Mechanisms of Chemoresistance in Malignant Pleural Mesothelioma: The Regulatory Role of miRNAs.

Malignant pleural mesothelioma (MPM) is a rare and aggressive neoplasm with limited long-term survival. We report a case of a 72-year-old woman diagnosed with epithelioid MPM and NF2 mutation in 2018, who presented with a solitary adrenal metastasis six years after initial diagnosis. After initial surgery and chemotherapy, disease progressed within one year. Immunotherapy with ipilimumab and nivolumab resulted in long-term disease control. This case highlights an exceptionally delayed metachronous adrenal metastasis and prolonged survival under sustained immunotherapy.

Diffuse malignant peritoneal mesothelioma (DMPM) is a very rare and life-threateningmalignant tumor. We present a report of a rare case of a 70-year-old female patient with emaciation and poor appetite as manifestations. The characteristics of signs and clinical manifestations in this case were atypical. Abdominal CT scan revealed a large mass in the right retroperitoneal region beside the inferior vena cava. A neurogenic tumor was considered, and a ganglioneuroma was highly likely. There was no indication of multiple peritoneal implants/seedings in the peritoneum, omentum and liver. Subsequently, an endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) was performed. The samples were processed into cell blocks, followed by hematoxylin-eosin (H&E) staining and immunohistochemical staining for observation. The results indicated a possible diagnosis of mesothelioma, while neurogenic tumors were ruled out. During the operation, Multiplenodular tumor lesions were observed between the hepatogastric ligament, on the surface of the liver, inthe omentum, and at the splenic hilum, indicating that enhanced CT has certain limitations. If PET-CThad been performed preoperatively, the diagnosis might have been more comprehensive. The diagnosisof DMPM was further verified by laparotomy biopsy. EUS-FNA is a good auxiliary diagnostic method.

Distinguishing epithelioid malignant mesothelioma (EMM) from poorly differentiated lung adenocarcinoma (PD-LUAD) remains challenging, particularly when 21.7% of PD-LUADs lack lineage-specific markers (thyroid transcription factor-1 (TTF-1)/Napsin A), creating a diagnostic blind spot. While GATA-binding protein 3 (GATA3) is established in sarcomatoid mesothelioma, its complementary diagnostic value and prognostic relevance in EMM are not well defined. This retrospective study analysed 115 tissue specimens (55 EMMs; 60 PD-LUADs). Immunohistochemistry for GATA3, calretinin, Wilms' tumour gene 1 (WT-1), TTF-1, Napsin A and pan-cytokeratin was performed. Results were correlated with clinicopathological parameters and overall survival (OS) using Kaplan-Meier and multivariate Cox regression analyses. GATA3 was expressed in 78.2% of EMM but only 6.7% of PD-LUAD cases (p<0.001). Although not specific enough for standalone diagnosis, GATA3 provided meaningful complementary value: in TTF-1/Napsin A-negative PD-LUAD, GATA3 remained negative in 92.3%, helping to exclude EMM when used within a broader panel. Incorporating GATA3 with calretinin and WT-1 improved panel sensitivity to 96.4% while maintaining 100% specificity.High GATA3 expression in EMM correlated significantly with advanced T stage, higher International Mesothelioma Interest Group stage and poor functional status (Karnofsky performance status/Eastern Cooperative Oncology Group). Multivariate analysis identified GATA3 expression (p=0.037), smoking (p=0.041) and clinical T stage (p<0.001) as independent predictors of shorter OS. A qualitative inverse relationship between tumorous GATA3 and GATA3-positive tumour-infiltrating lymphocytes was also noted. GATA3 serves as a useful adjunct within established immunohistochemical panels, particularly in resolving ambiguity in double-negative PD-LUAD. Beyond its supportive diagnostic role, GATA3 demonstrates independent prognostic significance and may reflect underlying immune-microenvironmental features, meriting further exploration in biomarker-guided therapeutic stratification.

Malignant peritoneal mesothelioma (MPM) is a rare and aggressive tumour with poor prognosis, often diagnosed late due to nonspecific symptoms. Current standard treatment involves systemic chemotherapy and cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC), but this approach is limited to selected patients. Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) has emerged as a novel technique improving drug delivery and penetration in the peritoneal cavity. This narrative review evaluates the role of PIPAC in the treatment of MPM, analysing data from clinical studies on its feasibility, safety, and efficacy. Evidence suggests that PIPAC is a well-tolerated procedure, with a manageable safety profile and potential to improve survival and tumour response in patients with unresectable or recurrent disease. Limitations in current studies include small cohorts and heterogeneous patient populations, underscoring the need for further research. PIPAC represents a promising therapeutic option, offering enhanced intraperitoneal chemotherapy (IPC) delivery with minimal systemic toxicity. Future investigations should focus on optimizing treatment protocols and evaluating long-term benefits to better define PIPAC's role in clinical practice.

Energy metabolism plays a crucial role in determining the aggressiveness of cancer. In this study, we assessed the impact of drug-induced modulation on the expression and prognostic significance of crucial factors involved in glycolytic metabolism: lactate dehydrogenase A (LDH-A) and glucose transporter type 1 (GLUT-1). In patient samples diagnosed with pleural Malignant Mesothelioma (MM), expression levels of LDH-A and GLUT-1 were studied both at baseline and after platinum-based-chemotherapy. High GLUT-1 and LDH-A levels were associated with shorter survival, and chemotherapy increased GLUT-1 expression, further correlating with poor prognosis. Utilizing LDH-A (NHI-2) and GLUT-1 (PGL14) inhibitors, we examined their effects on migration and apoptosis in immortalized (H2052, H2452) and primary (STO, MESO-II) MM cells. PGL14 and NHI-2 decreased migration, increased reactive oxygen species (ROS) and apoptosis rates. Inhibitors, both single and in combination, disintegrated the MM spheroids, while the bioluminescence from spheroid-forming cells decreased from 1.3 × 105 in the control group to 9.7 × 104 and 7.1 × 104 [RLU/s] after NHI-2 and PGL14/NHI-2 treatment, respectively. Overexpression and chemotherapy-induced modulation of LDH-A and GLUT-1 correlated with poor MM prognosis. Combined inhibition of these two metabolic determinants impeded MM cell migration, stimulated ROS production and apoptosis, and affected spheroids' growth, offering promise for new treatment development.

BAP-1 in the diagnosis of malignant pleural mesothelioma.

Mordenite is a naturally occurring zeolite mineral that is the seventh most common zeolite mineral globally, forming at low temperatures (≥100°C) in hydrothermal systems. In New Zealand, extensive deposits of mordenite are commonly associated with areas of hydrothermal alteration, particularly in the Coromandel and Taupo Volcanic Zones. Mordenite can form fibrous minerals, and several industries have the potential to disturb these naturally occurring mineral fibres, causing them to become aerosolised and potentially respirable. Nevertheless, mordenite is not currently known to be carcinogenic, in contrast to the fibrous zeolite, erionite. Indeed, erionite is a Group 1 carcinogen that has been linked to malignant mesothelioma due to its fibrous‐asbestiform shape and biodurability. In this study, mordenite from New Zealand is characterised and compared to erionite, using X‐ray powder diffraction (XRPD), scanning electron microscopy–energy dispersive spectroscopy (SEM–EDS), and an automated scanning electron microscope (SEM), in order to understand the extent, occurrence and morphology of mordenite in New Zealand. It also enables the evaluation of potential health implications, including whether these naturally occurring mineral fibres are respirable.

Tumours harbouring FET::CREB fusions, particularly those involving EWSR1/FUS and CREM, represent an emerging group that is distinct from and unclassifiable into established categories such as angiomatoid fibrous histiocytoma, clear cell sarcoma of soft tissue, or malignant gastrointestinal neuroectodermal tumour. This study aims to further delineate the clinicopathological, immunohistochemical, and molecular features of these rare mesenchymal neoplasms with EWSR1/FUS::CREM fusions, focusing on diagnostic challenges and aggressive potential. We analysed seven cases of mesenchymal neoplasms with EWSR1/FUS::CREM fusions through detailed clinicopathological evaluation, extensive immunohistochemical profiling, and molecular genetic analysis [RNA sequencing and fluorescence in situ hybridization (FISH)]. The cohort included five females and two males (age range: 5-55 years) with tumours involving diverse intra-abdominal and extra-abdominal locations. Histologically, all tumours were composed predominantly of monomorphic epithelioid to round cells, with one case showing focal spindling. The neoplastic cells were arranged in solid sheets, nests, and trabeculae, set within a variably collagenous stroma. Mitotic activity was variable, and tumour necrosis was present in two cases. A prominent lymphoplasmacytic infiltrate was noted in three cases. Immunohistochemistry revealed a strikingly heterogeneous profile, which directly led to a wide spectrum of initial misdiagnoses. These included: epithelial malignant mesothelioma in two intra-abdominal tumours co-expressing AE1/AE3 and WT1; Ewing sarcoma in one CD99-positive tumour; a sex cord-stromal tumour in one ovarian neoplasm co-expressing S100, SOX10, and α-inhibin; epithelioid hemangioendothelioma in one case co-expressing CD34 and ERG; a neurogenic tumour in one case with synaptophysin expression; and metastatic carcinoma in a lymph node in one case, which was misdiagnosed due to diffuse expression of AE1/AE3 and a dense lymphoplasmacytic infiltrate mimicking a nodal metastasis. Molecular analysis via targeted RNA sequencing identified in-frame EWSR1::CREM fusions in five cases and a FUS::CREM fusion in two cases, all of which were confirmed by FISH. Clinically, two patients presented with disseminated disease, and all three with follow-up had aggressive courses (recurrence or metastasis). Our series solidifies epithelioid mesenchymal neoplasms with EWSR1/FUS::CREM fusions, which constitute a distinct sarcoma characterized by a misleading immunophenotype, with potential for aggressive clinical behaviour. Accurate diagnosis requires molecular confirmation to avoid diagnostic pitfalls and guide management.

Background: Primary malignant pericardial mesothelioma (PMPM) is an exceptionally rare and aggressive cancer originating from the mesothelial lining of the heart. This distinct and challenging oncologic entity is typically discovered at an advanced stage due to vague, nonspecific symptoms—most commonly chest pain and dyspnea. These clinical features often mimic more common conditions, making early detection difficult. Diagnostic confirmation usually requires detailed histopathologic analysis, often obtained through surgical procedures or postmortem examination. The disease’s elusive nature and rapid progression contribute to its generally poor prognosis, underscoring the need for heightened clinical awareness and advanced diagnostic strategies.Case Report: A 58-year-old patient was diagnosed with malignant pericardial mesothelioma, which progressed rapidly and resulted in death within 1 month of diagnosis.Conclusions: PMPM remains a rare and highly aggressive cancer characterized by swift, fatal progression. Diagnosis is difficult because of nonspecific clinical symptoms. Accurate diagnosis is essential for subsequent treatment planning. Nonetheless, limited treatment alternatives, coupled with the minimal effectiveness of immunotherapy in advanced disease, highlight the pressing need for further research and therapeutic advances

Malignant mesothelioma is a rare but highly aggressive malignancy associated with a poor prognosis. Similar to many other solid tumors, cytotoxic chemotherapy has traditionally been the standard treatment for patients with locally advanced or metastatic malignant pleural mesothelioma (MPM). However, with increasing recognition of immune dysregulation, immune-directed therapies have assumed a growing role in the management of mesothelioma. Here, we report a case of epithelioid-type malignant pleural mesothelioma that demonstrated primary resistance to ipilimumab plus nivolumab, followed by a marked metabolic response on 18F-FDG PET/CT after switching to bevacizumab plus pemetrexed plus carboplatin.

A man in his 60s with asbestos exposure and pleural plaques was incidentally found to have a chest wall mass on computed tomography (CT). Positron emission tomography/CT (PET/CT) demonstrated intense 18F-fluorodeoxyglucose (FDG) uptake, raising concern for malignancy, including malignant pleural mesothelioma. CT and magnetic resonance imaging (MRI), however, showed a predominantly fat-containing lesion, suggesting hibernoma. Video-assisted thoracoscopic resection was performed, and histopathology confirmed hibernoma. Recognition of macroscopic fat on CT/MRI is essential to avoid misdiagnosis of FDG-avid benign lipomatous tumors.

Mesothelial cell inclusions within lymph nodes are rare and may closely mimic metastatic malignant mesothelioma, particularly on cytologic evaluation. We report a 19-year-old man who presented with bilateral chylothorax, mediastinal lymphadenopathy, and extensive venous thrombosis, raising an initial concern for malignancy. Fine-needle aspiration of an inframammary lymph node demonstrated numerous mesothelial cells. Subsequent histopathologic evaluation, immunohistochemistry and fluorescence in situ hybridization confirmed a benign reactive mesothelial proliferation. Recognition of mesothelial cell inclusions, particularly in uncommon nodal locations, is essential to avoid diagnostic error. This report highlights the importance of clinicopathologic correlation and the judicious use of ancillary studies in distinguishing benign mesothelial inclusions from metastatic disease.

Clinical, diagnostic and prognostic relevance of GATA3 in malignant pleural mesothelioma: a retrospective cohort study

This study aims to achieve accurate differentiation of malignant pleural mesothelioma (MPM) from metastatic pleural disease (MPD) and to predict the overall survival of MPM. This IRB-approved retrospective study included 385 subjects in total (85 patients with malignant mesothelioma and 290 with MPD secondary to lung adenocarcinoma). A ResNet-3D-18 model was trained on annotated pretreatment CT scans to distinguish MPM from MPD. Using chronological segregation, the training cohort included 70 histologically confirmed mesothelioma and 258 MPD cases, with an independent test cohort of 15 MPM and 32 MPD cases for validation. A multivariate logistic regression model served as the clinical benchmark for comparison. Deep learning features extracted from the trained ResNet model were then assessed for their prognostic utility in MPM patients using a random forest classifier. Model performance was evaluated at both lesion- and patient-levels, with metrics including the area under the ROC curve (AUC), accuracy, sensitivity, specificity, positive predictive value, and negative predictive value. The ResNet-3D-18 model demonstrated excellent discriminative performance in differentiating MPM from MPD, with mean AUCs of 0.972 (95% CI 0.947-0.990) and 0.840 (95% CI 0.757-0.929) in the training and independent test cohorts. Compared to the clinical model, the deep learning approach showed higher sensitivity (0.867 vs. 0.533) in the independent test dataset. For overall survival prediction in MPM patients, the random forest classifier achieved an AUC of 0.829 (95% CI 0.663-0.943) in 5-fold cross-validation. ResNet-3D-18 classification model has excellent abilities in differentiating MPM from MPD, and morphological distinctions between MPM and MPD also contain prognostic information. Question The rising global incidence of malignant pleural mesothelioma contrasts with persistent diagnostic challenges. Findings Deep learning-derived discriminative features simultaneously contain prognostic information. Clinical relevance This study bridges the gap between radiological findings and clinical decision-making in MPM, offering a reproducible tool for early diagnosis and personalized prognosis prediction based on CT imaging alone.

WCN26-5285 C3 GLOMERULOPATHY ASSOCIATED WITH IMMUNE CHECKPOINT INHIBITOR THERAPY IN A PATIENT WITH MALIGNANT PLEURAL MESOTHELIOMA: A CASE REPORT

High-dose ascorbic acid (AA) has shown promise as an adjunctive treatment for various cancers because of its prooxidant cytotoxicity at high concentrations and its multitargeting effects. However, identifying patients who may benefit from AA treatment remains an unmet need, as the therapeutic efficacy of AA is controversial. In this study, we aimed to use an AA analog-6-deoxy-6-18F-fluoro-l-AA (18F-FAA)-as a PET tracer and evaluate its uptake in various cancers, exploring its potential clinical application. Methods: This prospective study enrolled 116 patients with histopathologically confirmed malignant tumors who underwent 18F-FAA PET/CT. Tumors were quantitatively analyzed using the SUVmax, SUVpeak, and tumor-to-background ratio. Results: In total, 23 types of malignant tumors were assessed for their uptake of 18F-FAA, which was divided into tertiles using SUVmax percentiles. The highest uptake was observed in pheochromocytoma and paraganglioma, glioblastoma, and specific epithelial malignancies (e.g., nasopharyngeal, thyroid, and prostate carcinomas), with a median SUVmax exceeding 12.7, whereas the lowest uptake was found in breast, gastric, bladder, colorectal, and pancreatic cancers (median SUVmax, <8.2). Moderate uptake was noted in melanoma, diffuse large B-cell lymphoma, endometrial cancer, ovarian cancer, non-small cell lung cancer, cervical cancer, tumors of unknown primary origin, germ cell tumors, renal cancer, esophageal cancer, salivary duct carcinoma, malignant peritoneal mesothelioma, and hepatocellular carcinoma. The SUVpeak of these tumors was consistent with these findings. Both primary tumors and metastatic lesions exhibited tumor-specific degrees of 18F-FAA uptake and image contrast, with higher uptake in metastatic lesions (median SUVmax, 8.1 vs. 9.5, respectively; P = 0.026; tumor-to-background ratio, 12.9 vs. 14.9, respectively; P = 0.045). Conclusion: 18F-FAA PET/CT demonstrated distinct uptake characteristics across various tumor types and may provide new opportunities for the noninvasive assessment of tumor AA uptake characteristics and AA-based therapy.

One recurring challenge in cell therapy for solid tumors is poor tumor infiltration of adoptively transferred T cells. We previously showed that a subablative dose of tumor-targeted radiation generates a chemokine gradient that promotes infiltration, proliferation, and a memory phenotype of chimeric antigen receptor (CAR) T cells in solid tumors. However, radiation is cytotoxic to infiltrating CAR T cells, limiting its repeated use. We hypothesized that irreversible electroporation could generate a chemokine gradient that promotes CAR T-cell infiltration into solid tumors and that selective irreversible electroporation (sIRE) tuned for selective cancer cell lysis (thus, sparing infiltrating CAR T cells) can be used in a repeated fashion. Using experimental screening and simulation models, we optimized sIRE parameters to kill cancer cells while sparing T cells. Using 3D tumor mimics and mouse models of malignant pleural mesothelioma, we confirmed the therapeutic benefit of repeated sIRE. Chemokine secretion by cancer cells injured by sIRE promoted migration and tumor infiltration of systemically administered CAR T cells and facilitated sustained immunity in a tumor-rechallenge model. By leveraging a dual-purpose translational strategy-through direct cancer cell-targeted cytotoxicity and augmented CAR T-cell infiltration-sIRE can reduce cancer burden while preserving and enhancing CAR T-cell function.

WCN26-7324 MINIMAL CHANGE DISEASE ASSOCIATED WITH MALIGNANT PLEURAL MESOTHELIOMA ACHIEVING COMPLETE REMISSION FOLLOWING NIVOLUMAB TREATMENT

Hyperthermic intrathoracic chemotherapy (HITHOC) has emerged as a significant multimodal therapeutic adjunct for the management of aggressive pleural malignancies, primarily malignant pleural mesothelioma and stage IVA thymoma. By combining surgical cytoreduction with the local administration of heated chemotherapeutic agents, HITHOC aims to eliminate microscopic residual disease while minimizing systemic toxicity. A comprehensive Boolean search was conducted using PubMed/Medline, Google Scholar, Embase and Scopus to identify relevant studies on the use of HITHOC for pleural malignancies. Findings were summarised regarding HITHOC’s biological rationale, applications, integration with surgery and methodological challenges. While large retrospective analyses suggest meaningful improvements in overall survival and locoregional control, the technique is currently characterized by a high degree of protocol heterogeneity across global centers. This review synthesizes current evidence on the biological rationale, clinical outcomes across various histologies, safety profiles, and the methodological barriers that must be addressed for the formal consolidation of HITHOC into international treatment guidelines.