Pleural mesothelioma (PM) is an aggressive cancer caused by asbestos exposure, with limited treatment options and poor prognosis, highlighting the need for more effective therapies. Combining immune checkpoint blockade with anti-angiogenic therapy has shown potential in other cancers. Our study investigated the combined inhibition of PD-L1 and VEGFR2 in a mouse model of PM. Using C57BL/6 mice with subcutaneous AE17 mesothelioma tumors, we assessed the effects of anti-PD-L1 therapy with induction, concomitant, or consolidation anti-VEGFR2 treatment. Mice received intraperitoneal doses every three days for three treatments. Tumor growth, survival, tumor-infiltrating immune cells and intra-tumoral vasculature were analyzed. Results demonstrated that combining anti-PD-L1 with induction or concomitant anti-VEGFR2 significantly delayed tumor growth, improved survival, and promoted vascular maturation. Flow cytometry suggested T cell exhaustion in monotherapy groups, while no significant changes were seen with concomitant treatment. Depleting CD4+ T cells reversed the positive effects of concomitant treatment. These findings suggest that dual inhibition of PD-L1 and VEGFR2 is a promising therapeutic approach for PM, with CD4+ T cells playing a critical role in the immune response. This dual targeting of immune checkpoints and angiogenesis offers a potential new avenue for improving outcomes in PM treatment and warrants further clinical exploration.

Pleural mesothelioma (PM) is an aggressive cancer originating from the mesothelial lining of the pleura, with a rising global incidence since the mid-20th century due to asbestos and erionite exposure. PM accounts for 80-90% of all mesothelioma cases and is histologically classified into three subtypes-epithelioid, sarcomatoid, and biphasic- with epithelioid carrying the most favorable prognosis. Despite advances in surgery, chemotherapy, radiotherapy, and immunotherapy, PM prognosis remains poor, necessitating more effective, multimodal strategies. Hyperthermic intrathoracic chemoperfusion (HITHOC) has emerged as a promising adjunct to cytoreductive surgery by delivering heated chemotherapy directly to the pleural cavity, potentially improving survival-especially in patients with epithelioid PM. Combining HITHOC with post-surgical immunotherapy represents a novel approach to enhancing both local and systemic anti-tumor responses and targeting microscopic disease and distant metastases. This review explores surgical outcomes after surgery for PM, the therapeutic synergy of HITHOC and immunotherapy, ongoing clinical trials evaluating this multimodal strategy, and its implications for future patient care.

Pleural mesothelioma (PM) is a locally aggressive tumor associated with asbestos exposure. Despite legislative efforts to regulate asbestos use, its incidence continues to rise in some parts of the world. Chemotherapy and immunotherapy have improved survival in PM patients, but overall survival remains poor. Molecular analysis of PM patients has shown that most alterations occur in tumor suppressor genes, with BAP1 being the most frequently affected. Patients with germline BAP1 mutations have been reported to have a better prognosis, but this is not observed in those with somatic mutations. Interest in developing drugs targeting patients with BAP1 loss has led to several phase II studies in recent years. Unfortunately, initial results have not been very promising. In this review, we conclude that, at this time, with the contradictory results from studies and the limited number of patients evaluated, BAP1, the most commonly altered gene in PM, is not yet suitable for use in clinical practice as a prognostic or predictive factor. Future studies are needed to establish the prognostic or predictive value of BAP1.

The currently approved first-line treatments for diffuse pleural mesothelioma (DPM) are ipilimumab-nivolumab or platinum-pemetrexed. The addition of bevacizumab to chemotherapy improves overall survival (OS). While single-agent immunotherapy or chemotherapy-immunotherapy combinations are superior to chemotherapy monotherapy, there is a potential for synergistic triple combination of chemotherapy, bevacizumab, and immunotherapy.

BEAT-meso is an international, open-label, 1 : 1 randomised, phase III trial, with stratification factors histology and stage aiming to determine the efficacy and safety of adding atezolizumab [1200 mg, 3-week cycle (q3w) until progression] to bevacizumab (15 mg/kg, q3w until progression) and standard chemotherapy (4-6 cycles of carboplatin area under the curve with pemetrexed 500 mg/m2, q3w; ABC versus BC) as first-line treatment for advanced DPM. The primary endpoint is OS in all randomised patients, aiming for a relative benefit of 29% [hazard ratio (HR) 0.708]. Secondary endpoints include progression-free survival (PFS), adverse events (AEs), and symptom-specific and global quality of life (QoL).

Between 30 April 2019 and 7 March 2022, 400 patients were randomised, 200 per arm. Sixty-five percent had an Eastern Cooperative Oncology Group (ECOG) performance status of 1 and 78% had epithelioid histology. At a median follow-up of 35 months (data cut-off 1 September 2023), the median OS was 20.5 months for ABC versus 18.1 months for BC [HR 0.84, 95% confidence interval (CI) 0.66-1.06, P = 0.14]. Median PFS was significantly longer for ABC than for BC (9.2 versus 7.6 months) (HR 0.72, 95% CI 0.59-0.89, P = 0.0021). Histology showed significant treatment interaction for both PFS and OS, with an OS HR of 0.51 (95% CI 0.32-0.80) for non-epithelioid and 1.01 (95% CI 0.77-1.32) for epithelioid (interaction P = 0.012). Grade ≥3 treatment-related AEs were reported in 55% of patients in ABC and 47% in BC; QoL was maintained with ABC with no clinically meaningful differences from BC.

The significant benefit in median PFS for ABC found in this study translated into a numerical but not significant increase in median OS. Thus, the primary endpoint was not met. In the pre-specified analysis by histology, superior OS and PFS were found for ABC in non-epithelioid cases.

Pleural mesothelioma is an incurable cancer with unmet diagnostic and therapeutic needs. Due to its pattern of local spread, few patients are candidates for multimodality treatment and thus most patients only receive systemic therapy. Chemotherapy (pemetrexed plus platinum) was standard of care until the recent addition of immunotherapy (nivolumab plus ipilimumab, or pembrolizumab plus chemotherapy) as further first-line option. Physicians treating pleural mesothelioma should be aware of another option with Tumor Treating Fields (TTFields) therapy, a locoregionally-applied therapy utilizing electric fields generated by a portable medical device, and delivered to the tumor by skin-placed arrays. TTFields therapy delivered to the thorax using the NovoTTF- 100L device concomitant with pemetrexed and platinum agent is approved for unresectable pleural mesothelioma in the US, and received Conformité Européenne certification in Europe, based on results from the phase 2 STELLAR study (EF- 23; NCT02397928), where TTFields-related toxicity was limited to mild-to-moderate reversible skin reactions. Overall survival in the STELLAR study with TTFields therapy was 18.2 months, with further post-hoc analysis showing extended survival in patients with epithelioid histology. Within the evolving landscape of systemic treatments, TTFields therapy represents a novel and clinically versatile therapeutic option in the battle against pleural mesothelioma without introducing additional toxicities other than mild-to-moderate skin irritation. While promising, additional research is needed to optimize clinical application of TTFields therapy in patients with pleural mesothelioma, such as identifying the molecular determinants of therapy efficacy, and further investigation into the safe and effective delivery of TTFields therapy together with systemic agents, including immunotherapies.

Mesothelioma is characterized by the inactivation of tumor suppressor genes, with frequent mutations in neurofibromin 2 (NF2), BRCA1-associated protein 1 (BAP1), and cyclin-dependent kinase inhibitor 2A (CDKN2A). These mutations lead to disruptions in the Hippo signaling pathway and histone methylation, thereby promoting tumor growth. NF2 mutations result in Merlin deficiency, leading to uncontrolled cell proliferation, whereas BAP1 mutations impair chromatin remodeling and hinder DNA damage repair. Emerging molecular targets in mesothelioma include mesothelin (MSLN), oxytocin receptor (OXTR), protein arginine methyltransferase (PRMT5), and carbohydrate sulfotransferase 4 (CHST4). MSLN-based therapies, such as antibody-drug conjugates and immunotoxins, have shown efficacy in clinical trials. OXTR, upregulated in mesothelioma, is correlated with poor prognosis and represents a novel therapeutic target. PRMT5 inhibition is being explored in tumors with MTAP deletions, commonly co-occurring with CDKN2A loss. CHST4 expression is associated with improved prognosis, potentially influencing tumor immunity. Immune checkpoint inhibitors targeting PD-1/PD-L1 have shown promise in some cases; however, resistance mechanisms remain a challenge. Advances in multi-omics approaches have improved our understanding of mesothelioma pathogenesis. Future research will aim to identify novel therapeutic targets and personalized treatment strategies, particularly in the context of epigenetic therapy and combination immunotherapy.

We aimed to evaluate the efficacy (progression-free survival [PFS]) of bintrafusp alfa in patients with pleural mesothelioma (PM) who had progressed to platinum-based chemotherapy and had not previously received immunotherapy. We also assessed overall survival [OS], objective response rate [ORR], and safety and tolerability.

This open-label, non-randomised, multicentre, phase II, single-arm clinical trial was carried out by the Spanish Lung Cancer Group between October 2021 and March 2023 in 15 Spanish hospitals. We included patients ≥ 18 years old, with an ECOG PS of 0 or 1, with a histologically confirmed unresectable or metastatic PM, and with a life expectancy of at least three months.

46 patients were included in the analysis. Most patients were men (78.3 %), the mean age was 70.0 years (SD, 9.5), and most presented epithelioid PM (84.8 %). The median PFS was 1.9 months (95 % CI, 1.7-3.2 months), the median duration of bintrafusp alfa response was 3.8 months, and the ORR was 6.5 % (95 % CI, 2.1-18.8 %). The median OS was 11.9 months (95 % CI, 5.8-15.7 months). Grade 3 or higher adverse events were observed in 34.8 % of patients and no grade 5 adverse event was reported.

Bintrafusp alfa did not reach the expected efficacy in patients with advanced PM. We did not identify new safety signals with bintrafusp alfa, and no case of bleeding was reported. Our study suggested that bintrafusp alfa has limited efficacy in PM, as reported in other solid tumours.

The prognosis of pleural mesothelioma (PM) is poor and conventional chemotherapy regimens have shown limited antitumor activity. Recent use of immune checkpoint inhibitors (ICIs) has shown promise, with CheckMate-743 trial establishing nivolumab plus ipilimumab as first line treatment in unresectable PM. Nevertheless, real-world applicability as well as differential benefit of immunotherapy according to histologic are areas of active debate. In addition, increased incidence of immune-related adverse events (IRAEs) and high discontinuation rates highlight the need for careful patient selection. While ICIs represent a significant advancement in PM treatment, ongoing research is necessary to refine their use, potentially through biomarker-informed approaches, and manage associated toxicities. This review highlights the evolving landscape of immunotherapy and associated controversies in PM.

Activation of the receptor tyrosine kinases (RTKs) EGFR, MET, and AXL has been described in subsets of mesothelioma, suggesting that tyrosine kinases (TKs) might represent therapeutic targets in this chemotherapy resistant and highly lethal cancer. In the present study, activated TKs were identified in mesothelioma cells by phosphotyrosine immunoaffinity purification and tandem mass spectrometry, and biological functions were evaluated. The results showed that non-RTK activated-CDC42 kinase 1 (ACK1) was highly expressed and activated in 8 of 9 mesothelioma cell lines and 15 of 18 mesothelioma biopsies, but not in normal mesothelial cells. This ACK1 activation was in turn driven by the collective activation of EGFR, MET, and AXL. ACK1 inactivation by either a small molecule inhibitor (AIM-100) or RNAi had anti-proliferative, anti-migration, and pro-apoptotic effects in four mesothelioma cultures due to G1 arrest and xenograft model. These responses resulted from inhibition of the PI3K/AKT/mTOR and RAF/MAPK pathways, inhibition of cyclin A and cyclin D1, and up-regulation of cell cycle checkpoints TP53, CDKN1A (p21), and CDKN1B (p27). Combination treatment with AIM-100, cisplatin (CIS), and pemetrexed (PEM) had greater impact on mesothelioma response (apoptosis, proliferation arrest, and inhibition of migration and invasion) compared to administering only one or two of these agents. The current findings identify ACK1 as a single downstream target that can be inhibited to stymie these multiple receptor tyrosine kinase (EGFR, MET, and AXL) oncogenic programs in mesothelioma, and highlight that ACK1 inhibition, potentially in combination with PEM and CIS, warrants evaluation as a therapeutic strategy in mesothelioma.

There is a well-established relationship between cancer and venous thromboembolism (VTE). Thrombosis in cancer is of major concern as it is a leading cause of mortality, impairs quality of life, and can adversely impact treatment protocols. Despite the role of thrombosis in cancer, no singular source consolidates data on VTE incidence by cancer type worldwide. This systematic review aims to report the incidence of VTE by type of solid cancer worldwide. The current analysis used three databases (MEDLINE, Embase, Cochrane Library) to identify relevant articles. All articles were written in English, assessed solid cancers in adults (≥18; males, females), and reported the incidence of VTE, or information that could be used to calculate incidence. After completing the search and removing duplicates, 3077 articles were assessed. All articles were screened by title and abstract, followed by a full-text review. A total of 124 articles were included in the final evaluation. The cumulative reported incidence of VTE across all types of solid cancer was 9.74 %. The highest reported incidence of VTE was in gastroesophageal cancer (15.43 %), whereas the lowest incidence was in prostate cancer (1.58 %). The two most reported cancers by country within our study cohort were colorectal (n = 23) and lung cancer (n = 23). The reported incidence of VTE in colorectal cancer was highest in Mexico (22.10 %), and lung cancer was highest in Canada (32.91 %). In conclusion, gathering data on global VTE rates in solid cancer identified high-risk cancers and highlighted under-investigated areas that require attention to reduce VTE occurrence in cancer patients.

Primary diffuse malignant peritoneal mesothelioma (MPEM) is a malignant disease without standard treatments recommended. Recently, immunotherapy has revolutionized the field of tumor therapy. According to current clinical evidence, advanced MPEM may gain potential clinical benefits from immune checkpoint inhibitors. The present study reported a 61-year-old female patient with persistent low fever as the initial symptom, who was eventually diagnosed with MPEM. This patient obtained significant clinical benefits from pembrolizumab, with disappearance of symptoms, a lasting stable disease response with a progression-free survival of 10.0 months and a long overall survival of 26.2 months. The application of pembrolizumab was explored as an emerging effective treatment for patients with MPEM. In addition, the clinical characteristics, diagnosis, treatment, pathogenesis and target regulation in MPEM were discussed and previous studies were reviewed. Further evidence is needed from future extensive clinical trials.

Background and Objectives: This study aimed to evaluate the effectiveness of immunotherapy compared to chemotherapy across different treatment lines in patients with pleural mesothelioma. It also sought to identify factors influencing the success of immunotherapy, such as histological subtype, PD-L1 expression, type of asbestos exposure, and metastatic status. Materials and Methods: A retrospective analysis was conducted with 60 patients diagnosed with pleural mesothelioma. Data on age, gender, histological subtype, and asbestos exposure were collected for all patients and PD-L1 expression was assessed in a subset of patients. Patients received either chemotherapy or immunotherapy as first-, second-, and third-line treatments, and progression-free survival (PFS) and treatment responses were evaluated. Results: Among the 60 patients, 35 (58.3%) were male and the median age was 59 years. The majority (71.7%) had epithelioid histology and 28.3% had distant metastases. Asbestos exposure was documented in 65% of the cases. PD-L1 expression of ≥1% was found in 13 of 17 patients tested. First-line treatments included immunotherapy for 11 patients and chemotherapy for the others, with immunotherapy achieving median PFS of 9 months versus 6 months for chemotherapy, although the difference was not statistically significant. In third-line treatments, immunotherapy significantly outperformed chemotherapy with median PFS of 6 months compared to 3 months (p = 0.048). Absence of metastasis and prior asbestos exposure in an endemic region were linked to better immunotherapy outcomes. Conclusion: Immunotherapy shows increased efficacy in later treatment lines for pleural mesothelioma, especially for patients without metastases or with prior endemic asbestos exposure. Tailored therapeutic strategies should be further explored in prospective studies.

To provide evidence-based recommendations to practicing physicians and others on the management of pleural mesothelioma (PM).

ASCO convened an Expert Panel of medical oncology, thoracic surgery, radiation oncology, pathology, cancer genetics, and advocacy experts to conduct an updated literature search, which included systematic reviews, meta-analyses, randomized controlled trials, and prospective and retrospective comparative observational studies published from 2016 through 2024. Outcomes of interest included survival, disease-free or recurrence-free survival, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations.

The literature search identified 110 additional relevant studies to inform the evidence base for this guideline.

Evidence-based recommendations were developed for surgical cytoreduction, immunotherapy, chemotherapy, pathology, and germline testing in patients with PM.Additional information is available at www.asco.org/thoracic-cancer-guidelines.

We describe two patients who experienced serious multiple immune-related adverse events (irAEs), treatment interruption, and steroid administration. Despite these challenges, they achieved a remarkable antitumor effect beyond the expected. Various carcinomas demonstrated a possible correlation between the antitumor effect of immune checkpoint inhibitors and the intensity of irAEs, but few studies report on malignant pleural mesothelioma (MPM). Our two cases exhibited much stronger irAEs than usual. These two cases still demonstrated a complete response (CR) or near CR partial response, indicating a correlation between irAEs and the antitumor effect in MPM.

Malignant pleural mesothelioma (MPM) is a rare but aggressive cancer characterized by its unique growth patterns, presenting substantial diagnostic challenges. With the shift toward immunotherapy for MPM treatment, assessing therapeutic responses has become increasingly complex. Recent studies indicate that FDG PET/CT may provide more effective response criteria compared to traditional CT-based methods. This review emphasizes the important role of PET/CT in offering deep insights into the disease state and monitoring treatment responses. It also addresses the challenges associated with current imaging criteria, particularly the nonspecificity of FDG uptake that may represent inflammatory responses following treatments or procedures rather than tumor activity. Furthermore, the review discusses the potential of emerging radiopharmaceuticals and advanced volumetric assessments, discussing their implications for improving diagnostic accuracy and treatment evaluation in MPM.

Malignant mesothelioma (MM) is a rare but aggressive cancer linked to asbestos exposure and characterized by advanced‑stage disease at presentation. Despite advances in treatment, prognosis remains abysmal, highlighting the imperative for the development of novel biomarkers and treatment approaches. Telomere biology plays a pivotal role in the tumorigenic process and has emerged as a key area in oncology research. Short telomeres have been associated with genomic instability, and substantially shorter telomere length (TL) has been identified in MM, showcasing the potential of TL in risk assessment, early detection, and disease progression monitoring. MM predominantly maintains TL through telomerase activity (TA), which in research has been identified in >90% of MM cases, underscoring the potential of TA as a biomarker in MM. Telomerase reverse transcriptase (TERT) polymorphisms may serve as valuable biomarkers, with research identifying associations between single nucleotide polymorphisms (SNPs) and the risk and prognosis of MM. Additionally, TERT promoter mutations have been associated with poor prognosis and advanced‑stage disease, with the non‑canonical functions of TERT hypothesized to contribute to the development of MM. TERT promoter mutations occur in ~12% of MM cases; C228T, C250T and A161C are the most common, while the distribution and frequency differ depending on histological subtype. Research reveals the promise of the various approaches therapeutically targeting telomerase, with favorable results in pre‑clinical models and inconclusive findings in clinical trials. The present review examines the role of telomere biology in MM and its implications in diagnosis, prognosis, and therapy.

Pleural mesothelioma (PM) is a rare and highly aggressive malignancy originating from the pleural lining, with a median overall survival of merely 1 year. This cancer primarily arises from mesothelial cells following exposure to carcinogenic, biopersistent mineral fibers, particularly asbestos. The histological subtypes of mesothelioma are epithelioid (approximately 60%), sarcomatoid (20%), and biphasic (20%), exhibiting epithelioid and sarcomatoid characteristics. Classification is important for prognosis and guides the therapeutic strategy. Due to the typical late presentation, most patients with PM are ineligible for localized treatments such as surgery or radiotherapy. Systemic therapy, including cytotoxic chemotherapy, targeted therapies, and immunotherapy, is thus critical for managing advanced PM. For unresectable PM, decisions regarding systemic treatment are guided by patient suitability and histological characteristics. First-line therapies for advanced PM currently include the cisplatin-pemetrexed combination and the nivolumab-ipilimumab regimen. Historically, cisplatin-pemetrexed has been administered as first-line treatment, though recent advancements have introduced new therapies that significantly prolong patient survival. Innovative approaches combining immunotherapy and chemotherapy offer promising avenues for further improvement. Future treatment strategies should incorporate novel paradigms, such as combination chemo-immunotherapy, targeted agents, and potential cellular therapies, alongside companion biomarkers tailored to the histologic and molecular diversity of mesothelioma. This review explores the latest advancements in drug therapy for PM and provides an overview of current systemic treatment options.

Malignant pleural mesothelioma (MPM) is the most frequent aggressive tumor affecting the pleura, accounting for over 38,000 deaths worldwide. It originates from the mesothelial cells and is mostly associated to asbestos exposure. Depending on the extent of the disease, the management of MPM varies from surgical intervention to a combination of systemic chemotherapy, immunotherapy, and radiation therapy. Major International scientific societies provide continuous updates on proper management of the disease, including recommendations on the optimal imaging algorithms, which are crucial for determining effective treatment options and optimizing clinical outcomes. However, despite the continuous efforts to improve patients' prognosis, median overall survival remains poor, ranging from 8 to 14 months. And even in case of initial response to treatment, local or distant recurrences represent almost a certainty, requiring appropriate imaging for the assessment of tumor sites. The aim of the present article is to illustrate the current status of imaging for staging and restaging of MPM, not forgetting most recent novelties in the diagnostic work-up of the disease.

Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy with limited therapeutic options. To improve patients management and treatment, more precise stratification strategies are needed. This study aimed to characterize the phenogenomic landscapes of MPM and to understand their influence on patients clinical outcomes.

We conducted a phenogenomic analysis on 22 MPM patients using two high throughput approaches: imaging mass cytometry (IMC) with whole exome sequencing (WES). Resulting profiles were addressed for their clinical relevance to predict patients prognosis.

IMC revealed a highly heterogeneous tumor microenvironment (TME) with distinct tumor cell subpopulations. Notably, we identified a novel sarcomatoid-like cellular cluster associated with poor prognosis. The TME was also infiltrated with immune cells including macrophages and CD4+ T lymphocytes, that were more abundant in patients with favorable clinical outcomes. WES identified a complex genomic landscape with limited prognostic value for individual genetic alterations. However, tumor mutational burden (TMB) emerged as a potential predictive biomarker, inversely correlating with immune cell infiltration, particularly macrophages and CD4+ T lymphocytes.

Our findings underscore the intricate interplay between the tumor genome, TME composition, and clinical outcomes in MPM. These data support the potential of integrating genomic and TME profiling to develop more precise patient stratification strategies and potentially optimize therapeutic approaches, including immunotherapy.

Mesothelioma is a highly malignant condition arising from the pleura and peritoneum that is closely related to asbestos exposure. The prognosis for this condition has traditionally been poor due to the difficulty physicians have faced in diagnosing and treating this disease, even in its early phase. Fortunately, recent advances in both the molecular understanding of the development of this disease and innovative and novel treatment modalities have accelerated the discovery of new ways to treat mesothelioma. In this review, we first summarize the mechanism of mesothelioma pathophysiology and then relate it to emerging treatment modalities. These include immunotherapy or immune checkpoint inhibitors (ICIs), molecular targeted therapies, and cell-based therapies (such as CAR-T cells or dendritic cells). The scientific basis for the utilization of these treatment modalities, alongside the current clinical evidence for each option, will be explored in detail later on. The hope is that this review can elucidate how these emerging therapeutic options work clinically to help accelerate further developments in novel mesothelioma treatment modalities.

Malignant peritoneal mesothelioma (MPM) is a rare but aggressive cancer. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) was the preferred choice for selected patients. The purpose of this study was to thoroughly examine the impact of the combined treatment and the prognostic variables, particularly the neutrophil-to-lymphocyte ratio (NLR).

Characteristics of MPM patients who underwent CRS combined HIPEC treatment, followed by adjuvant chemotherapy were retrospectively collected. The univariable analysis was performed to identify the decisive influential factor. Using Kaplan-Meier analysis, the cumulative probability of survival was determined. Using Univariate Cox analysis, the prognostic factors-particularly NLR-and its correlation with survival were assessed. In the multivariate Cox proportional hazards model, predictive factors that demonstrated significance in univariate analysis were used. The degree of connection between predictors and survival was evaluated through the use of hazard ratios (HRs) and 95% confidence intervals (95% CIs).

A total of 64 patients were enrolled in this study. The 1, 3, 5 years survival rates were 70.3%, 65.6%, 59.4%, respectively. According to multivariate Cox analysis, patients' survival was found to be substantially associated with post-operative NLR (HR 0.180, 0.067-0.531), Ki-67 (HR 0.184, 0.024-0.817), post-operative neutrophil count (HR 0.228, 0.075-0.696), and bidirectional pathological type (HR, 0.375, 0.146-0.964).

NLR is associated with the patients' prognosis after CRS combined HIPEC treatment.

The incidence of pleural mesothelioma (PM) is slightly increasing, with 2417 new cases/year worldwide [...].

In unresectable pleural mesothelioma, pemetrexed+cisplatin as first line is considered the standard of care, but novel treatments have been recently proposed.

Our objective was to compare, albeit indirectly, the results of randomized controlled trials on overall survival (OS). The IPDfromKM method was employed for reconstruct individual patient data (IPD) from the graphs of Kaplan-Meier curves. Cox statistics was run to estimate hazard ratios (HRs).

After a literature search on Medline (via PubMed) and Scopus databases, six randomized controlled trials were identified in which five new treatments (nivolumab plus ipilimumab, bevacizumab plus pemetrexed plus cisplatin, chemotherapy plus pembrolizumab, ONCOS-102 plus pemetrexed plus cisplatin/carboplatin and cediranib plus pemetrexed+cisplatin with maintenance with cediranib) were evaluated. In five trials, pemetrexed plus cisplatin was the standard of care given to the control arms. Nivolumab plus ipilimumab, bevacizumab plus pemetrexed plus cisplatin and chemotherapy plus pembrolizumab showed a significantly better OS compared with controls. ONCOS-102 plus pemetrexed plus cisplatin/carboplatin did not significantly improve OS. In contrast, OS worsened with cisplatin alone and with cediranib plus pemetrexed+cisplatin with maintenance with cediranib.

Our analysis indicates that, in patients with unresectable pleural mesothelioma, three of the five novel treatments provided a significant survival benefit compared with the standard of care. Further research is needed to confirm the OS benefit found in our analysis with some treatments, whereas cisplatin alone and cediranib plus pemetrexed+cisplatin with maintenance with cediranib do not seem to deserve further research.

The goal of the American Association of Bronchology and Interventional Pulmonology Essential Knowledge in Interventional Pulmonology Series is to provide clinicians with concise, up-to-date reviews of important topics in the field of interventional pulmonology. This 3-year alternating rotation of primary topics will start with a focus on selected topics in malignant pleural disease. In this article, we update the reader on malignant pleural effusion in 3 parts: part 1-diagnosis, focusing on imaging and fluid biomarkers; part 2-management, with review of multimodal approaches, cost considerations, and evolving targeted therapies; and part 3-pleural mesothelioma. These reviews complement the Essential Knowledge in Interventional Pulmonology Lecture Series presented at the 2023 AABIP Annual Conference, available for viewing on the AABIP website (https://aabip.memberclicks.net/essential-knowledge-in-interventional-pulmonology-series).

Malignant pleural mesothelioma (MPM) is an aggressive cancer with long latency and poor prognosis. The real-world treatment patterns and humanistic burden of MPM in an international cohort of patients were recently published. Spanish data are currently lacking and are reported here.

Data were collected from three sources: physician-abstracted demographic, clinical and treatment characteristics of patients with MPM; patient-completed questionnaires on treatment satisfaction, symptoms, caregiver use, and impact of the disease; and caregiver-completed questionnaire reporting their activity and its impact on their daily life.

The 241 patients in Spain were primarily elderly (median age: 67 years), male, retired/unemployed/on long-term sick leave, and diagnosed at stage IV with unresectable disease. Exposure to asbestos was detected (54%, 101/188). First-line treatment (1L) consisted primarily of doublet chemotherapy (86%, 207/241). Of 102 patients who completed 1L at data abstraction, 67 were receiving maintenance therapy, most commonly singlet chemotherapy with pemetrexed. Best supportive care was given to 29 patients, primarily after 1L (86.2%, 25/29). Symptom burden was high and health-related quality of life was poor and declined with progression: mean (SD) EQ-5D score and EQ-5D visual analogue scale score were 0.615 (0.285) and 60.8 (17.1) in 1L and 0.497 (0.370) and 56.1 (19.5) in second line. Overall, 67% of patients (162/241) required daily assistance from their caregiver, who reported an impact on their psychological well-being.

Patients with MPM in Spain were overall treated according to treatment guidelines at the time. Nevertheless, a considerable burden of disease was reported by patients and caregivers.

Pleural mesothelioma is a rare neoplastic disease with aggressive features. Patient survival is poor due to the lack of early symptoms and the absence of effective therapeutic strategies. The development of pleural mesothelioma is mainly associated to asbestos exposure and related chronic inflammation. From a molecular-based perspective, this disease is a heterogeneous tumor lacking actionable alterations. The median overall survival of patients affected by this tumor does not exceed 16 months from diagnosis. Molecular and biochemical approaches have shown that this disease is characterized by resistance to drug-induced apoptosis associated with the activation of cell survival pathways and expression of anti-apoptotic proteins. Thus, there is an urgent need to develop efficient and safe therapeutic strategies. Here, we review the pharmacological options available for the treatment of this disease with specific reference to the antitumor agents used in systemic therapies. In addition, novel pharmacological approaches, such as drug delivery tools, to improve pleural mesothelioma treatment are discussed.

Malignant pleural mesothelioma (MPM) is a highly chemo-refractory and immune-evasive tumor that presents a median overall survival of 12-14 months when treated with chemotherapy and immunotherapy. New anti-tumor therapies as well as the concomitant reactivation of immune destruction are urgently needed to treat patients with this tumor. The aim of this work is to investigate the potential effect of ecteinascidin derivatives as lurbinectedin as new first-line treatment option in MPM, alone and in combination with immunotherapy.

The antitumor activity of ecteinascidin synthetic analogues: lurbinectedin, ecubectedin and PM54 was evaluated in an array of patient-derived MPM cells in terms of cell proliferation, cell cycle, apoptosis, DNA damage and repair. Immunoblot was used to assess the cGAS/STING pathway. ELISA and flow cytometry-based assays were used to evaluate immunogenic cell death parameters and the effect on the immunophenotype in autologous peripheral blood monocyte-MPM cells co-cultures. Patient-derived xenografts (PDX) in humanized mice were used to evaluate the efficacy of ecteinascidins in vivo.

Lurbinectedin, ecubectedin, and PM54 were effective in reducing cell proliferation and migration, as well as inducing S-phase cell cycle arrest and DNA damage in malignant pleural mesothelioma cells. These effects were more pronounced compared to the standard first-line treatment (platinum-based plus pemetrexed). Mechanistically, the drugs downregulated DNA repair genes, activated the cGAS/STING pathway, and promoted the release of pro-inflammatory cytokines. They also induced immunogenic cell death of mesothelioma cells, enhancing the activation of anti-tumor CD8+T-cells and natural killer cells while reducing tumor-tolerant T-regulatory cells and myeloid-derived suppressor cells in ex vivo co-cultures. These promising results were also observed in humanized patient-derived xenograft models, where the drugs were effective in reducing tumor growth and increasing the ratio anti-tumor/pro-tumor infiltrating immune populations, either alone or combined with the anti-PD-1L atezolizumab.

Collectively, these findings reveal a previously unknown mechanism of action of ecteinascidins that merits further investigation for potential clinical applications in the treatment of MPM, as new first line treatment in monotherapy or in association with immunotherapy.

To evaluate the real-world treatment patterns and outcomes for patients with pleural mesothelioma (PM) in the era of immunotherapy.

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.

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).

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.

Primary intrahepatic mesothelioma (PIHMM) has been rarely reported. Its typical clinical presentation, radiological features and pathology have not been defined. Here, we aimed to summarize its diagnosis and treatment.

We conducted a retrospective analysis of three cases of PIHMM in the First Affiliated Hospital of Zhejiang University School of Medicine and reviewed the current literature to investigate the clinical and pathological characteristics and prognosis of PIHMM.

Based on our case series and the literature, the mean age of PIHMM was 59.7 (41-83) years. Most patients present with nonspecific symptoms such as abdominal pain, fever, weight loss and weakness. On imaging, PIHMM usually presented as a solid, heterogeneous soft tissue mass with irregular margins and significant enhancement of the margins in the arterial phase. Immunohistochemical markers such as calretinin, cytokeratin (CK)5/6, D2-40, WT-1, mesothelin CK and vimentin may be useful for diagnosis. The 3-year relapse-free survival rate (RFS) was 51.85%, the 3-year overall survival (OS) rate was 83.33% and the 3-year postoperative overall survival rate was 100%.

PIHMM can only be diagnosed by careful postoperative pathology, because of its nonspecific clinical presentations, serological indicators or imaging features. Immunohistochemical staining is very useful to distinguish this tumor from other liver tumors. Surgery is the mainstay of treatment.

The phase 3 CheckMate-743 trial demonstrated a prolonged overall survival (OS) benefit with nivolumab plus ipilimumab over chemotherapy as first-line treatment in patients with unresectable pleural mesothelioma (PM). However, given that Latin American (LATAM) patients were notably underrepresented in this trial, we retrospectively assessed the effectiveness and safety of this regimen in this population.

This retrospective study included patients from 15 centers in LATAM with unresectable or metastatic PM treated with first-line nivolumab plus ipilimumab in a real-world data (RWD) scenario. Demographic, clinicopathological characteristics, and safety data were collected from medical charts. Progression-free survival (PFS), and OS were calculated using the Kaplan-Meier method.

From June 2017, and January 2024 96 patients were included: epithelioid 78% (n = 75), 81% were ECOG 0-1 (n = 78). With a median follow-up of 24.1 months, median PFS and OS were 8 months (95% CI, 6.6-9.4), and 22 months (95% CI, 18.9-25), respectively. No statistical difference in OS was observed between epithelioid versus nonepithelioid histology (median 23 months vs. 19 months, respectively; P = .29). Treatment efficacy was also consistent among different clinical subgroups. Any and grade 3-4 adverse events were found in 43.1% (n = 28), and 18.5% (n = 12) of patients, respectively. Remarkably, no OS impact was observed in patients who had dose delay or treatment discontinuation due to immune-related adverse events, and those who experienced any adverse event.

This multicenter RWD study demonstrated the clinically meaningful benefit of first-line ipilimumab and nivolumab in LATAM patients with unresectable or metastatic PM, and data is consistent with previous trial findings.

Malignant mesothelioma is an aggressive cancer with poor prognosis. Programmed cell death protein-1 (PD-1) and its ligand 1 (PD-L1) immune checkpoint inhibitors (ICIs) have recently presented as a viable option in some first line but primarily as a second-line treatment of advanced-stage malignant mesothelioma (asMM). Therefore, this systematic review and meta-analysis aims to assess the safety and efficacy of PD-1/L-1 ICIs in advanced-stage malignant mesothelioma.

PubMed, Scopus, and Cochrane databases were searched for all studies assessing the safety and efficacy of anti PD-1/PD-L1 agents. Primary outcomes were objective response rate (ORR) and disease control rate (DCR). Secondary outcomes were median progression free (mPFS) and overall survival (mOS). Safety outcomes were treatment- (TRAEs) and immune-related adverse events (IRAEs). A random-effects meta-analysis was performed to pool medians and to derive event rates.

A total of 15 studies were included with total of 1064 asMM patients. ORR and DCR were 16% and 57%, respectively. A pooled mPFS was 4.53 (CI: 3.40-5.65) and mOS was 10.51 (CI: 9.03-12.00). Overall TRAEs had an event rate of 0.69 (0.50-0.83) whereas IRAEs had an event rate of 0.28 (0.15-0.46). There were no significant differences between pembrolizumab, nivolumab primarily, and avelumab subgroups for all the outcomes. Additionally, meta-regression found no covariate to be a significant factor in ORR and DCR.

In this meta-analysis we found that anti-PD1/PD-L1 treatment could be useful in pretreated asMM as they had at least comparable or greater mPFS, mOS, ORR, and DCR than other second-line agents currently being used.

This systematic review was registered at PROSPERO prior to the literature search, CRD42023442350.