bims-mesote 2024-01-14 papers

bims-mesote

Biomed News

on Mesothelioma

Issue of 2024‒01‒14
six papers selected by
Laura Mannarino, Humanitas Research

Extended pleurectomy/decortication and hyperthermic intraoperative intrapleural cisplatin perfusion for malignant pleural mesothelioma.
Molecular and Immunohistochemical Testing in Mesothelioma and Other Mesothelial Lesions.
Serum Calretinin and Genetic Variability as a Prognostic and Predictive Factor in Malignant Mesothelioma.
Comparison of immunohistochemistry, next generation sequencing and fluorescence in situ hybridization for detection of MTAP loss in pleural mesothelioma.
Validation of Inflammatory Prognostic Biomarkers in Pleural Mesothelioma.
Single-cell transcriptomic analysis of human pleura reveals stromal heterogeneity and informs in vitro models of mesothelioma.

JTCVS Open. 2023 Dec;16 977-986

Extended pleurectomy/decortication and hyperthermic intraoperative intrapleural cisplatin perfusion for malignant pleural mesothelioma.

Kenichi Okubo, Hironori Ishibashi, Ryo Wakejima, Shunichi Baba, Ayaka Asakawa, Hiroshi Seshima.

  Objective: To evaluate the efficacy of multimodality treatment including extended pleurectomy/decortication (P/D) and hyperthermic intraoperative chemotherapy (HIOC) with cisplatin for malignant pleural mesothelioma (MPM), we investigated the pharmacokinetics of platinum, adverse events after HIOC, and survival outcome.Methods: Fifty-three patients with pathologically diagnosed MPM (cT1-3N0-1M0, excluding sarcomatoid) underwent an extended P/D and HIOC (cisplatin 80 mg/m2 in saline 2 L, 42°C, 60 minutes) since 2011. The protocol includes postoperative 4 cycles of cisplatin and pemetrexed. Platinum concentrations in the perfusate (before and after) and the serum (1, 2, 4, 8, 24, 48, 72 hours after perfusion) were measured in 10 patients. Mortality and morbidity, especially adverse events of renal function, were investigated, and survival and affecting factors were examined.
Results: All patients obtained macroscopic complete resection and pathologic staging revealed as follows: T1/2/3/4: 12/8/23/10, N0/1: 36/17, stage 1A/1B-3A/3B: 12/31/10, respectively. Platinum concentrations in the perfusate indicated that 28% of the dose remained in the pleural cavity, and the maximum concentration in the serum was 0.91 μg/mL. Six patients (11%) showed elevated max-creatinine (>2 mg/dL) postoperatively. Two patients (4%) received renal-replacement therapy, and one was weaned before discharge. There was no 30-day mortality and one in-hospital death (1.9%). Forty-six patients (87%) received multiple cycles of perioperative systemic chemotherapy. Median overall survival (OS) and disease-free survival (DFS) were 52.4 months and 18.7 months. Patents with stage 1A demonstrated a 5-year OS of 67.3% and a median DFS of 67.1 months, and patients with stage 1B-3A demonstrated a 5-year OS of 50.1% and a median DFS of 20.4 months. Univariate analysis showed histological subtype, p-T, p-stage, and multimodality treatment as significant factors affecting OS. Multivariate analysis revealed histology, p-stage, and multimodality as independent.
Conclusions: Extended P/D and HIOC with cisplatin for MPM is acceptable with limited acute kidney injury. This multimodality protocol provides promising favorable survival for stage 1A-3A disease.

Keywords:  acute kidney injury; cisplatin; concentration; hyperthermic intraoperative intrapleural chemotherapy; malignant pleural mesothelioma; pleurectomy/decortication; survival

DOI:  https://doi.org/10.1016/j.xjon.2023.09.005
Arch Pathol Lab Med. 2024 Jan 08.

Molecular and Immunohistochemical Testing in Mesothelioma and Other Mesothelial Lesions.

Yin P Hung, Lucian R Chirieac.

CONTEXT.—: Molecular testing has increasingly been utilized in the evaluation of mesothelioma. Diffuse mesothelioma comprises multiple distinct genetic subgroups. While most diffuse mesotheliomas lack oncogenic kinase mutations and instead harbor alterations involving tumor suppressors and chromatin regulators, a minor subset of tumors is characterized by uncommon alterations such as germline mutations, genomic near-haploidization, ALK rearrangement, ATF1 rearrangement, or EWSR1::YY1 fusion.OBJECTIVE.—: To provide updates on the salient molecular features of diffuse mesothelioma, mesothelioma in situ, and other mesothelial lesions: well-differentiated papillary mesothelial tumor, adenomatoid tumor, peritoneal inclusion cyst, and others. We consider the diagnostic, prognostic, and predictive utility of molecular testing in mesothelial lesions.
DATA SOURCES.—: We performed a literature review of recently described genetic features, molecular approaches, and immunohistochemical tools, including BAP1, MTAP, and merlin in mesothelioma and other mesothelial lesions.
CONCLUSIONS.—: Our evolving understanding of the molecular diversity of diffuse mesothelioma and other mesothelial lesions has led to considerable changes in pathology diagnostic practice, including the application of immunohistochemical markers such as BAP1, MTAP, and merlin (NF2), which are surrogates of mutation status. In young patients and/or those without significant asbestos exposure, unusual mesothelioma genetics such as germline mutations, ALK rearrangement, and ATF1 rearrangement should be considered.

DOI: https://doi.org/10.5858/arpa.2023-0213-RA
Int J Mol Sci. 2023 Dec 22. pii: 190. [Epub ahead of print]25(1):

Serum Calretinin and Genetic Variability as a Prognostic and Predictive Factor in Malignant Mesothelioma.

Cita Zupanc, Alenka Franko, Danijela Štrbac, Viljem Kovač, Vita Dolžan, Katja Goričar.

  Calretinin is a promising diagnostic biomarker for malignant mesothelioma (MM), but less is known about its prognostic role. Our aim was to evaluate the association between serum calretinin concentration or genetic factors and the survival or outcome of cisplatin-based chemotherapy in MM. Our study included 265 MM patients. Serum calretinin concentration was determined using ELISA. Patients were genotyped for seven polymorphisms in CALB2, E2F2, MIR335, NRF1, and SEPTIN7 using competitive allele-specific PCR. Nonparametric tests, logistic regression, and survival analysis were used for statistical analysis. Higher serum calretinin concentration was associated with shorter progression-free (PFS) (HR = 1.18 (1.02-1.37), p = 0.023) and overall survival (OS) (HR = 1.20 (1.03-1.41), p = 0.023), but the association was not significant after adjusting for clinical factors (HR = 1.05 (0.85-1.31), p = 0.653 and HR = 1.06 (0.84-1.34), p = 0.613, respectively). SEPTIN7 rs3801339 and MIR335 rs3807348 were associated with survival even after adjustment (HR = 1.76 (1.17-2.64), p = 0.007 and HR = 0.65 (0.45-0.95), p = 0.028, respectively). Calretinin concentration was higher in patients who progressed after treatment with cisplatin-based chemotherapy (1.68 vs. 0.45 ng/mL, p = 0.001). Calretinin concentration above 0.89 ng/mL was associated with shorter PFS and OS from the start of chemotherapy (HR = 1.88 (1.28-2.77), p = 0.001 and HR = 1.91 (1.22-2.97), p = 0.004, respectively), even after adjusting for clinical factors (p < 0.05). MIR335 rs3807348 was associated with a better response to chemotherapy (OR = 2.69 (1.17-6.18), p = 0.020). We showed that serum calretinin is associated with survival and chemotherapy treatment outcomes in MM and could serve as a predictive biomarker.

Keywords:  CALB2; biomarker; calretinin; malignant mesothelioma; polymorphism

DOI:  https://doi.org/10.3390/ijms25010190
Mod Pathol. 2024 Jan 05. pii: S0893-3952(23)00325-3. [Epub ahead of print] 100420

Comparison of immunohistochemistry, next generation sequencing and fluorescence in situ hybridization for detection of MTAP loss in pleural mesothelioma.

Christopher A Febres-Aldana, Jason C Chang, Achim A Jungbluth, Prasad S Adusumilli, Francis M Bodd, Denise Frosina, Jerica A Geronimo, Enmily Hernandez, Helen Irawan, Michael D Offin, Natasha Rekhtman, William D Travis, Chad Vanderbilt, Marjorie G Zauderer, Yanming Zhang, Marc Ladanyi, Soo-Ryum Yang, Jennifer L Sauter.

  9p21 deletions involving MTAP/CDKN2A genes are detected in diffuse pleural mesotheliomas (DPM) but absent in benign mesothelial proliferations. Loss of MTAP expression by immunohistochemistry (IHC) is well accepted as a surrogate for 9p21 deletion to support a diagnosis of DPM. Accurate interpretation can be critical in the diagnosis of DPM, but variations in antibody performance may impact interpretation. The objectives of this study are to compare the performance of MTAP monoclonal antibodies (mAbs) EPR6893 and 1813 and to compare MTAP expression by IHC with 9p21 copy number status in DPM. Cytoplasmic expression of MTAP IHC with mAbs EPR6893 (ab126770; Abcam, Cambridge, MA, USA) and 1813 (NBP2-75730, Novus Biologicals, Centennial, CO, USA) was evaluated in 56 DPM (47 epithelioid, 7 biphasic, and 2 sarcomatoid) profiled by targeted NGS. 9p21 copy number status was assessed by FACETS analysis and also by CDKN2A FISH in discrepant cases when material was available. MTAP mAb 1813 showed stronger immunoreactivity, more specific staining and no equivocal interpretations compared to mAb EPR6893 which showed equivocal staining in 19 (34%) of cases due to weak or heterogenous immunoreactivity, lack of definitive internal positive control, and/or non-specific background staining. MTAP expression with mAb 1813 showed near perfect agreement with 9p21 copy number by combined FACETS/FISH calls (Kappa=0.85; 95% IC: 0.71-0.99, P<0.001). MTAP IHC with mAb 1813 was 96% sensitive, 86% specific and 93% accurate for 9p21 homozygous deletion. The findings of this study suggest that interpretation of MTAP IHC is improved with mAb 1813 since mAb EPR6893 was often limited by equivocal interpretations. We show that MTAP IHC and molecular assays are complementary in detecting 9p21 homozygous deletion. MTAP IHC may be particularly useful for low tumor purity samples and in low-resource settings.

Keywords:  9p21 homozygous deletion; CDKN2A; MTAP; diffuse pleural mesothelioma; immunohistochemistry; next generation sequencing

DOI:  https://doi.org/10.1016/j.modpat.2023.100420
Cancers (Basel). 2023 Dec 24. pii: 93. [Epub ahead of print]16(1):

Validation of Inflammatory Prognostic Biomarkers in Pleural Mesothelioma.

Stephanie Iser, Sarah Hintermair, Alexander Varga, Ali Çelik, Muhammet Sayan, Aykut Kankoç, Nalan Akyürek, Betül Öğüt, Pietro Bertoglio, Enrico Capozzi, Piergiorgio Solli, Luigi Ventura, David Waller, Michael Weber, Elisabeth Stubenberger, Bahil Ghanim.

  Evoked from asbestos-induced inflammation, pleural mesothelioma represents a fatal diagnosis. Therapy ranges from nihilism to aggressive multimodality regimens. However, it is still unclear who ultimately benefits from which treatment. We aimed to re-challenge inflammatory-related biomarkers' prognostic value in times of modern immune-oncology and lung-sparing surgery. The biomarkers (leukocytes, hemoglobin, platelets, neutrophils, lymphocytes, monocytes, neutrophil-lymphocyte ratio (NLR), lymphocyte-monocyte ratio (LMR), platelet-lymphocyte ratio (PLR), C-reactive protein (CRP)) and clinical characteristics (age, sex, histology, therapy) of 98 PM patients were correlated to overall survival (OS). The median OS was 19.4 months. Significant OS advantages (Log-Rank) were observed in multimodal treatment vs. others (26.1 vs. 7.2 months, p < 0.001), surgery (pleurectomy/decortication) vs. no surgery (25.5 vs. 3.8 months, p < 0.001), a high hemoglobin level (cut-off 12 g/dL, 15 vs. 24.2 months, p = 0.021), a low platelet count (cut-off 280 G/L, 26.1 vs. 11.7 months, p < 0.001), and a low PLR (cut-off 194.5, 25.5 vs. 12.3 months, p = 0.023). Histology (epithelioid vs. non-epithelioid, p = 0.002), surgery (p = 0.004), CRP (cut-off 1 mg/dL, p = 0.039), and platelets (p = 0.025) were identified as independent prognostic variables for this cohort in multivariate analysis (Cox regression, covariates: age, sex, histology, stage, CRP, platelets). Our data verified the previously shown prognostic role of systemic inflammatory parameters in patients treated with lung-sparing surgery within multimodality therapy.

Keywords:  PLR; multimodal therapy; platelets; pleural mesothelioma; pleurectomy/decortication; prognostic biomarkers

DOI:  https://doi.org/10.3390/cancers16010093
Eur Respir J. 2024 Jan 11. pii: 2300143. [Epub ahead of print]

Single-cell transcriptomic analysis of human pleura reveals stromal heterogeneity and informs in vitro models of mesothelioma.

Joanna Obacz, Jose Antonio Valer, Reshma Nibhani, Taylor S Adams, Jonas C Schupp, Niki Veale, Amanah Lewis-Wade, Jasper Flint, John Hogan, Giuseppe Aresu, Aman S Coonar, Adam Peryt, Giulia Biffi, Naftali Kaminski, Hayley Francies, Doris M Rassl, Mathew J Garnett, Robert C Rintoul, Stefan J Marciniak.

The pleural lining of the thorax regulates local immunity, inflammation and repair. A variety of conditions, both benign and malignant including pleural mesothelioma, can affect this tissue. A lack of knowledge concerning the mesothelial and stromal cells comprising the pleura has hampered the development of targeted therapies. Here we present the first comprehensive single cell transcriptomic atlas of the human parietal pleura and demonstrate its utility in elucidating pleural biology. We confirm the presence of known universal fibroblasts and describe novel, potentially pleural-specific, fibroblast subtypes. We also present transcriptomic characterisation of multiple in vitro models of benign and malignant mesothelial cells, and characterise these through comparison with in vivo transcriptomic data. While bulk pleural transcriptomes have been reported previously, this is the first study to provide resolution at single cell level. We expect our pleural cell atlas will prove invaluable to those studying pleural biology and disease. For example, it has already enabled us to shed light on the transdifferentiation of mesothelial cells allowing us to develop a simple method for prolonging mesothelial cell differentiation in vitro.

DOI: https://doi.org/10.1183/13993003.00143-2023