bims-mesote 2023-09-17 papers

Issue of 2023–09–17
six papers selected by
Laura Mannarino, Humanitas Research

Cureus. 2023 Aug;15(8): e43205

A Worsening Cough: An Unusual Presentation of Malignant Mesothelioma.

Localized malignant pleural mesothelioma (LMPM) is a rare cancer with poor survival rates. Often affecting males with asbestos exposure, we report a case of a 56-year-old female with no history of occupational exposure presenting with a worsening cough. A radiological examination revealed left pleural effusion and pleural thickening. Cytological and pathological reports of pleural samples were consistent with malignant mesothelioma of epithelioid type, with the histological examination via video-assisted thoracoscopic surgery (VATS) consistent with a clear cell epithelioid mesothelioma. We discuss the rapid presentation of the disease with emphasis on considering the disease in young patients with no prior asbestos exposure.

Keywords: lmpm; localized malignant pleural mesothelioma; mediastinal mass; pleura; pleural mesothelioma; pleural tumor

DOI: https://doi.org/10.7759/cureus.43205

Transl Cancer Res. 2023 Aug 31. 12(8): 1929-1936

Induction of metallothionein expression by supplementation of zinc induces resistance against platinum-based treatment in malignant pleural mesothelioma.

Martine Wyrich, Henning Ohlig, Michael Wessolly, Elena Mairinger, Julia Steinborn, Luka Brcic, Balazs Hegedus, Thomas Hager, Kristina Greimelmaier, Jeremias Wohlschlaeger, Fabian D Mairinger, Sabrina Borchert.

Background: Malignant pleural mesothelioma (MPM) is an aggressive tumor with a dismal prognosis. Currently, multimodality treatment including chemotherapy with cisplatin or carboplatin in combination with pemetrexed offers the best options. Detoxification of heavy metals in the cell by metallothioneins (MT) is associated with early failure to platin-based chemotherapy. The induction of MTs gene expression or its enzyme results in saturation by exposure to metal ions such as zinc or cadmium. Its therapeutically effect is still not analyzed in depth.
Methods: In our study, we investigated three MPM cell lines and one fibroblast cell line in the course of cisplatin treatment and supplementation of zinc. Cell state analyses via an enzyme-activity based assay were performed. With this, we were able to analyze apoptosis, necrosis and viability of cells. Additionally, we tested treated cells for changes in metallothionein IIA (MT2A) expression by using quantitative realtime polymerase chain reaction.
Results: Zinc supplementation induces gene expression of MT2A. Overall, a zinc dose-dependent induction of apoptosis under platin-based treatment could be observed. This effect could be verified in all analyzed cell lines in varying intensity.
Conclusions: MT expression is induced by zinc in a dose-dependent manner and inhibits a successful cisplatin therapy. Therefore, heavy metal exposure during cisplatin therapy, e.g., via cigarette smoke, might be an important factor. This should be considered in further therapeutic approaches.

Keywords: Malignant pleural mesothelioma (MPM); cisplatin; metallothionein; zinc

DOI: https://doi.org/10.21037/tcr-22-2651

Pathol Res Pract. 2023 Sep 13. pii: S0344-0338(23)00517-4. [Epub ahead of print]250 154817

Melodic maestros: Unraveling the role of miRNAs in the diagnosis, progression, and drug resistance of malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a highly lethal form of pleural cancer characterized by a scarcity of effective therapeutic interventions, resulting in unfavorable prognoses for afflicted individuals. Besides, many patients experience substantial consequences from being diagnosed in advanced stages. The available diagnostic, prognostic, and therapeutic options for MPM are restricted in scope. MicroRNAs (miRNAs) are a subset of small, noncoding RNA molecules that exert significant regulatory influence over several cellular processes within cell biology. A wide range of miRNAs have atypical expression patterns in cancer, serving specific functions as either tumor suppressors or oncomiRs. This review aims to collate, epitomize, and analyze the latest scholarly investigations on miRNAs that are believed to be implicated in the dysregulation leading to MPM. miRNAs are also discussed concerning their potential clinical usefulness as diagnostic and prognostic biomarkers for MPM. The future holds promising prospects for enhancing diagnostic, prognostic, and therapeutic modalities for MPM, with miRNAs emerging as a potential trigger for such advancements.

Keywords: Diagnosis; Drug resistance; MPM; Malignant pleural mesothelioma; MiRNA; Prognosis

DOI: https://doi.org/10.1016/j.prp.2023.154817

Lung Cancer. 2023 Sep 07. pii: S0169-5002(23)00898-X. [Epub ahead of print]185 107360

Krebs von den Lungen 6 (KL-6) is a novel diagnostic and prognostic biomarker in pleural mesothelioma.

Paul Stockhammer, Hannah Baumeister, Till Ploenes, Francesco Bonella, Dirk Theegarten, Balazs Dome, Christine Pirker, Walter Berger, Luca Hegedüs, Marcell Baranyi, Martin Schuler, Sophie Deshayes, Servet Bölükbas, Clemens Aigner, Christophe Blanquart, Balazs Hegedüs.

OBJECTIVES: Pleural mesothelioma (PM) is a rare disease with dismal outcome. Systemic treatment options include chemotherapy and immunotherapy, but biomarkers for treatment personalization are missing. The only FDA-approved diagnostic biomarker is the soluble mesothelin-related protein (SMRP). Krebs von den Lungen-6 (KL-6) is a human mucin 1 (MUC1) glycoprotein, which has shown diagnostic and prognostic value as a biomarker in other malignancies. The present study investigated whether KL-6 can serve as a diagnostic and/or prognostic biomarker in PM.
MATERIALS AND METHODS: Using a fully-automated chemiluminescence enzyme immunoassay (CLEIA) for KL-6 and SMRP, pleural effusion samples from 87 consecutive patients with PM and 25 patients with non-malignant pleural disorders were studied. In addition, KL-6 and SMRP levels were determined in corresponding patient sera, and in an independent validation cohort (n = 122). MUC1 mRNA and protein expression, and KL-6 levels in cell line supernatants were investigated in PM primary cell lines in vitro.
RESULTS: PM patients had significantly higher KL-6 levels in pleural effusion than non-malignant controls (AUC 0.78, p < 0.0001). Among PM patients, levels were highest in those with epithelioid or biphasic histologies. There was a strong positive correlation between pleural effusion levels of KL-6 and SMRP (p < 0.0001). KL-6 levels in sera similarly associated with diagnosis of PM, however, to a lesser extent (AUC 0.71, p = 0.008). PM patients with high pleural effusion KL-6 levels (≥303 IU/mL) had significantly better overall survival (OS) compared to those with low KL-6 levels (HR 0.51, p = 0.004). Congruently, high tumor cell MUC1 mRNA expression in primary cell lines associated with prolonged corresponding patient OS (HR 0.35, p = 0.004). These findings were confirmed in an independent validation cohort.
CONCLUSION: This is the first study demonstrating KL-6 as a potential novel liquid-based diagnostic and prognostic biomarker in PM.

Keywords: Biomarker; KL-6; Mucins; Pleural effusion; Pleural mesothelioma; SMRP

DOI: https://doi.org/10.1016/j.lungcan.2023.107360

Cancer Res Commun. 2023 Sep;3(9): 1810-1822

Surgical Inflammation Alters Immune Response to Intraoperative Photodynamic Therapy.

Richard W Davis, Astero Klampatsa, Gwendolyn M Cramer, Michele M Kim, Joann M Miller, Min Yuan, Cassandra Houser, Emma Snyder, Mary Putt, Sergei A Vinogradov, Steven M Albelda, Keith A Cengel, Theresa M Busch.

Surgical cytoreduction for patients with malignant pleural mesothelioma (MPM) is used for selected patients as a part of multi-modality management strategy. Our group has previously described the clinical use of photodynamic therapy (PDT), a form of non-ionizing radiation, as an intraoperative therapy option for MPM. Although necessary for the removal of bulk disease, the effects of surgery on residual MPM burden are not understood. In this bedside-to-bench study, Photofrin-based PDT introduced the possibility of achieving a long-term response in murine models of MPM tumors that were surgically debulked by 60% to 90%. Thus, the addition of PDT provided curative potential after an incomplete resection. Despite this success, we postulated that surgical induction of inflammation may mitigate the comprehensive response of residual disease to further therapy. Utilizing a previously validated tumor incision (TI) model, we demonstrated that the introduction of surgical incisions had no effect on acute cytotoxicity by PDT. However, we found that surgically induced inflammation limited the generation of antitumor immunity by PDT. Compared with PDT alone, when TI preceded PDT of mouse tumors, splenocytes and/or CD8+ T cells from the treated mice transferred less antitumor immunity to recipient animals. These results demonstrate that addition of PDT to surgical cytoreduction significantly improves long-term response compared with cytoreduction alone, but at the same time, the inflammation induced by surgery may limit the antitumor immunity generated by PDT. These data inform future potential approaches aimed at blocking surgically induced immunosuppression that might improve the outcomes of intraoperative combined modality treatment.
Significance: Although mesothelioma is difficult to treat, we have shown that combining surgery with a form of radiation, photodynamic therapy, may help people with mesothelioma live longer. In this study, we demonstrate in mice that this regimen could be further improved by addressing the inflammation induced as a by-product of surgery.

DOI: https://doi.org/10.1158/2767-9764.CRC-22-0494

Histopathology. 2023 Sep 11.

New developments in mesothelial pathology.

Andrew Churg.

This review article examines some new and some problem areas in mesothelial pathology, four of which are discussed, as follows. (1) The concept of mesothelioma in situ: this lesion is defined as a single layer of bland mesothelial cells without evidence of invasion, but that have lost BAP1 and/or MTAP by immunohistochemistry. Benign reactions can exactly mimic mesothelioma in situ, but a hint to the correct diagnosis is a story of recurrent pleural effusions/ascites of unknown aetiology without radiological or direct visual evidence of tumour. (2) The nature of well-differentiated papillary mesothelial tumour (WDPMT): WDPMT has a long history of arguments regarding its behaviour, and this uncertainty can now be seen to arise, in part, from the observation that some forms of mesothelioma in situ microscopically look exactly like WDPMT. Hence, it is recommended to always run at least a BAP1 stain on any lesion that looks like WDPMT. Both flat and WDPMT-like mesothelioma in situ are strongly associated with eventual development of invasive mesothelioma, but this process is relatively slow. (3) New immunostains for separating mesothelioma from other tumours: here, it is proposed that in most cases, and particularly when the differential is epithelioid mesothelioma versus non-small cell lung cancer, one can make this separation with extremely high sensitivity and specificity using just two stains: HEG1 and claudin-4. (4) Markers for separating benign from malignant mesothelial proliferations: this topic is briefly reviewed, with an indication of which markers are generally accepted and the best utilisation and possible limitations of each marker.

Keywords: BAP1; HEG1; benign mesothelial reaction; claudin-4; mesothelioma in situ; well-differentiated papillary mesothelial tumour

DOI: https://doi.org/10.1111/his.15007