-
Cancer Discovery Apr 2023Cancer immunotherapy combinations have recently been shown to improve the overall survival of advanced mesotheliomas, especially for patients responding to those...
UNLABELLED
Cancer immunotherapy combinations have recently been shown to improve the overall survival of advanced mesotheliomas, especially for patients responding to those treatments. We aimed to characterize the biological correlates of malignant pleural mesotheliomas' primary resistance to immunotherapy and antiangiogenics by testing the combination of pembrolizumab, an anti-PD-1 antibody, and nintedanib, a pan-antiangiogenic tyrosine kinase inhibitor, in the multicenter PEMBIB trial (NCT02856425). Thirty patients with advanced malignant pleural mesothelioma were treated and explored. Unexpectedly, we found that refractory patients were actively recruiting CD3+CD8+ cytotoxic T cells in their tumors through CXCL9 tumor release upon treatment. However, these patients displayed high levels of somatic copy-number alterations in their tumors that correlated with high blood and tumor levels of IL6 and CXCL8. Those proinflammatory cytokines resulted in higher tumor secretion of VEGF and tumor enrichment in regulatory T cells. Advanced mesothelioma should further benefit from stratified combination therapies adapted to their tumor biology.
SIGNIFICANCE
Sequential explorations of fresh tumor biopsies demonstrated that mesothelioma resistance to anti-PD-1 + antiangiogenics is not due to a lack of tumor T-cell infiltration but rather due to adaptive immunosuppressive pathways by tumors, involving molecules (e.g., IL6, CXCL8, VEGF, and CTLA4) that are amenable to targeted therapies. This article is highlighted in the In This Issue feature, p. 799.
Topics: Humans; Mesothelioma, Malignant; Interleukin-6; Vascular Endothelial Growth Factor A; Lung Neoplasms; Mesothelioma; Immunotherapy; Genomic Instability; Inflammation; Pleural Neoplasms
PubMed: 36669143
DOI: 10.1158/2159-8290.CD-22-0886 -
PloS One 2020There is ongoing research into the development of novel molecular markers that may complement fluid cytology malignant pleural effusion (MPE) diagnosis. In this...
INTRODUCTION
There is ongoing research into the development of novel molecular markers that may complement fluid cytology malignant pleural effusion (MPE) diagnosis. In this exploratory pilot study, we hypothesized that there are distinct differences in the pleural fluid microbiome profile of malignant and non-malignant pleural diseases.
METHOD
From a prospectively enrolled pleural fluid biorepository, samples of MPE were included. Non-MPE effusion were included as comparators. 16S rRNA gene V4 region amplicon sequencing was performed. Exact Sequence Variants (ESVs) were used for diversity analyses. The Shannon and Richness indices of alpha diversity and UniFrac beta diversity measures were tested for significance using permutational multivariate analysis of variance. Analyses of Composition of Microbiome was used to identify differentially abundant bacterial ESVs between the groups controlled for multiple hypothesis testing.
RESULTS
38 patients with MPE and 9 with non-MPE were included. A subgroup of patients with metastatic adenocarcinoma histology were identified among MPE group (adenocarcinoma of lung origin (LA-MPE) = 11, breast origin (BA-MPE) = 11). MPE presented with significantly greater alpha diversity compared to non-MPE group. Within the MPE group, BA-MPE was more diverse compared to LA-MPE group. In multivariable analysis, ESVs belonging to family S24-7 and genera Allobaculum, Stenotrophomonas, and Epulopiscium were significantly enriched in the malignant group compared to the non-malignant group.
CONCLUSION
Our results are the first to demonstrate a microbiome signature according to MPE and non-MPE. The role of microbiome in pleural effusion pathogenesis needs further exploration.
Topics: Female; Humans; Male; Microbiota; Middle Aged; Neoplasm Metastasis; Pleural Effusion, Malignant
PubMed: 32384089
DOI: 10.1371/journal.pone.0232181 -
Thoracic Cancer May 2024Tumor recurrence remains the main barrier to survival after surgery for pleural mesothelioma (PM). Soluble mesothelin-related protein (SMRP) and cancer antigen 125...
BACKGROUND
Tumor recurrence remains the main barrier to survival after surgery for pleural mesothelioma (PM). Soluble mesothelin-related protein (SMRP) and cancer antigen 125 (CA-125) are established blood-based biomarkers for monitoring PM. We prospectively studied the utility of these biomarkers after pleurectomy decortication (PD).
METHODS
Patients who underwent PD and achieved complete macroscopic resection with available preoperative SMRP levels were included. Tumor marker levels were determined within 60 days of three timepoints: (1) preoperation, (2) post-operation, and (3) recurrence.
RESULTS
Of 356 evaluable patients, 276 (78%) had recurrence by the end of follow-up interval. Elevated preoperative SMRP levels were associated with epithelioid histology (p < 0.013), advanced TNM (p < 0.001) stage, and clinical stage (p < 0.001). Preoperative CA-125 levels were not significantly associated with clinical covariates. Neither biomarker was associated with survival or disease-free survival. With respect to nonpleural and nonlymphatic recurrences, mean SMRP levels were elevated in patients with pleural (p = 0.021) and lymph node (p = 0.042) recurrences. CA-125 levels were significantly higher in patients with abdominal (p < 0.001) and lymph node (p = 0.004) recurrences. Among patients with all three timepoints available, we observed an average decrease in SMRP levels by 1.93 nmol/L (p < 0.001) postoperatively and again an average increase at recurrence by 0.79 nmol/L (p < 0.001). There were no significant changes in levels of CA-125 across the study timepoints (p = 0.47).
CONCLUSIONS
Longitudinal changes in SMRP levels corresponded with a radiographic presence of disease in a subset of patients. SMRP surveillance could aid in detection of local recurrences, whereas CA-125 could be helpful in recognizing abdominal recurrences.
Topics: Humans; Male; Female; CA-125 Antigen; Aged; Pleural Neoplasms; Middle Aged; Biomarkers, Tumor; Mesothelioma; Neoplasm Recurrence, Local; Mesothelin; Mesothelioma, Malignant; Prospective Studies; Adult; Aged, 80 and over; GPI-Linked Proteins; Lung Neoplasms
PubMed: 38627917
DOI: 10.1111/1759-7714.15264 -
Seminars in Roentgenology Oct 2023
Topics: Humans; Diagnosis, Differential; Pleural Diseases; Tomography, X-Ray Computed; Pleura; Pleural Neoplasms
PubMed: 37973269
DOI: 10.1053/j.ro.2023.06.001 -
Modern Pathology : An Official Journal... Oct 2022BAP1 and MTAP immunostains play an important role in diagnosis of mesothelioma, but additional markers are needed to increase sensitivity. We analyzed 84 pleural...
BAP1 and MTAP immunostains play an important role in diagnosis of mesothelioma, but additional markers are needed to increase sensitivity. We analyzed 84 pleural mesotheliomas (51 epithelioid, 27 biphasic, 6 sarcomatoid) by a hybrid-capture next-generation sequencing (NGS) panel including complete coverage of coding and splicing regions for BAP1, CDKN2A/MTAP, NF2, and TP53 and correlated molecular findings with diagnostic immunostains for BAP1, MTAP, Merlin, and p53, respectively. Fifty-seven reactive mesothelial proliferations served as benign comparators. Loss of BAP1, MTAP, and Merlin protein expression were, respectively, 54%, 46%, and 52% sensitive and 100% specific for mesothelioma. Two-marker immunopanels of BAP1 + MTAP, BAP1 + Merlin, and MTAP + Merlin were 79%, 85%, and 71% sensitive for mesothelioma, while a three-marker immunopanel of BAP1 + MTAP + Merlin was 90% sensitive. Diffuse (mutant-pattern) p53 immunostaining was seen in only 6 (7%) tumors but represented the only immunohistochemical abnormality in 2 cases. Null-pattern p53 was not specific for malignancy. An immunopanel of BAP1 + MTAP + Merlin + p53 was 93% sensitive for mesothelioma, and panel NGS detected a pathogenic alteration in BAP1, MTAP, NF2, and/or TP53 in 95%. Together, 83 (99%) of 84 tumors showed a diagnostic alteration by either immunohistochemistry or panel NGS. Adding Merlin to the standard BAP1 + MTAP immunopanel increases sensitivity for mesothelioma without sacrificing specificity. p53 immunohistochemistry and panel NGS with complete coverage of BAP1, CDKN2A/MTAP, TP53, and NF2 may be useful in diagnostically challenging cases.
Topics: Biomarkers, Tumor; Diagnosis, Differential; Humans; Immunohistochemistry; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Neurofibromin 2; Pleural Neoplasms; Tumor Suppressor Protein p53; Tumor Suppressor Proteins; Ubiquitin Thiolesterase
PubMed: 35459788
DOI: 10.1038/s41379-022-01081-z -
Environmental Health : a Global Access... Jun 2022The Italian mesothelioma registry (ReNaM) estimates mesothelioma incidence and addresses its etiology by assessing cases' exposures but cannot provide relative risk...
BACKGROUND
The Italian mesothelioma registry (ReNaM) estimates mesothelioma incidence and addresses its etiology by assessing cases' exposures but cannot provide relative risk estimates.
OBJECTIVES
i) To estimate pleural mesothelioma relative risk by industry and occupation and by ReNaM categories of asbestos exposure; and ii) to provide quantitative estimates of the exposure-response relationship.
METHODS
A population-based mesothelioma case-control study was conducted in 2012-2014 in five Italian regions. Cases and age and gender frequency-matched controls were interviewed using a standard ReNaM questionnaire. Experts coded work histories according to international standard classifications of industries/occupations and assigned asbestos exposure according to ReNaM categories. Job codes were further linked to SYN-JEM, a quantitative job-exposure matrix. Cumulative exposure (CE, f/mL-years) was computed by summing individual exposures over lifetime work history. Unconditional logistic regression analyses adjusted by gender, centre and age were fitted to calculate odds ratios (OR) and 95% confidence intervals (CI).
RESULTS
Among men we observed increased risks of mesothelioma in many industries and associated occupations, including: asbestos-cement (OR = 3.43), manufacture of railroad equipment (OR = 8.07), shipbuilding and repairing (OR = 2.34), iron and steel mills (OR = 2.15), and construction (OR = 1.94). ORs by ReNaM exposure categories were as follows: definite/probable occupational exposure (OR = 15.8, men; OR = 8.80, women), possible occupational (OR = 2.82, men; OR = 3.70, women), sharing home with an exposed worker (OR = 2.55, men; OR = 10.3, women), residential (OR = 2.14, men; OR = 3.24, women). Based on SYN-JEM, mesothelioma risk increased by almost 30% per f/mL-year (OR = 1.28, CI 1.16-1.42).
CONCLUSIONS
Out study involved five regions with historically different types and levels of industrial development, encompassing one third of the Italian population and half of Italian mesothelioma cases. As expected, we found increased pleural mesothelioma risk in the asbestos industry and in trades with large consumption of asbestos materials. Clear associations were found using both qualitative (ReNaM classifications) and quantitative estimates (using SYN-JEM) of past asbestos exposure, with clear evidence of an exposure-response relationship.
Topics: Asbestos; Case-Control Studies; Female; Humans; Italy; Male; Mesothelioma; Mesothelioma, Malignant; Occupational Diseases; Occupational Exposure; Occupations; Pleural Neoplasms
PubMed: 35717324
DOI: 10.1186/s12940-022-00869-5 -
International Journal of Molecular... Apr 2023Aldehyde dehydrogenase 1A3 (ALDH1A3), one of the three members of the aldehyde dehydrogenase 1A subfamily, has been associated with increased progression and drug...
Aldehyde dehydrogenase 1A3 (ALDH1A3), one of the three members of the aldehyde dehydrogenase 1A subfamily, has been associated with increased progression and drug resistance in various types of solid tumours. Recently, it has been reported that high ALDH1A3 expression is prognostic of poor survival in patients with malignant pleural mesothelioma (MPM), an asbestos-associated chemoresistant cancer. We treated MPM cells, cultured as multicellular spheroids, with NR6, a potent and highly selective ALDH1A3 inhibitor. Here we report that NR6 treatment caused the accumulation of toxic aldehydes, induced DNA damage, expression and cell growth arrest. We observed that, in proficient cells, NR6 treatment induced expression, but abolished expression and IL-8 release, preventing both neutrophil recruitment and generation of neutrophil extracellular traps (NETs). Furthermore, we demonstrate that in response to ALDH1A3 inhibition, loss skewed cell fate from senescence to apoptosis. Dissecting the role of ALDH1A3 isoform in MPM cells and tumour microenvironment can open new fronts in the treatment of this cancer.
Topics: Humans; Aldehyde Dehydrogenase; Cell Line, Tumor; Enzyme Inhibitors; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Neutrophil Infiltration; Pleural Neoplasms; Spheroids, Cellular; Tumor Microenvironment; Retinal Dehydrogenase
PubMed: 37047661
DOI: 10.3390/ijms24076689 -
Zhongguo Fei Ai Za Zhi = Chinese... Apr 2022Patients with malignant pleural mesothelioma (MPM) usually present with poor prognosis and short survival period, and there has been a lack of effective treatment...
Patients with malignant pleural mesothelioma (MPM) usually present with poor prognosis and short survival period, and there has been a lack of effective treatment options for a long time. Chemotherapy has limited improvement in the clinical outcome of advanced patients (the median survival is less than one year), and it is difficult to find suitable targets for targeted therapy. Recent in-depth research on immunotherapy has changed the treatment pattern of MPM. Especially, the dual immunotherapy regimen significantly improved the survival outcome of patients across subgroups and prolonged the survival time of MPM patients. Therefore, it has been approved for unresectable MPM as first-line treatment for patients. The exploration of other mono or combo immunotherapy regimens in the first and second-line settings of MPM is also underway. How to identify the best beneficial population of each regimen through predictive biomarkers is also a hot spot for researchers. This article will focus on the most up-to-date progress of MPM epidemiology, histological characteristics, pathogenesis, treatment patterns and the advances of immunotherapy in the disease. .
Topics: Combined Modality Therapy; Humans; Immunotherapy; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Pleural Neoplasms
PubMed: 35477190
DOI: 10.3779/j.issn.1009-3419.2022.101.17 -
Respiration; International Review of... 2020Diagnosing and monitoring pulmonary diseases is highly dependent on imaging, physiological function tests and tissue sampling. Optical coherence tomography (OCT) and... (Review)
Review
Diagnosing and monitoring pulmonary diseases is highly dependent on imaging, physiological function tests and tissue sampling. Optical coherence tomography (OCT) and confocal laser endomicroscopy (CLE) are novel imaging techniques with near-microscopic resolution that can be easily and safely combined with conventional bronchoscopy. Disease-related pulmonary anatomical compartments can be visualized, real time, using these techniques. In obstructive lung diseases, airway wall layers and related structural remodelling can be identified and quantified. In malignant lung disease, normal and malignant areas of the central airways, lung parenchyma, lymph nodes and pleura can be discriminated. A growing number of interstitial lung diseases (ILDs) have been visualized using OCT or CLE. Several ILD-associated structural changes can be imaged: fibrosis, cellular infiltration, bronchi(ol)ectasis, cysts and microscopic honeycombing. Although not yet implemented in clinical practice, OCT and CLE have the potential to improve detection and monitoring pulmonary diseases and can contribute in unravelling the pathophysiology of disease and mechanism of action of novel treatments. Indeed, assessment of the airway wall layers with OCT might be helpful when evaluating treatments targeting airway remodelling. By visualizing individual malignant cells, CLE has the potential as a real-time lung cancer detection tool. In the future, both techniques could be combined with laser-enhanced fluorescent-labelled tracer detection. This review discusses the value of OCT and CLE in pulmonary medicine by summarizing the current evidence and elaborating on future perspectives.
Topics: Airway Remodeling; Bronchoscopy; Humans; Lung; Lung Diseases; Lung Diseases, Interstitial; Lung Diseases, Obstructive; Lung Neoplasms; Lymph Nodes; Microscopy, Confocal; Pleural Neoplasms; Pulmonary Arterial Hypertension; Tomography, Optical Coherence; Tomography, X-Ray Computed
PubMed: 31593955
DOI: 10.1159/000503261 -
International Journal of Molecular... Mar 2020Malignant mesothelioma is an infrequent tumor that initiates from the mesothelial cells lining of body cavities. The great majority of mesotheliomas originate in the... (Review)
Review
Malignant mesothelioma is an infrequent tumor that initiates from the mesothelial cells lining of body cavities. The great majority of mesotheliomas originate in the pleural cavity, while the remaining cases initiate in the peritoneal cavity, in the pericardial cavity or on the tunica vaginalis. Usually, mesotheliomas grow in a diffuse pattern and tend to enclose and compress the organs in the various body cavities. Mesothelioma incidence is increasing worldwide and still today, the prognosis is very poor, with a reported median survival of approximately one year from presentation. Thus, the development of alternative and more effective therapies is currently an urgent requirement. The aim of this review article was to describe recent findings about the anti-cancer activity of curcumin and some of its derivatives on mesotheliomas. The potential clinical implications of these findings are discussed.
Topics: Antineoplastic Agents; Curcumin; Humans; Mesothelioma, Malignant; Phytochemicals; Pleura; Pleural Neoplasms; Prognosis
PubMed: 32155978
DOI: 10.3390/ijms21051839