bims-mesote 2023-08-06 papers

Issue of 2023–08–06
five papers selected by
Laura Mannarino, Humanitas Research

Cureus. 2023 Jul;15(7): e41243

Malignant Pleural Mesothelioma (MPM) Presenting as Hydropneumothorax.

Masami Kuramochi, Takuma Muraoka, Mayumi Shinonaga, Haruo Ohtani, Setsuo Kuraoka.

An 86-year-old man presented with bilateral lower limb edema and was found to have hydropneumothorax on chest radiography. CT revealed a substantial pleural effusion and plaques. The patient had a history of working in a stone workshop, but the extent of asbestos exposure remained unknown. Thoracic drainage and subsequent thoracoscopic surgery confirmed the presence of biphasic malignant mesothelioma through pathological examination. Hydropneumothorax as a presentation of malignant pleural mesothelioma (MPM) is rare, with only a few similar cases reported. Remarkably, despite the coexistence of plural effusion and pneumothorax, the patient did not experience dyspnea. The examination also revealed tumor rupture and disruption of the pleura. Considering the possibility of MPM in patients with asymptomatic hydropneumothorax is essential for early diagnosis and appropriate management.

Keywords: hydropneumothorax; immune checkpoint inhibitor; malignant pleural mesothelioma; pleural effusion; pneumothorax

DOI: https://doi.org/10.7759/cureus.41243

Pharmacol Rep. 2023 Aug 04.

Changes in expression of mesothelial BBS genes in 2D and 3D after lithium chloride and ammonium sulphate induction of primary cilium disturbance: a pilot study.

Erasmia Rouka, Rajesh M Jagirdar, Ioannis Sarrigeorgiou, Eleanna Pitaraki, Sotirios I Sinis, Charalambos Varsamas, Eleftherios D Papazoglou, Ourania S Kotsiou, Peggy Lymberi, Anastasios Giannou, Chrissi Hatzoglou, Konstantinos I Gourgoulianis, Sotirios G Zarogiannis.

BACKGROUND: Malignant pleural mesothelioma (MPM), a rare and aggressive pleural tumor, has significant histological and molecular heterogeneity. Primary Cilium (PC), an organelle of emerging importance in malignancies, has been scarcely investigated in MPM. A critical molecular complex for the PC function is the BBSome and here we aimed at assessing its expression patterns in ordinary 2D and spheroid 3D cell cultures.
METHODS: A human benign mesothelial cell line (MeT-5A), MPM cell lines (M14K, epithelioid MPM; MSTO, biphasic MPM), and primary MPM cells (pMPM) were used. Primers specific for the human BBS1, 2, 4, 5, 7, 9, 18 transcripts were designed, and quantitative real-time PCR (qRT-PCR) was done with β-actin as the gene of reference. The relative gene expression across 2D and 3D cultures was analyzed by the expression factor (mean of 1/ΔCt values). With the 2-∆∆Ct method the gene expression fold changes were assessed from qRT-PCR data. Molecular changes using the PC-modulating drugs ammonium sulfate (AS) and lithium chloride (LC) were also determined.
RESULTS: PC was present in all cells used in the study at approximately 15% of the observed area. BBSome transcripts were differentially expressed in different dimensions of cell culture (2D vs. 3D) in all cell lines and pMPM. Treatment with AS and LC affected the expression of the ciliary BBS2 and BBS18 genes in the benign as well as in the MPM cells.
CONCLUSIONS: These data indicate distinct BBSome molecular profiles in human benign and MPM cells cultured in 2D and 3D dimensions and support the notion that PC genes should be investigated as potential MPM therapeutic targets.

Keywords: 3D cell cultures; BBSome; Malignant pleural mesothelioma; Mesothelial; Primary Cilium; Tumor spheroids

DOI: https://doi.org/10.1007/s43440-023-00513-0

Front Immunol. 2023 ;14 1196731

ChemR23 activation reprograms macrophages toward a less inflammatory phenotype and dampens carcinoma progression.

Margot Lavy, Vanessa Gauttier, Alison Dumont, Florian Chocteau, Sophie Deshayes, Judith Fresquet, Virginie Dehame, Isabelle Girault, Charlène Trilleaud, Stéphanie Neyton, Caroline Mary, Philippe Juin, Nicolas Poirier, Sophie Barillé-Nion, Christophe Blanquart.

Introduction: Tumor Associated Macrophages (TAM) are a major component of the tumor environment and their accumulation often correlates with poor prognosis by contributing to local inflammation, inhibition of anti-tumor immune response and resistance to anticancer treatments. In this study, we thus investigated the anti-cancer therapeutic interest to target ChemR23, a receptor of the resolution of inflammation expressed by macrophages, using an agonist monoclonal antibody, αChemR23.
Methods: Human GM-CSF, M-CSF and Tumor Associated Macrophage (TAM)-like macrophages were obtained by incubation of monocytes from healthy donors with GM-CSF, M-CSF or tumor cell supernatants (Breast cancer (BC) or malignant pleural mesothelioma (MPM) cells). The effects of αChemR23 on macrophages were studied at the transcriptomic, protein and functional level. Datasets from The Cancer Genome Atlas (TCGA) were used to study CMKLR1 expression, coding for ChemR23, in BC and MPM tumors. In vivo, αChemR23 was evaluated on overall survival, metastasis development and transcriptomic modification of the metastatic niche using a model of resected triple negative breast cancer.
Results: We show that ChemR23 is expressed at higher levels in M-CSF and tumor cell supernatant differentiated macrophages (TAM-like) than in GM-CSF-differentiated macrophages. ChemR23 activation triggered by αChemR23 deeply modulates M-CSF and TAM-like macrophages including profile of cell surface markers, cytokine secretion, gene mRNA expression and immune functions. The expression of ChemR23 coding gene (CMKLR1) strongly correlates to TAM markers in human BC tumors and MPM and its histological detection in these tumors mainly corresponds to TAM expression. In vivo, treatment with αChemR23 agonist increased mouse survival and decreased metastasis occurrence in a model of triple-negative BC in correlation with modulation of TAM phenotype in the metastatic niche.
Conclusion: These results open an attractive opportunity to target TAM and the resolution of inflammation pathways through ChemR23 to circumvent TAM pro-tumoral effects.

Keywords: ChemR23 receptor; agonist; antibody; cancer; macrophage

DOI: https://doi.org/10.3389/fimmu.2023.1196731

J Immunother Cancer. 2023 Aug;pii: e007070. [Epub ahead of print]11(8):

Adjuvant dendritic cell-based immunotherapy after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients with malignant peritoneal mesothelioma: a phase II clinical trial.

Michelle V Dietz, Katrien L A Quintelier, Job P van Kooten, Nadine L de Boer, Madelief Vink, Alexandra R M Brandt-Kerkhof, Cornelis Verhoef, Yvan Saeys, Joachim G J V Aerts, Marcella Willemsen, Sofie Van Gassen, Eva V E Madsen.

BACKGROUND: Malignant peritoneal mesothelioma (MPM) is an aggressive malignancy with a poor prognosis. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) improves survival outcomes, but recurrence rates remain high. Dendritic cell-based immunotherapy (DCBI) showed promising results in patients with pleural mesothelioma. The primary aim of this trial was to determine feasibility of adjuvant DCBI after CRS-HIPEC.
METHODS: This open-label, single-center, phase II clinical trial, performed in the Erasmus MC Cancer Institute Rotterdam, the Netherlands, included patients with epithelioid MPM. 4-6 weeks before CRS-HIPEC leukapheresis was performed. 8-10 weeks after surgery, DCBI was administered three times biweekly. Feasibility was defined as administration of at least three adjuvant vaccinations in 75% of patients. Comprehensive immune cell profiling was performed on peripheral blood samples prior to and during treatment.
RESULTS: All patients who received CRS-HIPEC (n=16) were successfully treated with adjuvant DCBI. No severe toxicity related to DCBI was observed. Median progression-free survival (PFS) was 12 months (IQR 5-23) and median overall survival was not reached. DCBI was associated with increased proliferation of circulating natural killer cells and CD4+ T-helper (Th) cells. Co-stimulatory molecules, including ICOS, HLA-DR, and CD28 were upregulated predominantly on memory or proliferating Th-cells and minimally on CD8+ cytotoxic T-lymphocytes (CTLs) after treatment. However, an increase in CD8+ terminally differentiated effector memory (Temra) cells positively correlated with PFS, whereas co-expression of ICOS and Ki67 on CTLs trended towards a positive correlation.
CONCLUSIONS: Adjuvant DCBI after CRS-HIPEC in patients with MPM was feasible and safe, and showed promising survival outcomes. DCBI had an immune modulatory effect on lymphoid cells and induced memory T-cell activation. Moreover, an increase of CD8+ Temra cells was more pronounced in patients with longer PFS. These data provide rationale for future combination treatment strategies.
TRIAL REGISTRATION NUMBER: NTR7060; Dutch Trial Register (NTR).

Keywords: CD4-positive T-lymphocytes; CD8-positive T-lymphocytes; clinical trials, phase II as topic; dendritic cells; immunotherapy

DOI: https://doi.org/10.1136/jitc-2023-007070

AJSP Rev Rep. 2022 May-Jun;27(3):27(3): 87-93

Sarcomatoid Mesothelioma with Bland Histologic Features: A Potential Pitfall in Diagnosis.

Allen P Burke, Naomi Hardy, Rachel Fanaroff, Teklu Legesse.

Sarcomatoid mesotheliomas can be challenging to diagnose on small biopsy specimens, where limited material may preclude definitive assessment of invasion and lesional cells can have relatively bland cytology with no mesothelial marker expression. We report a case of a patient who presented with a pleural effusion and had subsequent pleural biopsy that showed a bland, uniform spindle cell proliferation in a mildly myxoid background. There was little if any collagen; no chest wall, soft tissue, or fat; and mesothelial markers were negative. The cells were positive for pancytokeratin and GATA3 by immunohistochemistry, and in situ hybridization showed a "negative" result for homozygous loss of CDKN2A; however, there was partial (heterozygous) loss of one allele. A diagnosis of atypical spindle cell proliferation was made based on these findings. Several months later, the patient had a repeat pleural biopsy that showed spindled cells with more pleomorphism, areas of invasion into the chest wall, and the same partial loss of CDKN2A, consistent with a sarcomatoid mesothelioma. This case underscores the challenges present on small biopsy specimens, the fact that sarcomatoid mesotheliomas can be relatively bland appearing with focal pleomorphism, and that heterozygous loss of CDKN2A should be considered a positive result indicative of a neoplastic process.

DOI: https://doi.org/10.1097/PCR.0000000000000506