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Background: In clinical practice, peritoneal dissemination after curative-intent surgery for pleural mesothelioma occasionally recurs. This study investigated the risk factors and prognosis associated with post-pleurectomy/decortication peritoneal dissemination in pleural mesothelioma, which are rarely reported. Methods: This retrospective review included 160 patients who experienced recurrence after pleurectomy/decortication for pleural mesothelioma between January 2011 and December 2021. Patients with recurrence were classified according to the initial recurrence pattern. The P group experienced recurrence with peritoneal dissemination, and the non-P group experienced recurrence without peritoneal dissemination. The analysis determined the risk factors for peritoneal dissemination using multivariable logistic regression analysis. Survival was analyzed using the Kaplan–Meier method and the log-rank test. Results: Of the 160 patients, 20 (12.5%) exhibited peritoneal dissemination and were assigned to the P group, whereas 140 (87.5%) had recurrence without peritoneal dissemination and were assigned to the non-P group. Multivariable logistic regression analysis showed that diaphragm reconstruction (odds ratio [OR], 2.8; 95% confidence interval [CI], 1.0–8.0; p = 0.048) and female sex (OR, 3.7; 95% CI 1.26–10.8; p = 0.017) were associated with the P group. Post-recurrence survival was worse in the P group than in the non-P group (1-year post-recurrence survival: 22.2% vs. 65.3%; median: 6.7 months vs. 19.4 months; p = 0.0013). Conclusions: Peritoneal dissemination occurred in approximately one of every eight patients with recurrence after pleurectomy/decortication for pleural mesothelioma, and the incidence was significantly higher among females and patients undergoing diaphragm reconstruction. Moreover, postoperative recurrence of peritoneal dissemination was associated with a poor prognosis. [ABSTRACT FROM AUTHOR]

Simple Summary: Although immunotherapy is well established for treating pleural mesothelioma, it has not shown a breakthrough in improving the overall survival of these patients. A detailed study of the tumor microenvironment could lead to a better understanding of the factors that influence tumor growth to optimize treatment. In our cohort, T cell infiltrate differences were strongly associated with overall survival. 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. [ABSTRACT FROM AUTHOR]

Simple Summary: The phase I monocentric PACLIMES trial evaluates the effects of local administration of an innovative tool composed of mesenchymal stromal cells loaded with paclitaxel directly injected in the pleural space in mesothelioma patients in a neoadjuvant setting. The trial explores the safety and toxicity of the drug product, but also an exploratory objective aimed at evaluating its antiproliferative capacity. The results of this study will validate a promising therapeutic option for an unmet clinical need such as pleural mesothelioma and open the way to an efficient management of malignant pleural effusion in case of advanced cancers from different sites of primary origin. Background and rationale. Pleural mesothelioma (PM) is a rare and aggressive neoplasm that originates from the pleural mesothelium and whose onset is mainly linked to exposure to asbestos, which cannot be attacked with truly effective therapies with consequent poor prognosis. The rationale of this study is based on the use of mesenchymal stromal cells (MSCs) as a vehicle for chemotherapy drugs to be injected directly into the pathological site, such as the pleural cavity. Study design. The study involves the use of a conventional chemotherapeutic drug, Paclitaxel (PTX), which is widely used in the treatment of different types of solid tumors, including PM, although some limitations are related to pharmacokinetic aspects. The use of PTX-loaded MSCs to treat PM should provide several potential advantages over the systemically administered drug as reduced toxicity and increased concentration of active drug in the tumor-surrounding context. The PACLIMES trial explores the safety and toxicity of the local administration of Paclimes in chemonaive patients, candidates for pleurectomy. The secondary objective is to find the effective Paclimes dose for subsequent phase II studies and to observe and record the antitumor activity. Future direction. The experimental pre-clinical background and rationale are discussed as well. [ABSTRACT FROM AUTHOR]

Introduction: Pleural mesothelioma (PM) is a rare neoplasm with median survival time range from 8 to 14 months from diagnosis, and the 5-year survival rate less than 10%, indicating a poor prognosis. The standard treatment for unresectable PM for a long time has been polychemotherapy with pemetrexed and cisplatin for fit patients. Currently, the combination of the anti PD-1 inhibitor nivolumab and the anti-CTLA4 inhibitor ipilimumab has been recognized as the best possible frontline therapy (especially in the sarcomatoid or biphasic type) due to improved outcomes compared to the standard chemotherapy combination. There are still no established predictive biomarkers for any type of systemic therapy in this disease. Case presentation: Patient who presented with cough and dyspnea has been diagnosed with advanced epithelioid type PM in May 2016. He was treated with three lines of therapy, including an antiangiogenic agent and immunotherapy with pembrolizumab in the third line. Immunotherapy with the PD-1 inhibitor pembrolizumab achieved a complete and prolonged response that transferred to long- term survival. Seven years from diagnosis, the patient is still alive. Histological findings showed an unusually immune-inflamed tumor microenvironment possibly leading to excellent response on immunotherapy. Conclusions: The course of the disease in our patient points out that we need better predictive biomarkers to direct the treatment algorithm, as some of the patients, although chemorefractory to the best chemotherapy option, can sustain great benefit of second-line chemotherapy in combination with antiangiogenic agent, and especially immunotherapy, even in late lines of therapy. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the real‐world treatment patterns and outcomes for patients with pleural mesothelioma (PM) in the era of immunotherapy. Methods: This retrospective audit included patients with PM diagnosed within three tertiary referral centers in Queensland, Australia from January 2017 to July 2023. Patient and treatment characteristics and outcomes were recorded. Data was analyzed using descriptive statistics and the Kaplan‐Meier survival method. Results: A total of 90 patients were included: 84% were male, the median age was 75 years (range 70–79) and 85% had baseline Eastern Group Cooperative Group of 0–1. Subtypes included 54% epithelioid, 17% biphasic, 12% sarcomatoid, and 17% unspecified/unknown. First‐line treatment was received by 57/90 patients (63%) and 33/90 patients (37%) received the best supportive care (BSC). Chemotherapy was most used (63%) overall, but first‐line immunotherapy was more commonly used since ipilimumab/nivolumab was reimbursed by the Australian Pharmaceutical Benefits Scheme in July 2021. After first‐line treatment, only 40% received second‐line treatment and 60% received BSC. 12‐month overall survival (OS) and progression‐free survival for all patients were 53% (95% confidence interval [CI]: 43–65) and 25% (95% CI 15–40) respectively. 12‐month OS was 72%, 64%, and 29% for immunotherapy, chemotherapy, and BSC, respectively. There was no significant difference in survival between chemotherapy and immunotherapy (hazard ratio 1.28, 95% CI: 0.65–2.5, p = 0.5). Conclusion: In our unselected real‐world cohort, both chemotherapy and immunotherapy are active against PM, but the prognosis remains guarded. There remains a need for better treatment options, especially in the first‐line setting. Enrolment in clinical trials is crucial to improving outcomes in this debilitating disease. [ABSTRACT FROM AUTHOR]

Abstract Background This study aimed to investigate the effects of immune checkpoint inhibitors (ICIs) versus chemotherapy on the prognosis of real‐world diffuse pleural mesothelioma patients in China. Methods Clinical data of 90 patients with diffuse pleural mesothelioma from 2019 to 2022 were collected from Harbin Medical University Cancer Hospital. Patients were divided into two groups: the ICIs‐treated group (n = 46) and the chemotherapy‐only group (n = 44). The efficacy and safety of immunotherapy relative to chemotherapy at different treatment stages were explored. Results The median progression‐free survival (PFS) was 10.0 and 7.0 months, and the median overall survival (OS) was 24.7 and 15.8 months in the ICIs‐treated group and the chemotherapy group, respectively. The ICIs‐treated group showed an 11% increase in objective response rate (ORR) (52.2% vs. 41.0%) and an 8.0% increase in disease control rate (DCR) (78.3% vs. 70.0%) compared to the chemotherapy group. The Kaplan–Meier curves demonstrated significant PFS (HR: 0.61; 95% CI: 0.38–0.98; p = 0.038) and OS (HR: 0.47; 95% CI: 0.26–0.86; p = 0.011) benefits of receiving immunotherapy over chemotherapy alone. Subgroup analysis according to treatment timing showed the same trend. Conclusion In patients with nonsurgical diffuse pleural mesothelioma, immunotherapy achieved better survival benefits compared to chemotherapy in both first‐ and second‐/third‐line treatments. The early addition of immunotherapy improved survival in patients with nonsurgical diffuse pleural mesothelioma.

Background: This study aimed to investigate the effects of immune checkpoint inhibitors (ICIs) versus chemotherapy on the prognosis of real‐world diffuse pleural mesothelioma patients in China. Methods: Clinical data of 90 patients with diffuse pleural mesothelioma from 2019 to 2022 were collected from Harbin Medical University Cancer Hospital. Patients were divided into two groups: the ICIs‐treated group (n = 46) and the chemotherapy‐only group (n = 44). The efficacy and safety of immunotherapy relative to chemotherapy at different treatment stages were explored. Results: The median progression‐free survival (PFS) was 10.0 and 7.0 months, and the median overall survival (OS) was 24.7 and 15.8 months in the ICIs‐treated group and the chemotherapy group, respectively. The ICIs‐treated group showed an 11% increase in objective response rate (ORR) (52.2% vs. 41.0%) and an 8.0% increase in disease control rate (DCR) (78.3% vs. 70.0%) compared to the chemotherapy group. The Kaplan–Meier curves demonstrated significant PFS (HR: 0.61; 95% CI: 0.38–0.98; p = 0.038) and OS (HR: 0.47; 95% CI: 0.26–0.86; p = 0.011) benefits of receiving immunotherapy over chemotherapy alone. Subgroup analysis according to treatment timing showed the same trend. Conclusion: In patients with nonsurgical diffuse pleural mesothelioma, immunotherapy achieved better survival benefits compared to chemotherapy in both first‐ and second‐/third‐line treatments. The early addition of immunotherapy improved survival in patients with nonsurgical diffuse pleural mesothelioma. [ABSTRACT FROM AUTHOR]

Pleural mesothelioma (PM) is a highly aggressive tumor that is caused by asbestos exposure and lacks effective therapeutic regimens. Current procedures for PM diagnosis are invasive and can take a long time to reach a definitive result. Small extracellular vesicles (sEVs) have been identified as important communicators between tumor cells and their microenvironment via their cargo including circular RNAs (circRNAs). CircRNAs are thermodynamically stable, highly conserved, and have been found to be dysregulated in cancer. This study aimed to identify potential biomarkers for PM diagnosis by investigating the expression of specific circRNA gene pattern (hsa_circ_0007386) in cells and sEVs using digital polymerase chain reaction (dPCR). For this reason, 5 PM, 14 non-PM, and one normal mesothelial cell line were cultured. The sEV was isolated from the cells using the gold standard ultracentrifuge method. The RNA was extracted from both cells and sEVs, cDNA was synthesized, and dPCR was run. Results showed that hsa_circ_0007386 was significantly overexpressed in PM cell lines and sEVs compared to non-PM and normal mesothelial cell lines (p < 0.0001). The upregulation of hsa_circ_0007386 in PM highlights its potential as a diagnostic biomarker. This study underscores the importance and potential of circRNAs and sEVs as cancer diagnostic tools. [ABSTRACT FROM AUTHOR]

Background: Pleural mesothelioma, characterized by a dismal prognosis even with multimodal therapy, has seen emerging interest in immune checkpoint inhibitors (ICIs) due to their demonstrated efficacy. Here, we present a case of epithelioid-type pleural mesothelioma with chest wall invasion treated with definitive ICI therapy, resulting in a remarkable pretreatment effect. Case presentation: A 46-year-old man was diagnosed with an abnormal chest shadow on a medical check, and a computed tomography scan showed pleural thickening at the dorsal right upper chest wall. One of the nodules was suspected to have invaded the chest wall. A needle biopsy revealed epithelioid-type pleural mesothelioma. After five cycles of nivolumab plus ipilimumab, he underwent right pleurectomy/decortication (P/D). Pathological examination revealed a significant treatment effect, showing numerous lymphocytes infiltrating the tumor nodule and viable tumor cells localized at approximately 6 mm. Conclusion: Although further accumulation of cases is required to evaluate the effectiveness and case selection, P/D after immunotherapy is a useful curative treatment option for advanced pleural mesothelioma. [ABSTRACT FROM AUTHOR]

Objectives In Italy, the highest pleural cancer mortality and incidence have been observed among Italian regions where the 2 largest Italian shipyards were (and are) located. The objective of this study was to assess the exposure–response relationship for mesothelioma among male workers employed in the Monfalcone, Italy, shipyard. Methods We conducted a necropsy-based case–control study. Cases (N = 102) were mesothelioma decedents and controls were those with lung cancer (N = 84). Complete job histories were available; the lung fibre content was measured using a scanning electron microscope with X-ray fluorescence, after sample preparation according to the European Respiratory Society guidelines. Odds ratios and 95% confidence intervals of mesothelioma by fibre type and lung fibre burden, as a categorical or continuous variable, were assessed by unconditional logistic regression, adjusted for age and time since exposure cessation. Analyses for the amphibole and chrysotile lung fibre burden were mutually adjusted. We calculated a cumulative exposure index by applying a job-exposure matrix to the job histories of study cases and assessed its correlation with the lung fibre burden. Results We found an odds ratio of 22.0 (confidence intervals 5.66–85.7) for the highest lung fibre burden category (mean 43.8 million total asbestos fibres per gram of dry tissue) compared with the reference (mean 0.48). Using log10-transformed lung fibre burden, we found that the odds ratio was 3.71 (confidence intervals 2.03–6.79) for a 10-fold lung fibre burden increase. Results for the amphibole lung fibre burden were similar. Odds ratios increased over chrysotile lung fibre burden categories (P -trend = 0.025), and the odds ratio for a 10-fold increase was 4.73 (confidence intervals 0.32–70.4). Conclusions The cumulative exposure index was correlated with total and amphibole lung fibre burden, but not with chrysotile lung fibre burden. Mesothelioma risk was proportional to total, amphibole, and chrysotile lung fibre burden in shipyard workers. [ABSTRACT FROM AUTHOR]

Malignant peritoneal and pleural mesothelioma are rare in young patients, with a paucity of data regarding clinical characteristics and outcomes. We aimed to describe the clinical characteristics, treatment strategies, and outcomes for pediatric and adolescent/young adult (AYA) patients. The National Cancer Database (NCDB) was queried for malignant peritoneal and pleural mesothelioma in pediatric and AYA patients (ages 0–39) from 2004 to 2019. Stratification was performed for pediatric (age 0–21) and young adult (age 22–39) patients. Chi-squared, multivariable cox regression, and Kaplan–Meier analyses were performed. We identified 570 total patients, 46 pediatric and 524 young adult, with mesothelioma (363 peritoneal and 207 pleural). There were significant differences in sex distribution as patients with peritoneal mesothelioma were more frequently female (63.1%). Patients with peritoneal mesothelioma were more likely to have radical surgery compared to pleural mesothelioma (56.7% v. 24.6%, respectively). A majority of patients with peritoneal and pleural mesothelioma received chemotherapy (66.4% and 61.4%, respectively). For peritoneal mesothelioma, surgical resection was associated with improved overall survival, whereas male sex, neoadjuvant chemotherapy, and radiation were associated with worse overall survival. For pleural mesothelioma, intraoperative chemotherapy was associated with improved overall survival, whereas Black race was associated with worse overall survival. Mean overall survival was greater for patients with peritoneal mesothelioma (125 months) compared to those with pleural mesothelioma (69 months), which remained significant after stratification of pediatric and young adult patients. By analyzing a large cohort of pediatric and AYA mesothelioma, this study highlights clinical, prognostic, and survival differences between peritoneal and pleural disease. Level III. Retrospective [ABSTRACT FROM AUTHOR]

Background: The incidence and mortality of pleural mesothelioma (PM) reflect the production and consumption of asbestos over time. However, despite the current global concern, these data remain to be known. Objective: Our aim was to carry out a descriptive analysis of PM cases and mortality from some Portuguese databases between 2014 and 2020. Methods: A retrospective observational study was carried out between 2014 and 2020. Data on the number of PM cases were provided by the Portuguese Cancer Registry, and data on mortality were from the Portuguese Death Certificate Information System. Results: Between 2014 and 2020, 315 cases of PM were reported, with 222 (70.5%) men. The average age of patients was 72.1, with the highest number of cases in patients aged >70 years (n = 198; 62.9%). The highest number of cases was reported in 2018 (n = 62; 19.7%). Regarding mortality, 169 deaths were reported, with 126 (74.6%) men and mostly in individuals aged >70 years (n = 109; 64.5%). It is estimated that around 520 years of potential life were lost. The highest number of deaths occurred in 2015 (n = 33; 19.5%). Conclusion: It is mandatory to reinforce the need for surveillance programs that allow us to gather real and reliable data and eliminate asbestos-related diseases. [ABSTRACT FROM AUTHOR]

Abstract Background Tumor recurrence remains the main barrier to survival after surgery for pleural mesothelioma (PM). Soluble mesothelin‐related protein (SMRP) and cancer antigen 125 (CA‐125) are established blood‐based biomarkers for monitoring PM. We prospectively studied the utility of these biomarkers after pleurectomy decortication (PD). Methods Patients who underwent PD and achieved complete macroscopic resection with available preoperative SMRP levels were included. Tumor marker levels were determined within 60 days of three timepoints: (1) preoperation, (2) post‐operation, and (3) recurrence. Results Of 356 evaluable patients, 276 (78%) had recurrence by the end of follow‐up interval. Elevated preoperative SMRP levels were associated with epithelioid histology (p

Objective: The main objective of this study was to describe the translation, cultural adaptation, and content validation process of the French National Surveillance Programme for Pleural Mesothelioma (FNSPPM) questionnaire for the Portuguese context. Methods: A search was conducted in the PubMed database and Web of Science, in the period from January 1, 1960, to December 31, 2022, to select the questionnaire. Forward and reverse translations, calculation of the content validity index (CVI) by a panel of experts (n = 9), and cognitive interviewing with individuals with at least one exposure to asbestos (n = 10) were performed. Experts rated items on a Likert scale (1-4) based on their relevance. The item-level content validity index (I-CVI), scale-level content validity index based on the average method (S-CVI/Ave), and scale-level content validity index based on the universal agreement method (S-CVI/UA) were calculated. Results: The final version of the FNSPPM questionnaire for the Portuguese context resulted from a translation and content validation process. The panel of experts considered the questionnaire relevant, with an I-CVI of up to 0.78 in 68 of 69 of the questions, an S-CVI/Ave of 0.98, and an S-CVI/UA of 0.90. The participants in the cognitive interviews reported an understanding of the questionnaire. Conclusion: A validated FNSPPM questionnaire for the Portuguese context is now available to study individuals with pleural mesothelioma (PM) and asbestos exposure.

Pleural mesothelioma (PM) is characterized by rapid growth, local invasion, and limited therapeutic options. The multifunctional oncoprotein Y‐box‐binding protein‐1 (YB‐1) is frequently overexpressed in cancer and its inhibition reduces aggressive behavior in multiple tumor types. Here, we investigated the effects of YB‐1 on target gene regulation and PM cell behavior. Whereas siRNA‐mediated YB‐1 knockdown reduced cell motility, YB‐1 overexpression resulted in scattering, increased migration, and intravasation in vitro. Furthermore, YB‐1 stimulated PM cell spreading in zebrafish. Combined knockdown and inducible overexpression of YB‐1 allowed bidirectional control and rescue of cell migration, the pattern of which was closely followed by the mRNA and protein levels of EGFR and the protein level of snail, whereas the mRNA levels of MMP1, EPHA5, and PARK2 showed partial regulation by YB‐1. Finally, we identified snail as a critical regulator of YB‐1‐mediated cell motility in PM. This study provides insights into the mechanism underlying the aggressive nature of PM and highlights the important role of YB‐1 in this cancer. In this context, we found that YB‐1 closely regulates EGFR and snail, and, moreover, that YB‐1‐induced cell migration depends on snail.

Background: Tumor recurrence remains the main barrier to survival after surgery for pleural mesothelioma (PM). Soluble mesothelin‐related protein (SMRP) and cancer antigen 125 (CA‐125) are established blood‐based biomarkers for monitoring PM. We prospectively studied the utility of these biomarkers after pleurectomy decortication (PD). Methods: Patients who underwent PD and achieved complete macroscopic resection with available preoperative SMRP levels were included. Tumor marker levels were determined within 60 days of three timepoints: (1) preoperation, (2) post‐operation, and (3) recurrence. Results: Of 356 evaluable patients, 276 (78%) had recurrence by the end of follow‐up interval. Elevated preoperative SMRP levels were associated with epithelioid histology (p < 0.013), advanced TNM (p < 0.001) stage, and clinical stage (p < 0.001). Preoperative CA‐125 levels were not significantly associated with clinical covariates. Neither biomarker was associated with survival or disease‐free survival. With respect to nonpleural and nonlymphatic recurrences, mean SMRP levels were elevated in patients with pleural (p = 0.021) and lymph node (p = 0.042) recurrences. CA‐125 levels were significantly higher in patients with abdominal (p < 0.001) and lymph node (p = 0.004) recurrences. Among patients with all three timepoints available, we observed an average decrease in SMRP levels by 1.93 nmol/L (p < 0.001) postoperatively and again an average increase at recurrence by 0.79 nmol/L (p < 0.001). There were no significant changes in levels of CA‐125 across the study timepoints (p = 0.47). Conclusions: Longitudinal changes in SMRP levels corresponded with a radiographic presence of disease in a subset of patients. SMRP surveillance could aid in detection of local recurrences, whereas CA‐125 could be helpful in recognizing abdominal recurrences. [ABSTRACT FROM AUTHOR]

Simple Summary: Pleural mesothelioma (PM) is characterized by its poor prognosis due to late-stage diagnosis, limited effective treatment options and the lack of biomarkers for treatment decision. The role of macroscopic radical surgery has therefore been questioned. Thus, there is an urgent need for predictive biomarkers aiding clinicians in tailoring more personalized and effective therapeutic strategies. Besides validating the prognostic role of Ki67 expression in tumor samples in 70 PM patients from two different centers with detailed clinical characteristics, here we suggest for the first time Ki67 as a biomarker to predict the patient's benefit from lung-sparing surgery within multimodality therapy in epithelioid mesothelioma. Pleural mesothelioma (PM), linked to asbestos-induced inflammation, carries a poor prognosis. Therapy ranges from therapy limitation to aggressive multimodality treatment. Given the uncertainty about treatment benefits for patients, this study aimed to assess the role of Ki67 as a prognostic and predictive parameter in PM. Ki67 was measured in the specimens of 70 PM patients (17 female, 53 male) from two centers and correlated to overall survival (OS) and therapy outcome. The median OS was 16.1 months. The level of Ki67 expression was divided into low (≤15%) and high (>15%). A low value of Ki67 expression was associated with a longer OS (Ki67 ≤ 15%: 31.2 (95% CI 6.5–55.8) months vs. Ki67 > 15%: 11.1 (95% CI 7.7–14.6) months, p = 0.012). The 5-year survival represents 22% in the low Ki67 expression group, in contrast to 5% in the high Ki67 expression group. We found a significant interaction term of Ki67 with multimodality treatment (p = 0.031) translating to an OS of 48.1 months in the low expression Ki67 group compared to 24.3 months in the high Ki67 expression group when receiving surgery within multimodality therapy. Therefore, Ki67 stands out as a validated prognostic and, most importantly, novel predictive biomarker for treatment benefits, particularly regarding surgery within multimodality therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Pleural Mesothelioma is a rare and highly aggressive illness with a grim prognosis. Surgical procedures are crucial in achieving accurate diagnosis and staging. In selected patients, long-term survival is attained when several modalities, including surgery, are combined with the aim of macroscopic complete resection. Surgery plays a central role in the diagnosis, staging, and management of pleural mesothelioma. Achieving an accurate diagnosis through surgical intervention and identifying the specific histologic subtype is crucial for determining the appropriate course of treatment. The histologic subtype guides decisions regarding the use of chemotherapy, immunotherapy, or multimodality treatment. The goal of surgery as part of multimodality treatment is to accomplish macroscopic complete resection with the eradication of grossly visible and palpable disease. Over the past two decades, many medical centers worldwide have shifted from performing extra-pleural pneumonectomy (EPP) to pleurectomy decortication (PD). This transition is motivated by the lower rates of short-term mortality and morbidity associated with PD and similar or even better long-term survival outcomes, compared to EPP. This review aims to outline the role of surgery in diagnosing, staging, and treating patients with pleural mesothelioma. [ABSTRACT FROM AUTHOR]

Objective: The main objective of this study was to describe the translation, cultural adaptation, and content validation process of the French National Surveillance Programme for Pleural Mesothelioma (FNSPPM) questionnaire for the Portuguese context. Methods: A search was conducted in the PubMed database and Web of Science, in the period from January 1, 1960, to December 31, 2022, to select the questionnaire. Forward and reverse translations, calculation of the content validity index (CVI) by a panel of experts (n = 9), and cognitive interviewing with individuals with at least one exposure to asbestos (n = 10) were performed. Experts rated items on a Likert scale (1-4) based on their relevance. The item-level content validity index (I-CVI), scale-level content validity index based on the average method (S-CVI/Ave), and scale-level content validity index based on the universal agreement method (S-CVI/UA) were calculated. Results: The final version of the FNSPPM questionnaire for the Portuguese context resulted from a translation and content validation process. The panel of experts considered the questionnaire relevant, with an I-CVI of up to 0.78 in 68 of 69 of the questions, an S-CVI/Ave of 0.98, and an S-CVI/UA of 0.90. The participants in the cognitive interviews reported an understanding of the questionnaire. Conclusion: A validated FNSPPM questionnaire for the Portuguese context is now available to study individuals with pleural mesothelioma (PM) and asbestos exposure. [ABSTRACT FROM AUTHOR]

The role of immunotherapy in the multimodal treatment for pleural mesothelioma (PM) is still under investigation, particularly in the preoperative setting. Pathological complete response (pCR) has been previously described after chemotherapy and immunotherapy; however, there is no prior experience reported with immunotherapy alone before surgery. We report the case of a 58-year-old male with biphasic PM treated with immunotherapy, resulting in a major clinical partial response. Following a multidisciplinary evaluation between thoracic surgeons, medical oncologists, pathologists, radiologists and radiation oncologists, the patient underwent surgery with radical intent through a right extended pleurectomy/decortication (eP/D). Histopathological examination of the specimen confirmed a pathological Complete Response (pCR). This case supports the feasibility and potential efficacy of combining preoperative immunotherapy with surgery in the management of advanced PM. [ABSTRACT FROM AUTHOR]

Simple Summary: Cytoreductive surgery combined with intraoperative hyperthermic chemoperfusion (HITOC) within a multimodal treatment approach has a positive impact on the survival of highly selected patients with epithelioid pleural mesothelioma. The addition of chemotherapy significantly affects the interval to tumor recurrence. Cytoreductive surgery (CRS) combined with hyperthermic intrathoracic chemoperfusion (HITOC) is a promising treatment strategy for pleural mesothelioma (PM). The aim of this study was to evaluate the impacts of this multimodal approach in combination with systemic treatment on disease-free survival (DFS) and overall survival (OS). In this retrospective multicenter study, clinical data from patients after CRS and HITOC for PM at four high-volume thoracic surgery departments in Germany were analyzed. A total of 260 patients with MPM (220 epithelioid, 40 non-epithelioid) underwent CRS and HITOC as part of a multimodal treatment approach. HITOC was administered with cisplatin alone (58.5%) or cisplatin and doxorubicin (41.5%). In addition, 52.1% of patients received neoadjuvant and/or adjuvant chemotherapy. The median follow-up was 48 months (IQR = 38 to 58 months). In-hospital mortality was 3.5%. Both the resection status (macroscopic complete vs. incomplete resection) and histologic subtype (epithelioid vs. non-epithelioid) had significant impacts on DFS and OS. In addition, adjuvant chemotherapy (neoadjuvant/adjuvant) significantly increased DFS (p = 0.003). CRS and HITOC within a multimodal treatment approach had positive impacts on the survival of patients with epithelioid PM after macroscopic complete resection. The addition of chemotherapy significantly prolonged the time to tumor recurrence or progression. [ABSTRACT FROM AUTHOR]

Pleural mesothelioma (PM) is characterized by rapid growth, local invasion, and limited therapeutic options. The multifunctional oncoprotein Y‐box‐binding protein‐1 (YB‐1) is frequently overexpressed in cancer and its inhibition reduces aggressive behavior in multiple tumor types. Here, we investigated the effects of YB‐1 on target gene regulation and PM cell behavior. Whereas siRNA‐mediated YB‐1 knockdown reduced cell motility, YB‐1 overexpression resulted in scattering, increased migration, and intravasation in vitro. Furthermore, YB‐1 stimulated PM cell spreading in zebrafish. Combined knockdown and inducible overexpression of YB‐1 allowed bidirectional control and rescue of cell migration, the pattern of which was closely followed by the mRNA and protein levels of EGFR and the protein level of snail, whereas the mRNA levels of MMP1, EPHA5, and PARK2 showed partial regulation by YB‐1. Finally, we identified snail as a critical regulator of YB‐1‐mediated cell motility in PM. This study provides insights into the mechanism underlying the aggressive nature of PM and highlights the important role of YB‐1 in this cancer. In this context, we found that YB‐1 closely regulates EGFR and snail, and, moreover, that YB‐1‐induced cell migration depends on snail. [ABSTRACT FROM AUTHOR]

OBJECTIVES Postoperative empyema is a severe, potentially lethal complication also present, but poorly studied in patients undergoing surgery for pleural mesothelioma. We aimed to analyse which perioperative characteristics might be associated with an increased risk for postoperative empyema. METHODS From September 1999 to February 2023 a retrospective analysis of consecutive patients undergoing surgery for pleural mesothelioma at the University Hospital of Zurich was performed. Uni- and multivariable logistic regression was used to identify associated risk factors of postoperative empyema after surgery. RESULTS A total of 400 PM patients were included in the analysis, of which n  = 50 patients developed empyema after surgery (12.5%). Baseline demographics were comparable between patients with (E yes) and without empyema (E no). 39% (n  = 156) patients underwent extrapleural pneumonectomy (EPP), of whom 22% (n  = 35) developed postoperative pleural empyema; 6% (n = 15) of the remaining 244 patients undergoing pleurectomy and decortication (n  = 46), extended pleurectomy and decortication (n  = 114), partial pleurectomy (n  = 54) or explorative thoracotomy (n  = 30) resulted in postoperative empyema. In multivariable logistic regression analysis, EPP (odds ratio 2.8, 95% confidence interval 1.5–5.4, P  = 0.002) emerged as the only risk factor associated with postoperative empyema when controlled for smoking status. Median overall survival was significantly worse for E yes (16 months, interquartile range 5–27 months) than for E no (18 months, interquartile range 8–35 months). CONCLUSIONS Patients undergoing EPP had a significantly higher risk of developing postoperative pleural empyema compared to patients undergoing other surgery types. Survival of patients with empyema was significantly shorter. [ABSTRACT FROM AUTHOR]

Pleural mesothelioma (PM) is a tumor related to adverse prognosis. The PM WHO classification has mainly identified three major subtypes of PM which are epithelioid, biphasic, and sarcomatoid. Sarcopenia is a medical issue related to a reduction in muscle mass and strength. It represents a major health issue globally because it is related to adverse effects such as hospitalization, increased length of stay, disability, increased morbidity and mortality and augmented health care expenditures. In this literature review, we attempted to examine the upcoming association between sarcopenia and PM. As recorded by the current literature, muscle loss in PM subjects was related to poorer survival and lower levels of activity. Subjects with PM had increased rates of pre-sarcopenia and malnutrition, while pre-sarcopenia was related to worse activity levels, and malnutrition was related to worse quality of life (QoL). Both tumor volume and sarcopenia were related to long-term mortality in surgically treated PM subjects, while sarcopenia was present both pre-operatively and post-operatively in these subjects. In addition, post-operative sarcopenic subjects showed a decreased 3-year overall survival (OS) in comparison with those who did not have sarcopenia, while pre-operative sarcopenia was importantly related to an increased rate of post-operative adverse outcomes. More studies are needed to validate these claims. [ABSTRACT FROM AUTHOR]

IntroductionPleural mesothelioma (PM) is a rare neoplasm with median survival time range from 8 to 14 months from diagnosis, and the 5-year survival rate less than 10%, indicating a poor prognosis. The standard treatment for unresectable PM for a long time has been polychemotherapy with pemetrexed and cisplatin for fit patients. Currently, the combination of the anti PD-1 inhibitor nivolumab and the anti-CTLA4 inhibitor ipilimumab has been recognized as the best possible frontline therapy (especially in the sarcomatoid or biphasic type) due to improved outcomes compared to the standard chemotherapy combination. There are still no established predictive biomarkers for any type of systemic therapy in this disease.Case presentationPatient who presented with cough and dyspnea has been diagnosed with advanced epithelioid type PM in May 2016. He was treated with three lines of therapy, including an antiangiogenic agent and immunotherapy with pembrolizumab in the third line. Immunotherapy with the PD-1 inhibitor pembrolizumab achieved a complete and prolonged response that transferred to long- term survival. Seven years from diagnosis, the patient is still alive. Histological findings showed an unusually immune-inflamed tumor microenvironment possibly leading to excellent response on immunotherapy.ConclusionsThe course of the disease in our patient points out that we need better predictive biomarkers to direct the treatment algorithm, as some of the patients, although chemorefractory to the best chemotherapy option, can sustain great benefit of second-line chemotherapy in combination with antiangiogenic agent, and especially immunotherapy, even in late lines of therapy.

A caucasian 62-year-old woman, diagnosed with biphasic pleural mesothelioma (PM) of II stage and BAP1 loss, was treated with therapies included in clinical trial and Early Access Programmes (EAP). During her clinical history, radiological images presented an unusual representation of the disease, with a pseudo progression discussed many times by several specialists. The patient's overall survival improved as a result of the multidisciplinary team and the availability of medicines outside of clinical practice.

Objectives: This study aims to determine whether the sequencing of DNA extracted from pleural fluids (PFs) of Pleural Mesothelioma (PM) patients accurately represents the genetic information obtained from the solid tissue counterpart biopsies with particular attention to the identification of single nucleotide variants (SNVs). Materials and methods: Single pleural biopsy, PFs, and blood were collected from PM patients. DNA was extracted from these samples and then subjected to Whole-Exome Sequencing. Results: A higher number of SNVs was identified in PFs than in solid tissue biopsies (STBs). Most SNVs were detected in PFs samples but not in STBs samples, while only a few SNVs were detected in STBs samples but not in PFs samples. Conclusion: The current findings support the notion that PFs might offer a more robust depiction of cancer's molecular diversity. Nonetheless, the current outcomes challenge the assertion that liquid biopsies can encompass the entirety of intra-patient variations. Indeed, a subset of potential cancer-driver SNVs was exclusively identified in STBs. However, relying solely on STBs would have precluded the detection of significant SNVs that were exclusively present in PFs. This implies that while PFs serve as a valuable complement to STBs, they do not supplant them.

Pleural mesothelioma (PM) is a tumor related to adverse prognosis. The PM WHO classification has mainly identified three major subtypes of PM which are epithelioid, biphasic, and sarcomatoid. Sarcopenia is a medical issue related to a reduction in muscle mass and strength. It represents a major health issue globally because it is related to adverse effects such as hospitalization, increased length of stay, disability, increased morbidity and mortality and augmented health care expenditures. In this literature review, we attempted to examine the upcoming association between sarcopenia and PM. As recorded by the current literature, muscle loss in PM subjects was related to poorer survival and lower levels of activity. Subjects with PM had increased rates of pre-sarcopenia and malnutrition, while pre-sarcopenia was related to worse activity levels, and malnutrition was related to worse quality of life (QoL). Both tumor volume and sarcopenia were related to long-term mortality in surgically treated PM subjects, while sarcopenia was present both pre-operatively and post-operatively in these subjects. In addition, post-operative sarcopenic subjects showed a decreased 3-year overall survival (OS) in comparison with those who did not have sarcopenia, while pre-operative sarcopenia was importantly related to an increased rate of post-operative adverse outcomes. More studies are needed to validate these claims.

Due to the scarcity of large‐sized prospective databases, the Japanese Joint Committee for Lung Cancer Registry conducted a nationwide prospective registry for newly diagnosed and untreated pleural mesothelioma. All new cases diagnosed pathologically as any subtype of pleural mesothelioma in Japan during the period between April 1, 2017, to March 31, 2019, were included before treatment. Data on survival were collected in April 2021. The eligible 346 patients (285 men [82.3%]; 61 women [17.7%]; median age, 71.0 years [range, 44–88]) were included for analysis. Among these patients, 138 (39.9%) underwent surgery, 164 (47.4%) underwent non‐surgical therapy, and the remaining 44 (12.7%) underwent best supportive care. The median overall survival for all 346 patients was 19.0 months. Survival rates at 1, 2, and 3 years for all patients were, 62.8%, 42.3%, and 26.5%, respectively. Median overall survival was significantly different among patients undergoing surgery, non‐surgical treatment, and best supportive care (32.2 months vs. 14.0 months vs. 3.8 months, p < 0.001). The median overall survival of patients undergoing pleurectomy/decortication and extrapleural pneumonectomy was 41.8 months and 25.0 months, respectively. Macroscopic complete resection resulted in longer overall survival than R2 resection and partial pleurectomy/exploratory thoracotomy (41.8 months vs. 32.2 months vs. 16.8 months, p < 0.001). Tumor shape, maximum tumor thickness, and sum of three level thickness were significant prognostic factors. The data in the prospective database would serve as a valuable reference for clinical practice and further studies for pleural mesothelioma. [ABSTRACT FROM AUTHOR]

Pleural mesothelioma (PM) is an aggressive and rare disease, characterized by a very poor prognosis. For almost two decades, the world standard treatment regimen for unresectable PM has consisted of a platinum-based drug plus pemetrexed, leading to an overall survival of approximately 12 months. The dramatic therapeutic scenario of PM has recently changed with the entry into the clinic of immune checkpoint inhibition, which has proven to be an effective approach to improve the survival of PMpatients. The aimof the present review is to provide a comprehensive overview of the most promising immunotherapeuticbased strategies currently under investigation for advanced PM. [ABSTRACT FROM AUTHOR]

Simple Summary: Asbestos exposure is known as the main elicitor of pleural mesothelioma (PM) development. The pathology's rarity, wide range of growth patterns, and devastating prognosis have hindered a standardized treatment to date. This study intended to determine possible prognosticators contributing to adjusting the treatment allocation. This initiated the analysis of the readily available biomarkers (from blood withdrawal) and clinical characteristics of 98 consecutive patients regarding their impact on overall survival (OS) in a retrospective and multicentered manner. Surgery (pleurectomy/decortication (P/D)), multimodal therapy (chemotherapy and surgery), a high hemoglobin level, a low platelet count, and a low platelet–lymphocyte ratio (PLR) were identified as favorable prognosticators. In multivariate analysis, histology, P/D, low C-reactive protein (CRP), and platelet levels were independent prognostic variables for this cohort. These validating results support further application of (lung-sparing) interventions and accompanying research on prognostic and predictive biomarkers. Evoked from asbestos-induced inflammation, pleural mesothelioma represents a fatal diagnosis. Therapy ranges from nihilism to aggressive multimodality regimens. However, it is still unclear who ultimately benefits from which treatment. We aimed to re-challenge inflammatory-related biomarkers' prognostic value in times of modern immune-oncology and lung-sparing surgery. The biomarkers (leukocytes, hemoglobin, platelets, neutrophils, lymphocytes, monocytes, neutrophil–lymphocyte ratio (NLR), lymphocyte–monocyte ratio (LMR), platelet–lymphocyte ratio (PLR), C-reactive protein (CRP)) and clinical characteristics (age, sex, histology, therapy) of 98 PM patients were correlated to overall survival (OS). The median OS was 19.4 months. Significant OS advantages (Log-Rank) were observed in multimodal treatment vs. others (26.1 vs. 7.2 months, p < 0.001), surgery (pleurectomy/decortication) vs. no surgery (25.5 vs. 3.8 months, p < 0.001), a high hemoglobin level (cut-off 12 g/dL, 15 vs. 24.2 months, p = 0.021), a low platelet count (cut-off 280 G/L, 26.1 vs. 11.7 months, p < 0.001), and a low PLR (cut-off 194.5, 25.5 vs. 12.3 months, p = 0.023). Histology (epithelioid vs. non-epithelioid, p = 0.002), surgery (p = 0.004), CRP (cut-off 1 mg/dL, p = 0.039), and platelets (p = 0.025) were identified as independent prognostic variables for this cohort in multivariate analysis (Cox regression, covariates: age, sex, histology, stage, CRP, platelets). Our data verified the previously shown prognostic role of systemic inflammatory parameters in patients treated with lung-sparing surgery within multimodality therapy. [ABSTRACT FROM AUTHOR]

Pleural mesothelioma (PM) is an aggressive disease that has a strong causal relationship with asbestos exposure and represents a major challenge from both a diagnostic and therapeutic viewpoint. Despite recent improvements in patient care, PM typically carries a poor outcome, especially in advanced stages. Therefore, a timely and effective diagnosis taking advantage of currently available imaging techniques is essential to perform an accurate staging and dictate the most appropriate treatment strategy. Our aim is to provide a brief, but exhaustive and up-to-date overview of the role of multimodal medical imaging in the management of PM. [ABSTRACT FROM AUTHOR]

Simple Summary: Pleural mesothelioma is a neoplastic disease originating from mesothelium and is commonly associated with asbestos exposure. Despite the progress made, mortality is still high both because of late diagnosis and treatment resistance. With this review, we want to reassess all aspects of this disease from pathogenesis to diagnosis, and the most recent proposed treatment in order to inspire further research to cover unmet needs. Pleural mesothelioma is an aggressive disease with diffuse nature, low median survival, and prolonged latency presenting difficulty in prognosis, diagnosis, and treatment. Here, we review all these aspects to underline the progress being made in its investigation and to emphasize how much work remains to be carried out to improve prognosis and treatment. [ABSTRACT FROM AUTHOR]

Methods: Human Vδ2 T cells were expanded from peripheral blood mononuclear cells using Tetrakis‐pivaloyloxymethyl 2‐(thiazole‐2‐ylamino) ethylidene‐1,1‐bisphosphonate (PTA) plus IL-2 for 13 days, before used to test for cytotoxicity against mesothelioma cell lines. Mesothelioma-bearing mice was established by Intrapleural administration of mesothelioma cell lines to test for the efficacy of Vδ2 T cells plus anti-PD-1 antibody combination treatment. Pyroptosis was evaluated by cell morphology, western blot analysis, and ELISA experiments. Flow cytometry was used to examine expression of BTN2A1, BTN3A1, PD-L1, PD-L2 on mesothelioma cell lines. Immunofluorescence staining was performed to detect Vδ2 T cells post adoptive transfer and characteristics of pyroptosis in ex vivo mesothelioma tissue sections. Results: Indeed, our data demonstrated that Vδ2 T cells killing mesothelioma can be enhanced by anti-PD-1 antibody in vitro, especially for high PD-1 expressing cells, and in vivo in the intrapleural mesothelioma mice model established by us. Adoptive transfer of Vδ2 T cells into these mice leads to tumor regression by 30-40% compared to control. Immunofluorescence of the tumor section confirmed infiltration of Vδ2 T cells into the tumor, especially to cells with BTN2A1 expression (a Vδ2 T cell activating molecule) despite PD-L1 co-localization. Interestingly, these cells co-expressed cleaved gasdermin D, suggesting that pyroptosis was induced by Vδ2 T cells. This was verified by Vδ2 T/mesothelioma co-culture experiments demonstrating membrane ballooning morphology, increased cleaved caspase-3 and gasdermin E, and upregulated IL-1β and IL-18. Discussion: Vδ2 T cells plus anti-PD1 exhibited cytotoxicity against mesothelioma in vivo. However, we found no advantage for anti-PD-1 against PD-1 high expressing Vδ2 T cells in promoting pyroptosis. Taken together, our work demonstrated that Vδ2 T cells combined with anti-PD-1 antibody can be developed as a potential combination immunotherapy for mesothelioma. [ABSTRACT FROM AUTHOR]

Stem cells are undifferentiated cells presenting extensive self-renewal features and the ability to differentiate "in vitro" and "in vivo" into a range of lineage cells, like chondrogenic, osteogenic and adipogenic lineages when cultured in specific inducing media. Two major domains of clinical applications of stem cells in thoracic surgery have been investigated: regenerative medicine, which is a section of translational research in tissue engineering focusing on the replacement, renewal or regeneration of cells, tissues and organs to re-establish damaged physiologic functions; drug loading and delivery, representing a new branch proposing stem cells as carriers to provide selected districts with anti-cancer agents for targeted treatments. [ABSTRACT FROM AUTHOR]

Simple Summary: Pleural effusions are common clinical manifestations of pleural mesothelioma (PM) and often constitute the only available biological material for diagnosis. However, the cytological diagnosis of PM can be challenging. Over the years, ancillary tests, mainly based on the analysis of single biomarkers, have been developed to differentiate malignant from benign effusions, but their sensitivity is limited. In this study, we validated, on a consecutive series, a previously defined 117-gene expression panel as a diagnostic tool for the cytological diagnosis of PM. This gene panel proved to be useful not only in the differential diagnosis of PM and mesothelial hyperplasia but also in the discrimination of the two most common PM subtypes (epithelioid and biphasic) on cytology. Once the malignancy is assessed, the PM subtype definition strongly impacts therapy and prognosis. In this context, the 117-gene panel could be a powerful diagnostic tool to improve the clinical management of PM patients. Cytological diagnosis of pleural mesothelioma (PM) is controversial, even using ancillary markers (BAP1, MTAP and CDKN2A). Here, we aimed to prospectively validate a previously developed 117-gene expression panel for the differential cytological diagnosis of epithelioid, biphasic PM and mesothelial hyperplasia. Seventy-seven pleural effusions were classified using the 117-gene expression levels (NanoString system). Sixty-eight cases were also screened for ancillary markers. The performance of both gene panel and ancillary markers was evaluated using ROC metrics. A score using the top consistently deregulated genes between epithelioid and biphasic PM was built to subtype malignant effusions. The panel alone reached a diagnostic accuracy (0.89) comparable to the best marker combination (BAP1 plus MTAP: 0.88). Ancillary tests missed 8 PMs, 7 of which were correctly classified by the panel. The score built by averaging the expression levels of MSLN, CLDN15 and CFB showed an accuracy of 0.80 in subtyping epithelioid and biphasic effusions. The 117-gene panel is effective for PM cytological diagnosis of epithelioid and biphasic PM. This tool can be complementary to ancillary markers, reducing invasive procedures and allowing an earlier diagnosis. Finally, the possibility to subtype PM on effusions strengthens the panel's role in PM diagnosis and management. [ABSTRACT FROM AUTHOR]

Pleural mesothelioma is a devastating malignancy primarily associated with asbestos exposure. However, emerging evidence suggests that exposure to fluoro-edenite fibers, a naturally occurring mineral fiber, can also lead to the development of pleural mesothelioma. In this study, based on the hypothesis that pituitary adenylate cyclase-activating polypeptide (PACAP) and PACAP-preferring receptor (PAC1R) expressions could be dysregulated in pleural mesothelioma samples and that they could potentially act as diagnostic or prognostic biomarkers, we aimed to investigate the immunohistochemical expression of PACAP and PAC1R in pleural biopsies from patients with pleural mesothelioma exposed to fluoro-edenite fibers. A total of 12 patients were included in this study, and their biopsies were processed for immunohistochemical analysis to evaluate the expression of PACAP and its receptor. The study revealed a correlation between the overexpression of PACAP and PAC1R and shorter overall survival in patients with malignant mesothelioma. These findings suggest that PACAP and PAC1R expression levels could serve as potential prognostic biomarkers for malignant mesothelioma. Furthermore, the immunohistochemical analysis of PACAP and PAC1R may provide valuable information for clinicians to guide therapeutic decisions and identify patients with poorer prognosis.

The role of immunotherapy in the multimodal treatment for pleural mesothelioma (PM) is still under investigation, particularly in the preoperative setting. Pathological complete response (pCR) has been previously described after chemotherapy and immunotherapy; however, there is no prior experience reported with immunotherapy alone before surgery. We report the case of a 58-year-old male with biphasic PM treated with immunotherapy, resulting in a major clinical partial response. Following a multidisciplinary evaluation between thoracic surgeons, medical oncologists, pathologists, radiologists and radiation oncologists, the patient underwent surgery with radical intent through a right extended pleurectomy/decortication (eP/D). Histopathological examination of the specimen confirmed a pathological Complete Response (pCR). This case supports the feasibility and potential efficacy of combining preoperative immunotherapy with surgery in the management of advanced PM.

Abstract Background Pleurectomy and decortication (PD) in malignant pleural mesothelioma has a high morbidity mostly associated with aspiration pneumonia (PNA), deep vein thrombosis (DVT), and foreign catheter sepsis. We instituted four strategies to reduce these complications and report our experience. Methods This was a retrospective review of patients who underwent PD at the University of Pennsylvania between 2015 and 2022. Our patients underwent standard of care PD in addition to tracheostomy and gastrostomy/jejunostomy tube with therapeutic anticoagulation (AC) leading up to surgery. Measured outcomes were postoperative PNA, DVT, and sepsis. The predicted risk of those same outcomes had patients not undergone the interventions was calculated based on the American College of Surgeons (ACS) surgical risk calculator (SRC). A McNemar's test was used to determine whether the risk of having PNA, DVT and sepsis differed between the two subgroups. Results Fifty‐five patients were included in the study. The mean age was 70 years (SD 6.2) with a mean of 21 (SD 19) pack‐years of smoking. PNA, DVT, and catheter‐related sepsis occurred in 12, four, and seven patients, respectively. Upon using the ACS SRC prediction model of the nonintervention group, PNA, DVT and catheter related sepsis was predicted to occur in 24 (paired data OR 5, 95% CI: 1.4–17.2; McNemar's test p = 0.008), 14 (paired data OR 3.5, 95% CI: 1.15–10.6; McNemar's test p = 0.03), and 17 (paired OR 3, 95% CI: 1.09–8.3; McNemar's test p = 0.04) patients, respectively. Discussion Patients undergoing tracheostomy creation, therapeutic AC at the time of diagnosis, and gastrostomy tube placement had a reduced risk of aspiration PNA, DVT, and catheter sepsis.

Pleural mesothelioma (PM) is a highly aggressive tumor that is caused by asbestos exposure and lacks effective therapeutic regimens. Current procedures for PM diagnosis are invasive and can take a long time to reach a definitive result. Small extracellular vesicles (sEVs) have been identified as important communicators between tumor cells and their microenvironment via their cargo including circular RNAs (circRNAs). CircRNAs are thermodynamically stable, highly conserved, and have been found to be dysregulated in cancer. This study aimed to identify potential biomarkers for PM diagnosis by investigating the expression of specific circRNA gene pattern (hsa_circ_0007386) in cells and sEVs using digital polymerase chain reaction (dPCR). For this reason, 5 PM, 14 non-PM, and one normal mesothelial cell line were cultured. The sEV was isolated from the cells using the gold standard ultracentrifuge method. The RNA was extracted from both cells and sEVs, cDNA was synthesized, and dPCR was run. Results showed that hsa_circ_0007386 was significantly overexpressed in PM cell lines and sEVs compared to non-PM and normal mesothelial cell lines (p < 0.0001). The upregulation of hsa_circ_0007386 in PM highlights its potential as a diagnostic biomarker. This study underscores the importance and potential of circRNAs and sEVs as cancer diagnostic tools.

Abstract Background Pleural mesothelioma (PM) is a relatively rare malignancy with limited treatment options and dismal prognosis. We have previously found elevated FGF18 expression in PM tissue specimens compared with normal mesothelium. The objective of the current study was to further explore the role of FGF18 in PM and evaluate its suitability as a circulating biomarker. Methods FGF18 mRNA expression was analyzed by real‐time PCR in cell lines and in silico in datasets from the Cancer Genome Atlas (TCGA). Cell lines overexpressing FGF18 were generated by retroviral transduction and cell behavior was investigated by clonogenic growth and transwell assays. Plasma was collected from 40 PM patients, six patients with pleural fibrosis, and 40 healthy controls. Circulating FGF18 was measured by ELISA and correlated to clinicopathological parameters. Results FGF18 showed high mRNA expression in PM and PM‐derived cell lines. PM patients with high FGF18 mRNA expression showed a trend toward longer overall survival (OS) in the TCGA dataset. In PM cells with low endogenous FGF18 expression, forced overexpression of FGF18 resulted in reduced growth but increased migration. Surprisingly, despite the high FGF18 mRNA levels observed in PM, circulating FGF18 protein was significantly lower in PM patients and patients with pleural fibrosis than in healthy controls. No significant association of circulating FGF18 with OS or other disease parameters of PM patients was observed. Conclusions FGF18 is not a prognostic biomarker in PM. Its role in PM tumor biology and the clinical significance of decreased plasma FGF18 in PM patients warrant further investigation.

Mesotheliomas are aggressive malignant tumors which can occur most commonly in the pleural space, however can occur in the peritoneum in those with an extensive history of asbestos exposure. Primary peritoneal mesothelioma is relatively rare and is a fatal diagnosis. The prognosis of primary peritoneal mesothelioma is very poor and individuals are at high risk of developing mesothelioma in another cavity within the first year after initial diagnosis. Herein, we present a case of primary peritoneal mesothelioma, presenting as small bowel obstruction.

Abstract Background The efficacy of immune checkpoint inhibitors (ICIs) in pleural mesothelioma has recently been established. The response to ICIs can be predicted by quantitative analysis of cells and their spatial distribution in the tumor microenvironment (TME). However, the detailed composition of the TME in pleural mesothelioma has not been reported. We evaluated the association between the TME and response to ICIs in this cancer. Methods A retrospective analysis of 22 pleural mesothelioma patients treated with nivolumab in different centers was performed using surgical specimens. Four patients had a partial response to nivolumab (response group) and 18 patients had stable or progressive disease (nonresponse group). The number of CD4, CD8, FoxP3, CK, and PD‐L1 positive cells, cell density, and cell‐to‐cell distance were analyzed by multiplex immunofluorescence. Results PD‐L1 expression did not differ significantly between the response and nonresponse groups. The density of total T cells and of CD8+ T cells was significantly higher in the response than in the nonresponse group. CD8+ T cells were more clustered and located closer to tumor cells, whereas regulatory T cells were located further from tumor cells in the response than in the nonresponse group. Conclusions High density and spatial proximity of CD8+ T cells to tumor cells were associated with better response to nivolumab, whereas the proximity of regulatory T cells to tumor cells was associated with worse response, suggesting that the distinct landscape of the TME could be a potential predictor of ICI efficacy in pleural mesothelioma.

Pleural mesothelioma (PM) is an aggressive and rare disease, characterized by a very poor prognosis. For almost two decades, the world standard treatment regimen for unresectable PM has consisted of a platinum-based drug plus pemetrexed, leading to an overall survival of approximately 12 months. The dramatic therapeutic scenario of PM has recently changed with the entry into the clinic of immune checkpoint inhibition, which has proven to be an effective approach to improve the survival of PM patients. The aim of the present review is to provide a comprehensive overview of the most promising immunotherapeutic-based strategies currently under investigation for advanced PM.

A 71-year-old male visited a hospital with a chief complaint of exertional dyspnea. A chest CT revealed multiple nodular lesions on the parietal pleura. Thoracoscopic pleural biopsy was performed resulting in a diagnosis of pleural mesothelioma with epithelioid type. When chemotherapy was initially initiated, his serum level of Krebs von den Lungen-6 (KL-6) was high. However, once chemotherapy was started, the serum KL-6 level gradually decreased with tumor shrinkage. Immunohistochemical staining revealed the expression of KL-6 from the tumor cells. This is the first report of KL-6 production directly from tumor cells in epithelial-type pleural mesothelioma.