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Journal For Immunotherapy of Cancer Jun 2023Immune checkpoint inhibitors (ICIs) are now a first-line treatment option for patients with pleural mesothelioma with the recent approval of ipilimumab and nivolumab.... (Clinical Trial)
Clinical Trial
BACKGROUND
Immune checkpoint inhibitors (ICIs) are now a first-line treatment option for patients with pleural mesothelioma with the recent approval of ipilimumab and nivolumab. Mesothelioma has a low tumor mutation burden and no robust predictors of survival with ICI. Since ICIs enable adaptive antitumor immune responses, we investigated T-cell receptor (TCR) associations with survival in participants from two clinical trials treated with ICI.
METHODS
We included patients with pleural mesothelioma who were treated with nivolumab (NivoMes, NCT02497508) or nivolumab and ipilimumab (INITIATE, NCT03048474) after first-line therapy. TCR sequencing was performed with the ImmunoSEQ assay in 49 and 39 pretreatment and post-treatment patient peripheral blood mononuclear cell (PBMC) samples. These data were integrated with TCR sequences found in bulk RNAseq data by TRUST4 program in 45 and 35 pretreatment and post-treatment tumor biopsy samples and TCR sequences from over 600 healthy controls. The TCR sequences were clustered into groups of shared antigen specificity using GIANA. Associations of TCR clusters with overall survival were determined by cox proportional hazard analysis.
RESULTS
We identified 4.2 million and 12 thousand complementarity-determining region 3 (CDR3) sequences from PBMCs and tumors, respectively, in patients treated with ICI. These CDR3 sequences were integrated with 2.1 million publically available CDR3 sequences from healthy controls and clustered. ICI-enhanced T-cell infiltration and expanded T cell diversity in tumors. Cases with TCR clones in the top tertile in the pretreatment tissue or in circulation had significantly better survival than the bottom two tertiles (p<0.04). Furthermore, a high number of shared TCR clones between pretreatment tissue and in circulation was associated with improved survival (p=0.01). To potentially select antitumor clusters, we filtered for clusters that were (1) not found in healthy controls, (2) recurrent in multiple patients with mesothelioma, and (3) more prevalent in post-treatment than pretreatment samples. The detection of two-specific TCR clusters provided significant survival benefit compared with detection of 1 cluster (HR<0.001, p=0.026) or the detection of no TCR clusters (HR=0.10, p=0.002). These two clusters were not found in bulk tissue RNA-seq data and have not been reported in public CDR3 databases.
CONCLUSIONS
We identified two unique TCR clusters that were associated with survival on treatment with ICI in patients with pleural mesothelioma. These clusters may enable approaches for antigen discovery and inform future targets for design of adoptive T cell therapies.
Topics: Humans; Immunotherapy; Ipilimumab; Leukocytes, Mononuclear; Mesothelioma; Mesothelioma, Malignant; Nivolumab; Pleural Neoplasms; Receptors, Antigen, T-Cell
PubMed: 37279993
DOI: 10.1136/jitc-2022-006035 -
Journal of Veterinary Diagnostic... Jan 2021Herein we describe a rare case of systemic infection with concurrent pleural mesothelioma in a stray cat that was found dead and submitted for autopsy. Gross pathology...
Herein we describe a rare case of systemic infection with concurrent pleural mesothelioma in a stray cat that was found dead and submitted for autopsy. Gross pathology changes consisted of thoracic clear yellow fluid admixed with suspended fibrin strands; clear-to-tan, variably sized, <3 mm diameter pulmonary nodules; and enlargement of the submandibular, retropharyngeal, and prescapular lymph nodes. Histologic changes consisted of extensive areas of suppurative inflammation and necrosis with mineralization that partially effaced the pulmonary parenchyma and lymph nodes. Random, distinct necrotic foci were present throughout the hepatic parenchyma. Extending from the pleura, within perinecrotic alveolar spaces, and infiltrating the submandibular, retropharyngeal, and prescapular lymph nodes were dense sheets of neoplastic epithelioid cells with moderate pleomorphism and occasional karyomegaly and multinucleation. Neoplastic cells exhibited immunolabeling for pancytokeratin AE1/AE3 and vimentin, consistent with pleural mesothelioma. Aerobic bacterial culture of lung yielded heavy growth of . Immunohistochemistry (IHC) for revealed clusters of bacteria in the lung, lymph node, and liver. Pathologic changes were consistent with systemic listeriosis, confirmed by bacterial culture and IHC, and concurrent pleural mesothelioma.
Topics: Animals; Cat Diseases; Cats; Diagnosis, Differential; Female; Listeria monocytogenes; Listeriosis; Mesothelioma; Pleural Neoplasms
PubMed: 33054600
DOI: 10.1177/1040638720966321 -
Respirology (Carlton, Vic.) Feb 2021Probe based confocal laser endomicroscopy (pCLE) is an optical imaging technique allowing live tissue imaging at a cellular level. Currently, this tool remains...
BACKGROUND AND OBJECTIVE
Probe based confocal laser endomicroscopy (pCLE) is an optical imaging technique allowing live tissue imaging at a cellular level. Currently, this tool remains experimental. Two studies regarding pleural disease have been published and suggest that pCLE could be valuable for pleural disease investigations. However, normal and malignant pleural pCLE features remain unknown. Therefore, we conducted a prospective trial of pCLE during medical thoracoscopy to study and describe the malignant and benign pleural pCLE features.
METHODS
Every patient >18 years referred to our department for medical thoracoscopy was eligible. Medical thoracoscopy was performed under sedation, allowing spontaneous breathing. Five millilitres of fluorescein (10%) was intravenously administrated 5 min before image acquisition. The pCLE was introduced through the working channel of the thoracoscope and gently placed on the parietal pleura to record videos. Afterwards, biopsies were performed on the corresponding sites. Malignant and benign pleural pCLE features were precisely described and compared using 11 preselected criteria.
RESULTS
A total of 62 patients were included in the analysis including 36 benign and 26 malignant pleura. Among our preselected criteria, 'abnormal tissue architecture' and 'dysplastic vessels' were strongly associated with malignancies (100% and 85% ss, 721% and 74% sp, respectively) whereas, the 'full chia seeds sign' and 'cell shape homogeneity' were associated with benignity (36% and 56% ss, 100% and 70% sp, respectively). No study-related adverse events occurred.
CONCLUSION
Benign and malignant pleural involvement have clearly distinct pCLE features.
Topics: Feasibility Studies; Female; Humans; Male; Microscopy, Confocal; Middle Aged; Pleural Neoplasms; Prospective Studies
PubMed: 33001538
DOI: 10.1111/resp.13945 -
Interactive Cardiovascular and Thoracic... Oct 2022Although the diagnosis of malignant pleural mesothelioma at an in situ stage was traditionally challenging, it is now possible owing to advances in molecular biological...
Although the diagnosis of malignant pleural mesothelioma at an in situ stage was traditionally challenging, it is now possible owing to advances in molecular biological methods such as P16 fluorescence in situ hybridization or BRCA1-associated protein 1 immunohistochemistry. Here, we report the first case, to our knowledge, of total parietal pleurectomy for mesothelioma in situ. Future follow-up and accumulation of cases are necessary to determine whether total parietal pleurectomy could be applied as a treatment for mesothelioma in situ or not.
Topics: Humans; Mesothelioma, Malignant; Pleural Neoplasms; In Situ Hybridization, Fluorescence; Lung Neoplasms; Mesothelioma
PubMed: 36205712
DOI: 10.1093/icvts/ivac255 -
Molecular and Cellular Probes Feb 2022Body cavity fluids accumulating in progressive malignancies are potential subjects of regular clinical testing for cancer-related features. Besides the cellular... (Review)
Review
Body cavity fluids accumulating in progressive malignancies are potential subjects of regular clinical testing for cancer-related features. Besides the cellular component, the supernatant of the fluid proved to gain diagnostic impact as the cell-free DNA (cfDNA) fraction ideally reflects general molecular features of the related tumorous process, e.g. in lung carcinoma. Thus, malignant pleural effusions can be used for lung cancer genetic profiling and this might remain the only source for testing in critical cases. The cfDNA concentration of the pleural effusion depends on many factors in both benign and malignant conditions. Further to direct pleural metastatic spread, the redirection of tissue lymphatic circulation, tumor angiogenesis, inflammatory processes and other variables may contribute to or enhance the enrichment of the effusion tumor DNA from the earliest stages of carcinogenesis. Our review addresses the traffic of cfDNA in the pleural space and the diagnostic utility of effusion cfDNA from the perspective of the complex pleural pathophysiology.
Topics: Cell-Free Nucleic Acids; Circulating Tumor DNA; DNA, Neoplasm; Genotype; Humans; Lung Neoplasms; Pleural Effusion, Malignant
PubMed: 35114325
DOI: 10.1016/j.mcp.2022.101793 -
BMC Pulmonary Medicine Apr 2022As promising novel treatments develop for malignant pleural mesothelioma (MPM), early prognostication has become increasingly important. Circulating and local... (Observational Study)
Observational Study
BACKGROUND
As promising novel treatments develop for malignant pleural mesothelioma (MPM), early prognostication has become increasingly important. Circulating and local inflammatory cells are known to play a significant role in other tumour types. We assessed the proportion of lymphocyte populations within blood, pleural fluid and tumour stroma to prognosticate patients with MPM at diagnosis.
METHODS
Consecutive patients diagnosed with biopsy-proven MPM were prospectively recruited to an observational cohort study and followed up for a minimum of 7.5 years. Blood and pleural fluid results at presentation were extracted from the medical records. Biopsy specimens were independently reviewed by 2 pathologists who scored the degree of lymphocytic and neutrophilic infiltration.
RESULTS
Baseline results were available for 184 patients. The predominant pleural fluid cell type was calculable for 84 patients and 118 patients had biopsy specimens available for review. A low blood neutrophil/lymphocyte ratio (NLR < 4) inferred a better prognosis with a median survival of 420 days versus 301 days (p < 0.01). Survival was better for patients with a lymphocyte-predominant pleural effusion (430 vs 306 days, p < 0.01). Lymphocyte infiltration of tumour stroma was also associated with improved survival (n = 92, survival 430 days) compared with neutrophilic or acellular samples (n = 26, survival 342 days p < 0.01). In multivariable modelling lymphocyte predominance in blood, pleural fluid and tumour stroma were all associated with a better prognosis.
CONCLUSIONS
Lymphocyte predominance within tumour stroma, pleural fluid or blood infers a better prognosis in patients with MPM.
Topics: Humans; Lymphocytes; Mesothelioma; Mesothelioma, Malignant; Pleural Neoplasms; Prognosis
PubMed: 35501755
DOI: 10.1186/s12890-022-01968-2 -
Polish Journal of Pathology : Official... 2023Mesothelioma is a locally aggressive malignant tumor that arises on the mesothelial surfaces of the pleura, peritoneum and tunica vaginalis. There are three histologic...
Mesothelioma is a locally aggressive malignant tumor that arises on the mesothelial surfaces of the pleura, peritoneum and tunica vaginalis. There are three histologic subtypes of mesothelioma: epithelioid, biphasic, and sarcomatoid. Pleural mesothelioma is usually characterized by diffuse pleural thickening. Disease progression is characterized by local invasion of the chest wall and lung. Lymphatic metastasis is rare and hematogenous metastasis is much rarer. The purpose of these case reports is to emphasize that pleural mesothelioma metastases can occur in unexpected places and to contribute to the literature.
Topics: Humans; Scalp; Mesothelioma, Malignant; Mesothelioma; Pleural Neoplasms; Lung; Lung Neoplasms; Biomarkers, Tumor
PubMed: 38477094
DOI: 10.5114/pjp.2023.134322 -
Journal For Immunotherapy of Cancer May 2022Soluble human leucocyte antigen (sHLA) molecules, released into the plasma, carry their original peptide cargo and provide insight into the protein synthesis and...
BACKGROUND
Soluble human leucocyte antigen (sHLA) molecules, released into the plasma, carry their original peptide cargo and provide insight into the protein synthesis and degradation schemes of their source cells and tissues. Other body fluids, such as pleural effusions, may also contain sHLA-peptide complexes, and can potentially serve as a source of tumor antigens since these fluids are drained from the tumor microenvironment. We explored this possibility by developing a methodology for purifying and analyzing large pleural effusion sHLA class I peptidomes of patients with malignancies or benign diseases.
METHODS
Cleared pleural fluids, cell pellets present in the pleural effusions, and the primary tumor cells cultured from cancer patients' effusions, were used for immunoaffinity purification of the HLA molecules. The recovered HLA peptides were analyzed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) and the resulting LC-MS/MS data were analyzed with the MaxQuant software tool. Selected tumor antigen peptides were tested for their immunogenicity potential with donor peripheral blood mononuclear cells (PBMCs) in an in vitro assay.
RESULTS
Mass spectrometry analysis of the pleural effusions revealed 39,669 peptides attributable to 11,305 source proteins. The majority of peptides identified from the pleural effusions were defined as HLA ligands that fit the patients' HLA consensus sequence motifs. The membranal and soluble HLA peptidomes of each individual patient correlated to each other. Additionally, soluble HLA peptidomes from the same patient, obtained at different visits to the clinic, were highly similar. Compared with benign effusions, the soluble HLA peptidomes of malignant pleural effusions were larger and included HLA peptides derived from known tumor-associated antigens, including cancer/testis antigens, lung-related proteins, and vascular endothelial growth factor pathway proteins. Selected tumor-associated antigens that were identified by the immunopeptidomics were able to successfully prime CD8 T cells.
CONCLUSIONS
Pleural effusions contain sHLA-peptide complexes, and the pleural effusion HLA peptidome of patients with malignant tumors can serve as a rich source of biomarkers for tumor diagnosis and potential candidates for personalized immunotherapy.
Topics: Antigens, Neoplasm; CD8-Positive T-Lymphocytes; Chromatography, Liquid; Histocompatibility Antigens Class I; Humans; Leukocytes, Mononuclear; Male; Peptides; Pleural Effusion, Malignant; Tandem Mass Spectrometry; Tumor Microenvironment; Vascular Endothelial Growth Factor A
PubMed: 35580925
DOI: 10.1136/jitc-2021-003733 -
Medicina 2022The pathological diagnosis of diffuse pleural mesothelioma (DPM) contributes to treatment selection and clinical trials interpretation. To know its characteristics and...
The pathological diagnosis of diffuse pleural mesothelioma (DPM) contributes to treatment selection and clinical trials interpretation. To know its characteristics and evaluate the viability of comprehensive pathological diagnosis of DPM in Argentina we did a retrospective descriptive study of DPM cases reported from 2009 to 2018. We analyzed 398 cases corresponding to 238 (60%) men and 160 (40%) women, median age 66 years, from surgical biopsies (78%), small biopsies (16.5%) and surgical resections (5.5%). The 77% were epithelioid (E-DPM), 12% biphasic, 10% sarcomatoid, and 4 cases transitional variant. In E-DPM the main pattern was tubular in 36% and solid in 33%. There was a second pattern in 179 cases. Considering the main pattern and the second together, 48% presented tubular subtype and 48% solid subtype. Stroma, necrosis, and nuclear score showed significant differences between E-DPM and non-epithelioid mesotheliomas. Overall tumor grade was predominantly low in E-DPM, except for 42% of the solid main pattern. We recognized the transitional variant extensively in 4 cases and focally in 8. The immunohistochemical antibody panel used included pan-cytokeratin, calretinin, WT-1, cytokeratin 5, CEA and TTF-1. The expression of cytokeratin 5, calretinin and WT-1 was lower in the sarcomatoid type (43%, 87 and 37%) than in the epithelioid type (92%, 98% and 93%). This study highlights the tumor heterogeneity of DPM that shows the diagnostic difficulty, and the feasibility of evaluating histological aggressiveness in E-DPM, B-DPM and S-DPM in our country.
Topics: Aged; Biomarkers, Tumor; Calbindin 2; Female; Humans; Keratin-5; Lung Neoplasms; Male; Mesothelioma; Pleural Neoplasms; Retrospective Studies; Sarcoma
PubMed: 35417384
DOI: No ID Found -
Cancer Medicine Jun 2023Malignant pleural mesothelioma (MPM) is an aggressive cancer of the cells lining the pleural cavity with a low overall incidence. The National Cancer Database (NCDB)... (Review)
Review
BACKGROUND
Malignant pleural mesothelioma (MPM) is an aggressive cancer of the cells lining the pleural cavity with a low overall incidence. The National Cancer Database (NCDB) released in August 2022 updated data that reflect the newest trends in MPM.
METHODS
The NCDB was queried for patients diagnosed with MPM between 2004 and 2020. Variables collected included demographics, tumor characteristics, and treatment. Student's t-test and independent-samples proportions test were used for means analysis. Survival was assessed by the Kaplan-Meier method using SPSS version 28.
RESULTS
A total of 41,074 patients were diagnosed with mesothelioma, with a steady incidence (0.25%) between 2004 and 2017. The mean age of diagnosis was 70 (SD 13). 73.2% of the patients were males, 69% had no comorbidities, and 93.3% were white. More patients were diagnosed at Stage 1 after 2008 (p < 0.001). Since 2010, there has been a significant increase in patients offered treatment with 73.9% receiving some therapy (p < 0.01): 50.5% received chemotherapy, 27.6% surgery, 8.6% radiation, and 5.4% immunotherapy. The median overall survival was 10.3 months from diagnosis [95% CI: 10.2-10.5]. Risk factors associated with 30-day mortality from surgical intervention included age (OR = 1.02, p < 0.001), male gender (OR = 1.3, p = 0.03), poorly differentiated grade (OR = 2.1, p < 0.001), Stage 4 (OR = 1.4, p = 0014), and epithelioid histology (OR = 0.51, p = 0.03).
CONCLUSION
The current management of MPM is based on stage and histologic subtype. Due to the small numbers of patients at most academic centers, the NCDB provides a robust dataset to draw upon broad data points in treatment discussions with patients.
Topics: Female; Humans; Male; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Pleural Neoplasms; Retrospective Studies; Risk Factors; Middle Aged; Aged; Aged, 80 and over
PubMed: 37062067
DOI: 10.1002/cam4.5915