Malignant pleural mesothelioma: Description of pleural decortication and hyperthermic chemotherapy technique in multimodal therapy.

The current treatment for mesothelioma, in selected cases, consists of extended pleurodecortication and intrathoracic hyperthermic chemotherapy. This technique is laborious and detailed and must be followed step by step to achieve good results. We present the case of a patient with epithelioid mesothelioma meeting surgical criteria who underwent the mentioned technique, experiencing an adequate postoperative period and an early discharge. This experience demonstrates that the technique is safe when performed in centres with experience and the means to address this complex pathology.

Identifying malignant mesothelioma by a pathological survey using the São Paulo state hospital cancer registry, Brazil.

OBJECTIVE: To review the pathological diagnosis of possible cases and/or hidden cases of malignant mesothelioma (MM) between 2000 and 2012 using the Hospital-Based Cancer Registry database in the state of São Paulo, Brazil. METHODS: Possible cases were retrieved by assessing the database. Inclusion criteria were being older than 30 years of age and having ICD-O-3 topography and morphology codes related to MM. A board of expert pathologists reviewed the pathology reports and requested paraffin blocks in cases that demanded revision. After staining with calretinin, D2-40, WT-1 (as positive MM markers) and Ber-EP4 and MOC31 (as negative MM markers), cases were divided and studied independently by a pair of pathologists to confirm or discard the diagnosis of MM. RESULTS: Our sample comprised 482 cases from 25 hospitals, and 130 needed further histological revision. We received 73 paraffin blocks with adequate material. After board analysis, there were 9 cases with a definitive diagnosis of MM, improving the diagnostic rate in 12%. Two cases of previously diagnosed MM were discarded by review. CONCLUSIONS: Our results confirm that part of MM underdiagnosis and underreporting in Brazil is due to incomplete or mistaken pathological diagnosis.

Linc00941 fuels ribogenesis and protein synthesis by supporting robust cMYC translation in malignant pleural mesothelioma.

Malignant pleural mesothelioma is a rare and lethal cancer caused by exposure to asbestos. The highly inflammatory environment caused by fibers accumulation forces cells to undergo profound adaptation to gain survival advantages. Prioritizing the synthesis of essential transcripts is an efficient mechanism coordinated by multiple molecules, including long non-coding RNAs. Enhancing the knowledge about these mechanisms is an essential weapon in combating mesothelioma. Linc00941 correlates to bad prognosis in various cancers, but it is reported to partake in distinct and apparently irreconcilable processes. In this work, we report that linc00941 supports the survival and aggressiveness of mesothelioma cells by influencing protein synthesis and ribosome biogenesis. Linc00941 binds to the translation initiation factor eIF4G, promoting the selective protein synthesis of cMYC, which, in turn, enhances the expression of key genes involved in translation. We analyzed a retrospective cohort of 97 mesothelioma patients' samples from our institution, revealing that linc00941 expression strongly correlates with reduced survival probability. This discovery clarifies linc00941's role in mesothelioma and proposes a unified mechanism of action for this lncRNA involving the selective translation of essential oncogenes, reconciling the discrepancies about its function.

Pleural mesothelioma from fluoro-edenite exposure: PACAP and PAC1 receptor. A preliminary report.

Pleural mesothelioma is a devastating malignancy primarily associated with asbestos exposure. However, emerging evidence suggests that exposure to fluoro-edenite fibers, a naturally occurring mineral fiber, can also lead to the development of pleural mesothelioma. In this study, based on the hypothesis that pituitary adenylate cyclase-activating polypeptide (PACAP) and PACAP-preferring receptor (PAC1R) expressions could be dysregulated in pleural mesothelioma samples and that they could potentially act as diagnostic or prognostic biomarkers, we aimed to investigate the immunohistochemical expression of PACAP and PAC1R in pleural biopsies from patients with pleural mesothelioma exposed to fluoro-edenite fibers. A total of 12 patients were included in this study, and their biopsies were processed for immunohistochemical analysis to evaluate the expression of PACAP and its receptor. The study revealed a correlation between the overexpression of PACAP and PAC1R and shorter overall survival in patients with malignant mesothelioma. These findings suggest that PACAP and PAC1R expression levels could serve as potential prognostic biomarkers for malignant mesothelioma. Furthermore, the immunohistochemical analysis of PACAP and PAC1R may provide valuable information for clinicians to guide therapeutic decisions and identify patients with poorer prognosis.

Mesothelioma-Associated Fibroblasts Modulate the Response of Mesothelioma Patient-Derived Organoids to Chemotherapy via Interleukin-6.

Malignant pleural mesothelioma (MPM) remains an incurable disease. This is partly due to the lack of experimental models that fully recapitulate the complexity and heterogeneity of MPM, a major challenge for therapeutic management of the disease. In addition, the contribution of the MPM microenvironment is relevant for the adaptive response to therapy. We established mesothelioma patient-derived organoid (mPDO) cultures from MPM pleural effusions and tested their response to pemetrexed and cisplatin. We aimed to evaluate the contribution of mesothelioma-associated fibroblasts (MAFs) to the response to pemetrexed and cisplatin (P+C). Organoid cultures were obtained from eight MPM patients using specific growth media and conditions to expand pleural effusion-derived cells. Flow cytometry was used to verify the similarity of the organoid cultures to the original samples. MAFs were isolated and co-cultured with mPDOs, and the addition of MAFs reduced the sensitivity of mPDOs to P+C. Organoid formation and expression of cancer stem cell markers such as ABCG2, NANOG, and CD44 were altered by conditioned media from treated MAFs. We identified IL-6 as the major contributor to the attenuated response to chemotherapy. IL-6 secretion by MAFs is correlated with increased resistance of mPDOs to pemetrexed and cisplatin.

Nonmesothelial Spindle Cell Tumors of Pleura and Pericardium.

Spindle cell lesions of the pleura and pericardium are rare. Distinction from sarcomatoid mesothelioma, which has a range of morphologic patterns, can be difficult, but accurate diagnosis matters. This article provides practical guidance for the diagnosis of pleural spindle cell neoplasms, focusing on primary lesions.

FK228 suppress the growth of human malignant pleural mesothelioma tumor independent to epithelioid or non-epithelioid histology.

Human malignant pleural mesothelioma (hMPM) is an aggressive, rare disease with a poor prognosis. Histologically, MPM is categorized into epithelioid, biphasic, and sarcomatoid subtypes, with the epithelioid subtype generally displaying a better response to treatment. Conversely, effective therapies for the non-epithelioid subtypes are limited. This study aimed to investigate the potential role of FK228, a histone deacetylase inhibitor, in the suppression of hMPM tumor growth. We conducted a comprehensive analysis of the histological and molecular characteristics of two MPM cell lines, CRL-5820 (epithelioid) and CRL-5946 (non-epithelioid). CRL-5946 cells and non-epithelioid patient-derived xenografted mice exhibited heightened growth rates compared to those with epithelioid MPM. Both CRL-5946 cells and non-epithelioid mice displayed a poor response to cisplatin. However, FK228 markedly inhibited the growth of both epithelioid and non-epithelioid tumor cells in vitro and in vivo. Cell cycle analysis revealed FK228-induced G1/S and mitotic arrest in MPM cells. Caspase inhibitor experiments demonstrated that FK228-triggered apoptosis occurred via a caspase-dependent pathway in CRL-5946 but not in CRL-5820 cells. Additionally, a cytokine array analysis showed that FK228 reduced the release of growth factors, including platelet-derived and vascular endothelial growth factors, specifically in CRL-5946 cells. These results indicate that FK228 exhibits therapeutic potential in MPM by inducing cytotoxicity and modulating the tumor microenvironment, potentially benefiting both epithelioid and non-epithelioid subtypes.

Leveraging the pleural space for anticancer therapies in pleural mesothelioma.

Most patients with pleural mesothelioma (PM) present with symptomatic pleural effusion. In some patients, PM is only detectable on the pleural surfaces, providing a strong rationale for intrapleural anticancer therapy. In modern prospective studies involving expert radiological staging and specialist multidisciplinary teams, the population incidence of stage I PM (an approximate surrogate of pleura-only PM) is higher than in historical retrospective series. In this Viewpoint, we advocate for the expansion of intrapleural trials to serve these patients, given the paucity of data supporting licensed systemic therapies in this setting and the uncertainties involved in surgical therapy. We begin by reviewing the unique anatomical and physiological features of the PM-bearing pleural space, before critically appraising the evidence for systemic therapies in stage I PM and previous intrapleural PM trials. We conclude with a summary of key challenges and potential solutions, including optimal trial designs, repurposing of indwelling pleural catheters, and new technologies.

Combination of calretinin, MALAT1, and GAS5 as a potential prognostic biomarker to predict disease progression in surgically treated mesothelioma patients.

BACKGROUND: The role of cytoreductive surgery for epithelioid pleural mesothelioma within a multimodal treatment approach remains controversial. Carefully selected patients benefit from cytoreductive surgery and adjuvant chemotherapy, but there is no established biomarker to predict tumor recurrence or progression during the course of the disease. The aim of this study was to identify potential biomarkers to predict therapeutic response in terms of progression-free survival. METHODS: Between 03/2014 and 08/2022, preoperative blood samples were collected from 76 patients with epithelioid pleural mesothelioma who underwent cytoreductive surgery as part of a multimodal treatment approach. Identification of potential biomarkers was performed by determination of mesothelin and calretinin, as well as specific long non-coding RNAs and microRNAs. Receiver operating characteristic analysis, Kaplan-Meier survival analysis, and Cox regression were used to assess the association between biomarker concentrations and patient recurrence status and survival. RESULTS: MALAT1, GAS5, and calretinin showed statistically significant increased biomarker levels in patients with recurrence in contrast to recurrence-free patients after surgical treatment (p < 0.0001, p = 0.0190, and p = 0.0068, respectively). The combination of the three biomarkers resulted in a sensitivity of 68 % and a specificity of 89 %. CONCLUSION: MALAT1, GAS5, and calretinin could be potential biomarkers for the prediction of tumor recurrence, improving the benefit from multimodal treatment including cytoreductive surgery.

Synchronous Well-Differentiated Papillary Mesothelioma and Endometrioid Adenocarcinoma Arising From Endometriosis.

Well-differentiated papillary mesothelioma (WDPM) is a rare mesothelial tumor of uncertain malignant potential. We present a unique case of a woman with synchronous WDPM and well-differentiated endometrioid adenocarcinoma (EA) arising from extraovarian endometriosis. A 56-year-old postmenopausal woman presented with a several-month history of right lower quadrant abdominal pain. She had a history of supracervical hysterectomy and bilateral salpingo-oophorectomy secondary to endometriosis. Imaging reported a mass in the right lower quadrant originating from the distal ileum. At laparotomy, the patient underwent a right colectomy with resection of the terminal ileum and excision of a solitary peritoneal nodule. Pathology was consistent with a diagnosis of well-differentiated EA (arising from extraovarian endometriosis) and WDPM. Further treatment consisted of complete surgical staging/debulking and adjuvant chemotherapy directed toward metastatic well-differentiated EA. Surgeons should be familiar with WDPM as a potential finding in women of reproductive age undergoing abdominal surgery for any indication.

Extrapleural pneumonectomy for sarcoma: Outcomes of adult patients at a specialized center.

BACKGROUND: Extrapleural pneumonectomy (EPP) is a complex surgical procedure involving en-bloc resection of the parietal and visceral pleura, lung, pericardium, and ipsilateral diaphragm. Small case series of pleural-based sarcoma of predominantly pediatric patients suggest EPP may be a life-prolonging surgical option. We aimed to describe the characteristics and outcomes of adults who underwent EPP at a specialized sarcoma center. METHODS: Clinicopathologic variables, surgical details, and follow-up information were extracted for patients undergoing EPP for pleural-based sarcoma between August 2017 and December 2020. Primary outcomes were event-free survival (EFS) and overall survival (OS) from the date of EPP. Secondary outcomes were disease-free interval (DFI) prior to EPP, and early and late postoperative complications. RESULTS: Eight patients were identified, seven with soft tissue sarcoma and one with bone sarcoma. Patients had either localized disease with a primary thoracic sarcoma, sarcoma recurrent to the thorax, or de novo metastatic disease. All patients underwent resection of their pleural-based sarcoma by an experienced cardiothoracic surgeon, and some patients had pre or postoperative treatment. The perioperative morbidity was comparable with previously published reports of EPP performed in mesothelioma patients. At median follow-up of 22.5 months, median EFS was 6.0 months and OS was 20.7 months. Six patients (75%) had disease recurrence; five (62.5%) died of progressive disease. Two patients (25%) had not recurred: one died of a radiation-related esophageal rupture, and one was alive with no evidence of disease at 37.0 months. Characteristics of those with the longest EFS included low-grade histology and achieving a metabolic response to preoperative chemotherapy. CONCLUSIONS: In adults with pleural-based sarcoma, EPP is rarely curative but appears to be a feasible salvage procedure when performed at specialized centers. Patient selection is critical with strong consideration given to multimodal therapy to optimize patient outcomes. In the absence of a confirmed response to neoadjuvant treatment, long term survival is poor and EPP should not be recommended.

Diagnosis and treatment of malignant retroperitoneal mesothelioma: A case report.

RATIONALE: Malignant peritoneal mesothelioma (MPM) is a rare clinical disease. Although there are several reports describing intraperitoneal mesothelioma of the lung, liver, and intestine, retroperitoneal mesothelioma is, to our knowledge, very rare and rarely reported. In recent years, our best clinical protocols for the treatment and diagnosis of retroperitoneal mesothelioma have not been proven and the diagnosis and treatment are challenging. PATIENT CONCERNS: A 37-year-old Chinese woman complained of bilateral low back pain for a month, with obvious symptoms of low back pain on the left side. To treat low back pain, retroperitoneal masses were found during physical examination. The patient consulted a urological specialist for further treatment. DIAGNOSIS: After the operation, pathological biopsy confirmed retroperitoneal epithelioid diffuse mesothelioma. INTERVENTIONS: After exclusion of surgical contraindications, the patient underwent laparoscopic retroperitoneal lesion resection under tracheal intubation and general anesthesia, and the operation was successful. OUTCOMES: On the tenth day after surgery, the patient vital signs were stable, and he was discharged. LESSONS: Patients with malignant peritoneal mesothelioma may have no typical clinical symptoms, and the diagnosis is based on pathological and immunohistochemical examination. In selected patients, surgical cell reduction and intraoperative intraperitoneal heat chemotherapy have become the first choice of treatment, which can achieve ideal therapeutic effects and prolong survival.

Retrospective evaluation of toceranib phosphate (Palladia) in the treatment of canine carcinomatosis and mesothelioma.

Canine carcinomatosis (CC) and mesothelioma (CM) are rare but aggressive neoplasms that historically have been associated with poor prognoses. There is limited information regarding treatment for CC and CM. The purpose of this retrospective study was to evaluate the efficacy and tolerability of toceranib phosphate (Palladia) in dogs with CC and CM. Cases were solicited from the American College of Veterinary Internal Medicine (ACVIM) Oncology listserv and retrospectively reviewed. For eligibility, a cytologic and/or histopathologic diagnosis of CC or CM was required. A total of 23 cases were included (CC = 14, CM = 8, both = 1). Eighty-two percent (19/23) of dogs presented with effusion. The best overall response rate (BORR) was 30.4% (13% complete response [CR], 17.3% partial response [PR]). Stable disease (SD) was appreciated in 14 dogs (60.8%) including the four dogs without effusion. The most common toceranib-related adverse events were either Grade 1 and 2 diarrhea or hyporexia. The median progression-free survival (PFS) was 171 days (range, 7-519 days) and overall median survival time (MST) was 301 days (range, 49-875 days) for all dogs. When evaluating dogs solely with effusion, the median PFS and overall MST were 171 days (range, 7-519 days) and 285 days (range, 49-875 days), respectively. This report demonstrates that toceranib is both well tolerated and a potential treatment for CC and CM. A randomised, controlled, prospective study would be needed to objectively assess the survival benefit of toceranib in the management of CC and CM, with and without effusion.

Identification of the ferroptosis-related prognostic gene signature in mesothelioma.

Mesothelioma, an uncommon yet highly aggressive malignant neoplasm, presents challenges in the effectiveness of current therapeutic approaches. Ferroptosis, a non-apoptotic mechanism of cellular demise, exhibits a substantial association with the progression of diverse cancer forms. It is important to acknowledge that there exists a significant association between ferroptosis and the advancement of various forms of cancer. Nevertheless, the precise role of ferroptosis regulatory factors within the context of mesothelioma remains enigmatic. In our investigation, we initially scrutinized the prognostic significance of 24 ferroptosis regulatory factors in the realm of mesothelioma. Our observations unveiled that heightened expression levels of CARS1, CDKN1A, TFRC, FANCD2, FDFT1, HSPB1, SLC1A5, SLC7A11, coupled with reduced DPP4 expression, were indicative of an unfavorable prognosis. Built upon the nine previously discussed prognostic genes, the ferroptosis prognostic model offers a reliable means to forecast mesothelioma patients' survival with a substantial degree of precision. Furthermore, a notable correlation emerged between these prognostic ferroptosis regulators and parameters such as immune cell infiltration, tumor mutation burden, microsatellite instability, and PD-L1 expression in the context of mesothelioma. Within this cadre of nine ferroptosis regulatory factors with prognostic relevance, FANCD2 exhibited the most pronounced prognostic influence, as elucidated by our analyses. Subsequently, we executed a validation process employing clinical specimens sourced from our institution, thus confirming that heightened FANCD2 expression is a discernible harbinger of an adverse prognosis in the context of mesothelioma. In vitro experiments revealed that knocking down FANCD2 markedly suppressed the proliferation, migration, and ability of mesothelioma cells to attract immune cells. Furthermore, our findings also showed that reducing FANCD2 levels heightened the vulnerability of mesothelioma cells to inducers of ferroptosis. Furthermore, an extensive pan-cancer analysis uncovered a robust association between FANCD2 and the gene expression linked to immune checkpoints, thereby signifying an adverse prognosis across a broad spectrum of cancer types. Additional research is warranted to validate these findings.

Circulating SMRP and CA-125 before and after pleurectomy decortication for pleural mesothelioma.

BACKGROUND: Tumor recurrence remains the main barrier to survival after surgery for pleural mesothelioma (PM). Soluble mesothelin-related protein (SMRP) and cancer antigen 125 (CA-125) are established blood-based biomarkers for monitoring PM. We prospectively studied the utility of these biomarkers after pleurectomy decortication (PD). METHODS: Patients who underwent PD and achieved complete macroscopic resection with available preoperative SMRP levels were included. Tumor marker levels were determined within 60 days of three timepoints: (1) preoperation, (2) post-operation, and (3) recurrence. RESULTS: Of 356 evaluable patients, 276 (78%) had recurrence by the end of follow-up interval. Elevated preoperative SMRP levels were associated with epithelioid histology (p < 0.013), advanced TNM (p < 0.001) stage, and clinical stage (p < 0.001). Preoperative CA-125 levels were not significantly associated with clinical covariates. Neither biomarker was associated with survival or disease-free survival. With respect to nonpleural and nonlymphatic recurrences, mean SMRP levels were elevated in patients with pleural (p = 0.021) and lymph node (p = 0.042) recurrences. CA-125 levels were significantly higher in patients with abdominal (p < 0.001) and lymph node (p = 0.004) recurrences. Among patients with all three timepoints available, we observed an average decrease in SMRP levels by 1.93 nmol/L (p < 0.001) postoperatively and again an average increase at recurrence by 0.79 nmol/L (p < 0.001). There were no significant changes in levels of CA-125 across the study timepoints (p = 0.47). CONCLUSIONS: Longitudinal changes in SMRP levels corresponded with a radiographic presence of disease in a subset of patients. SMRP surveillance could aid in detection of local recurrences, whereas CA-125 could be helpful in recognizing abdominal recurrences.

Reliably making the primary diagnosis of mesothelioma utilizing serous fluid cytology specimens: an institutional experience.

INTRODUCTION: The diagnosis of mesothelioma has historically been challenging, especially on serous fluid cytology (SFC). Distinguishing between reactive and neoplastic mesothelial cells can be difficult on cytomorphology alone. However, additional ancillary tests, such as BRCA1 associated protein-1 immunohistochemistry and fluorescence in situ hybridization for cyclin-dependent kinase inhibitor 2A deletion, can provide a sensitive and highly specific method of proving malignancy. MATERIALS AND METHODS: SFC specimens diagnosed as mesothelioma, suspicious for mesothelioma (SM), and atypical mesothelial cells (AMCs) since 2012 were identified by querying the laboratory information system. Clinical data and pathologic parameters were gathered. RESULTS: One hundred ten cases of mesothelioma, SM, and AMC were identified. Of these, 61 cases had a definitive diagnosis of mesothelioma on SFC. Average age at SFC diagnosis was 67 years (26-87 years), with most patients being male (67%). Out of the 61 cases, 11 cases (18%) had an initial diagnosis of mesothelioma made on SFC specimens, with 5 of these 11 cases being in patients that never received a histologic diagnosis of mesothelioma. Ancillary studies were utilized in all 11 cases. An initial diagnosis of metastatic mesothelioma was made on SFC in 9 cases (15%). For 6 of these 9 cases, the SFC diagnosis was the sole diagnosis of metastatic mesothelioma without a companion histologic diagnosis. In addition, 15 cases were diagnosed as SM, with 11 of these cases following a definitive mesothelioma diagnosis. Thirty-four cases were diagnosed as AMC, with 27 cases following a definitive mesothelioma diagnosis. CONCLUSIONS: The diagnosis of mesothelioma can be reliably made on SFC with the appropriate cytomorphology criteria and/or confirmatory ancillary testing.

Establishing mesothelioma patient-derived organoid models from malignant pleural effusions.

OBJECTIVES: Pleural mesothelioma is a cancer arising in the cells that line the lungs and chest wall with poor survival and poor response to first-line therapy. Organoid models of cancer can faithfully recapitulate the genetic and histopathological characteristics of individualized tumors and have potential to be used for precision medicine, however methods of establishing patient-derived mesothelioma organoids have not been well established in the published literature. MATERIALS AND METHODS: Long-term mesothelioma patient-derived organoids were established from ten malignant pleural effusion fluids. Mesothelioma patient-derived organoids were compared to the corresponding biopsy tissue specimens using immunohistochemistry labelling for select diagnostic markers and the TruSight Oncology-500 sequencing assay. Cell viability in response to the chemotherapeutic drug cisplatin was assessed. RESULTS: We established five mesothelioma patient-derived organoid cultures from ten malignant pleural effusion fluids collected from nine individuals with pleural mesothelioma. Mesothelioma patient-derived organoids typically reflected the histopathological and genomic features of patients' matched biopsy specimens and displayed cytotoxic sensitivity to cisplatin in vitro. CONCLUSION: This is the first study of its kind to establish long-term mesothelioma organoid cultures from malignant pleural effusions and report on their utility to test individuals' chemotherapeutic sensitivities ex vivo.

Combination of EZH2 and ATM inhibition in BAP1-deficient mesothelioma.

BACKGROUND: More than half of mesothelioma tumours show alterations in the tumour suppressor gene BAP1. BAP1-deficient mesothelioma is shown to be sensitive to EZH2 inhibition in preclinical settings but only showed modest efficacy in clinical trial. Adding a second inhibitor could potentially elevate EZH2i treatment efficacy while preventing acquired resistance at the same time. METHODS: A focused drug synergy screen consisting of 20 drugs was performed by combining EZH2 inhibition with a panel of anti-cancer compounds in mesothelioma cell lines. The compounds used are under preclinical investigation or already used in the clinic. The synergistic potential of the combinations was assessed by using the Bliss model. To validate our findings, in vivo xenograft experiments were performed. RESULTS: Combining EZH2i with ATMi was found to have synergistic potential against BAP1-deficient mesothelioma in our drug screen, which was validated in clonogenicity assays. Tumour growth inhibition potential was significantly increased in BAP1-deficient xenografts. In addition, we observe lower ATM levels upon depletion of BAP1 and hypothesise that this might be mediated by E2F1. CONCLUSIONS: We demonstrated the efficacy of the combination of ATM and EZH2 inhibition against BAP1-deficient mesothelioma in preclinical models, indicating the potential of this combination as a novel treatment modality using BAP1 as a biomarker.