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The Hippo tumor suppressor pathway controls transcription by regulating nuclear abundance of YAP and TAZ, which activate transcription with the TEAD1-TEAD4 DNA-binding proteins. Recently, several small-molecule inhibitors of YAP and TEADs have been reported, with some entering clinical trials for different cancers with Hippo pathway deregulation, most notably, mesothelioma. Using genome-wide CRISPR/Cas9 screens we reveal that mutations in genes from the Hippo, MAPK, and JAK-STAT signaling pathways all modulate the response of mesothelioma cell lines to TEAD palmitoylation inhibitors. By exploring gene expression programs of mutant cells, we find that MAPK pathway hyperactivation confers resistance to TEAD inhibition by reinstating expression of a subset of YAP/TAZ target genes. Consistent with this, combined inhibition of TEAD and the MAPK kinase MEK, synergistically blocks proliferation of multiple mesothelioma and lung cancer cell lines and more potently reduces the growth of patient-derived lung cancer xenografts in vivo. Collectively, we reveal mechanisms by which cells can overcome small-molecule inhibition of TEAD palmitoylation and potential strategies to enhance the anti-tumor activity of emerging Hippo pathway targeted therapies. Synopsis: Genome-wide CRISPR/Cas9 screens identify mechanisms by which mesothelioma cells respond to TEAD palmitoylation inhibitors, which are the first Hippo pathway targeted therapies. MAPK pathway targeted therapies enhance the anti-tumor activity of TEAD inhibitors. Mutating the Hippo, MAPK, and JAK-STAT pathways modulates the cellular response to TEAD inhibitors. MAPK pathway hyperactivation confers resistance to TEAD inhibition by reinstating expression of a subset of YAP/TAZ targets. Combined inhibition of TEAD and MEK synergistically blocks proliferation of mesothelioma and lung cancer cell lines. MEK inhibitors enhance the ability of TEAD inhibitors to suppress the growth of patient-derived lung cancer xenografts. Genome-wide CRISPR/Cas9 screens identify mechanisms by which mesothelioma cells respond to TEAD palmitoylation inhibitors, which are the first Hippo pathway targeted therapies. MAPK pathway targeted therapies enhance the anti-tumor activity of TEAD inhibitors. [ABSTRACT FROM AUTHOR]

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Scrotal malignant mesothelioma is an aggressive tumor arising from the tunica vaginalis. Due to its rarity, this tumor is often accidentally found during histological evaluation and there are no recommendations for treatment. Based on three case presentations we try to draw attention for this rare disease and highlight the importance of referring these patients to a tertiary center. [ABSTRACT FROM AUTHOR]

Myristoylation, the N-terminal addition of the fatty acid myristate to proteins, regulates membrane-bound signal transduction pathways important in cancer cell biology. This modification is catalyzed by two N-myristoyltransferases, NMT1 and NMT2. Zelenirstat is a first-in-class potent oral small molecule inhibitor of both NMT1 and NMT2 proteins. Patients with advanced solid tumors and relapsed/refractory (R/R) B-cell lymphomas were enrolled in an open label, phase I dose escalation trial of oral daily zelenirstat, administered in 28-day cycles until progression or unacceptable toxicity. The endpoints were to evaluate dose-limiting toxicities (DLT) to establish a maximum tolerated dose (MTD), pharmacokinetic parameters, and anticancer activity. Twenty-nine patients were enrolled (25 advanced solid tumor; 4 R/R B-cell lymphoma) and 24 were DLT-evaluable. Dosing ranged from 20 mg once daily (OD) to 210 mg OD without DLT, but gastrointestinal DLTS were seen in the 280 mg cohort. MTD and recommended phase 2 dose were 210 mg OD. Common adverse events were predominantly Gr ≤ 2 nausea, vomiting, diarrhea, and fatigue. Plasma concentrations peaked at 2 h with terminal half-lives averaging 10 h. Steady state was achieved by day 15, and higher doses achieved trough concentrations predicted to be therapeutic. Stable disease as best response was seen in eight (28%) patients. Progression-free survival and overall survival were significantly better in patients receiving 210 mg OD compared to those receiving lower doses. Zelenirstat is well-tolerated, achieves plasma exposures expected for efficacy, and shows early signs of anticancer activity. Further clinical development of zelenirstat is warranted. [ABSTRACT FROM AUTHOR]

Wolffian tumor and its nosologic relative, the recently defined STK11 adnexal tumor are rare neoplasms thought to arise from mesonephric remnants. These tumors typically arise in the broad ligament, fallopian tube, and ovarian hilum and although most are associated with a good prognosis, up to 50% of STK11 adnexal tumors demonstrate aggressive clinical behavior. The chief differential diagnoses include endometrioid adenocarcinoma and sex cord stromal tumors. However, the morphologic and immunohistochemical features of these tumors exhibit considerable overlap with peritoneal mesothelioma. To fully characterize their immunophenotypic signature, we examined a total of 21 cases (18 Wolffian and 3 STK11 adnexal tumors) with standard markers used in the diagnosis of mesothelioma. Morphologic and immunohistochemical (IHC) features were reviewed and additional IHC performed for cases with available material. Patient age ranged from 25 to 73 (mean: 51) years. Sites included adnexa/broad ligament (6, 28%), paratubal (5, 24%), ovary/paraovarian (5, 24%), tubal (intraluminal) (2, 9.5%), pelvis (2, 9.5%), and liver (1, 5%). The mean tumor size was 9.3 cm (range: 0.2 to 22 cm). The histomorphology in most cases (14/21, 66%) consisted of tubular to solid sheets of neoplastic cells lined by columnar to cuboidal cells containing uniform round to oval nuclei. Compressed tubules with slit-like lumens and sieve-like pattern were also seen in at least 7 (33%) cases. Three cases demonstrated interanastomosing cords and trabeculae of epithelioid cells with cribriform and microacinar patterns growing within prominent myxoid stroma as described in STK11 adnexal tumors. In the cases with available IHC for 3 mesothelial markers (calretinin, WT1, D2-40), 55.5% (5 of 9) showed reactivity with all 3 markers. In cases with at least 2 available mesothelial markers, 69% (11/16) were positive for 2 markers (mostly calretinin and WT1). Claudin-4, MOC31, and BER-EP4 were negative in most cases tested (78% [7/9], 71.4% [5/7], and 100% [6/6], respectively). Given the resemblance to mesothelioma, there was initial strong consideration and/or actual misdiagnosis of mesothelioma in 3 cases (14%). In summary, the morphologic and immunohistochemical features of Wolffian tumor and its recently defined relative, STK11 adnexal tumor, can lead to misdiagnosis of mesothelioma, particularly when encountered in the disseminated or metastatic setting. Wolffian tumor and STK11 adnexal tumor should be considered in the differential diagnosis of all pelvic and peritoneal mesotheliomas. [ABSTRACT FROM AUTHOR]

Background: It has been observed that under the single isocenter conditions, the potential shifts of the electronic portal imaging devices (EPID) may be introduced when executing portal dosimetry (PD) plans for bilateral breast cancer, pleural mesothelioma, and lymphoma. These shifts are relative to the calibration positions of EPID and result in significant discrepancies in the plan verification results. Purpose: To explore methods including correction model and specific correction matrices to revise the data obtained from displaced EPID. Methods: Two methods, the correction model and the specific correction matrices, were applied to correct the data. Five experiments were designed and conducted to build correction model and to validate the effectiveness of these two methods. Gamma passing rates were calculated and data profiles along X‐axis and Y‐axis were captured. Results: The gamma passing rates for the EPID‐displaced IMRT validation plans after applying correction model, along with the application of specific correction matrices to VMAT and IMRT validation plans, exhibit results that are comparable to the cases with non‐displaced EPID. Except for the VMAT plans applied correction model which showed larger discrepancies (0.041 ± 0.028, 0.049 ± 0.030), the other three exhibit minimal differences in discrepancy values. In all profiles, the corrected data from displaced EPID exhibit a high level of agreement with data obtained from non‐displaced EPID. Good consistency is observed in actual application of the correction model and the specific correction matrices between gamma passing rates of data corrected and those of non‐displaced data. Conclusions: The proposed methods involving correction model and specific correction matrices can correct the data collected from the displaced EPID, and the gamma passing rates of the corrected data show results that are comparable to some extent with those of non‐displaced data. Particularly, the results corrected by specific correction matrices closely resemble the data from non‐displaced EPID. [ABSTRACT FROM AUTHOR]

Jointpoint Regression Software from the National Cancer Institute was used to model age-adjusted male and female pleural and peritoneal mesothelioma rates in the surveillance, epidemiology, and end results (SEER) 8, SEER 12, and SEER 22 cancer registries. Linear mixed models were then used to determine if there was a statistical association between U.S. cosmetic talc consumption and the 30-year lagged age-adjusted mesothelioma rates (1) over the reporting period for each registry and (2) for the periods of time identified by the jointpoint model where changes in the rate of mesothelioma occurred. Regardless of the SEER registry used, from the early-1980s through 2020, rates of peritoneal mesothelioma have remained steady or declined. Female pleural mesothelioma rates were unchanged from the early-1980s until 2017 when rates declined, while male rates peaked in the early 1990s and have since declined. Cosmetic talc consumption was not statistically associated with an increased rate of pleural or peritoneal mesothelioma in males or females, suggesting that the use of cosmetic talc products is not associated with the development of mesothelioma. [ABSTRACT FROM AUTHOR]

We report that ~1.8% of all mesothelioma patients and 4.9% of those younger than 55, carry rare germline variants of the BRCA1 associated RING domain 1 (BARD1) gene that were predicted to be damaging by computational analyses. We conducted functional assays, essential for accurate interpretation of missense variants, in primary fibroblasts that we established in tissue culture from a patient carrying the heterozygous BARD1V523A mutation. We found that these cells had genomic instability, reduced DNA repair, and impaired apoptosis. Investigating the underlying signaling pathways, we found that BARD1 forms a trimeric protein complex with p53 and SERCA2 that regulates calcium signaling and apoptosis. We validated these findings in BARD1-silenced primary human mesothelial cells exposed to asbestos. Our study elucidated mechanisms of BARD1 activity and revealed that heterozygous germline BARD1 mutations favor the development of mesothelioma and increase the susceptibility to asbestos carcinogenesis. These mesotheliomas are significantly less aggressive compared to mesotheliomas in asbestos workers. [ABSTRACT FROM AUTHOR]

Simple Summary: Hyperthermic intrathoracic chemotherapy (HITHOC) is an intraoperative and topical administration of chemotherapeutic drugs with simultaneous warming of the thoracic cavity. This procedure was first described by Spratt in 1980 as a thermal transfusion infiltration system, performed on canine models to treat malignant effusions of metastatic abdominal cancers. The main tumors causing malignant pleural effusion, which have been seen to benefit from hyperthermic intrathoracic chemotherapy, are mesothelioma, thymic malignancies and lung cancer: despite the high prevalence of MPE in patients with metastatic breast and ovarian cancers, there are still inadequate data on the use of HITHOC as a treatment option for these malignancies. Pleural mesothelioma (PM) is a rare but aggressive thoracic tumor with a poor prognosis. Multimodal treatment—including induction chemotherapy, aggressive surgical resection, radiotherapy and immunotherapy in selected cases—currently represents the best therapeutic option. Single-center studies advocate hyperthermic intrathoracic chemotherapy (HITHOC) during surgical resection as an additional therapeutic option, although its impact on post-operative morbidity and survival has not yet been evaluated on a larger scale. HITHOC can be applied not only in the case of mesothelioma, but also in the case of thymoma with pleural involvement or—in very selected cases—in patients with secondary pleural metastases. Despite favorable outcomes and reduced clinical risks, there is no uniform approach to HITHOC, and a wide variety of indications and technical applications are still reported. Based on available data, HITHOC seems to offer a clear benefit in regard to overall survival of all mesothelioma patients; however, multicenter randomized controlled trials are required to validate and standardize this approach. The aim of this review is to focus on the present role of HITHOC in thoracic tumors with pleural involvement as well as on future challenges, particularly in the light of possible combined therapy of thoracic tumors still presenting poor prognoses. [ABSTRACT FROM AUTHOR]

Dinuclear Au(I) complexes with bisphosphine ligands, namely [Au2Cl2(L)], where L = 4,6-bis(diphenylphosphino)pyrimidine (Au1) or 1,7-bis(di-o-tolylphosphinyl)-m-carborane (Au2), have been synthesized. The complexes were characterized by analytical and spectroscopic methods and their crystal structures were determined by X-ray diffraction analysis. Both complexes demonstrated photoluminescence in the solid state at 300 K when excited at 300–400 nm: from blue emission (∼400 nm) for Au1 to green emission (∼500 mn) for Au2. The lifetimes of the excited state were determined to be in the microsecond range, indicating the triplet nature of the emission levels. Preliminary bioactivity tests for complexes Au1 and Au2 in comparison with the respective ligands and cisplatin have been performed. [ABSTRACT FROM AUTHOR]

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

Introduction: Diffuse pleural mesothelioma (DPM) of the pleura is a highly aggressive and treatment-resistant cancer linked to asbestos exposure. Despite multimodal treatment, the prognosis for DPM patients remains very poor, with an average survival of 2 years from diagnosis. Cisplatin, a platinum-based chemotherapy drug, is commonly used in the treatment of DPM. However, the development of resistance to cisplatin significantly limits its effectiveness, highlighting the urgent need for alternative therapeutic strategies. New selective inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) have shown promise in various malignancies by inhibiting cell cycle progression and suppressing tumor growth. Recent studies have indicated the potential of abemaciclib for DPM therapy, and a phase II clinical trial has shown preliminary encouraging results. Methods: Here, we tested abemaciclib, palbociclib, and ribociclib on a panel of DPM cell lines and non-tumor mesothelial(MET-5A) cells. Results: Specifically, we focused on abemaciclib, which was the mosteffective cytotoxic agent on all the DPM cell lines tested. Abemaciclib reduced DPM cell viability, clonogenic potential, and ability to grow as three-dimensional (3D) spheroids. In addition, abemaciclib induced prolonged effects, thereby impairing second-generation sphere formation and inducing G0/G1 arrest and apoptosis/necrosis. Interestingly, single silencing of RB family members did not impair cell response to abemaciclib, suggesting that they likely complement each other in triggering abemaciclib's cytostatic effect. Interestingly, abemaciclib reduced the phosphorylation of AKT, which is hyperactive in DPM and synergized with the pharmacological AKT inhibitor (AKTi VIII). Abemaciclib also synergized with cisplatin and reduced the viability of DPM cells with acquired resistance to cisplatin. Discussion: Overall, our results suggest that CDK4/6 inhibitors alone or in combination with standard of care should be further explored for DPM therapy. [ABSTRACT FROM AUTHOR]

Benign multicystic peritoneal mesothelioma (BMPM) is a rare condition, particularly in men, and the preoperative diagnosis poses a challenge. Here, we present a case involving single‐incision laparoscopic surgery (SILS) for BMPM in a 24‐year‐old man with a pelvic mass and a history of ulcerative colitis. Pelvic imaging revealed multifocal cysts, prompting the performance of SILS. The tumor was successfully resected with no residual lesions, and pathology confirmed the diagnosis of BMPM. This case represents the first documented instance of SILS being employed for BMPM in a man. BMPM, characterized by pelvic multifocal cysts, is a differential diagnosis, and SILS emerges as a viable option for both diagnosis and treatment. [ABSTRACT FROM AUTHOR]

It has long been recognized that amphibole minerals, such as cleavage fragments of tremolite and anthophyllite, may exist in some talc deposits. We reviewed the current state of the science regarding the factors influencing mesotheliogenic potency of cleavage fragments, with emphasis on those that may co-occur in talc deposits, including dimensional and structural characteristics, animal toxicology, and the most well-studied cohort exposed to talc-associated cleavage fragments. Based on our review, multiple lines of scientific evidence demonstrate that inhaled cleavage fragments associated with talc do not pose a mesothelioma hazard. [ABSTRACT FROM AUTHOR]

The surgical treatment of malignant pleural mesothelioma (MPM) involves procedures to achieve macroscopic complete resection, depending on the patient's condition. We reviewed the evolution of surgical approaches for resectable MPM. Since surgery is no more than a single step in the set of processes in multimodality treatment (MMT), we concluded that these procedures should give precedence to lung preservation and minimize resection whenever possible. Postoperative quality of life must be prioritized when the patient can receive appropriate adjuvant therapy. [ABSTRACT FROM AUTHOR]

Objective: Psychological suffering in patients with Malignant Mesothelioma (MM) is different from the one experienced by patients with other cancers due to its occupational or environmental etiology and its peculiar symptomatology and prognosis (i.e., poor prognosis, reduced effectiveness of the therapies, poor quality of residual life, and advanced age at the time of diagnosis). Therefore, the Mesothelioma Psychological Distress Tool‐Patients (MPDT‐P) has been developed to evaluate the specific profile of psychological suffering in this population. This paper describes the item selection, factor analysis, and psychometric evaluation of the revised MPDT‐P. Methods: The analyses of the current work aimed to confirm the factorial structure found in the first version of the MPDT‐P. In the case of nonfit, it aimed to find an alternative structure and causes of nonfit in the model. The search for the fit of the factorial model was conducted using a Bayesian approach. Results: The two‐factor model reported in the first version of the instrument did not fit the data. Confirmatory Bayesian analyses showed adequate fit for the three‐factor solution. Based on the content of the items, we labeled the factors as dysfunctional emotions, claims for justice, and anxieties about the future. Conclusions: Integrating the MPDT‐P into clinical practice could help clinicians gain insight into the specific suffering related to MM and investigate potential differences related to different occupational and environmental exposure contexts. [ABSTRACT FROM AUTHOR]

Simple Summary: STING is a key element in the cGAS/STING cytosolic sensing pathway and several STING agonists are currently being evaluated as anticancer drugs in the field of cancer immunotherapy. This study provides a unique catalog of STING expressions in tumor cells as well as its clinical relevance and association with PD-L1 expression in tumor and inflammatory cells in more than 130 different tumor entities. Stimulator of interferon genes protein (STING) activates the immune response in inflammatory cells. STING expression in cancer cells is less well characterized, but STING agonists are currently being evaluated as anticancer drugs. A tissue microarray containing 18,001 samples from 139 different tumor types was analyzed for STING by immunohistochemistry. STING-positive tumor cells were found in 130 (93.5%) of 139 tumor entities. The highest STING positivity rates occurred in squamous cell carcinomas (up to 96%); malignant mesothelioma (88.5%–95.7%); adenocarcinoma of the pancreas (94.9%), lung (90.3%), cervix (90.0%), colorectum (75.2%), and gallbladder (68.8%); and serous high-grade ovarian cancer (86.0%). High STING expression was linked to adverse phenotypes in breast cancer, clear cell renal cell carcinoma, colorectal adenocarcinoma, hepatocellular carcinoma, and papillary carcinoma of the thyroid (p < 0.05). In pTa urothelial carcinomas, STING expression was associated with low-grade carcinoma (p = 0.0002). Across all tumors, STING expression paralleled PD-L1 positivity of tumor and inflammatory cells (p < 0.0001 each) but was unrelated to the density of CD8+ lymphocytes. STING expression is variable across tumor types and may be related to aggressive tumor phenotype and PD-L1 positivity. The lack of relationship with tumor-infiltrating CD8+ lymphocytes argues against a significant IFN production by STING positive tumor cells. [ABSTRACT FROM AUTHOR]

Simple Summary: Aldehyde dehydrogenases of the subfamily 1A (ALDH1A) are enzymes involved in the synthesis of retinoic acid, which is necessary for the normal development and maintenance of epithelia, reproduction, memory, and immune function in adults. ALDH1A3, one of the enzymes that belong to the ALD1A subfamily, is also expressed at high levels in many human cancers like glioblastoma and mesothelioma. Herein, we review the role of ALDH1A3 in cancer, showing its relation with excessive proliferation, chemoresistance, and invasiveness. We also illustrate the current attempts to develop ALDH1A3-selective inhibitors and specific fluorescent probes that are potentially useful for cancer therapy and fluorescence-guided tumor resection. Aldehyde dehydrogenases of the subfamily 1A (ALDH1A) are enzymes necessary for the oxidation of all-trans or 9-cis retinal to retinoic acid (RA). Retinoic acid and its derivatives are important for normal development and maintenance of epithelia, reproduction, memory, and immune function in adults. Moreover, in recent years, it has been demonstrated that ALDH1A members are also expressed and functional in several human cancers where their role is not limited to the synthesis of RA. Here, we review the current knowledge about ALDH1A3, one of the 1A isoforms, in cancers with an emphasis on two of the deadliest tumors that affect humans: glioblastoma multiforme and mesothelioma. In both tumors, ALDH1A3 is considered a negative prognostic factor, and its level correlates with excessive proliferation, chemoresistance, and invasiveness. We also review the recent attempts to develop both ALDH1A3-selective inhibitors for cancer therapy and ALDH1A3-specific fluorescent substrates for fluorescence-guided tumor resection. [ABSTRACT FROM AUTHOR]

Dendritic cell immunotherapy has proven to be safe and induces an immune response in humans. We aimed to establish the efficacy of dendritic cells loaded with allogeneic tumour cell lysate (MesoPher, Amphera BV, 's-Hertogenbosch, Netherlands) as maintenance therapy in patients with pleural mesothelioma. In this open-label, randomised, phase 2/3 study, patients with histologically confirmed unresectable pleural mesothelioma, aged 18 years or older, with an Eastern Cooperative Oncology Group performance status score of 0–1, and non-progressing disease after four to six cycles of standard chemotherapy (with pemetrexed 500 mg/m2 plus platinum [cisplatin 75 mg/m2 or carboplatin area under the curve of 5]) were recruited from four centres in Belgium, France, and The Netherlands. Participants were randomly assigned (1:1), using block randomisation (block size of 4), stratified by centre and histology (epithelioid vs other), to MesoPher treatment plus best supportive care or best supportive care alone. Patients received up to a maximum of five MesoPher infusions, with treatment administered on days 1, 15, and 29, and weeks 18 and 30. At each timepoint, participants received an injection of 25 × 106 dendritic cells (two-thirds of the dendritic cells were administered intravenously and a third were injected intradermally). Best supportive care was per local institutional standards. The primary endpoint was overall survival, assessed in all participants randomly assigned to treatment (full analysis set) and safety assessed in all randomly assigned participants, and who underwent leukapheresis if they were in the MesoPher group. This study is registered with ClinicalTrials.gov , NCT03610360 , and is closed for accrual. Between June 21, 2018, and June 10, 2021, 176 patients were screened and randomly assigned to the MesoPher group (n=88) or best supportive care alone group (n=88). One participant in the MesoPher group did not undergo leukapheresis. Mean age was 68 years (SD 8), 149 (85%) of 176 were male, 27 (15%) were female, 173 (98%) were White, two were Asian (1%), and one (1%) was other race. As of data cutoff (June 24, 2023), after a median follow up of 15·1 months (IQR 9·5–22·4), median overall survival was 16·8 months (95% CI 12·4–20·3; 61 [69%] of 88 died) in the MesoPher group and 18·3 months (14·3–21·9; 59 [67%] of 88 died) in the best supportive care group (hazard ratio 1·10 [95% CI 0·77–1·57]; log-rank p=0·62). The most common grade 3–4 treatment-emergent adverse events were chest pain (three [3%] of 87 in the MesoPher group vs two [2%] of 88 in the best supportive care group), dyspnoea (none vs two [2%]), anaemia (two [2%] vs none), nausea (none vs two [2%]), and pneumonia (none vs two [2%]). No deaths due to treatment-emergent adverse events were recorded. Treatment-related adverse events consisted of infusion-related reactions (fever, chills, and fatigue), which occurred in 64 (74%) of 87 patients in the MesoPher group, and injection-site reactions (itch, erythema, and induration), which occurred in 73 (84%) patients, and all were grade 1–2 in severity. No deaths were determined to be treatment related. MesoPher did not show improvement in overall survival in patients with pleural mesothelioma. Immune checkpoint therapy is now standard of care in pleural mesothelioma. Further randomised studies are needed of combinations of MesoPher and immune checkpoint therapy, which might increase efficacy without adding major toxicities. Amphera BV and EU HORIZON. [ABSTRACT FROM AUTHOR]

Background: Malignant mesothelioma (MM) is an exceedingly rare tumor with poor prognosis due to the limited availability of effective treatment. Immunotherapy has emerged as a novel treatment approach for MM, but less than 40% of the patients benefit from it. Thus, it is necessary to identify accurate and effective biomarkers that can predict the overall survival (OS) and immunotherapy efficacy for MM. Methods: DNA sequencing was used to identify the genomic landscape based on the data from 86 Chinese patients. T cell receptor (TCR) sequencing was used to characterize MM TCR repertoires of 28 patients between October 2016 and April 2023. Results: Patients with TP53, NF2, or CDKN2A variants at the genomic level, as well as those exhibiting lower Shannon index (<6.637), lower evenness (<0.028), or higher clonality (≥0.194) according to baseline tumor tissue TCR indexes, demonstrated poorer OS. Furthermore, patients with TP53, CDKN2A, or CDKN2B variants and those with a lower evenness (<0.030) in baseline tumor tissue showed worse immunotherapy efficacy. The present study is the first to identify five special TCR Vβ‐Jβ rearrangements associated with MM immunotherapy efficacy. Conclusions: The present study reported the largest‐scale genomic landscape and TCR repertoire of MM in Chinese patients and identified genomic and TCR biomarkers for the prognosis and immunotherapy efficacy in MM. The study results might provide new insights for prospective MM trials using specific genes, TCR indexes, and TCR clones as biomarkers and offer a reference for future antitumor drugs based on TCR‐specific clones. [ABSTRACT FROM AUTHOR]

We report a case of a 69‐year‐old woman with pleural mesothelioma presenting in the posterior mediastinum with a maximum diameter of 25 cm. She had a chronic cough and a pleural effusion was noted on chest X‐ray. The examination of the effusion showed high hyaluronic acid levels, and mesothelioma was suspected. A chest computed tomography scan showed a huge mediastinal mass, which caused rapid progression of respiratory failure and compression of the heart. Sufficient tissue samples could not be obtained before death. The patient died approximately 1 month after the initial visit, and a pathological autopsy was performed. The diagnosis of malignant pleural mesothelioma was made. Malignant pleural mesothelioma with a huge posterior mediastinal mass such as in this case is considerably rare; however, it is a rapidly progressing form of the disease and is reported here as an important differential diagnosis for mediastinal tumours. [ABSTRACT FROM AUTHOR]

Pulmonary pathologists often must make a diagnosis based on small specimens derived from aspirated or solid tissue fragments, extracted under radiological guidance, containing limited diagnostic material. This poses a diagnostic challenge. Advances in treatment also demand tissue is analysed for multiple molecular anomalies therefore pathologists must be judicious in their use of ancillary tests such as immunohistochemistry. Whilst the majority of tumours encountered are non-small cell lung carcinomas, the lungs and thorax are a common metastatic site and can display a wide variety of different tumour types. Some tumours can closely mimic the appearances of non-small cell carcinomas and failure to recognise these can result in misdiagnosis and incorrect treatment and management for the patient. In this article we specifically focus on a variety of different tumours that can masquerade as non-small cell carcinomas. This includes both benign and malignant primary lung tumours, sarcomas, melanomas and germ cell tumours. We describe how to approach and recognise these entities, with specific focus on the histological and immunohistochemical appearances, and identify potential pitfalls to avoid in routine practice. [ABSTRACT FROM AUTHOR]

Primary cardiac malignant tumors are extremely rare, making up about 10% of all primary cardiac tumors. Most of these tumors are primary sarcomas, with primary mesothelioma being even less common. This report details a 53-year-old male patient diagnosed with primary cardiac malignant mesothelioma. The patient had symptoms of chest pain and difficulty breathing. A CT scan showed an enlarged heart, fluid around the heart, and irregular thickening of the pericardium. Diagnosis was confirmed through a surgical biopsy, which showed the presence of malignant mesothelioma. After the procedure, the patient received appropriate cardiac support. Although stable at discharge, the patient unfortunately died three months later due to severe wheezing. There may be a potential link between exposure to radioactive iodine treatment and this outcome. This case highlights the diagnostic and treatment challenges of primary cardiac malignant tumors and reminds physicians to consider this rare disease when evaluating patients with similar symptoms. [ABSTRACT FROM AUTHOR]

Abstract The combination of cisplatin and pemetrexed remains the gold standard chemotherapy for malignant pleural mesothelioma (MPM), although resistance and poor response pose a significant challenge. Cytidine deaminase (CDA) is a key enzyme in the nucleotide salvage pathway and is involved in the adaptive stress response to chemotherapy. The cytidine analog capecitabine and its metabolite 5′-deoxy-5-fluorocytidine (5’-DFCR) are converted via CDA to 5-fluorouracil, which affects DNA and RNA metabolism. This study investigated a schedule-dependent treatment strategy, proposing that initial chemotherapy induces CDA expression, sensitizing cells to subsequent capecitabine treatment. Basal CDA protein expression was low in different mesothelioma cell lines but increased in the corresponding xenografts. Standard chemotherapy increased CDA protein levels in MPM cells in vitro and in vivo in a schedule-dependent manner. This was associated with epithelial-to-mesenchymal transition and with HIF-1alpha expression at the transcriptional level. In addition, pretreatment with cisplatin and pemetrexed in combination sensitized MPM xenografts to capecitabine. Analysis of a tissue microarray (TMA) consisting of samples from 98 human MPM patients revealed that most human MPM samples had negative CDA expression. While survival curves based on CDA expression in matched samples clearly separated, significance was not reached due to the limited sample size. In non-matched samples, CDA expression before but not after neoadjuvant therapy was significantly associated with worse overall survival. In conclusion, chemotherapy increases CDA expression in xenografts, which is consistent with our in vitro results in MPM and lung cancer. A subset of matched patient samples showed increased CDA expression after therapy, suggesting that a schedule-dependent treatment strategy based on chemotherapy and capecitabine may benefit a selected MPM patient population.

Introduction: Iris retraction syndrome (IRS) is a rare clinical condition characterized by a backbowing of the iris positioned on the lens with a complete pupillary block. Immune checkpoint inhibitors (ICIs) are a new class of immunomodulating agents used in cancer therapy, and although they have high response rates, ophthalmic-related side effects have been reported. We report a rare case of bilateral IRS with hypotony after therapy with nivolumab. Case Presentation: We present a case of bilateral IRS with hypotony, 3 mm Hg OD and 5 mm Hg OS, after therapy with nivolumab. The patient presented with decreased vision, corneal edema, keratic precipitates, deep anterior chamber with posterior synechiae, and hypotony maculopathy. Anterior segment OCT revealed a sharp posterior displacement of the iridolenticular diaphragm consistent with IRS. Discontinuation of nivolumab until ocular improvement was suggested, following oncologic consultation. Four months later, the patient exhibited iris bombé with angle closure and increased IOP. This was managed with phacoemulsification and concomitant surgical iridectomy. One month after surgery, the patient’s IOP had returned to physiologic values, and the iris configuration had returned to normal. Conclusion: The exact mechanism of IRS remains unclear, but it is suggested that an aqueous imbalance, in conjunction with uveitis and hypotony, creates an anterio-posterior movement of the iridolenticular diaphragm when the pupillary block is present. Our case highlights the importance of monitoring patients receiving ICIs for ophthalmic adverse effects and prompt management to prevent permanent visual damage. In conclusion, this is the first reported case of IRS after therapy with ICIs. Further research is needed to fully understand the exact mechanism by which it is induced.

Abstract The clinical impact of soluble molecules in pleural effusion (PE) is unclear in patients with malignant pleural mesothelioma (MPM). In this single-center, retrospective, observational study, we assessed soluble forms of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and PD-1 ligand 1 (PD-L1) using enzyme-linked immunosorbent assays; three TGF-β isoforms were measured via multiplex assay in PE of patients with fibrinous pleuritis (FP) or MPM, to assess relationships between the levels of six molecules, clinicopathological characteristics, and efficacy of immune checkpoint inhibitors. Soluble forms of CTLA-4, PD-L1, PD-1, TGF-β1, TGF-β2, and TGF-β3 were variably produced in PE of FP (n = 34) and MPM (n = 79); we found significant relationships between the six molecules and clinicopathological features. Although none of the three soluble immune checkpoint molecules showed diagnostic or prognostic effects in patients with MPM, TGF-β2 level in PE is a useful differential diagnostic marker between FP and MPM. Both TGF-β1 and TGF-β3 levels are promising prognostic markers for MPM. Moreover, we found that higher baseline levels of PD-1 soluble forms predicted the response to anti-PD1 monotherapy. Our findings identify novel diagnostic, prognostic, and predictive biomarkers for anti-PD1 therapy in patients with MPM.

BACKGROUND: Tumor Treating Fields (TTFields) is a non-invasive modality for cancer treatment that utilizes a specific sinusoidal electric field ranging from 100 kHz to 300 kHz, with an intensity of 1 V/cm to 3 V/cm. Its purpose is to inhibit cancer cell proliferation and induce cell death. Despite promising outcomes from clinical trials, TTFields have received FDA approval for the treatment of glioblastoma multiforme (GBM) and malignant pleural mesothelioma (MPM). Nevertheless, global acceptance of TTFields remains limited. To enhance its clinical application in other types of cancer and gain a better understanding of its mechanisms of action, this review aims to summarize the current research status by examining existing literature on TTFields clinical trials and mechanism studies. CONCLUSIONS: Through this comprehensive review, we seek to stimulate novel ideas and provide physicians, patients, and researchers with a better comprehension of the development of TTFields and its potential applications in cancer treatment.

PURPOSE/OBJECTIVES: Malignant pleural mesothelioma (MPM) is a rare but aggressive cancer arising from the cells of the thoracic pleura with a poor prognosis. We aimed to develop a model, via interpretable machine learning (ML) methods, predicting overall survival for MPM following radiotherapy based on dosimetric metrics as well as patient characteristics. MATERIALS/METHODS: Sixty MPM (37 right, 23 left) patients treated on a Tomotherapy unit between 2013 and 2018 were retrospectively analyzed. All patients received 45 Gy (25 fractions). The multivariable Cox regression (Cox PH) model and Survival Support Vector Machine (sSVM) were applied to build predictive models of overall survival (OS) based on clinical, dosimetric, and combined variables. RESULTS: Significant differences in dosimetric endpoints for critical structures, i.e., the lung, heart, liver, kidney, and stomach, were observed according to target laterality. The OS was found to be insignificantly different (p = 0.18) between MPM patients who tested left- and right-sided, with 1-year OS of 77.3% and 75.0%, respectively. With Cox PH regression, considering dosimetric variables for right-sided patients alone, an increase in PTV_Min, Total_Lung_PTV_Mean, Contra_Lung_Volume, Contra_Lung_V20, Esophagus_Mean, and Heart_Volume had a greater hazard to all-cause death, while an increase in Total_Lung_PTV_V20, Contra_Lung_V5, and Esophagus_Max had a lower hazard to all-cause death. Considering clinical variables alone, males and increases in N stage had greater hazard to all-cause death; considering both clinical and dosimetric variables, increases in N stage, PTV_Mean, PTV_Min, and esophagus_Mean had greater hazard to all-cause death, while increases in T stage and Heart_V30 had lower hazard to all-cause-death. In terms of C-index, the Cox PH model and sSVM performed similarly and fairly well when considering clinical and dosimetric variables independently or jointly. CONCLUSIONS: Clinical and dosimetric variables may predict the overall survival of mesothelioma patients, which could guide personalized treatment planning towards a better treatment response. The identified predictors and their impact on survival offered additional value for translational application in clinical practice.

The presentations in this session of the Monticello II conference were aimed at summarizing what is known about asbestiform and non-asbestiform elongate mineral particles (EMPs) and mesothelioma risks based on evidence from experimental and epidemiology studies. Dr. Case discussed case reports of mesothelioma over the last several decades. Dr. Taioli indicated that the epidemiology evidence concerning non-asbestiform EMPs is weak or lacking, and that progress would be limited unless mesothelioma registries are established. One exception discussed is that of taconite miners, who are exposed to grunerite. Drs. Mandel and Odo noted that studies of taconite miners in Minnesota have revealed an excess rate of mesothelioma, but the role of non-asbestiform EMPs in this excess incidence of mesothelioma is unclear. Dr. Becich discussed the National Mesothelioma Virtual Bank (NMVB), a virtual mesothelioma patient registry that includes mesothelioma patients' lifetime work histories, exposure histories, biospecimens, proteogenomic information, and imaging data that can be used in epidemiology research on mesothelioma. Dr. Bernstein indicated that there is a strong consensus that long, highly durable respirable asbestiform EMPs have the potential to cause mesothelioma, but there is continued debate concerning the biodurability required, and the dimensions (both length and diameter), the shape, and the dose associated with mesothelioma risk. Finally, Dr. Nel discussed how experimental studies of High Aspect Ratio Engineered Nanomaterials have clarified dimensional and durability features that impact disease risk, the impact of inflammation and oxidative stress on the epigenetic regulation of tumor suppressor genes, and the generation of immune suppressive effects in the mesothelioma tumor microenvironment. The session ended with a discussion of future research needs.