Survival In Pleural Mesothelioma Research Articles

Impact of T Cell Ratios on Survival in Pleural Mesothelioma: Insights from Tumor Microenvironment Analysis

Background: Immunotherapy has significantly improved overall survival in patients with pleural mesothelioma, yet this benefit does not extend to those with the epithelioid subtype. Tumor growth is believed to be influenced by the immune response. This study aimed to analyze the tumor microenvironment to gain a better understanding of its influence on tumor growth. Methods: The tumor immune cell infiltration of 188 patients with pleural mesothelioma was characterized by multiplex immunofluorescence staining for CD3+ cells (CD3+), CD4+ cells (CD3+/CD4+), CD8+ cells (CD3+/CD8+), Treg (CD3+/CD4+/CD8-/CD163-/Foxp3+), PD1 cells (PD1+), and T helper cells (CD3+/CD4+/CD8-/CD163-/FoxP3-). The distribution of specific immune cells was correlated with clinical parameters. Results: A total of 188 patients with pleural mesothelioma (135 epithelioid, 9 sarcomatoid, 44 biphasic subtypes) were analyzed. The median age was 64.8 years. Overall survival was significantly longer in the epithelioid subtype than in the non-epithelioid subtype (p = 0.016). The presence of PD-L1 expression had a negative effect on overall survival (p = 0.041). A high ratio of CD4+ cells to regulatory T cells was associated with a significantly longer overall survival of more than 12 months (p = 0.015). The ratio of CD4+ cells to regulatory T cells retained its significant effect on overall survival in the multivariate analysis. Conclusions: Distinct differences in the T cell immune infiltrates in mesothelioma are strongly associated with overall survival. The tumor microenvironment could therefore serve as a source of prognostic biomarkers.

Characteristics of long-term survivors with malignant pleural mesothelioma

Pleural mesothelioma (PM) is a cancer with usually a dismal prognosis. However, long-term survivors do exist. Herein, we analyzed long-term survivors (>5 years after surgery) from high-volume centres around the world. This is a multicenter retrospective descriptive analysis of long-term survivors (overall survival ≥ 5 years from surgery) treated within a multimodality therapy approach including macroscopic complete resection. Overall survival was calculated with Kaplan Meier analysis and cases were matched by center and surgery year and compared with a control group of short-term survivors (<2 years) in a conditional logistic regression analysis. There were 276 long-term survivors, most were male (n=166, 63%) with a median age of 59 (range 21-83) years at time of diagnosis. The histology for 246 was epithelioid and non-epithelioid for 30 patients. The disease was on the right side in 58% of the patients. As of this analysis, 148 patients were dead, 104 were alive and 10 were lost to follow-up. Pathological tumor stages were: pT1 (n=50), pT2 (n=63), pT3 (n=90) or pT4 (n=16), pN0 (n=150), pN1 (n=20) and pN2 (n=39). The matched control dataset included 333 patients, 95 cases and 238 controls. Comparing short- with long-term survivors, there was moderate evidence that a low white blood cell (WBC) count before surgery was more often observed in long-term survivors. The data show that long-term survival in PM is possible in a subgroup of surgically treated patients; histological subtype and WBC count seem to be prognosticators for longer survival.

Effects of the changes between preand post-treatment 18F-FDG PET-CT volumetric parameters on overall survival in pleural mesothelioma

Effects of the changes between preand post-treatment 18F-FDG PET-CT volumetric parameters on overall survival in pleural mesothelioma

Cancer-Associated Fibroblasts Influence Survival in Pleural Mesothelioma: Digital Gene Expression Analysis and Supervised Machine Learning Model.

The exact mechanism of desmoplastic stromal reaction (DSR) formation is still unclear. The interaction between cancer cells and cancer-associated fibroblasts (CAFs) has an important role in tumor progression, while stromal changes are a poor prognostic factor in pleural mesothelioma (PM). We aimed to assess the impact of CAFs paracrine signaling within the tumor microenvironment and the DSR presence on survival, in a cohort of 77 PM patients. DSR formation was evaluated morphologically and by immunohistochemistry for Fibroblast activation protein alpha (FAP). Digital gene expression was analyzed using a custom-designed CodeSet (NanoString). Decision-tree-based analysis using the "conditional inference tree" (CIT) machine learning algorithm was performed on the obtained results. A significant association between FAP gene expression levels and the appearance of DSR was found (p = 0.025). DSR-high samples demonstrated a statistically significant prolonged median survival time. The elevated expression of MYT1, KDR, PIK3R1, PIK3R4, and SOS1 was associated with shortened OS, whereas the upregulation of VEGFC, FAP, and CDK4 was associated with prolonged OS. CIT revealed a three-tier system based on FAP, NF1, and RPTOR expressions. We could outline the prognostic value of CAFs-induced PI3K signaling pathway activation together with FAP-dependent CDK4 mediated cell cycle progression in PM, where prognostic and predictive biomarkers are urgently needed to introduce new therapeutic strategies.

High mesothelin expression by immunohistochemistry predicts improved survival in pleural mesothelioma.

Mesothelin (MSLN) is a cancer-associated antigen that is overexpressed in malignancies such as mesothelioma, pancreatic and ovarian cancer. It is also a target for novel personalised therapies, including antibodies, antibody-drug conjugates and chimeric antigen receptor T cells. Immunohistochemistry may predict those who would best respond to anti-mesothelin therapies and guide decisions in therapeutic strategy. This study aimed to assess the intensity and distribution of MSLN immunostaining in mesothelioma, and to determine the prognostic value of MSLN expression by histochemical-score (H-score). The MN1 anti-MSLN antibody was used to stain a formalin-fixed paraffin-embedded tissue microarray of histologically confirmed mesothelioma from 75 consecutive patients who had undergone pleurectomy with or without decortication. MSLN positivity, the staining intensity, distribution of staining and H-score were evaluated. The correlation of H-score with prognosis was investigated. Sixty-six per cent of epithelioid tumours were MSLN-positive (with expression in > 5% tumour cells). Of MSLN-expressing epithelioid tumours, 70.4% had moderate (2+) or strong (3+) intensity MSLN immunostaining, although only 37% of samples had staining in ≥ 50% of tumour cells. In multivariate analysis, MSLN H-score as a continuous variable and an H-score ≥ 33 were independent predictors of improved survival (P = 0.04 and P < 0.001, respectively). MSLN expression was more heterogenous in epithelioid mesothelioma than reported previously. Therefore, it would be appropriate to perform an immunohistochemical assessment of MSLN expression to stratify and assess patient suitability for mesothelin-targeted personalised therapies, such as chimeric antigen receptor T cells.

The Association Between Pleural Fluid Exposure and Survival in Pleural Mesothelioma

Most patients with malignant pleural mesothelioma (MPM) seek treatment with malignant pleural effusion (MPE). Invitro evidence suggests that MPE may not be a simple bystander of malignancy, but rather potentially has biological properties that improve cancer cell survival and promote cancer progression. If this is the case, MPE management may need to shift from current symptomatic strategies to aggressive fluid removal to impact survival. Is there an association between pleural fluid exposure and survival in MPM? Data from 761 patients who received a diagnosis of MPM between 2008 and 2018 were collected from patient medical records in three UK pleural units. Data included factors previously identified as influencing prognosis in MPM. Medical imaging was reviewed for presence, size, and duration of pleural effusion. Time-dependent covariate analysis of pleural fluid exposure and survival (model included weight loss, serum albumin, hemoglobin, MPM subtype, performance status, chemotherapy, and age) and multivariate Cox regression analysis of pleurodesis and survival were conducted. Median overall survival was 278days (interquartile range, 127-505days; 95%CI, 253-301days). Pleural fluid exposure duration showed no association with survival (hazard ratio, 1.0; 95%CI, 1.0-1.0). Median survival was 473, 378, and 258days with complete, partial, and no pleurodesis (P= .008). Pleurodesis success seems to be associated with improved survival; however, it is unclear whether duration of MPM exposure to pleural fluid is associated with survival within the limitations of this retrospective study. Future prospective studies are required to assess this potentially important mechanism.

The epithelioid BAP1-negative and p16-positive phenotype predicts prolonged survival in pleural mesothelioma.

Mesothelioma is a relatively uncommon but highly malignant neoplasm. Most patients die of disease within 1 year of diagnosis, but some have prolonged survival. Prospective identification of these longer-term survivors may help to guide treatment. We therefore sought to investigate the role of p16 immunohistochemistry (IHC) both alone and in combination with other markers as a potential predictor of prolonged survival in mesothelioma. P16 IHC was performed on unselected pleural mesotheliomas biopsied from 1991 to 2014; 153 of 208 (74%) cases were p16-negative, which correlated significantly with poor overall survival in both univariate (median survival 7.6 versus 13.6 months; P = 0.001) and multivariate analysis [hazard ratio (HR): 1.632; 95% confidence interval (CI): 1.103-2.415; P = 0.014]. Other independent factors associated with prolonged survival included loss of expression of BAP1 and epithelioid morphology. We therefore stratified patients further based on these three independent prognostic variables and demonstrated an unusually prolonged survival in mesotheliomas which were epithelioid, BAP1 IHC negative and p16 IHC positive (12% of cases, median survival 31.7 months, P < 0.0001). In conclusion, p16 IHC is an independent prognostic biomarker in pleural mesothelioma. When used in combination with BAP1 IHC and morphological subtyping, patients with exceptionally prolonged survival can potentially be identified.

Peritoneal Mesothelioma

Malignant peritoneal mesothelioma (MPM) is an aggressive neoplasm that rapidly spreads within the confines of the abdominal cavity to involve most accessible peritoneal and omental surfaces. Current treatment options are unsatisfactory, and new approaches are needed. Recent publications have reported improved survival with an intensive loco-regional treatment strategy including cytoreductive surgery (CRS) along with hyperthermic intraperitoneal chemotherapy (HIPEC). We have noted at our institution prolonged survival in selected patients after intensive multimodality treatment. Our most recently reported trial included initial laparatomy with omentectomy, resection of peritoneal implants, and placement of bilateral peritoneal Portacath; repeated courses of intraperitoneal chemotherapy with doxorubicin, cisplatin, and interferon gamma; second-look laparotomy; and intraoperative hyperthermic perfusion with mitomycin and cisplatin, followed by whole abdominal radiation. To date there have been no universally accepted treatments for MPM. Unless referred to a specialty center, patients are routinely treated with pemetrexed and cisplatin which has been shown to increase survival in pleural mesothelioma.