Search Results (471)

Background: Pleural mesothelioma (PM) is characterised by often rapid therapeutic failure and chemotherapy resistance. While terminal resistance is well studied, the initial transition into a drug-tolerant phenotype remains poorly understood. Methods: We established patient-derived organoids (PDOs) from malignant pleural effusions to model this transition. Cisplatin-tolerant lines were generated via repeated incremental exposure to cisplatin and compared to time-matched treatment-naive controls using RNA sequencing and Seahorse XFe96 metabolic flux analysis. Results: Integrated profiling suggested that the route to tolerance may be influenced by the underlying mutational profile. In this cohort, all BAP1-retained models (including those with KRAS mutations or MTAP loss) adopted an elevated basal metabolic hybrid phenotype, significantly upregulating baseline oxidative phosphorylation and glycolysis to fuel survival mechanisms. Conversely, BAP1-deficient models entered a hypometabolic state of dormancy, characterised by baseline bioenergetic suppression and reduced Ki-67 proliferation. Transcriptomic analysis identified a vesicular transport signature (SYNGR3, VPS52, PROM2) in plastic models, suggesting altered membrane trafficking as a potential survival strategy. Conclusions: Our findings demonstrate that mesothelioma therapeutic escape is not a uniform process. Identifying these patient-specific metabolic and transcriptomic trajectories via 3D PDOs provides a hypothesis-generating framework to explore potential avenues for future personalised therapy. Full article

Malignant mesothelioma is an aggressive cancer with limited therapeutic options, highlighting the need for novel strategies targeting metabolic vulnerabilities. Natural polyphenols have gained attention due to their ability to modulate cellular metabolism and apoptosis-related signaling pathways. In this study, we investigated the combined anticancer effects of quercetin (QUE) and arctigenin (ATG) in human malignant mesothelioma cells. QUE and ATG reduced the viability of MSTO-211H cells in a time-dependent manner, while non-malignant mesothelial MeT-5A cells showed relatively limited sensitivity under the tested conditions. Compared with single treatment, the combination treatment further enhanced growth inhibition, with combination index analysis suggesting a potential synergistic interaction. Co-treatment significantly decreased intracellular ATP levels and increased caspase-3/7 activity, suggesting metabolic stress-associated apoptotic responses. Annexin V analysis confirmed increased apoptotic cell populations following combination treatment. Western blot analysis demonstrated reduced expression of anti-apoptotic proteins Mcl-1 and Bcl-xL, along with increased cleavage of caspase-3 and PARP, consistent with involvement of intrinsic apoptosis-associated signaling pathways. In addition, increased phosphorylation of AMPK and altered expression of mitochondrial oxidative phosphorylation (OXPHOS) complex proteins were associated with potential alterations in mitochondrial respiratory protein expression. Collectively, these findings suggest that QUE and ATG co-treatment is associated with increased apoptotic cell death in malignant mesothelioma cells in association with metabolic stress–related mitochondrial functional alterations. Full article

Background and Objectives: The presence of comorbidities in both the pre- and post-diagnostic periods is a critical consideration in the diagnosis and management of patients with cancer. This study aimed to investigate the prevalence and burden of pulmonary and extrapulmonary comorbidities in patients diagnosed with lung cancer (LC) and malignant pleural mesothelioma (MPM). Materials and Methods: The data were obtained from official patient records of the Turkish Ministry of Health. Patients diagnosed with either lung cancer (LC) or malignant pleural mesothelioma (MPM) between 2015 and 2018 were included in the study. Comorbidities were classified as pulmonary or extrapulmonary. Results: A total of 74,835 patients with LC and 1678 patients with MPM were included. The burden of comorbid conditions increased significantly in the post-diagnostic period in both males and females across both cancer types. When the two cancer groups were compared with respect to diagnostic periods, comorbidities such as hypertension (HT), phlebitis/venous thrombosis/thrombophlebitis, pulmonary embolism, pneumothorax, and pleural effusion were significantly more prevalent in the MPM group (p < 0.05). Compared with the pre-diagnostic period, the comorbidity risk in LC was highest for pulmonary embolism, ARF, and pneumonia in the post-diagnostic period, whereas renal failure was the most frequent comorbidity in the MPM group (p < 0.001 and p = 0.024). When comparing changes in comorbidity burden between sexes in the lung cancer group, male patients had higher frequencies of pulmonary embolism, pneumonia, pneumothorax, and coronary artery disease than females. In contrast, in the female lung cancer group, the prevalence of chronic renal failure was higher than in males (OR = 2.14 vs. 2.00), whereas acute renal failure was more prominent in the male patient group (OR = 2.64 vs. 1.94). In gender-based comparison of comorbid conditions among patients with MPM, the risk of renal failure was higher in females than in males (CRF and ARF respectively: OR = 2.63 vs. 2.16 and OR = 6.80 vs. 5.44). Additionally, increased rates of COPD were observed in male patients within this group (OR = 1.93 vs. 1.81). Conclusions: Patients with LC and MPM are burdened not only by their primary malignancies but also by a wide spectrum of comorbidities, particularly in the post-diagnostic period. Comprehensive knowledge of comorbid conditions is essential for clinicians to guide clinical decision-making, anticipate disease progression, and optimize treatment strategies, thereby informing national healthcare policies. Future studies incorporating matched control groups or longitudinal designs with standardized surveillance protocols may help conduct better research. Full article

Pleural Mesothelioma (PM) is a rare, incurable malignancy of the pleura. Lung-sparing surgery, considered investigational, aims to prolong survival and improve quality of life (QOL). Beyond the standard quantitative measures used to determine successful surgical outcomes, an understanding of an individual’s perception of the impact surgery has had on their symptom burden and QOL has not been reported in the literature. The primary aim of this study was to explore the lived experience of dyspnea and QOL before and after lung-sparing surgery. The philosophical approach to this study was grounded in hermeneutical phenomenology. Participants underwent in-depth semi-structured interviews before and 3–4 months post-surgery, analyzed through Interpretive Phenomenological analysis. The analysis identified Group Experiential Themes (GETs) before and after surgery: Psychological (mind supports body), Physiological (body fighting, enduring, and adapting), Social (others sharing and supporting), and Existential (facing an uncertain future). The emotional impact of PM is multidimensional, involving time, internal psychological struggles, and coping with the diagnosis. The physical impact disrupts normal routines and interactions, while social interactions influence the perception of the illness experience. Facing PM disrupts normal bodily routines and interactions with the world. This study provides qualitative evidence that perceptions of dyspnea and QOL significantly impact the patient experience before and after surgery. The enriched understanding of living with mesothelioma and enduring lung-sparing surgery comes from the patients’ voices, highlighting the continuum of dyspnea and QOL influenced by various factors. Healthcare teams must consider patients’ physical, emotional, social, and existential experiences beyond measurable outcomes. Full article

Background/Objectives: Malignant mesothelioma has a poor prognosis and limited therapeutic options. C-ERC/mesothelin is highly expressed in mesotheliomas and is a potential target for radioimmunotherapy (RIT). This study evaluated the radiolabeled anti-C-ERC/mesothelin antibody mAb 22A31 as a therapeutic agent. Methods: C-ERC/mesothelin expression in mesothelioma cell lines was assessed by Western blotting, and the specific binding of ¹²⁵I-labeled mAb 22A31 was examined. Biodistribution of ¹¹¹In-labeled mAb 22A31 was evaluated in a mesothelioma cell line, MSTO-211H tumor-bearing mice. The therapeutic efficacy of ⁹⁰Y-labeled mAb 22A31 was evaluated in subcutaneous and pleural dissemination models. Results: mAb 22A31 showed specific binding considering the level of C-ERC/mesothelin expression in each mesothelioma cell line. ¹¹¹In-mAb 22A31 accumulated in tumors with minimal uptake in normal tissues. ⁹⁰Y-mAb 22A31 significantly delayed the growth of subcutaneous tumors and improved survival in a pleural dissemination model. Conclusions: Radiolabeled mAb 22A31 specifically targeted C-ERC/mesothelin and demonstrated therapeutic efficacy in a mesothelioma xerograph model. Therefore, ⁹⁰Y-mAb 22A31 is a promising RIT agent and supports the further development of C-ERC/mesothelin-targeted therapy for mesothelioma. Full article

Pregnancy-associated plasma protein A (PAPPA) is a metalloproteinase that regulates insulin-like growth factor availability via cleavage of IGF-binding proteins, yet its role in cancer remains incompletely understood. Using integrated public datasets, we systematically examined PAPPA expression, prognostic relevance, cellular localization, and stromal associations across multiple tumor types. PAPPA was reduced in several cancers and primarily localized to stromal cells, whereas in cholangiocarcinoma and thyroid carcinoma it was elevated and also detected in malignant cells. High PAPPA expression was associated with poorer overall survival in bladder, cervical, lung squamous, mesothelioma, pancreatic, and gastric cancers, but exhibited a protective effect in lower-grade glioma. In tumors with adverse prognosis, PAPPA strongly correlated with cancer-associated fibroblast (CAF) infiltration and CAF marker genes; however, multivariable Cox analyses indicated that PAPPA generally retained an independent prognostic factor, whereas CAF infiltration was mostly not independently associated with overall survival. Interestingly, in LGG, despite negative PAPPA–CAF correlations, multivariable analysis showed that PAPPA remained protective while CAF infiltration was associated with worse survival. Pathway analyses linked PAPPA-associated genes to proteoglycans in cancer and PI3K–AKT and RAS signaling. Collectively, these findings establish PAPPA as an independent prognostic factor across most cancers, while its expression frequently coincides with high CAF infiltration in select tumor types, highlighting the need for further investigation. Full article

Background/Objectives: Tissue-agnostic therapy has transformed oncology by enabling treatment selection based on molecular alterations rather than tumor origin. Since 2017, nine U.S. Food and Drug Administration approvals across six biomarker classes have defined this paradigm. Thoracic and head and neck (H&N) cancers have been underrepresented in the registrational evidence supporting these approvals. This review systematically evaluated biomarker representation, histologic distribution, and clinical applicability of tissue-agnostic therapies in thoracic and H&N malignancies. Methods: A narrative systematic review was conducted using PubMed, ClinicalTrials.gov, and regulatory documents for all tissue-agnostic approvals between January 2017 and October 2025. Data were extracted from pivotal trials, including total enrollment, objective response rate (ORR), histologic distribution, and thoracic/H&N representation. Emerging biomarkers and resistance mechanisms were assessed from phase I–III studies and basket trials. Results: Nine tissue-agnostic approvals encompassing six biomarkers were identified: MSI-H/dMMR, TMB-High, NTRK, RET, BRAF V600E, and HER2 (IHC 3+). Across pivotal datasets (3800 patients), thoracic and H&N cancers accounted for fewer than 8% (n = 290) of enrolled patients. Thoracic representation was dominated by non-small-cell lung cancer (NSCLC) in RET, NTRK, and HER2 programs (150 patients, 4%), while small-cell lung, mesothelioma, and thymic carcinomas contributed <1% combined. H&N cancers comprised 140 patients (3–4%), primarily secretory salivary carcinoma in NTRK trials (n = 12–20), thyroid carcinoma in BRAF (n = 36) and RET (n = 45) programs, and rare HER2-positive salivary duct carcinomas. Conventional HNSCC and sinonasal cancers were limited to 1–2 cases per trial. Only two of nine trials (22%) reported prespecified CNS endpoints, and RNA-based fusion testing was employed in <40%, underscoring diagnostic variability and limited applicability. Conclusions: Although tissue-agnostic therapy has expanded the reach of precision oncology, thoracic and H&N cancers remain underrepresented in registrational evidence. Most approvals rely on single-arm basket studies with small, heterogeneous subsets that preclude histology-specific conclusions. Future research should prioritize histology-enriched trial designs, standardized molecular diagnostics, and real-world validation to establish reliable, equitable standards of care for these underrepresented malignancies. Full article

Background/Objectives: Peritoneal mesothelioma is a rare malignancy characterized by limited therapeutic options and a poor prognosis. Genomic characterization can enhance the understanding of the molecular mechanisms that lead to this disease and can contribute to improved survival outcomes through therapeutic targets. Methods: Analysis was performed using a dataset from the AACR GENIE database (v17.0-public) comprising 204 samples from 192 patients. Data were analyzed to identify patterns in genomic alterations and clinical demographics. Within the GENIE cohort, histologic subtype information was incomplete and inconsistently reported across contributing institutions. Hence, histological subtype genomic analysis was not viable. Results: The most common somatic mutation was found in the BAP1 gene (25.98%). Other common mutations were found in the NF2 (15.19%), TP53 (9.3%) and SETD2 (8.3%) genes. Several pathways were found as potential treatment targets including the chromatin remodeling, Hippo, and p53 signaling pathways. Given the size of our dataset, we were unable to draw significant conclusions about certain demographics. Conclusions: This study presents data that can help draw conclusions on common mutations, mutual exclusivity patterns, and demographics at risk for peritoneal mesothelioma. Genomic analysis of peritoneal mesothelioma may inform possible intervention targets for therapeutic treatment. Full article

Malignant pleural mesothelioma (MPM) is a rare and aggressive tumor associated with asbestos exposure, which represents a current problem. MPM is characterized by a poor prognosis and an unsatisfactory therapeutic approach. Therefore, improving MPM prognosis is the real challenge for research today. Regarding preclinical data, Transforming Growth Factor-β (TGF-β) plays a crucial role in cancer, and its alteration has been associated with tumor progression and invasiveness, in particular through the Epithelial to Mesenchymal Transition (EMT) event. We investigated the role of TGF-β inhibition in proliferation, cell cycle, migration, and invasiveness in human MPM cells. Data obtained clearly highlighted how TGF-β inhibition, through the silencing or treatment of MPM cells with antibody anti-TGF-β (Fresolimumab), significantly reduces cell proliferation (MTT, PCNA) and prevents metastasis, reducing EMT and decreasing the invasiveness and migration of MPM cells. Finally, we also evaluated TGF-β inhibitory effects in 3D MPM cellular models (spheroids), highlighting a significant slowdown in the growth rate of spheroids treated with anti-TGF-β antibody or Fresolimumab, confirming the results previously obtained. Taken as a whole, targeting TGF-β will represent a starting point for future improvements in MPM management. This is particularly important as we foresee a growing increase in MPM in the coming years. Full article

Pleural mesothelioma (PM) is a rare malignancy with opportunities for improvement in current treatment paradigms despite recent advances in systemic therapy. While histology remains the most clinically relevant prognostic indicator, the expanding use of immunotherapy and ongoing clinical trials involving targeted therapies have increased interest in the development of predictive and prognostic biomarkers in this disease. This review summarizes the current biologic and therapeutic landscape of PM and the biomarkers that influence prognosis and treatment response. Biomarkers such as programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB) demonstrate inconsistent predictive value in PM and are not currently used in clinical decision pathways in the real-world setting. This review highlights the developing role of dynamic biomarkers such as circulating tumor DNA (ctDNA) for molecular response assessment and minimal residual disease (MRD) detection. This review also examines important genomic and transcriptomic alterations in PM, such as MTAP, BAP1, CDKN2A, and NF2/YAP/TEAD. These alterations provide potential targets for ongoing early-phase clinical trials. Future advances in PM will depend on the development and integration of comprehensive biomarker models that combine clinicopathologic, immune, and molecular features of this complex and heterogenous disease. Full article

Immunotherapy has significantly reshaped the management of malignant pleural mesothelioma (MPM), offering new therapeutic opportunities after decades in which platinum–pemetrexed chemotherapy represented the only systemic option. However, clinical benefit remains markedly heterogeneous, with outcomes strongly influenced by histologic subtype, patient characteristics, and real-world treatment conditions. Evidence from monotherapy trials has been inconsistent, whereas combination approaches—particularly nivolumab plus ipilimumab—have demonstrated improved survival compared with chemotherapy, mainly in non-epithelioid tumors. Nevertheless, real-world data consistently show lower efficacy and higher toxicity than registrational studies, especially among elderly and unselected populations. Recent translational work has highlighted the relevance of the tumor microenvironment and recurrent genomic alterations such as BAP1, NF2, and CDKN2A in shaping immune activity and potentially modulating response to immune checkpoint inhibitors. Transcriptomic signatures and circulating biomarkers—including soluble mesothelin-related peptide—have shown prognostic associations but no validated predictive value. Overall, current evidence suggests that sensitivity to immunotherapy in MPM arises from a complex interplay of genomic, immunologic, and clinical factors, and that no biomarker is yet suitable for guiding treatment decisions. Prospective studies integrating molecular and immune profiling will be essential to refine patient selection and advance toward a more rationally personalized use of immunotherapy Full article

SATB2 (special AT-rich binding protein 2) functions as a chromatin-associated epigenetic regulator that modulates gene expression, in part by serving as a transcriptional cofactor. This study assessed whether SATB2 overexpression is sufficient to promote in vitro transformation of human mesothelial cells and whether SATB2 suppression in mesothelioma cancer stem cell (CSC)–enriched populations is associated with altered chemoresistance. SATB2 expression was high in human malignant pleural mesothelioma (MPM) cell lines but absent in Met5A mesothelial cells. Ectopic SATB2 expression in Met5A cells was associated with acquisition of malignant and stem cell–like phenotypes, including increased expression of stem cell markers and pluripotency-associated factors, as well as anchorage-independent growth in soft agar and spheroid formation in suspension culture. In contrast, Met5A cells transduced with an empty vector did not form colonies or mesospheres. SATB2 overexpression in Met5A cells was also associated with increased motility, migration, and invasion, accompanied by induction of epithelial–mesenchymal transition (EMT)–related transcription factors relative to empty vector controls. Conversely, shRNA-mediated SATB2 knockdown in an MPM cell line attenuated proliferation, EMT-associated features, and CSC-like characteristics. Chromatin immunoprecipitation assays identified SATB2 occupancy at promoter regions of Bcl2, XIAP, KLF4, c-Myc, NANOG, and SOX2, consistent with a role in transcriptional regulation of genes linked to transformation, pluripotency, cell survival, proliferation, and EMT. In CSC-enriched cells, SATB2 inhibition was associated with increased sensitivity to cisplatin and pemetrexed, concomitant with reduced OCT4 and SOX2 expression. Collectively, these findings support SATB2 as a candidate therapeutic target in MPM and suggest that SATB2 suppression may enhance chemotherapy response when combined with standard agents. Full article

Background: Malignant pleural mesothelioma (MPM) is an aggressive neoplasm, the major cause of which is asbestos exposure. Adjuvant radiotherapy after pleurectomy/decortication (P/D) aims at reducing locoregional recurrence but is limited by the risk of radiation pneumonitis (RP). In this study, we attempted to evaluate the predictive value of conventional and functional dosimetric parameters in assessing RP risk. Methods: This retrospective study analyzed 68 patients with non-metastatic MPM treated with adjuvant radiotherapy after P/D. Dosimetric parameters, including V20, V5, and mean lung dose (MLD), were calculated for both total lung volume and functional lung volume (FLV), with emphysematous regions excluded based on CT imaging thresholds. Statistical analyses assessed correlations between these parameters and acute RP incidence. Results: Acute RP developed in 42% of patients, and 28% had moderate-to-severe (Grade 2–3) events. V20 and FCL_V20 were significantly associated with the risk of RP (p = 0.017 and p = 0.028, respectively). Predictive accuracy for conventional V20 (AUC = 0.668) and Functional Contralateral Lung V20 (FCL_V20) (AUC = 0.655) showed moderate efficacy, without further significant improvement in using functional parameters. A V20 threshold > 1.8% predicted severe RP with high specificity (89.8%). Conclusions: While functional lung delineation provides an alternative in dosimetry, conventional V20 is a robust predictor of RP. Optimization of dosimetric constraints, in an effort to reduce pulmonary toxicity in MPM patients, should be further combined with advanced radiotherapy techniques and biomarkers. Full article

Malignant pleural mesothelioma (MPM) is a very aggressive tumor. The prognostic value of PD-L1 and BAP1 expression has been investigated in many studies. A retrospective study was conducted that analyzed PD-L1 and BAP1 expression as prognostic biomarkers in patients with MPM. The study included 53 patients with MPM. PD-L1 expression ≥ 1% was found in 39.6%, and BAP1 loss was found in 81.1% of patients. The median overall survival (mOS) was 11 months. Subtype of MPM (p = 0.045), early tumor stage (p = 0.049), therapy (p = 0.002), and good PS (0–1) (p = 0.012) were associated with better survival. Expression of PD-L1 and BAP1 did not show statistical significance regarding OS, but OS was numerically shorter in patients with PD-L1 ≥ 10% (5 vs. 12 months) and longer in patients with BAP1 loss (12 vs. 4 months). In patients with PD-L1 ≥ 1% and BAP1 loss, the median progression-free survival (mPFS) was numerically longer (10 vs. 7 months) but in patients with PD-L1 ≥ 1% and BAP1 positivity, PFS was statistically significantly shorter (1 vs. 7 months, p = 0.048). Our results did not show that PD-L1 and BAP1 are prognostic biomarkers for MPM, but positive PD-L1 expression and BAP1 loss were associated with worse survival in patients with MPM. Full article

The present review paper focuses on the peculiar environmental and health implications of fibrous amphibole “fluoro-edenite”, a new mineral first reported in Biancavilla (Etna Mount, Sicily, Italy). Its presence has been linked to an unusually high incidence of malignant pleural mesothelioma, as seen from national surveys during 1988–1997, marking the first case study of natural occurrence of fibrous amphibole in a volcanic context. Despite remediation efforts since the cessation of quarrying activities at the “Il Calvario” quarry, the risk of fiber exposure may extend beyond urban areas to surrounding soils and volcanic formation, not fully characterized yet. This review synthesizes relevant existing literature on mineralogical and chemical features of fluoro-edenite, while also enriching current understanding with new observations from optical microscopy, stereomicroscopy, and Scanning Electron Microscopy (SEM). Our analyses reveal the presence of fluoro-edenite amphibole not only in the altered samples but, significantly, within the massive rock samples. This finding expands its known distribution and offers initial consideration on public health implications related to massive lava rock, which crops out. This study highlights the importance of ongoing monitoring, detailed geological surveys, and further research into fiber occurrences and distribution in the volcanic systems, of which Mt. Etna represents the first case of natural occurrences, in order to fully assess their impact on public health. Full article