Potential treatment approaches for malignant peritoneal mesothelioma: in vivo and in vitro experimental study of natural killer cell immunotherapy.

OBJECTIVE: Malignant peritoneal mesothelioma (MPM) is a rare primary malignant tumor with an extremely poor prognosis that currently lacks effective treatment options. This study investigated the in vitro and in vivo efficacy of natural killer (NK) cells for treatment of MPM. METHODS: An in vitro study was conducted to assess the cytotoxicity of NK cells from umbilical cord blood to MPM cells with the use of a high-content imaging analysis system, the Cell Counting Kit-8 assay, and Wright-Giemsa staining. The level of NK cell effector molecule expression was detected by flow cytometry and enzyme-linked immunosorbent assays. The ability of NK cells to kill MPM cells was determined based on live cell imaging, transmission electron microscopy, and scanning electron microscopy. An in vivo study was conducted to assess the efficacy and safety of NK cell therapy based on the experimental peritoneal cancer index, small animal magnetic resonance imaging, and conventional histopathologic, cytologic, and hematologic studies. RESULTS: NK cells effectively killed MPM cells through the release of effector molecules (granzyme B, perforin, interferon-γ, and tumor necrosis factor-α) in a dose- and density-dependent manner. The NK cell killing process potentially involved four dynamic steps: chemotaxis; hitting; adhesion; and penetration. NK cells significantly reduced the tumor burden, diminished ascites production, and extended survival with no significant hematologic toxicity or organ damage in NOG mice. CONCLUSIONS: NK cell immunotherapy inhibited proliferation of MPM cells in vitro and in vivo with a good safety profile.

Biomarkers to predict the benefits of immune­checkpoint blockade­based therapy in patients with malignant peritoneal mesothelioma (Review).

Malignant peritoneal mesothelioma (MPeM) is a type of rare and highly lethal tumor. Immune checkpoint blockade (ICB)-based therapy has shown encouraging clinical activity for MPeM. However, no definitive biomarkers have been identified for predicting which patients with MPeM will benefit from ICB-based therapy. At present, there are several novel potential biomarkers proposed for predicting the response to ICB-based therapy, and biomarkers available in MPeM cells and in the tumor microenvironment have been identified with the potential to predict the efficacy of ICB-based therapy in MPeM. According to the molecular characteristics of MPeM itself, the feasibility of biomarkers in practice, and the body of available evidence, we hypothesize that the following five types of biomarkers can be used to predict the response of ICB-based therapy in patients with MPeM: Tertiary lymphoid structures, immune checkpoints and their ligands, fusion gene neoantigen burden, BRCA1-associated protein-1 haploinsufficiency and transcriptome-based biomarkers. The present review discusses the value and limitations of each type of biomarker, and potential solutions to address the limitations are proposed. The aim of the present review is to provide a background for future studies on ICB-based therapy for MPeM.

A Case of Malignant Pleural Mesothelioma With Unknown Asbestos Exposure.

Malignant pleural mesothelioma (MPM) is a rare, locally invasive tumor that develops from mesothelial cells lining the lung's pleura. It is mostly associated with prolonged asbestos exposure. The long latency period between asbestos exposure and clinical symptoms makes diagnosing MPM challenging. This report describes a 57-year-old Hispanic female who presented with a persistent nonproductive cough and was ultimately diagnosed with advanced-stage pleural mesothelioma after extensive work-up. It highlights the difficulties in diagnosing MPM in patients without apparent asbestos exposure independent of age or gender.

Case Report: A case of primary pericardial mesothelioma treated with multimodal combined therapy.

Background: Primary pericardial mesothelioma (PMPM) is a rare, aggressive, and lethal form of cancer. Due to its rarity, low incidence and poor prognosis, PMPM has no accepted standard-of-care treatment options with management and outcomes often extrapolated from diffuse pleural mesothelioma. Disease-specific studies are needed to better define PMPM. We report a case of PMPM highlighting the potential role for multimodal combined therapy. Case report: The patient is a 62 years old female who had nonspecific syndromes and inconclusive image findings in May 2023. Then monthly follow-up echocardiography was performed. Two months later, cardiac ultrasound showed pericardial fluid. Pericardiocentesis with pericardial drain was performed. The fluid was bloody, cultivations for tuberculosis were negative and cytological analysis of the fluid showed no malignant cells. Positron emission tomography-computed tomography revealed that the lesion was localized at the anterior and left part of the mediastinum without distant metastasis. Followed up a pericardiectomy was operated. The diagnosis of PMPM is determined by pathological and immunohistochemical evaluation of tissue specimens. Postoperative patient experienced chest pain, right shoulder and upper limb swelling and pain. Pain management and anticoagulant therapy were administered. The patient underwent multimodal therapy consisting of surgical resection, six cycles of chemotherapy (carboplatin plus pemetrexed) in combination with pembrolizumab, and sequential adjuvant intensity-modulated radiation therapy, totaling 50 Gy in 25 fractions, as the first-line treatment, resulting in complete relief of symptoms and satisfactory outcomes with no complications. Presently, the tumor is under local control, with no signs of distant metastasis, and maintenance immunotherapy is scheduled. Continued observation is necessary for monitoring subsequent disease progression. Conclusion: PMPM represents a distinct disease with no universally accepted treatment options. The case suggests that multimodal treatment may improve outcomes in selected patients with PMPM.

Double immune checkpoint inhibitor therapy for unresectable pleural mesothelioma rarely induces hyperprogressive disease: a case report.

Background: Use of immune checkpoint inhibitors (ICIs) is associated with new response types, such as hyperprogressive disease (HPD), whose definition is still being discussed. Some authors use dynamic indexes to define HPD. However, since the Checkmate-743 study, ICIs have been a first-line therapy for pleural mesothelioma (PM), thereby making use of dynamic indexes less appropriate. The aim of this study is to describe two cases of HPD and then discuss its definitions and implications. Case Description: Herein, we report two cases of PM HPD on first-line ICI therapy. A 67-year-old man with right unresectable epithelioid PM, without BAP1 or CDKN2A losses, high neutrophil/lymphocyte ratio and rapid-onset pulmonary and mediastinal HPD after two ICI cycles, died of respiratory failure 1 month after starting treatment. A 40-year-old woman with left unresectable epithelioid PM had HPD at first assessment after 4 ICI infusions with jugular thrombosis, liver metastases and more dismal biological parameters. There are multiple different ways to describe HPD, some not applicable to PM. Suspected mechanisms include macrophage reprogramming to M2 cells. There are no known predictive factors of HPD, and future works should focus on identifying them. Conclusions: HPD is a mode of progression for ICI-treated PM patients. Further investigation is needed to better define and anticipate HPD in these patients.

Stem-like exhausted CD8 T cells in pleural effusions predict improved survival in non-small cell lung cancer (NSCLC) and mesothelioma.

Background: Anti-tumor CD8 T cells are important for immunity but can become 'exhausted' and hence ineffective. Tumor-infiltrating exhausted CD8+ T cells include less differentiated stem-like exhausted T (Texstem) cells and terminally exhausted T (Texterm) cells. Both subsets have been proposed as prognostic biomarkers in cancer patients. In this study, we retrospectively investigated their prognostic significance in patients with metastatic non-small cell lung cancer (NSCLC) and validated our findings in a mesothelioma cohort. Methods: Pre-treatment malignant pleural effusions (PEs) from 43 NSCLC (41 non-squamous, 2 squamous) patients were analyzed by flow cytometry. The percentages of Texstem and Texterm CD8 T cells were correlated with overall survival (OS) after adjusting for clinicopathological variables. Findings were validated using a mesothelioma cohort (n=49). Mass cytometry was performed on 16 pre-treatment PE samples from 5 mesothelioma and 3 NSCLC patients for T-cell phenotyping. Single-cell multi-omics analysis was performed on 4 pre-treatment PE samples from 2 NSCLC patients and 2 mesothelioma patients for analysis of the transcriptomic profiles, surface markers and T cell receptor (TCR) repertoire. Results: Higher frequency of Texstem was associated with significantly increased OS [median 9.9 vs. 3.4 months, hazard ratio (HR) 0.36, 95% CI: 0.16-0.79, P=0.01]. The frequency of Texterm was not associated with OS. These findings were validated in the mesothelioma cohort (high vs. low Texstem, median OS 32.1 vs. 19.8 months, HR 0.31, 95% CI: 0.10-0.96, P=0.04). Detailed single-cell sequencing and mass cytometry profiling revealed that exhausted T cells from NSCLC expressed greater stem-likeness and less inhibitory markers than those from mesothelioma and that Texstem cells also contained 'bystander' virus-specific T cells. Conclusions: This study demonstrates that PE CD8 Texstem cell abundance is associated with better survival outcomes, and thus may be a useful prognostic biomarker.

Flow cytometry of non-hematopoietic cells in canine effusions.

The identification of non-hematopoietic cells in effusions is a diagnostic challenge in cytology. Biopsies from mesothelium or primary lesions are infrequently performed in clinical settings and immunochemistry on smears or immunohistochemistry on cell blocks are the most common ancillary test to refine the cytological diagnosis. Cavitary effusions are an ideal matrix for flow cytometry and the availability of a cytometric panel to describe non-hematopoietic cells would represent a useful tool. Here we present the results of the flow cytometric and immunohistochemical determination of cytokeratin (CK), vimentin (VIM) and desmin (DES) in 36 canine effusions. The concordance between the two methods was perfect for CK (100%), substantial for VIM (77.8%), and almost perfect for DES (97.2%). The panel was interpreted to define the epithelial (CK+VIM-DES-), mesothelial (CK+VIM+DES+), or mesenchymal (CK-VIM+DES-) origin of the cells. Unexpected profiles were considered doubtful and observed patterns were individually discussed. The concordance of the panel interpretation between two methods was 75%. The evaluation of discordant and doubtful cases suggests a lower sensitivity of flow cytometry in detecting VIM expression and revealed a high frequency of VIM+ epithelial cells, variable expression of VIM in mesothelial cells, and an important role of DES in excluding an epithelial origin when positive. Multicentric studies based on histopathological diagnoses are necessary to confirm these findings and evaluate the diagnostic utility of the panel to refine cytological diagnosis. Our results show that flow cytometry can be a timesaving alternative to IHC on cell blocks in clinical settings to detect CK, VIM and DES expression. The interpretation of the panel is similar in most cases; however, occasional discordant results, particularly for VIM, may occur.

Crispr-mediated genome editing reveals a preponderance of non-oncogene addictions as targetable vulnerabilities in pleural mesothelioma.

Pleural mesothelioma (PM) is an aggressive cancer with limited treatment options. In particular, the frequent loss of tumor suppressors, a key oncogenic driver of the disease that is therapeutically intractable, has hampered the development of targeted cancer therapies. Here, we interrogate the PM genome using CRISPR-mediated gene editing to systematically uncover PM cell susceptibilities and provide an evidence-based rationale for targeted cancer drug discovery. This analysis has allowed us to identify with high confidence numerous known and novel gene dependencies that are surprisingly highly enriched for non-oncogenic pathways involved in response to various stress stimuli, in particular DNA damage and transcriptional dysregulation. By integrating genomic analysis with a series of in vitro and in vivo functional studies, we validate and prioritize several non-oncogene addictions conferred by CDK7, CHK1, HDAC3, RAD51, TPX2, and UBA1 as targetable vulnerabilities, revealing previously unappreciated aspects of PM biology. Our findings support the growing consensus that stress-responsive non-oncogenic signaling plays a key role in the initiation and progression of PM and provide a functional blueprint for the development of unprecedented targeted therapies to combat this formidable disease.

The aftermath of asbestos prohibition in industry and its association with malignant mesothelioma in the south of Iran: An enduring predicament yet to be resolved.

Purpose: Malignant Mesothelioma (MM) is a rare malignancy of the serosa membranes with a high mortality rate and long latent period. The relationship between a group of mineral fibers known as asbestos and mesothelioma is now well accepted in which people can be exposed to these fibers by various means during their lifetime and has been its usage has banned in many countries, such as Iran, which announced its gradual elimination from 1999 over a period of 7 years by using safe substitutes. However, the mineral particles are able to sustain itself in the environment, air, water, and soil and on the other hand, symptoms may take up to half a century to develop in exposed individuals. Also, there remains a shortage of comprehensive investigation on the effects of asbestos exposure within the familial context (household or domestic exposure) or on individuals residing in proximity to asbestos mines or factories (environmental exposure). Based on the high number of MM cases in Iran, and also our hypothesis that residuals of asbestos in the environment and petroleum products may be the etiological factor for MM, we conducted this study to evaluate the clinic epidemiological features of MM in the south of Iran its relation to possible asbestos exposure. Methods: In this study, we analyzed the demographic features and occupations of confirmed cases of MM in Shiraz, southern Iran along with the follow-up of the patients' disease from 2008 to 2018, while also comparing the features of our patients with a control group compromising of 105 non-MM patients. Results: Among the 35 confirmed cases of MM, with an average age of 61 years, 9 (25.7%) were female, and 26 (74.3%) were male. During our assessment, 12 patients had already died, with a mean time of 11.26 months post-diagnosis. Our findings revealed a higher prevalence of MM among housekeepers and employees of oil companies. In comparison to the control group, individuals with occupational exposure and those residing near refinery locations were at a heightened risk of developing MM. However, based on regression analysis, only occupations associated with refineries exhibited a significant correlation with MM (p = 0.028; OR: 14.602; 95% CI: 1.328-160.499). Conclusion: Both occupational and para-occupational exposure demonstrated a significant correlation with MM, whereas our regression analysis did not affirm geographical and environmental factors as contributors to MM. Despite the industry's prohibition of direct asbestos usage, the persistent existence of asbestos particles in the environment for decades, coupled with the long latency period of MM, warrants further investigation. Health authorities and policymakers should recognize this potential hazard, prompting an enhancement of early detection within at-risk groups.

A case of benign multicystic peritoneal mesothelioma.

Benign Multicystic Peritoneal Mesothelioma (BMPM) is an exceedingly rare benign abdominal neoplasm with fewer than 200 cases reported worldwide. Owing to its rarity, vague clinical picture, and elusive causes, diagnosis is often delayed or missed. Histopathological examination and immunohistochemical staining are crucial for definitive diagnosis. However, due to lack of substantial literature, the standard of care and future prognosis remain subjects of inquiry. We present a case report of one female patient diagnosed with BMPM and treated with surgical resection.

[Expression changes of miRNAs and EMT-related genes in human mesothelial cells induced by long-term exposure to asbestos].

Objective: To investigate the effects of long-term exposure to chrysotile and crocidolite on miRNAs and epithelial mesenchymal transformation (EMT) -related gene expression in human pleural mesothelial cells. Methods: In November 2020, fluorescence quantitative polymerase chain reaction (RT-qPCR) was used to detect the expressions of EMT-related genes in human pleural mesothelioma cells (NCl-H2052 cells, NCl-H2452 cells) and human normal mesothelial cells (Met-5A cells). MiRNAs with abnormal expression in human pleural mesothelioma cells were screened out from the previous miRNA chip data of research group, and target genes of differentially expressed miRNAs were predicted using miRWalk database (http: //mirwalk.umm.uni-heidelberg.de). RT-qPCR was used to verify the abnormal expression of EMT-related miRNAs in cell lines. Met-5A cells were treated with 5µg/cm(2) chrysotile and crocidolite respectively for 48 h a time, once a week and a total of 10 times. Chrysotile group, crocidolite group and control group were set up. And the control group was added with the same volume of PBS. The expression changes of EMT-related genes and abnormal expression miRNAs in each group were detected by RT-qPCR. The differences among the groups were compared by one-way ANOVA, and the differences between the control group and the experimental group were compared by dunnet-t test. Results: Compared with Met-5A cells, the expression levels of Vimentin and Twist genes were increased, and the expression level of E-cadherin genes was decreased in NCl-H2052 cells and NCl-H2452 cells (P<0.001). Target genes of miRNAs with abnormal expression in miRNA chip were predicted, and the results showed four abnormally expressed miRNAs associated with EMT and verified the expression of these four miRNAs in the cell lines. Compared with Met-5A cells, the expression level of hsa-miR-155-5p was increased in NCl-H2052 cells and NCl-H2452 cells, the expression levels of hsa-miR-34b-5p, hsa-miR-34c-5p and hsa-miR-28-5p were decreased in NCl-H2052 cells and NCl-H2452 cells (P<0.001), which was consistent with the results of chip analysis. After exposure of Met-5A cells, it was found that compared with the control group, the expression levels of Vimentin and Twist genes, hsa-miR-155-5p, hsa-miR-34b-5p and hsa-miR-34c-5p in the crocidolite group were increased, while the expression level of E-cadherin gene was decreased (P<0.05). Compared with the control group, the expression levels of Vimentin, Twist and E-cadherin genes in chrysotile group were increased, while the expression levels of hsa-miR-34b-5p, hsa-miR-34c-5p and hsa-miR-28-5p were decreased (P<0.05) . Conclusion: Long-term exposure to chrysotile and crocidolite could cause Met-5A cells to produce miRNAs and EMT-related gene expression changes similar to mesothelioma cells.

Soluble Mesothelin-Related Peptide as a Prognosticator in Pleural Mesothelioma Patients Receiving Checkpoint Immunotherapy.

OBJECTIVE: Immune checkpoint therapy (ICT) has significantly impacted malignant pleural mesothelioma (MPM) treatment. Despite some promising results from combination therapies, nearly half of MPM patients do not benefit, underscoring the urgent need for reliable predictive biomarkers. This study assesses the prognostic value of serum soluble mesothelin-related peptide (SMRP) and PD-L1 levels in MPM patients receiving ICT. METHODS: We conducted a retrospective analysis of 125 MPM patients treated with ICT by measuring pre-ICT serum levels of SMRP and PD-L1. We also examined the correlation of these serum levels with tumor mRNA expressions of MSLN and PD-L1. Both univariable and multivariable Cox regression analyses were used to determine independent prognosticators for overall survival (OS). A prospective ICT clinical trial and our historical cohort were included for validation. RESULTS: Seventy-seven patients (62%) were treated with either anti-PD-(L)1 monotherapy, and the remaining 38% were given combination ICT. Higher pre-ICT SMRP levels were observed in epithelioid versus non-epithelioid MPM. Serum PD-L1 levels did not show significant differences between the groups. Univariable analysis identified durable clinical benefit, development of immune-related adverse events, and SMRP levels as significantly associated with OS. Multivariable analysis confirmed SMRP as an independent prognostic factor, with lower levels (≤1.35 nmol/L) correlating with improved OS. The association of high SMRP with worse prognosis was validated in the prospective ICT clinical trial cohort and not in our historical cohort treated without ICT. CONCLUSIONS: SMRP is a promising serum biomarker for predicting survival in MPM patients treated with ICT and warrants prospective investigation.

Determinants of Mortality Among US Patients Diagnosed With Malignant Pleural Mesothelioma Over the Past Decade.

Background: Malignant Pleural Mesothelioma (MPM) is a primary pleural tumor with scarce prognostic data estimates given its rarity. This study aims to explore the epidemiologic and survival predictors amongst patients with MPM, extending from the largest and most recent study conducted between 1973 and 2009. Methods: 3384 patients diagnosed with MPM between 2010 and 2017 were enrolled from the Surveillance, Epidemiology, and End Results (SEER) database. Demographics, clinical characteristics, overall mortality (OM), and cancer-specific mortality (CSM) estimates were analyzed. Multivariate Cox model was used to identify independent prognostic factors, where a hazard ratio (HR) greater than 1 denotes adverse prognostic factors. Results: Our cohort revealed a male predominance (77.16%), with over 80% diagnosed after age 59, peaking between 60 and 79 years old (60.17%). Epithelioid mesothelioma (41.78%), non-Hispanic whites (78.13%), and diagnosis at distant stage (71.60%) were the most common subgroups in their respective categories. 365 patients (10.79%) lacked pleural effusion at diagnosis. In multivariate analyses, higher overall mortality (OM) was associated with male gender (HR = 1.24, 95% CI 1.14-1.37, p < 0.01), age >80 years (HR = 2.17, 95% CI 1.41-3.35, p < 0.01), fibrous mesothelioma (HR = 2.21, 95% CI 1.95-2.51, p < 0.01), and distant stage (HR = 1.55, 95% CI 1.34-1.81, p < 0.01). Higher cancer-specific mortality (CSM) was associated with male gender (HR = 1.25, 95% CI 1.13-1.38, p < 0.01), age >80 years (HR = 2.02, 95% CI 1.29-3.15, p < 0.01), fibrous mesothelioma (HR = 2.24, 95% CI 1.97-2.55, p < 0.01), and distant stage (HR = 1.59, 95% CI 1.36-1.87, p < 0.01). Lower OM and CSM was observed in patients who underwent any type of treatment. Nonmalignant pleural effusion, based on histology, was associated with higher CSM (HR = 1.22, 95% CI 1.05-1.4, p < 0.05). Conclusion: Fibrous mesothelioma, older age, and distant disease were associated with increased mortality. All intervention strategies were associated with improved survival outcomes. Earlier diagnosis may improve outcomes, as available interventions are associated with lower mortality when feasible at diagnosis. The study paves the way for further prospective and retrospective studies to focus on the identification of patient subsets that may benefit from early mesothelioma screening.

Efficacy of First-Line Nivolumab Plus Ipilimumab in Unresectable Pleural Mesothelioma: A Multicenter Real-World Study (ImmunoMeso LATAM).

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Immunotherapy for Treatment of Pleural Mesothelioma: Current and Emerging Therapeutic Strategies.

Pleural mesothelioma is a rare malignancy associated with asbestos exposure and very poor prognosis, with a 5-year overall survival of 12%. Outcomes may vary according to stage at time of diagnosis and histologic subtype. Most recently, clinical trials utilizing dual checkpoint inhibitor regimens and chemotherapy in combination with immune oncologic agents have demonstrated impactful changes in outcomes. In this article, we review studies that have led to the successful implementation of immunotherapy in clinical practice for the treatment of this disease and highlight ongoing clinical trials exploring the use of different immunotherapy strategies for the treatment of pleural mesothelioma. We also discuss the challenges of immunotherapy-based approaches in the context of mesothelioma and future strategies currently being investigated to overcome them.

Phase I Clinical Trial on Pleural Mesothelioma Using Neoadjuvant Local Administration of Paclitaxel-Loaded Mesenchymal Stromal Cells (PACLIMES Trial): Study Rationale and Design.

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.

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

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

Malignant Pleural Mesothelioma: A Comprehensive Review.

Mesotheliomas are hyperplastic tumors that envelop the serosal membranes that safeguard the body's external surfaces. Although certain instances may exhibit indolent characteristics, a significant number of tumors demonstrate rapid progression and a poor prognosis. Mesotheliomas are typically categorized as benign or malignant, with malignant mesothelioma being more frequently linked to asbestos exposure. Malignant pleural mesothelioma (MPM) predominantly impacts males and often emerges in the late 50 s or beyond, characterized by a median age of early 70 s among patients exposed to asbestos lasting from 2 to 4 decades. Respiratory exposure to asbestos particles leads to the development of malignant mesothelioma, characterized by recurrent inflammation, disruption of cell division, activation of proto-oncogenes, and generation of free radicals. In pleural mesothelioma, BAP1, CDKN2A, and NF are the most often mutated genes. Accurate diagnosis and assessment usually require the use of chest computed tomography (CT) scans, magnetic resonance imaging (MRI), and positron emission tomography (PET). Radiation therapy, immunotherapy, chemotherapy, and surgery are some of the treatment options that are currently available. This systematic review provides a comprehensive analysis of the latest research, biomarkers, evaluation, and management strategies for malignant pleural mesothelioma.

Malignant STK11 adnexal tumor harboring a somatic mutation in a woman previously diagnosed with mesothelioma, a case report.

STK11 germline pathogenic variants are typically associated with Peutz-Jeghers syndrome, an autosomal dominant disease characterized by hamartomatous polyps in the gastrointestinal tract, hyperpigmented patches, and increased risk of stomach, colorectal, small bowel, and breast cancers (Beggs et al., 2010). Mutations in this gene have also been identified in skin, pancreatic, testicular, and stromal ovarian cancer (Fagerberg et al., 2014). To date, there have been less than 30 cases of ovarian cancer reported associated with mutated STK11 (Bennett et al., 2021). In this report, we discuss a rare case of a STK11 adnexal tumor in a 39-year-old woman previously diagnosed with malignant mesothelioma. After 33 months with no evidence of disease following cytoreductive surgery with HIPEC and adjuvant chemotherapy, a new retroperitoneal lesion was noted on imaging. After resection, molecular testing indicated an STK11 mutation, and histology was consistent with an STK11 adnexal tumor. A high index of suspicion is required to make the diagnosis of STK11 adnexal tumor due to its non-distinct pathology and IHC staining. Due to the rarity of this neoplasm, analysis of current and future cases of the STK11 adnexal tumor is necessary to understand its pathogenesis, genetic mutational analysis, clinical course, and best treatment options.

Malignant Mesothelioma of the Tunica Vaginalis: About a Rare Clinical Case.

Malignant mesothelioma (MM) of the tunica vaginalis is an exceedingly rare neoplasm, with fewer than 300 cases reported in the medical literature. Due to its rarity, epidemiology, and risk factors are still unclear, and it is unknown whether asbestos or chronic inflammatory conditions play a role in etiology. This case study presents a 70-year-old male patient with MM of the tunica vaginalis, detailing the diagnostic challenges, treatment procedures, and eventual progression to palliative care. The study underscores the importance of accurate diagnosis and the aggressive nature of the disease despite treatment efforts.