Malignant Pleural Mesothelioma Patients Research Articles

Diagnostic Accuracy of Ultrasound Guided Percutaneous Pleural Needle Biopsy for Malignant Pleural Mesothelioma.

Background/Objectives: Ultrasound (US) has been progressively spreading as the most useful technique for guiding biopsies and fine-needle aspirations that are performed percutaneously. Malignant pleural mesothelioma (MPM) represents the most common malignant pleural tumour. Thoracoscopy represents the gold standard for diagnosis, although conditions hampering such diagnostic approach often coexist. The Objective was to determine whether ultrasound-guided percutaneous needle biopsy (US-PPNB) has a high diagnostic accuracy and represents a safe option for diagnosis of MPM. Methods: US-PPNB of pleural lesions suspected for MPM in patients admitted from January 2021 to June 2023 have been retrospectively analyzed. An 18-gauge semi-automatic spring-loaded biopsy system (Medax Velox 2®) was used by experienced pneumologists. The obtained specimens were histologically evaluated and defined as adequate or non-adequate for diagnosis according to whether the material was considered appropriate or not for immunohistochemistry (IHC) analysis. The primary objective of the study was the diagnostic yield for a tissue diagnosis. Results: US-PPNB was diagnostic of MPM in 15 out of 18 patients (sensitivity: 83.39%; specificity: 100%; PPV: 100%). Three patients with non-adequate US-PPNB underwent thoracoscopy for diagnosis. We found significant differences in terms of mean pleural lesion thickness between patients with adequate and not-adequate biopsy (15.4 mm (SD: 9.19 mm) and 3.77 mm (SD: 0.60 mm), p < 0.0010. In addition, a significant positive correlation has been observed between diagnostic accuracy and FDG-PET avidity value. Conclusions: US-PPNB performed by a pneumologist represents a valid procedure with a high diagnostic yield and accuracy for the diagnosis of MPM, and may be considered as an alternative option in patients who are not suitable for thoracoscopy.

Expression and prognostic significance of KAP1 gene in malignant pleural mesothelioma

Objective: To explore the expression of KAP1 (KRAB-associated protein 1, KAP1) in Malignant pleural mesothelioma (MPM) based on the cancer genome atlas (TCGA) and clinical trials. And elucidate the correlation between the expression of KAP1 and the clinical pathological parameters of patients with MPM and its prognosis. Methods: In April 2022, Based on the second generation KAP1mRNA sequencing data and clinicopathological data of MPM patients downloaded from TCGA database, the correlation between KAP1mRNA expression and clinical parameters was analyzed, and the correlation between KAP1 protein expression and clinicopathological parameters and its prognostic value were analyzed based on Chuxiong data set cohort clinical samples. The expression of KAP1 mRNA in MPM samples and matched normal tumor adjacent tissues was detected by qRT-PCR, and the expression of KAP1 protein in MPM and normal pleural tissues was detected by immunohistochemistry and Westernblotting. To construct a Kaplan-Meier model to explore the effect of KAP1 expression on the prognosis of MPM patients, and to analyze the prognostic factors of MPM patients by Cox regression. Results: qRT-PCR and Western blotting detection showed that the expression levels of KAP1 gene in four different MPM cells (NCI-H28, NCI-H2052, NCI-H2452, and MTSO-211H) were significantly higher than those in normal pleural mesothelial cells Met-5A. qRT-PCR, Western blotting and IHC results demonstrated that the mRNA and protein expression levels of KAP1 in MPM tissues was significantly higher than that in matching normal mesothelial tissues, and the expression level of KAP1 protein was correlated with TP 53 protein expression levels and serum CEA levels (P<0.05) . The mRNA expression level was significantly correlated with the prognosis, The overall survival time of mesothelioma patients with high KAP1mRNA expression was significantly shorter (HR=3.7, Logrank P<0.001) . Tumor type, age and the mRNA expression were related to the prognosis of MPM patients (P<0.05) . Multivariate analysis showed that tumor type and KAP1 mRNA expression level were independent prognostic factors of MPM patients (P<0.05) . Conclusion: In this study, TCGA database and Chuxiong cohort experiment samples were used to collect the relevant information of KAP1 expression in malignant melanoma tissues. It was confirmed that KAP1 is highly expressed in MPM tissues. The mRNA expression level and pathological type are correlated with the prognosis of patients.

Abstract 4085: The anti-VISTA x MSLN bispecific antibody-interferon beta mutein fusion protein: A trispecific immunocytokine with potent therapeutic efficacy against malignant pleural mesothelioma

Abstract Background Malignant pleural mesothelioma (MPM) is a rare and highly fatal cancer primarily induced by asbestos exposure. The 5-year overall survival rate for MPM patients is less than 20%. Before the FDA approval of the combination of immune checkpoint inhibitors (Nivolumab + Ipilimumab, CHECKMATE-743), chemotherapy was the only systemic therapy for MPM. However, the predominant histological type of MPM, epithelioid MPM, comprising approximately 70% of cases, showed limited clinical benefits from immune checkpoint inhibitors when compared to non-epithelioid histology. Consequently, there is an unmet medical need to develop a new anti-cancer drug specifically for the treatment of epithelioid MPM. In this study, we discovered that V-domain Ig suppressor of T cell activation (VISTA), an immune checkpoint protein, and Mesothelin (MSLN), a tumor differentiation antigen, are co-expressed in epithelioid MPM. Subsequently, we developed a biomarker-based anti-VISTA x MSLN bispecific antibody (BsAb) and anti-VISTA x MSLN BsAb-IFN-β mutein fusion protein (trispecific immunocytokine) for the treatment of epithelioid MPM. Method We designed and screened various structures of the anti-VISTA x MSLN BsAb. To produce the trispecific immunocytokine, we fused IFN-β mutein (R27T/C17S), which exhibits improved stability, productivity, and pharmacokinetic properties compare to recombinant IFN-β. The in vitro efficacy of the trispecific immunocytokine was tested in human MPM cell lines, and its in vivo efficacy was evaluated in a human MPM xenograft mouse model and a human IFNAR1/2 Knock-in (KI) mouse model. Results We demonstrated a strong positive correlation between the expression levels of VISTA and MSLN in epithelioid MPM. The Anti-VISTA x MSLN BsAb showed improved binding affinity and antibody-dependent cell cytotoxicity (ADCC) activity. The trispecific immunocytokine displays analogous biological activities to both Anti-VISTA x MSLN BsAb and IFN-β mutein. The trispecific immunocytokine exhibited potent in vivo and in vitro anti-cancer activities against epithelioid MPM preclinical models, operating through both direct cytotoxicity and indirect activation of immune cells. Conclusion The trispecific immunocytokine demonstrated robust in vitro and in vivo anti-cancer efficacy in the epithelioid MPM model. Our findings suggest that the trispecific immunocytoine is a promising drug candidate for epithelioid MPM. Citation Format: Hee Geon Park, Hyeon Ju Kim, Myeung Ryun Seo, Ji Eun Park, Tae Won Kim, Jeung Hoo Choi, Jay Park, Kyoung Song, Chan Gyu Lee, Hae Min Jeong, Jun Young Choi, Yeong Jeong Jeon, Yoon La Choi, Sung Youl Hong, Young Kee Shin. The anti-VISTA x MSLN bispecific antibody-interferon beta mutein fusion protein: A trispecific immunocytokine with potent therapeutic efficacy against malignant pleural mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4085.

Clonal gene signatures predict prognosis in mesothelioma and lung adenocarcinoma

Malignant pleural mesothelioma (MPM) is a rare but lethal pleural cancer with high intratumor heterogeneity (ITH). A recent study in lung adenocarcinoma has developed a clonal gene signature (ORACLE) from multiregional transcriptomic data and demonstrated high prognostic values and reproducibility. However, such a strategy has not been tested in other types of cancer with high ITH. We aimed to identify biomarkers from multi-regional data to prognostically stratify MPM patients. We generated a multiregional RNA-seq dataset for 78 tumor samples obtained from 26 MPM patients, each with one sample collected from a superior, lateral, and inferior region of the tumor. By integrating this dataset with the Cancer Genome Atlas MPM RNA-seq data, we selected 29 prognostic genes displaying high variability across different tumors but low ITH, which named PRACME (Prognostic Risk Associated Clonal Mesothelioma Expression). We evaluated PRACME in two independent MPM datasets and demonstrated its prognostic values. Patients with high signature scores are associated with poor prognosis after adjusting established clinical factors. Interestingly, the PRACME and the ORACLE signatures defined respectively from MPM and lung adenocarcinoma cross-predict prognosis between the two cancer types. Further investigation indicated that the cross-prediction ability might be explained by the high similarity between the two cancer types in their genomic regions with copy number variation, which host many clonal genes. Overall, our clonal signature PRACME provided prognostic stratification in MPM and this study emphasized the importance of multi-regional transcriptomic data for prognostic stratification based on clonal genes.

Correlation between prognostic nutritional index and pleural thickness with survival time of epithelial malignant pleural mesothelioma patients

Objective: To explore the role of prognostic nutritional index (PNI) and pleural thickness in the prognostic evaluation of patients with epithelial malignant pleural mesothelioma (MPM) . Methods: In April 2022, a retrospective analysis was conducted on the data and laboratory data of 41 patients with epithelial MPM admitted to the cardiothoracic surgery department of Chuxiong Yi Autonomous Prefecture People's Hospital from January 2018 to May 2021. Univariate and multivariate analysis were used to evaluate the relationships between total survival time, clinical characteristics, PNI and pleural thickness in patients. Results: The 41 patients were mostly male (26 cases, 63.4%) , with a median age of 55 years old. The main clinical manifestations were chest pain (53.7%) , bloody pleural effusion (75.6%) , and chest pain combined with bloody pleural effusion (36.6%) . The median survival time of patients with different TNM stage, efficacy after 4 cycles of chemotherapy, PNI, maximum pleural thickness after chemotherapy (post max) , sum of post max in 3 zones after chemotherapy (post sum) were statistically different (χ(2)=3.89, 14.51, 15.33, 4.33, 12.05, P<0.05) . Compared with patients with high PNI and post sum<32.26 mm, MPM patients with low PNI and post sum≥32.26 mm have higher risk of death, and the differences were statistically significant (HR=1.52, 95%CI: 1.75-11.93, P=0.002; HR=1.70, 95%CI: 1.84-16.23, P=0.002) . Conclusion: PNI and post sum can be used to predict the prognosis of patients with epithelial MPM.

Involvement of Palliative Care in Malignant Pleural Mesothelioma Patients and Associations with Survival and End-of-Life Outcomes.

Malignant pleural mesothelioma is a rare, aggressive, and incurable cancer with a poor prognosis and high symptom burden. For these patients, little is known about the impact of palliative care consultation on outcomes such as mortality, hospital admissions, or emergency department visits. The aim of this study is to determine if referral to supportive and palliative care in patients with malignant pleural mesothelioma is associated with survival and decreased hospital admissions and emergency department visits. This is a retrospective chart review. Study participants include all malignant pleural mesothelioma patients seen at The Ottawa Hospital-an acute care tertiary center-between January 2002 and March 2019. In total, 223 patients were included in the study. The mean age at diagnosis was 72.4 years and 82.5% were male. Of the patients diagnosed between 2002 and 2010, only 11 (9.6%) were referred to palliative care. By comparison, of those diagnosed between 2011 and 2019, 49 (45.4%) were referred to palliative care. Median time from diagnosis to referral was 4.1 months. There was no significant difference in the median survival of patients referred for palliative care compared to those who did not receive palliative care (p = 0.46). We found no association between receiving palliative care and the mean number of hospital admissions (1.04 vs. 0.91) from diagnosis to death, and an increase in mean number of emergency department visits in the palliative care group (2.30 vs. 1.18). Although there was increased utilization of palliative care services, more than half of the MPM patients did not receive palliative care despite their limited survival. There was an increase in emergency department visits in the palliative care group; this may represent an increase in the symptom burden (i.e., indication bias) in those referred to palliative care.

Overexpression of estrogen receptor beta and its prognostic significance among malignant pleural mesothelioma patients

Abstract Background The overexpression of estrogen receptor beta (ERβ) and its correlation with prognosis of malignant mesothelioma remains controversial and unexplored. This study aimed at studying ERβ expression in tumour tissue in patients with pleural mesothelioma and its association with clinical and pathological factors and survival analysis. Material and methods A prospective cohort study was conducted on patients who were diagnosed with malignant pleural mesothelioma (MPM) in Ain Shams university hospitals, the primary end point was to correlate ERβ overexpression that was analysed by immunohistochemistry (IHC) on paraffin tissue blocks with 1-year overall survival (OS) among MPM patients, the secondary endpoint was to correlate ERβ overexpression with 1-year progression free survival (PFS) and response to platinum-based chemotherapy among MPM patients. Results A total 42 MPM patients were included, High ERβ expression (modified Allred score 7-9) was reported in 9.5% of the patients (4 cases), moderate expression (modified Allred score 4-6) was reported in 28.6% of the patients(12 cases), weak and negative expression ( modified Allred score 0-3) was reported in 61% of the patients(26 cases), percent of ERβ positive cases was 69% of the total patients, there was no statistical difference as regard age (p value:0.8), sex(p value:0.4), stage (p value: 0.71), ECOG (p value :0.84) , histological subtype(p value:0.17) and response to platinum based treatment (p value:0.5) across the 3 groups of patients (high, moderate , weak and negative ER beta on tumour tissues).there was no statistically significant difference in OS and PFS for ERβ overexpression. Conclusion The overexpression of ERβ was not associated with improved OS or PFS in mesothelioma patients, despite high rate of ERβ positive cases in our analysis, larger sample size would be recommended for more solid conclusions

In-depth profiling of tumor tissue derived from malignant pleural mesothelioma patients identifies potential biomarkers predicting response to immune-checkpoint inhibitor therapy

In-depth profiling of tumor tissue derived from malignant pleural mesothelioma patients identifies potential biomarkers predicting response to immune-checkpoint inhibitor therapy

EP14.01-02 Treatment Response in Malignant Pleural Mesothelioma Patients Can Be Predicted by Exhaled Breath Analysis

EP14.01-02 Treatment Response in Malignant Pleural Mesothelioma Patients Can Be Predicted by Exhaled Breath Analysis

EP14.04-02 Expression of TILs and Patterns of Gene Expression from Paired Samples of Malignant Pleural Mesothelioma (MPM) Patients (p)

EP14.04-02 Expression of TILs and Patterns of Gene Expression from Paired Samples of Malignant Pleural Mesothelioma (MPM) Patients (p)

Malignant pleural mesothelioma with resolution of pleural effusion.

In malignant pleural mesothelioma patients, pleural effusion may improve during the course of the disease. Pleural effusion with nodular shadows bordering the pleura should be followed up even if the pleural effusion improves.

P53 dry gene powder enhances anti-cancer effects of chemotherapy against malignant pleural mesothelioma.

Dry gene powder is a novel non-viral gene-delivery system, which is inhalable with high gene expression. Previously, we showed that the transfection of p16INK4a or TP53 by dry gene powder resulted in growth inhibitions of lung cancer and malignant pleural mesothelioma (MPM) in vitro and in vivo. Here, we report that dry gene powder containing p53- expression-plasmid DNA enhanced the therapeutic effects of cisplatin (CDDP) against MPM even in the presence of endogenous p53. Furthermore, our results indicated that the safe transfection with a higher plasmid DNA (pDNA) concentration suppressed MPM growth independently of chemotherapeutic agents. To develop a new therapeutic alternative for MPM patients without safety concerns over "vector doses", our in vitro data provide basic understandings for dry gene powder.

Malignant Pleural Mesothelioma and Radiotherapy: Lung Toxicity Results of an Interim Analysis in Prospective Pilot Trial

Malignant Pleural Mesothelioma (MPM) is a rare but aggressive intrathoracic malignancy with an overall poor prognosis. Neoadjuvant chemotherapy, surgery and then radiotherapy is the standard of care in early-stage disease. Our study aim is to evaluate the feasibility and toxicity of the novel adjuvant RT in accelerated hypofractionation. We report the lung toxicity preliminary results of the first patients entreated. Starting in 2017, 29 MPM patients were enrolled in the trial (IRST trial 163). All patients were treated with accelerated hypofractionated radiotherapy using a helical 3-D CRT and IMRT system and intensity-modulated arc therapy. We conducted a prospective mono-institutional clinical trial enrolling cyto-histological proven, MPM patients. The major exclusion criteria were: previous thorax radiotherapy, contralateral mediastinum involvement (N3) and/or M1, interstitial pneumopathy, active pneumonitis, and fissural disease. The prescription dose was 30 Gy in five daily fractions, while an inhomogeneous dose escalation to 40 Gy was prescribed based solely upon the presence of gross residual tumor. All patients were treated in a 3-D CRT and IMRT system. Patients underwent functional lung study before to start radiotherapy treatment, 2 months and 6 months after the end of the treatment. The organs at risk dose-volume histograms were converted to a 2-Gy equivalent dose, and we closely adhered to the dose constraints of the literature data. We in particular analyzed lung toxicity of the first 20 patients. No G3/G4 lung toxicity was found. We reported 65.0% G1 pneumonitis and 10% G2 as acute lung toxicity. The majority of the G1 patients had only mild symptoms and pneumonitis was described only for radiologic features with no need for medical therapy. Other respiratory toxicities were G1-G2 cough in 50% of the patients; G1 dyspnea occurred in 65% of the patients and G2 in the 15%. The total lung mean dose was 18 Gy (range 13 Gy-23 Gy), and the contralateral lung mean dose was 2 Gy (range 1 Gy-2 Gy). The median value of Forced Expired Volume in one second (FEV1) recorded was 75.5% (range: 46%-137%) before the treatment was started, the median value of Forced Vital Capacity (FVC) at baseline was 74 (range 46-123) with progressive decreasing values through time. DLCO has also been reported with a progressive decrease over time after radiotherapy treatment. No case of respiratory failure was reported after treatment. Treatment of the intact lung with pleural intensity-modulated arc irradiation is a novel treatment strategy that appears to be safe, feasible, and without a high grade of lung toxicity. More investigations are mandatory. The protocol is ongoing.

Phase II Study of Hemithoracic Intensity-Modulated Pleural Radiation Therapy (IMPRINT) for Patients with Pleural Metastases from Thymic Malignancies

Pleural metastases are common sites for recurrence and progression in patients with thymic malignancies. The management of pleural metastases typically involves surgical resection with or without neoadjuvant or adjuvant systemic therapy. After surgical resection of pleural metastases, the 5-year progression-free survival (PFS) rate is about 29-45%. While radiation therapy (RT) is standardly used in the management of locally-advanced thymic malignancies, the role of RT in patients with pleural metastases in unclear. Intensity-modulated pleural radiation therapy (IMPRINT) is a RT technique currently being used to treat malignant pleural mesothelioma (MPM) patients with 2 intact lungs at centers that specialize in MPM treatment. This IMPRINT technique can potentially be extrapolated to thymic patients with pleural metastases. Because the risk of toxicity is of greater concern for thymic patients given their overall relatively favorable prognosis, the rate of toxicity, particularly radiation pneumonitis, needs to be established in the thymic patient population. This is a single-arm, single institution Phase II study of hemithoracic IMPRINT for patients with pleural metastases from thymic malignancies. The primary endpoint of this study is grade 3 or higher radiation pneumonitis within 4 months of completing RT. Secondary endpoints include any toxicity, progression-free survival, patterns of failure and overall survival. Patients must have a pathologically confirmed diagnosis of a thymic malignancy with radiologic or pathologic evidence of pleural metastases. Thymoma or thymic carcinoma are allowed. Patients may have de novo stage IVA disease or recurrent disease in the pleura. There must be no evidence of extrathoracic metastatic disease or contralateral pleural/pericardial disease. Surgical resection of the pleural nodules (ex: pleurectomy/decortication, debulking/metastasectomy) are allowed. Extrapleural pneumonectomy is not allowed. Patients are excluded if they have undergone prior thoracic radiation therapy preventing hemithoracic pleural IMRT, whereas prior thymic bed radiation and/or prior pleural SBRT are allowed. RT will be administered to the ipsilateral pleura to 50.4 Gy in 28 fractions. An optional dose-painting boost to gross disease up to 60 Gy while respecting normal tissue constraints is allowed. Patients can be treated with photon or proton therapy. Simulation, contouring and RT planning guidelines have been developed. Patients will be followed per protocol at regular intervals for at least 12 months following RT. The expected accrual is 36 patients over 4 years. Further information can be found on clinicaltrials.gov (NCT05354570). To be determined. To be determined.

Prognostic significance and immune cell infiltration analysis of differentially expressed genes in malignant pleural mesothelioma

Objective: To explore and analyze differential expressed genes in malignant pleural mesothelioma (MPM) by bioinformatics method, and to study their prognostic value in MPM and their potential role in immunotherapy. Methods: In January 2022, the dataset GSE51024 was downloaded from the GEO database, and MPM (55 cases) and normal tissue (41 cases) samples were obtained. Using R software and HMDD and miRNet database, MPM-related differential genes were screened and co-expressed genes were identified. Co-expressed genes were enriched and functionally annotated, and protein-protein interaction (PPI) networks were constructed and key genes were identified using the STRING database and Cytoscape software. TRRUST and GEPIA databases were used to predict transcription factors of key genes and to analyze prognosis and survival. The correlation between key genes and the degree of infiltration of immune cells was analyzed using TIMER. Results: A total of 435 co-expressed genes were obtained, which were mainly concentrated in the extracellular matrix tissue and the signaling pathways of cell adhesion molecules. Combined with PPI and TRRUST database, seven key MPM prognostic genes were identified. Among them, cyclin 20 (CDC20) , cell cycle checkpoint kinase 1 (CHEK1) , enhancer of Zeste homolog 2 (EZH2) , ribonucleotide reductase subunit M2 (RRM2) , topoisomerase 2A (TOP2A) , ubiquitin like plant homeodomain and ring finger domain 1 (UHRF1) were significantly up-regulated in MPM, while cyclin A1 (CCNA1) was significantly down-regulated. The expressions of CCNA1, CDC20, CHEK1, EZH2, RRM2, TOP2A and UHRF1 genes were significantly associated with MPM overall survival (P<0.05) . The expressions of CDC20, CHEK1, EZH2, RRM2 and TOP2A genes were positively correlated with B cells and dendritic cells (P<0.05) , and negatively correlated with neutrophils (P<0.05) . Conclusion: CCNA1, CDC20, CHEK1, EZH2, RRM2, TOP2A and UHRF1 may be potential prognostic markers in MPM patients, and their expressions may be related to MPM tumor immunity.

Pleural Fluid-to-Blood BNP Ratio May Contribute to Prognosis in Malignant Pleural Mesothelioma.

Brain natriuretic peptide (BNP) seems to be produced from malignant mesothelial cells other than cardiomyocytes. We aimed to evaluate whether an increased pleural fluid-to-blood BNP ratio in patients with malignant pleural mesothelioma (MPM) could facilitate prognosis beyond diagnosis. Patients with MPM were included (observational study). One- and two-year survival and factors affecting it were tested. To evaluate the prognostic significance of the natriuretic peptide precursor B (NPPB) gene expression in MPM, we constructed a survival curve from data derived from The Cancer Genome Atlas. Nineteen consecutive patients with MPM were included (age: 67 (61, 80), male 78.9%). One- and two-year survival were 52.6% and 31.6%, respectively. Age, performance status, and the other variables tested did not differ between survivors and non-survivors. Non-survivors presented higher pleural fluid BNP in two years (699 (210, 5000) vs. 379.5 (5, 567), p = 0.036) and BNP ratios than survivors (1-year: 28.75 (4.05, 150.24) vs. 3.49 (0.3, 26) p = 0.001, 2-years: 22.8 (2.42, 150.24) vs. 3.49 (0.3, 7.76), p = 0.001). One- and two-year survival rates in patients with BNP ratios above/equal to the median value (8.82) were 20% and 0%, and 88.9% and 66.7%, respectively, in patients with BNP ratios below 8.82 (p = 0.006 and p = 0.002, respectively). MPM patients with low NPPB expression presented significantly higher survival rates compared to patients with higher expressions (p = 0.032). A high pleural fluid/blood BNP ratio, an easily performed in everyday practice, costless biomarker seems to predict poorer survival better than the commonly reported prognostic factors in MPM.

Longitudinal monitoring of response to chemotherapy in patients with malignant pleural mesothelioma by biomarkers.

The aim of the study was to longitudinally investigate the serum levels of mesothelin, sestrin1, hyaluronan synthase 2 (HAS2), midkine, and high mobility group box 1 (HMGB1) before and after chemotherapy and at the time of relapse in malignant pleural mesothelioma (MPM) patients treated with chemotherapy and to compare the changes in biomarker levels with radiological treatment outcome. A total of 64 MPM patients treated with chemotherapy were enrolled in the study and longitudinally followed for changes in biomarker levels in response to treatment. Biomarkers evels were measured in serum using a human ELISA kit. Relative and absolute changes in biomarker levels were compared with the best radiological overall response at each time point. Median survival was 20.0 ± 2.4 (15.3-24.7) months in patients with partial and complete response, 17.0 ± 1.0 (15.0-19.0) months in patients with stable disease, and 9.0 ± 1.0 (7.0-11.0) months in patients with progressive disease. A significant decrease in serum levels of mesothelin, midkine, and HMGB1 was observed in patients with radiologically partial and complete responses to chemotherapy (p< 0.001, p= 0.016, and p= 0.039, respectively). In these patients, mesothelin levels decreased by 15%, midkine levels by 7%, and HMGB1 levels by 15%. In addition, HMGB1 serum levels were found to significantly increase by 15% in patients with radiologically progressive responses to chemotherapy compared to pretreatment serum levels (p= 0.035). In patients with partial and complete response to chemotherapy, mesothelin levels increased by 15%, midkine by 12%, and sestrin1 by 8% when the disease recurred (p= 0.004, p= 0.004 and p= 0.044, respectively). Biomarkers may be useful in the longitudinal monitoring of response to treatment in MPM. However, the results of our study should be validated in larger groups with sufficient case numbers from multicenter institutions.

Epithelioid Mesothelioma Patients with Very Long Survival Display Defects in DNA Repair.

DNA repair has an important role in malignant pleural mesothelioma (MPM) tumorigenesis and progression. Prognostic/predictive biomarkers for better management of MPM patients are needed. In the present manuscript, we analyzed the expression of more than 700 genes in a cohort of MPM patients to possibly find biomarkers correlated with survival. A total of 54 MPM patients, all with epithelioid histology, whose survival follow-up and formalin-fixed paraffin-embedded tumors were available, were included in the study. Gene expression profiles were evaluated using a Nanostring platform analyzing 760 genes involved in different cellular pathways. The percentages of proliferating tumor cells positive for RAD51 and BRCA1 foci were evaluated using an immunofluorescence assay, as a readout of homologous recombination repair status. Patient median survival time was 16.9 months, and based on this value, they were classified as long and short survivors (LS/SS) with, respectively, an overall survival ≥ and <16.9 months as well as very long and very short survivors (VLS/VSS) with an overall survival ≥ than 33.8 and < than 8.45 months. A down-regulation in the DNA damage/repair expression score was observed in LS and VLS as compared to SS and VSS. These findings were validated by the lower number of both RAD51 and BRCA1-positive tumor cells in VLS as compared to VSS. The down-regulation of DNA repair signature in VLS was functionally validated by a lower % of RAD51 and BRCA1-positive tumor cells. If these data can be corroborated in a prospective trial, an easy, cost-effective test could be routinely used to better manage treatment in MPM patients.

Use of PET/CT in Diagnosis and Staging of Malignant Pleural Mesothelioma

Background The pleural space is formed by two pleural membranes: the parietal pleura and the visceral pleura. Each is comprised of a single layer of mesothelial cells, a basement membrane, and a layer of connective tissue which contains blood vessels and lymphatics. Various benign, malignant, and tumor-like conditions can involve the pleura. Malignant neoplasms are more common than benign neoplasms. Pleural tumors can have a varied imaging spectrum – may be unilateral or bilateral, calcified, or noncalcified, and focal or diffuse. Aim of the Work To elucidate the role of PET/CT in diagnosing and staging of malignant pleural mesothelioma (MPM) patients. Patients and Methods A cross sectional analysis of all cases of malignant mesothelioma referred to Elmaadi Military hospital during the period from Nov. 2020 to Jun. 2021 for assessment of the role of F18-FDG PET/CT in staging, restaging and monitor of therapy response compared to CT. The total number of patients with mesothelioma was 30 patients, 20 males and 10 females. Results In the present study, 27 patients out of 30 patients evaluated with PET/CT showed positive findings at primary sites in pleura and accurately localized tumor sites in them. Also 9 patients of them had local lesions in pleura only with 6 patients had loco-regional lesions. Furthermore 12 patients had loco-regional and metastatic lesions. We demonstrate that PET/CT has high sensitivity than CT in detecting MPM lesions specially intrathoracic lymph node and extrathoracic metastasis as (37% vs. 18 %) of PET/CT and CT respectively. Conclusion FDG PET/CT increases the accuracy of overall staging in patients with MPM and significantly improves the selection of patients for curative surgical resection. Specifically, FDG PET/CT is particularly useful in identifying mediastinal lymph node involvement and detection of distant metastases.

Predicting Overall Survival for Patients with Malignant Mesothelioma Following Radiotherapy via Interpretable Machine Learning.

Malignant pleural mesothelioma (MPM) is a rare but aggressive cancer arising from the cells of the thoracic pleura with a poor prognosis. We aimed to develop a model, via interpretable machine learning (ML) methods, predicting overall survival for MPM following radiotherapy based on dosimetric metrics as well as patient characteristics. Sixty MPM (37 right, 23 left) patients treated on a Tomotherapy unit between 2013 and 2018 were retrospectively analyzed. All patients received 45 Gy (25 fractions). The multivariable Cox regression (Cox PH) model and Survival Support Vector Machine (sSVM) were applied to build predictive models of overall survival (OS) based on clinical, dosimetric, and combined variables. Significant differences in dosimetric endpoints for critical structures, i.e., the lung, heart, liver, kidney, and stomach, were observed according to target laterality. The OS was found to be insignificantly different (p = 0.18) between MPM patients who tested left- and right-sided, with 1-year OS of 77.3% and 75.0%, respectively. With Cox PH regression, considering dosimetric variables for right-sided patients alone, an increase in PTV_Min, Total_Lung_PTV_Mean, Contra_Lung_Volume, Contra_Lung_V20, Esophagus_Mean, and Heart_Volume had a greater hazard to all-cause death, while an increase in Total_Lung_PTV_V20, Contra_Lung_V5, and Esophagus_Max had a lower hazard to all-cause death. Considering clinical variables alone, males and increases in N stage had greater hazard to all-cause death; considering both clinical and dosimetric variables, increases in N stage, PTV_Mean, PTV_Min, and esophagus_Mean had greater hazard to all-cause death, while increases in T stage and Heart_V30 had lower hazard to all-cause-death. In terms of C-index, the Cox PH model and sSVM performed similarly and fairly well when considering clinical and dosimetric variables independently or jointly. Clinical and dosimetric variables may predict the overall survival of mesothelioma patients, which could guide personalized treatment planning towards a better treatment response. The identified predictors and their impact on survival offered additional value for translational application in clinical practice.