electric field ranging from 100 kHz to 300 kHz, with an intensity of 1 V/cm to 3 V/cm. Its purpose is to inhibit cancer cell proliferation and induce cell death. Despite promising outcomes from clinical trials, TTFields have received FDA approval for the treatment of glioblastoma multiforme (GBM) and malignant pleural mesothelioma (MPM). Nevertheless, global acceptance of TTFields remains limited. To enhance its clinical application in other types of cancer and gain a better understanding of its mechanisms of action, this review aims to summarize the current research status by examining existing literature on TTFields' clinical trials and mechanism studies.
CONCLUSIONS
Through this comprehensive review, we seek to stimulate novel ideas and provide physicians, patients, and researchers with a better comprehension of the development of TTFields and its potential applications in cancer treatment.
Topics: Humans; Glioblastoma; Mesothelioma, Malignant; Cell Death; Cell Proliferation
PubMed: 37665740
DOI: 10.2478/raon-2023-0044 -
BMC Pulmonary Medicine Jul 2023Pleural disease (PD), particularly malignant pleural effusion (MPE), is a common cause of hospital admission and its prevalence is rising worldwide. Recent advances in...
BACKGROUND
Pleural disease (PD), particularly malignant pleural effusion (MPE), is a common cause of hospital admission and its prevalence is rising worldwide. Recent advances in diagnostic and therapeutic options, such as Indwelling Pleural Catheters (IPCs), have simplified PD treatment, allowing an effective outpatients management. Therefore, dedicated pleural services can improve PD care, guaranteeing specialized management and optimizing time and cost. We aimed to provide an overview on MPE management in Italy, mainly focused on distribution and characteristics of pleural services and IPCs use.
METHODS
A nationwide survey, endorsed by the Italian Thoracic Society, was distributed by email to members of selected subgroups in 2021.
RESULTS
Ninety (23%) members replied, most of whom being pulmonologists (91%). MPE resulted the most common cause of pleural effusion and was managed with heterogenous approaches, including talc pleurodesis via slurry (43%), talc poudrage (31%), repeated thoracentesis (22%) and IPCs insertion (2%). The setting of IPC insertion was inpatient care in 48% of cases, with a predominance of draining frequency every other day. IPC management mainly relied on caregivers (42%). The presence of a pleural service was reported by 37% of respondents.
CONCLUSIONS
The present study provides an extensive overview of MPE management in Italy, showing a highly heterogeneous approach, a scarce prevalence of out-patient pleural services, and a still limited adoption of IPCs, mainly due to lack of dedicated community care systems. This survey emphasizes the need of promoting a higher spreading of pleural services and an innovative healthcare delivery with more favourable cost-benefit ratio.
Topics: Humans; Pleural Effusion, Malignant; Talc; Pleura; Pleural Diseases; Italy
PubMed: 37430219
DOI: 10.1186/s12890-023-02530-4 -
Respiratory Investigation Jan 2024Several markers for the diagnosis of pleural effusion have been reported; however, a comprehensive evaluation using those markers has not been performed. Therefore, this...
BACKGROUND
Several markers for the diagnosis of pleural effusion have been reported; however, a comprehensive evaluation using those markers has not been performed. Therefore, this study aimed to develop a diagnostic flowchart for tuberculous pleurisy, pleural infection, malignant pleural effusion, and other diseases by using these markers.
METHODS
We retrospectively collected data from 174 patients with tuberculous pleurisy, 215 patients with pleural infection other than tuberculous pleurisy, 360 patients with malignant pleural effusion, and 209 patients with other diseases at Fukujuji Hospital from January 2012 to October 2022. The diagnostic flowchart for four diseases was developed by using several previously reported markers.
RESULTS
The flowchart was developed by including seven markers: pleural ADA ≥40 IU/L, pleural fluid LDH <825 IU/L, pleural fluid ADA/TP < 14, neutrophil predominance or cell degeneration, peripheral blood WBC ≥9200/μL or serum CRP ≥12 mg/dL, pleural amylase ≥75 U/L, and the presence of pneumothorax according to the algorithm of a decision tree. The accuracy ratio of the flowchart was 71.7 % for the diagnosis of the four diseases, with 79.3 % sensitivity and 75.4 % positive predictive value (PPV) for tuberculosis pleurisy, 75.8 % sensitivity and 83.2 % PPV for pleural infection, 88.6 % sensitivity and 68.8 % PPV for malignant pleural effusion, and 33.0 % sensitivity and 60.0 % PPV for other diseases in the flowchart. The misdiagnosis ratios were 4.6 % for tuberculosis pleurisy, 6.8 % for pleural infection, and 8.3 % for malignant pleural effusion.
CONCLUSION
This study developed a useful diagnostic flowchart for tuberculous pleurisy, pleural infection, malignant pleural effusion, and other diseases.
Topics: Humans; Tuberculosis, Pleural; Pleural Effusion, Malignant; Retrospective Studies; Software Design; Pleural Effusion; Biomarkers; Diagnosis, Differential; Pleurisy; Sensitivity and Specificity
PubMed: 38141528
DOI: 10.1016/j.resinv.2023.11.005 -
Journal of Translational Medicine Oct 2023Mesothelioma is a cancer typically caused by asbestos. Mechanistically, asbestos carcinogenesis has been linked to the asbestos-induced release of HMGB1 from the nucleus... (Review)
Review
Mesothelioma is a cancer typically caused by asbestos. Mechanistically, asbestos carcinogenesis has been linked to the asbestos-induced release of HMGB1 from the nucleus to the cytoplasm, where HMGB1 promotes autophagy and cell survival, and to the extracellular space where HMGB1 promotes chronic inflammation and mesothelioma growth. Targeting HMGB1 inhibited asbestos carcinogenesis and the growth of mesothelioma. It is hoped that targeting HMGB1 will be a novel therapeutic strategy that benefits mesothelioma patients. Severe restrictions and/or a complete ban on the use of asbestos were introduced in the 80 and early 90s in the Western world. These measures have proven effective as the incidence of mesothelioma/per 100,000 persons is decreasing in these countries. However, the overall number of mesotheliomas in the Western world has not significantly decreased. There are several reasons for that which are discussed here: (1) the presence of asbestos in old constructions; (2) the development of rural areas containing asbestos or other carcinogenic mineral fibers in the terrain; (3) the discovery of an increasing fraction of mesotheliomas caused by germline genetic mutations of BAP1 and other tumor suppressor genes; (4) mesotheliomas caused by radiation therapy; (5) the overall increase in the population and of the fraction of older people who are much more susceptible to develop all types of cancers, including mesothelioma. In summary, the epidemiology of mesothelioma is changing, the ban on asbestos worked, there are opportunities to help mesothelioma patients especially those who develop in a background of germline mutations and there is the opportunity to prevent a mesothelioma epidemic in the developing world, where the use of asbestos is increasing exponentially. We hope that restrictive measures similar to those introduced in the Western world will soon be introduced in developing countries to prevent a mesothelioma epidemic.
Topics: Humans; Asbestos; Carcinogenesis; HMGB1 Protein; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Tumor Suppressor Proteins; Ubiquitin Thiolesterase
PubMed: 37880686
DOI: 10.1186/s12967-023-04614-5 -
Cancer Letters Oct 2023Pleural mesothelioma (PM) is characterized by poor prognosis and limited therapeutic options. Y-box-binding protein 1 (YB-1) was shown to drive growth and migration of...
Pleural mesothelioma (PM) is characterized by poor prognosis and limited therapeutic options. Y-box-binding protein 1 (YB-1) was shown to drive growth and migration of PM cells. Here, we evaluated the effect of genetic and pharmacological targeting of YB-1 on PM growth and response to cisplatin and radiation treatment. YB-1 knockdown via siRNA resulted in reduced PM cell growth, which significantly correlated with wt BAP1 and mutant NF2 and P53 status. Entinostat inhibited YB-1 deacetylation and its efficacy correlated with YB-1 knockdown-induced growth inhibition in 20 PM cell lines. Tumor growth inhibition by siRNA as well as entinostat was confirmed in mouse xenotransplant models. Furthermore, both YBX1-targeting siRNA and entinostat enhanced sensitivity to cisplatin and radiation. In particular, entinostat showed strong synergistic interactions with cisplatin which was linked to significantly increased cellular platinum uptake in all investigated cell models. Importantly, in a mouse model, the combination of cisplatin and entinostat also resulted in stronger growth inhibition than each treatment alone. Our study highlights YB-1 as an attractive target in PM and demonstrates that targeting YB-1 via entinostat is a promising approach to enhance cisplatin and radiation sensitivity.
Topics: Cisplatin; Animals; Humans; Pyridines; Benzamides; Cell Line, Tumor; Y-Box-Binding Protein 1; Pleural Neoplasms; Xenograft Model Antitumor Assays; Drug Synergism; Mesothelioma; Mice; Cell Proliferation; Antineoplastic Combined Chemotherapy Protocols; Mice, Nude; Antineoplastic Agents; Acetylation; Female; Tumor Suppressor Proteins; Ubiquitin Thiolesterase
PubMed: 37730104
DOI: 10.1016/j.canlet.2023.216395 -
JCO Precision Oncology Sep 2023Pleural mesothelioma is an aggressive disease that is enriched for inactivating alterations in tumor suppressor genes. Systemic therapeutic strategies for pleural... (Review)
Review
Pleural mesothelioma is an aggressive disease that is enriched for inactivating alterations in tumor suppressor genes. Systemic therapeutic strategies for pleural mesothelioma generally involve chemotherapies and immunotherapies that are chosen without consideration of the tumor's molecular profile. As this generalized approach to treatment rarely yields durable responses, alternative therapeutic regimens are urgently indicated. Preclinical studies have identified synthetic lethal protein and metabolic interactions, recurrently overexpressed proteins, and frequent pathway perturbations that may be therapeutically exploited in mesothelioma. This review discusses the mechanism of action of emerging investigational therapies and summarizes findings from phase I-II clinical trials exploring selective, biomarker-driven therapeutic strategies for mesothelioma, with a focus on five common targets. Finally, using lessons learned from these clinical trials, imperatives for successful implementation of targeted therapy in mesothelioma are discussed.
Topics: Humans; Lung Neoplasms; Mesothelioma, Malignant; Mesothelioma; Pleural Neoplasms; Immunotherapy
PubMed: 37992257
DOI: 10.1200/PO.23.00344