MPM Patients Research Articles

Impact of surgical intervention on overall survival in malignant pleural mesothelioma: A population-based cohort study with propensity score matching

BackgroundMalignant pleural mesothelioma (MPM) is a rare and aggressive cancer with limited treatment options. This study aims to assess the impact of surgical intervention on overall survival (OS) in patients with MPM and to identify prognostic factors influencing survival outcomes. MethodsData from the SEER-17 Database between 2000 and 2019 were analyzed. Patients were categorized into surgery and no-surgery groups. Survival analyses were conducted using Kaplan-Meier curves and Cox proportional hazards models. Propensity score matching (PSM) was applied to reduce biases. ResultsThe study included a total of 3901 MPM patients, with 1190 in the surgery group and 2711 in the no-surgery group. The median OS for the entire cohort was 10 months. The surgery group had a median OS of 15 months compared to 8 months in the no-surgery group (p < 0.001). The 1-year and 5-year OS rates for surgery patients were 56.9% and 11.2%, respectively, while for no-surgery patients, they were 34.9% and 3.7% (p < 0.001). Multivariate analysis indicated that no-surgery was an independent risk factor for worse OS (HR 1.38, 95% CI 1.21-1.39, p < 0.001). After PSM, no-surgery remained an independent risk factor influencing OS. Subgroup analysis indicated that surgery benefited most groups except those aged ≥80 years, bilateral disease, N3 stage, and certain histological grades. ConclusionSurgical intervention significantly improves survival in patients with MPM. However, benefits vary across subgroups, and careful consideration of patient-specific factors is essential.

Is extereme cytoreductive surgery beneficial to survival ın malignant peritoneal mesothelioma?

Introduction Malign peritoneal mesothelioma (MPM) is an uncommon disease that is difficult to treat. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) are the gold standards for treating MPM. Sometimes extreme cytoreductive surgery (eCRS) is required to achieve complete cytoreduction, which is one of the most important prognostic factors. There is limited information in the literature about the contribution of eCRS in patients with MPM. In this study, we aimed to investigate the impact of eCRS on survival and perioperative outcomes. Methods The Department of Surgical Oncology at Cumhuriyet University database was retrospectively reviewed for MPM patients who underwent CRS-HIPEC between January 2004 and December 2018. Patients who underwent CRS-HIPEC were divided into eCRS and less extensive CRS (leCRS) groups. A resection of ≥5 organs or ≥3 small bowel anastomoses were defined as eCRS. Both groups were compared regarding survival, demographic information, and perioperative outcomes. Results A total of 31 patients were included. eCRS-HIPEC was used in 15 patients. Complete cytoreduction (CC score 0/1) was achieved in all 31 patients. Compared to leCRS, the eCRS group had a longer median length of stay, longer intensive care unit stay, a higher median peritoneal cancer index (PCI), higher intraoperative blood loss, more frequent occurrence of any complication, and a longer operative time (all p values < 0.001). Clavien Dindo 3–4 complications, ASA, and gender were similar in both groups of patients (p > 0.05). It was found that there was no significant difference between the OS of the eCRS and leCRS groups (37.5 vs. 42.8 months, p = 0.895). Conclusions Rates of serious complications and morbidity are similar in patients undergoing eCRS compared to leCRS. In patients with high PCI and multiorgan involvement, complete cytoreduction can be achieved by performing eCRS, and survival results equivalent to those with low PCI can be achieved.

Risk factors and prognosis of malignant peritoneal mesothelioma with paraneoplastic syndrome

BackgroundMalignant peritoneal mesothelioma (MPM) is a rare and highly aggressive tumor. Its clinical manifestations are diverse, and the symptoms are not specific. Some patients will develop paraneoplastic syndrome (PS) during the disease course. This study aims to analyze the risk factors of PS in patients with MPM and their impacts on prognosis.MethodsThe clinical data of MPM patients who underwent cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) at our center from June 2015 to May 2023 were retrospectively analyzed. MPM patients were divided into PS group and non-PS group according to the diagnostic criteria. Univariate and multivariate analyses were performed to explore the risk factors of PS in MPM patients, and to analyze the impact of PS on prognosis.ResultsThere were 146 MPM patients in this study, including 60 patients (41.1%) with PS and 86 patients (58.9%) without PS. The highest incidence of PS was thrombocytosis (33.6%), followed by neoplastic fever (9.6%). Univariate analysis revealed 8 factors (P < 0.05) with statistically significant differences between the two groups: prior surgical scores, targeted therapy history, Karnofsky performance status score, preoperative carbohydrate antigen (CA) 125 level, vascular tumor embolus, peritoneal cancer index, completeness of cytoreduction (CC) score and intraoperative ascites. Multivariate analysis identified 3 independent factors associated with PS: preoperative CA 125 level, vascular tumor embolus, and CC score. Survival analysis demonstrated that MPM patients with PS had worse prognosis, although PS was not an independent prognostic factor.ConclusionsPS is not rare in patients with MPM, and is independently associated with preoperative CA 125 level, vascular tumor embolus and CC score. PS often indicates advanced disease and poor prognosis.

Organoids derived from patients provide a new opportunity for research and individualized treatment of malignant peritoneal mesothelioma

BackgroundMalignant peritoneal mesothelioma (MPM) is an extremely rare and highly invasive tumor. Due to the lack of accurate models that reflect the biological characteristics of primary tumors, studying MPM remains challenging and is associated with an exceedingly unfavorable prognosis. This study was aimed to establish a new potential preclinical model for MPM using patient-derived MPM organoids (MPMOs) and to comprehensively evaluate the practicality of this model in medical research and its feasibility in guiding individualized patient treatment.MethodsMPMOs were constructed using tumor tissue from MPM patients. Histopathological analysis and whole genome sequencing (WGS) were employed to determine the ability of MPMOs to replicate the original tumor's genetic and histological characteristics. The subcutaneous and orthotopic xenograft models were employed to assess the feasibility of establishing an in vivo model of MPM. MPMOs were also used to conduct drug screening and compare the results with retrospective analysis of patients after treatment, in order to evaluate the potential of MPMOs in predicting the effectiveness of drugs in MPM patients.ResultsWe successfully established a culture method for human MPM organoids using tumor tissue from MPM patients and provided a comprehensive description of the necessary medium components for MPMOs. Pathological examination and WGS revealed that MPMOs accurately represented the histological characteristics and genomic heterogeneity of the original tumors. In terms of application, the success rate of creating subcutaneous and orthotopic xenograft models using MPMOs was 88% and 100% respectively. Drug sensitivity assays demonstrated that MPMOs have different medication responses, and these differences were compatible with the real situation of the patients.ConclusionThis study presents a method for generating human MPM organoids, which can serve as a valuable research tool and contribute to the advancement of MPM research. Additionally, these organoids can be utilized as a means to evaluate the effectiveness of drug treatments for MPM patients, offering a model for personalized treatment approaches.

Evening Primrose Extract Modulates TYMS Expression via SP1 Transcription Factor in Malignant Pleural Mesothelioma.

To determine the mechanism of EPE in downregulating TYMS in MPM cancer. The TYMS mRNA expression with epithelial-to-mesenchymal transition biomarkers and nuclear factor SP1 was assessed using the GEO database in a data set of MPM patients (GSE51024). Invasive MPM cell lines were in vitro models for the investigation of TYMS expression after EPE treatment. The tyms promoter SP1 binding sequences were determined using Genomatix v 3.4 software Electrophoretic mobility shift and dual-luciferase reporter assays revealed specific SP1 motifs in the interaction of EPE and reference compounds. Chromatin immunoprecipitation and Re-ChIP were used for the co-occupancy study. In MPM patients, a positive correlation of overexpressed TYMS with mesenchymal TWIST1, FN1 and N-cadherin was observed. EPE and its major components, gallic and ellagic acid (GA and EA, respectively), downregulated TYMS in invasive MPM cells by interacting with particular SP1 motifs on the tyms promoter. The luciferase constructs confirmed the occupation of two SP1 regulatory regions critical for the promotion of TYMS expression. Both EPE and reference standards influenced SP1 translocation into the nucleus. EPE components reduced TYMS expression by occupation of SP1 motifs on the tyms promoter and reversed the EMT phenotype of invasive MPM cells. Further in-depth analysis of the molecular docking of polyphenol compounds with SP1 regulatory motifs is required.

Assessment of Quality of Life in Patients with Malignant Pleural Mesothelioma

Background Pleural mesothelioma represents 92% of all malignant mesotheliomas. There is no MPM curative treatment. Multimodality treatment is commonly used including chemotherapy, targeted therapy and radiotherapy. Because of MPM poor prognosis (OS 8-14 months), maintaining quality of life of patients became more important in MPM treatment. Aim of the Work To investigate the quality of life (QOL) of patients with malignant pleural mesothelioma and to determine the factors that correlate with their QOL comparing different therapies. Patients and Methods This is a prospective, observational multi-center study conducted between November 2018 and November 2019. 55 consecutive patients with newly diagnosed MPM were enrolled in Ain Shams University Hospital, El-Nasr Hospital in Helwan and Ismailia Oncology Hospital. The study was approved by the ethical committee at the faculty of medicine, Ain Shams University. Results In our study we evaluated quality of life of MPM patients using EORTC questionnaires (QLQ-C30 &amp; QLQ-LC-13), and correlated the score with different chemotherapy types and other factors. Conclusion Our study found correlation between QLQ baseline scores and both weight loss &amp; chest pain, and no correlation of QLQ scores change with types of chemotherapy. Median Progression-free survival was 6.5 months and correlated with disease stage and chemotherapy used.

The clinicopathological significance of TOP2A expression in malignant peritoneal mesothelioma

BackgroundMalignant peritoneal mesothelioma (MPM) is a rare malignant tumor with a high mortality rate and extremely poor prognosis. TOP2A expression is associated with cell proliferation and cell cycle progression. We aimed to demonstrate the expression profile of TOP2A in MPM and its correlation with clinicopathological features. MethodsClinicopathological information from 100 MPM cases was collected at Beijing Shijitan Hospital, Capital Medical University. Immunohistochemistry (IHC) was performed to evaluate TOP2A levels. The associations between TOP2A levels and clinicopathological features or prognosis were analyzed. Clinical follow-up data were reviewed to determine correlations among the pathological prognostic factors using the Kaplan–Meier estimator and univariate/multivariate Cox proportional hazards regression models. ResultsAmong the 100 MPM patients, there were 48 males and 52 females, with a median age of 54 years (range: 24–72 years). The cutoff curve was used to find the boundary value of the TOP2A-positive rate. TOP2A positive rate ≥ 11.97 % accounted for 48 % in tumor tissue. The TOP2A-positive rate was not associated with sex, age, asbestos exposure, peritoneal carcinomatosis index (PCI) score, or completeness of cytoreduction (CC) score in MPM. Univariate analysis revealed survival-related pathological parameters, including asbestos exposure, CA125, histological type, PCI score, CC score, Ki-67 index, and TOP2A positive rate. Multivariate analysis identified that asbestos exposure history, PCI score, Ki-67 proliferation index and TOP2A positive rate in tissue are independent prognostic factors. ConclusionsHigh expression of TOP2A is linked to better prognosis of MPM.

ATG5 as biomarker for early detection of malignant mesothelioma

ObjectivesMalignant pleural mesothelioma (MPM) is an aggressive disease with grim prognosis due to lack of effective treatment options. Disease prediction in association with early diagnosis may both contribute to improved MPM survival. Inflammation and autophagy are two processes associated with asbestos-induced transformation. We evaluated the level of two autophagic factors ATG5 and HMGB1, microRNAs (miRNAs) such as miR-126 and miR-222, and the specific biomarker of MPM, soluble mesothelin related proteins (Mesothelin) in asbestos-exposed individuals, MPM patients, and healthy subjects. The performance of these markers in detecting MPM was investigated in pre-diagnostic samples of asbestos-subjects who developed MPM during the follow-up and compared for the three groups.ResultsThe ATG5 best distinguished the asbestos-exposed subjects with and without MPM, while miR-126 and Mesothelin were found as a significant prognostic biomarker for MPM. ATG5 has been identified as an asbestos-related biomarker that can help to detect MPM with high sensitivity and specificity in pre-diagnostic samples for up to two years before diagnosis. To utilize this approach practically, higher number of cases has to be tested in order to give the combination of the two markers sufficient statistical power. Performance of the biomarkers should be confirmed by testing their combination in an independent cohort with pre-diagnostic samples.

Establishment and validation of nomograms to predict survival probability of advanced malignant pleural mesothelioma based on the SEER database and a Chinese medical institution.

The purpose of this study was to build nomograms for predicting the survival of individual advanced pleural mesothelioma (MPM) patients using the Surveillance, Epidemiology, and End Results (SEER) database. The 1251 patients enrolled from the SEER database were randomized (in a 7:3 ratio) to a training cohort and an internal validation cohort. Eighty patients were enrolled from the Harbin Medical University Cancer Hospital as the external validation cohort. Nomograms were constructed from variables screened by univariate or multivariate Cox regression analyses and evaluated by consistency indices (C-index), calibration plots, and receiver operating characteristic (ROC) curves. Patients from the SEER database who received chemotherapy alone and chemoradiotherapy were statistically paired using propensity score matching of the two groups and performed subgroup analysis in the screened variables. The nomograms are well-structured and well-validated prognostic maps constructed from four variables: gender, histology, AJCC stage, and treatment. All individuals were allocated into high-risk versus low-risk groups based on the median risk score of the training cohort, with the high-risk group having worse OS and CSS in all three cohorts (P<0.05). The outcomes of the subgroup analysis indicated that the advanced MPM patients receiving chemotherapy with or without local radiotherapy do not affect OS or CSS. The accurate nomograms to predict the survival of patients with advanced MPM were built and validated based on an analysis of the SEER database with an external validation cohort. The study suggests that the additional local radiotherapy to chemotherapy does not increase the survival benefit of patients.

Prognostic significance of inflammation-related and electrolyte laboratory variables in patients with malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a kind of pleural cancer characterized by low incidence but high invasiveness. There is heterogeneity in survival among patients with MPM. Inflammation-related and electrolyte laboratory variables were previously reported as potential predictors of survival. We evaluated the relationship between overall survival and pre-treatment biomarkers. Patients diagnosed with MPM in Beijing Chaoyang Hospital for more than 10 years were screened for this study. All basic, clinical, radiologic and laboratory variables were collected. The COX univariable and multivariable analysis were used to explore prognostic related risk factors. Ninety patients with MPM were included. The median follow-up of all patients was 57 months [interquartile range (IQR): 27-100 months]. The median survival time was 24 months (IQR: 12-52 months). Univariate survival analyses indicated that age, Eastern Cooperative Oncology Group Performance Status, treatment, erythrocyte sedimentation rate, calcium, lymphocyte, hemoglobin, platelet-to-lymphocyte ratio (PLR), and monocyte-to-white blood cell ratio (MWR) were significantly related to survival. Multivariable analysis demonstrated that age [hazard ratio (HR), 2.548; 95% confidence interval (CI) 1.145-5.666; p = 0.022], calcium (HR, 0.480; 95% CI 0.270-0.855; p = 0.013), PLR (HR, 2.152; 95% CI 1.163-3.981; p = 0.015), and MWR (HR, 3.360; 95% CI 1.830-6.170; p < 0.001) might have a significant impact on the prognosis. Calcium, MWR, and PLR might be related to the prognosis of MPM patients. Analyzing the relationship between the results of inflammation-related and electrolyte laboratory variables in peripheral blood and prognosis could help clinicians evaluate the situation of patients.

Damage-associated molecular patterns and sensing receptors based molecular subtypes in malignant pleural mesothelioma and implications for immunotherapy.

Malignant pleural mesothelioma (MPM) is characterized as an incredibly aggressive form of cancer with a dismal diagnosis and a dearth of specific biomarkers and therapeutic options. For MPM patients, the effectiveness of immunotherapy may be influenced by damage-associated molecular pattern (DAMP)-induced immunogenic cell death (ICD).The objective of this work is to create a molecular profile associated with DAMPs to categorize MPM patients and predict their prognosis and response to immunotherapy. The RNA-seq of 397 patients (263 patients with clinical data, 57.2% male, 73.0% over 60 yrs.) were gathered from eight public datasets as a training cohort to identify the DAMPs-associated subgroups of MPMs using K-means analysis. Three validation cohorts of patients or murine were established from TCGA and GEO databases. Comparisons were made across each subtype's immune status, gene mutations, survival prognosis, and predicted response to therapy. Based on the DAMPs gene expression, MPMs were categorized into two subtypes: the nuclear DAMPs subtype, which is classified by the upregulation of immune-suppressed pathways, and the inflammatory DAMPs subtype, which is distinguished by the enrichment of proinflammatory cytokine signaling. The inflammatory DAMPs subgroup had a better prognosis, while the nuclear DAMPs subgroup exhibited a worse outcome. In validation cohorts, the subtyping system was effectively verified. We further identified the genetic differences between the two DAMPs subtypes. It was projected that the inflammatory DAMPs subtype will respond to immunotherapy more favorably, suggesting that the developed clustering method may be implemented to predict the effectiveness of immunotherapy. We constructed a subtyping model based on ICD-associated DAMPs in MPM, which might serve as a signature to gauge the outcomes of immune checkpoint blockades. Our research may aid in the development of innovative immunomodulators as well as the advancement of precision immunotherapy for MPM.

A molecular phenotypic map of malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a rare understudied cancer associated with exposure to asbestos. So far, MPM patients have benefited marginally from the genomics medicine revolution due to the limited size or breadth of existing molecular studies. In the context of the MESOMICS project, we have performed the most comprehensive molecular characterization of MPM to date, with the underlying dataset made of the largest whole-genome sequencing series yet reported, together with transcriptome sequencing and methylation arrays for 120 MPM patients. We first provide comprehensive quality controls for all samples, of both raw and processed data. Due to the difficulty in collecting specimens from such rare tumors, a part of the cohort does not include matched normal material. We provide a detailed analysis of data processing of these tumor-only samples, showing that all somatic alteration calls match very stringent criteria of precision and recall. Finally, integrating our data with previously published multiomic MPM datasets (n = 374 in total), we provide an extensive molecular phenotype map of MPM based on the multitask theory. The generated map can be interactively explored and interrogated on the UCSC TumorMap portal (https://tumormap.ucsc.edu/?p=RCG_MESOMICS/MPM_Archetypes ). This new high-quality MPM multiomics dataset, together with the state-of-art bioinformatics and interactive visualization tools we provide, will support the development of precision medicine in MPM that is particularly challenging to implement in rare cancers due to limited molecular studies.

Loss of NPM2 expression is a potential immunohistochemical marker for malignant peritoneal mesothelioma: a single-center study of 92 cases

BackgroundMalignant peritoneal mesothelioma (MPM) is a rare malignant tumor with a high mortality rate and extremely poor prognosis. In-depth pathological analysis is essential to assess tumor biological behaviors and explore potential therapeutic targets of MPM. Nucleoplasmin 2 (NPM2) is a molecular chaperone that binds histones and may play a key role in the development and progression of tumors. This study aimed to analyze the correlation between the expression level of NPM2 and the main clinicopathological characteristics and prognosis of MPM.MethodsNinety-two postoperative specimens from MPM patients following cytoreductive surgery were collected. Postoperative specimens were stained with immunohistochemistry. The expression level of NPM2 was quantitatively analyzed by QuPath-0.3.2 software. Univariate and multivariate analyses were conducted to investigate the correlation between NPM2 expression and other conventional clinicopathological characteristics.ResultsAmong the 92 MPM patients, there were 47 males (48.9%) and 45 females (51.1%), with a median age of 56 (range: 24–73). There were 70 (76.0%) cases with loss of NPM2 protein expression, 11 (12.0%) cases with low expression, and 11 (12.0%) cases with high expression. Univariate analysis showed that NPM2 protein expression level (negative vs. low expression vs. high expression) was negatively correlated with the following three clinicopathological factors: completeness of cytoreduction (CC) score, vascular tumor emboli, and serious adverse events (SAEs) (all P < 0.05). Multivariate analysis showed that NPM2 protein expression level (negative vs. low expression vs. high expression) was independently negatively correlated with the following two clinicopathological factors: CC score [odds ratio (OR) = 0.317, 95% CI: 0.317–0.959, P = 0.042] and vascular tumor emboli (OR = 0.092, 95% CI = 0.011–0.770, P = 0.028). Survival analysis showed that loss of NPM2 protein expression (negative vs. positive) was associated with poor prognosis of MPM.ConclusionsLoss of NPM2 expression is a potential immunohistochemical marker for MPM.

Unraveling tumor microenvironment heterogeneity in malignant pleural mesothelioma identifies biologically distinct immune subtypes enabling prognosis determination.

BackgroundMalignant 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.MethodsHerein, 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.ResultsThe 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.ConclusionsWe 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.

Immune cells in mesothelioma microenvironment simplistic marker of response to nivolumab plus ipilimumab?

IntroductionMalignant pleural mesothelioma (MPM) is a malignant disease of the pleura which recently can be treated with immune checkpoint inhibitors (ICI). To optimize this treatment, a better understanding of the tumor micro environment is needed. We investigated subgroups of immune cells in subsequent tumor biopsies of patients treated with ICI. MethodsBiopsies from MPM patients included in two clinical ICI trials (nivolumab alone and an ipilimumab/nivolumab combination) were examined. At baseline and after 6 weeks of treatment, pleural biopsies were taken to examine the tumor microenvironment (CD20+, CD4+, CD8+, FoxP3+ and PD-1+ ). Cell density was defined as the number of marker positive cells per mm2. Radiological responses were evaluated as partial response, stable disease or progressive disease according to modified RECIST criteria. ResultsThirty-four and 36 patients were included in the nivolumab and ipiliumumab/nivolumab trial respectively. In the nivolumab trial, no significant differences in cell densities were seen in baseline biopsies of patients with partial response versus progressive disease. In contrast, in the ipilimumab/nivolumab trial, a higher cell density of CD4+, CD8+, FoxP3+ and PD-1+ cells at baseline was significantly correlated with partial responses. On-treatment biopsies of both trials did not show significant changes when compared to baseline biopsies. ConclusionBiopsies from patients responding to nivolumab plus ipilimumab treatment show a significant higher cell density of CD4+, CD8+, FoxP3+ and PD-1+ cells, without a change after 6 weeks of treatment. This observation is a first step in exploring the tumor microenvironment as predictor of response in ICI treatment in MPM.

KRAS Pathway Alterations in Malignant Pleural Mesothelioma: An Underestimated Player.

Simple SummaryMalignant pleural mesothelioma (MPM) is a rare, incurable cancer. KRAS pathway alterations are frequent in human MPM but have been likely underestimated by next generation sequencing studies.Malignant pleural mesothelioma (MPM) is a rare, incurable cancer of the mesothelial cells lining the lungs and the chest wall that is mainly caused by asbestos inhalation. The molecular mechanisms of mesothelial carcinogenesis are still unclear despite comprehensive studies of the mutational landscape of MPM, and the most frequently mutated genes BAP1, NF2, CDKN2A, TP53, and TSC1 cannot cause MPM in mice in a standalone fashion. Although KRAS pathway alterations were sporadically detected in older studies employing targeted sequencing, they have been largely undetected by next generation sequencing. We recently identified KRAS mutations and copy number alterations in a significant proportion of MPM patients. Here, we review and analyze multiple human datasets and the published literature to show that, in addition to KRAS, multiple other genes of the KRAS pathway are perturbed in a significant proportion of patients with MPM.

1637P Impact of immune-related adverse events (irAEs) and survival (OS) in a cohort of MPM patients (p) treated with immunotherapy (IT)

Studies in solid tumors reported that p treated with IT who developed irAEs presented favorable OS. CheckMate-743 trial demonstrated survival benefit of IT over chemotherapy in 1st line. In a post-hoc analysis on 52 p who discontinued treatment due to irAEs, the survival benefit was not negatively impacted. We aimed to assess the impact of irAEs and survival outcomes in our series of p treated with IT.

Organoids as a Model for Precision Medicine in Malignant Pleural Mesothelioma: Where Are We Today?

Simple SummaryMalignant pleural mesothelioma (MPM) is an extremely lethal cancer, notoriously known for its limited treatment options, lack of targeted therapies, and catastrophic survival rates. MPM tumors are highly heterogeneous and exhibit substantial variance in the genome landscape among individual patients, characterized by widespread loss-of-function mutations of tumor suppressor genes (TSGs) that are difficult to target. Therefore, there is an urgent and unmet need for novel therapeutic targets and strategies for personalized treatment. Patient-derived organoids (PDOs), the next generation tumor models that have significantly influenced the discovery of anticancer drugs and biomarkers of response to therapies in many other cancers, are emerging and promise to play a critical role in understanding the biology of MPM and, importantly, in identifying and developing precision oncology approaches tailored to specific subsets of MPM patients.MPM is an aggressive tumor originating from pleural mesothelial cells. A characteristic feature of the disease is the dominant prevalence of therapeutically intractable inactivating alterations in TSGs, making MPM one of the most difficult cancers to treat and the epitome of a cancer characterized by a significant lack of therapy options and an extremely poor prognosis (5-year survival rate of only 5% to 10%). Extensive interpatient heterogeneity poses another major challenge for targeted therapy of MPM, warranting stratified therapy for specific subgroups of MPM patients. Accurate preclinical models are critical for the discovery of new therapies and the development of personalized medicine. Organoids, an in vitro ‘organ-like’ 3D structure derived from patient tumor tissue that faithfully mimics the biology and complex architecture of cancer and largely overcomes the limitations of other existing models, are the next-generation tumor model. Although organoids have been successfully produced and used in many cancers, the development of MPM organoids is still in its infancy. Here, we provide an overview of recent advances in cancer organoids, focusing on the progress and challenges in MPM organoid development. We also elaborate the potential of MPM organoids for understanding MPM pathobiology, discovering new therapeutic targets, and developing personalized treatments for MPM patients.

A comprehensive study of alternative splicing in malignant pleural mesothelioma identifies potential therapeutic targets in a new cluster with poor survival.

BackgroundMalignant pleural mesothelioma (MPM) is one of the most aggressive tumors with few effective treatments worldwide. It has been suggested that alternative splicing at the transcriptome level plays an indispensable role in MPM.MethodsWe analyzed the splicing profile of 84 MPM patients from the TCGA cohort by using seven typical splicing types. We classified MPM patients based on their splicing status and conducted a comprehensive analysis of the correlation between the splicing classification and clinical characteristics, genetic variation, pathway changes, immune heterogeneity, and potential therapeutic targets.ResultsThe expression of the alternative splicing regulator SRPK1 is significantly higher in MPM tissues than in normal tissues, and correlates with poor survival. SRPK1 deficiency promotes MPM cell apoptosis and inhibits cell migration in vitro. We divided the MPM patients into four clusters based on their splicing profile and identified two clusters associated with the shortest (cluster 3) and longest (cluster 4) survival time. We present the different gene signatures of each cluster that are related to survival and splicing. Comprehensive analysis of data from the GDSC and TCGA databases revealed that cluster 3 MPM patients could respond well to the small‐molecule inhibitor CHIR‐99021, a small‐molecule inhibitor of GSK‐3.ConclusionWe performed unsupervised clustering of alternative splicing data from 84 MPM patients from the TCGA database and identified a cluster associated with the worst prognosis that was sensitive to a GSK‐3 inhibitor.

Malignant pleural mesothelioma: treatment patterns and humanistic burden of disease in Europe

BackgroundMalignant pleural mesothelioma (MPM) is an aggressive and rare tumour with poor prognosis. Most patients are diagnosed with advanced disease and there is a paucity of data on the humanistic burden of MPM in terms of impact on health-related quality of life (HRQoL) and activity. This study examined real-world treatment patterns and humanistic disease burden of MPM in Europe.MethodsPhysicians abstracted demographic/clinical characteristics and treatment data from MPM-patient medical records; MPM patients self-completed a questionnaire including symptoms, 3-level-EQ-5D questionnaire and Visual Analogue Scale (VAS), Lung Cancer Symptom Scale for Mesothelioma (LCSS-Meso), and Work Productivity and Activity Impairment (WPAI) questionnaire.ResultsPhysicians (n = 171) abstracted data of 1390 patients; 767/1390 patients self-completed questionnaires. Patients were elderly with advanced, unresectable MPM. Treatment patterns followed guidelines with most (81%) patients receiving platinum+antifolate chemotherapy at first line (1 L). Maintenance treatment use was high (51.1%) despite no recommended maintenance therapies. Symptom burden was high and health states and HRQoL were poor at 1; declining further with progression. Overall mean (SD): LCSS-Average Symptom Burden Index score was 48.8 (19.3; n = 758); EQ-5D Utility Index score was 0.510 (0.349; n = 763); EQ-5D VAS score was 54.2 (20.3;n = 766); LCSS-3-Item Global Index score was 143.2 (64.5; n = 762); LCSS-normal activities score was 51.9 (24.6;n = 765); WPAI-activity impairment was 56.0% (23.2%; n = 737).ConclusionThe humanistic burden of MPM is high, despite treatments being prescribed as per available guidance. Treatments that delay progression and provide palliation of symptoms are most likely to improve/maintain HRQoL.