bims-mesote 2023-02-19 papers

bims-mesote

Biomed News

on Mesothelioma

Issue of 2023–02–19
eleven papers selected by
Laura Mannarino, Humanitas Research

Medical application of the monoclonal antibody SKM9-2 against sialylated HEG1, a new precision marker for malignant mesothelioma.
Immunotherapy with immune checkpoint inhibitors and predictive biomarkers in malignant mesothelioma: Work still in progress.
Molecular Characterization of Testicular Mesothelioma and the Role of Asbestos as a Causative Factor.
Neurofibromatosis Type 2-Yes-Associated Protein and Transcriptional Coactivator With PDZ-Binding Motif Dual Immunohistochemistry Is a Reliable Marker for the Detection of Neurofibromatosis Type 2 Alterations in Diffuse Pleural Mesothelioma.
Genomic and transcriptomic analyses identify a prognostic gene signature and predict response to therapy in pleural and peritoneal mesothelioma.
Rare recurrence of malignant mesothelioma spreading to the perineum.
Asbestos exposure as an additional risk factor for small duct intrahepatic cholangiocarcinoma: a pilot study.
Pleural plaques and the role of exposure to mineral particles in the Asbestos Post-Exposure Survey.
Global Incidence, Risk Factors, and Temporal Trends of Mesothelioma: a population-based study.
Applications of Neural Network-Based Plan-Cancer Method for Primary Diagnosis of Mesothelioma Cancer.
Overcoming clinical resistance to EZH2 inhibition using rational epigenetic combination therapy.

Proc Jpn Acad Ser B Phys Biol Sci. 2023 ;99(2): 39-47

Medical application of the monoclonal antibody SKM9-2 against sialylated HEG1, a new precision marker for malignant mesothelioma.

Shoutaro Tsuji, Kohzoh Imai.

  Malignant pleural mesothelioma (MPM) is an aggressive tumor of the pleural cavity. Pathologically distinguishing MPM from other pleural lesions is often difficult. We searched for marker antigens to facilitate the pathological diagnosis of MPM and found useful markers for the pathological detection of malignant mesothelioma. Among them, the anti-mesothelioma monoclonal antibody SKM9-2, which was isolated as a clone binding to specimens of MPM (but not to specimens of lung adenocarcinoma) by immunohistochemical screening, showed higher specificity and sensitivity than traditional mesothelioma markers. SKM9-2 recognizes both sialylated O-glycans and peptide sequences in HEG1, and its glycan modifications are specific to mesothelioma. New effective treatments for MPM are needed because the prognosis of patients with MPM is usually poor. SKM9-2 can be used as a seed for next-generation antibody drugs with strong cytotoxic activities. In this review, we have summarized our research on antibody development for MPM diagnosis and treatment.

Keywords:  antibody; diagnosis; glycopeptide; mesothelioma; mucin

DOI:  https://doi.org/10.2183/pjab.99.003
Front Immunol. 2023 ;14 1121557

Immunotherapy with immune checkpoint inhibitors and predictive biomarkers in malignant mesothelioma: Work still in progress.

Matteo Perrino, Fabio De Vincenzo, Nadia Cordua, Federica Borea, Marta Aliprandi, Armando Santoro, Paolo Andrea Zucali.

  Malignant mesothelioma (MM) is a rare and aggressive neoplasm, usually associated with a poor prognosis (5 years survival rate <10%). For unresectable disease, platinum and pemetrexed chemotherapy has been the only standard of care in first line for more than two decades, while no standard treatments have been approved in subsequent lines. Recently, immunotherapy has revolutionized the therapeutic landscape of MM. In fact, the combination of ipilimumab plus nivolumab has been approved in first line setting. Moreover, immune checkpoint inhibitors (ICIs) showed promising results also in second-third line setting after platinum-based chemotherapy. Unfortunately, approximately 20% of patients are primary refractory to ICIs and there is an urgent need for reliable biomarkers to improve patient's selection. Several biological and molecular features have been studied for this goal. In particular, histological subtype (recognized as prognostic factor for MM and predictive factor for chemotherapy response), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (widely hypothesized as predictive biomarkers for ICIs in several solid tumors) have been evaluated, but with unconclusive results. On the other hand, the deep analysis of tumor infiltrating microenvironment and the improvement in genomic profiling techniques has led to a better knowledge of several mechanisms underlying the MM biology and a greater or poorer immune activation. Consequentially, several potential biomarkers predictive of response to immunotherapy in patients with MM have been identified, also if all these elements need to be further investigated and prospectively validated. In this paper, the main evidences about clinical efficacy of ICIs in MM and the literature data about the most promising predictive biomarkers to immunotherapy are reviewed.

Keywords:  biomarkers; immune checkpoint inhibitors; immunotherapy; malignant mesothelioma; predictive of response

DOI:  https://doi.org/10.3389/fimmu.2023.1121557
Arch Pathol Lab Med. 2023 Feb 16.

Molecular Characterization of Testicular Mesothelioma and the Role of Asbestos as a Causative Factor.

Ashleigh Jean Hocking, Elaine May Thomas, Sarita Prabhakaran, Alexandra Jolley, Susan Lesley Woods, Matthew J Soeberg, Sonja Klebe.

CONTEXT.—: Mesothelioma of the tunica vaginalis testis (TVT) is an extremely rare form of mesothelioma.
OBJECTIVE.—: To compare the clinical and molecular characteristics of mesothelioma of the TVT with those of mesothelioma at other more common sites, including the relationship with exposure to asbestos.
DESIGN.—: We present clinical and pathological data for 9 cases of primary TVT mesothelioma. We performed whole-genome sequencing on 3 cases for the first time.
RESULTS.—: The majority (7 of 9 cases) of TVT mesotheliomas were epithelioid, with the remaining 2 cases showing biphasic morphology. Morphology and immunohistochemical profiles were indistinguishable from mesothelioma elsewhere. Asbestos exposure was documented for 7 of the 9 cases, with no information for 2 cases. The 3 TVT mesothelioma cases that underwent whole-genome sequencing displayed a mutational profile similar to that of mesothelioma at other sites, including NF2 and TP53 mutations.
CONCLUSIONS.—: The clinical and molecular profile of TVT mesothelioma is similar to that of mesothelioma elsewhere.

DOI: https://doi.org/10.5858/arpa.2022-0283-OA
Mod Pathol. 2023 Jan 10. pii: S0893-3952(22)00030-8. [Epub ahead of print]36(3): 100030

Neurofibromatosis Type 2-Yes-Associated Protein and Transcriptional Coactivator With PDZ-Binding Motif Dual Immunohistochemistry Is a Reliable Marker for the Detection of Neurofibromatosis Type 2 Alterations in Diffuse Pleural Mesothelioma.

Yan Li, Soo-Ryum Yang, Ying-Bei Chen, Prasad S Adusumilli, Ann Bialik, Francis M Bodd, Marc Ladanyi, Jessica Lopardo, Michael D Offin, Valerie W Rusch, William D Travis, Marjorie G Zauderer, Jason C Chang, Jennifer L Sauter.

  Neurofibromatosis type 2 (NF2) loss occurs in approximately 30% to 50% of diffuse pleural mesothelioma (DPM) with accumulation of yes-associated protein (YAP) 1 and transcriptional coactivator with PDZ-binding motif (TAZ) in tumor nuclei. NF2 and YAP/TAZ represent potential therapeutic targets. We investigated the performance of NF2-YAP/TAZ dual immunohistochemistry (IHC) in identifying DPM that harbors NF2 alterations and in distinguishing DPM from benign mesothelial proliferations. NF2-YAP/TAZ IHC was subsequently performed in a Discovery cohort of DPMs with (n = 10) or without (n = 10) NF2 alterations detected by next-generation sequencing (NGS) and 9 benign cases. The cutoff values for loss of NF2 expression and YAP/TAZ overexpression using IHC were determined in the Discovery cohort. The performance characteristics of NF2-YAP/TAZ IHC were investigated in a Validation cohort (20 DPMs and 10 benign cases). In the Discovery cohort, all DPMs with NF2 alterations using NGS showed NF2 IHC scores of <2, whereas all NF2-wild-type DPMs showed scores of ≥2. NF2-altered DPMs had significantly higher YAP/TAZ H-scores (P < .001) than NF2-wild-type DPM and benign pleura (median H-scores: 237.5 [range, 185-275], 130.0 [range, 40-225], and 10.0 [range, 0-75], respectively). NF2-YAP/TAZ IHC demonstrated 95.2% sensitivity, 100% specificity, 100% positive predictive value, and 95% negative predictive value for detecting NF2 alterations in DPM (n = 40) with NGS as the gold standard and 87.5% sensitivity and 100% specificity for distinguishing DPM (n = 40) from benign mesothelial proliferations (n = 19). NF2-YAP/TAZ IHC has a high sensitivity and specificity for detecting NF2 alterations in DPM and a high specificity for malignancy, highlighting potential utility for guiding NF2-targeted therapies and distinguishing DPM from benign mimics.

Keywords:  diffuse pleural mesothelioma; dual immunohistochemistry; neurofibromatosis type 2; next-generation sequencing; yes-associated protein

DOI:  https://doi.org/10.1016/j.modpat.2022.100030
Cell Rep Med. 2023 Feb 08. pii: S2666-3791(23)00030-7. [Epub ahead of print] 100938

Genomic and transcriptomic analyses identify a prognostic gene signature and predict response to therapy in pleural and peritoneal mesothelioma.

Nishanth Ulhas Nair, Qun Jiang, Jun Stephen Wei, Vikram Alexander Misra, Betsy Morrow, Chimene Kesserwan, Leandro C Hermida, Joo Sang Lee, Idrees Mian, Jingli Zhang, Alexandra Lebensohn, Markku Miettinen, Manjistha Sengupta, Javed Khan, Eytan Ruppin, Raffit Hassan.

  Malignant mesothelioma is an aggressive cancer with limited treatment options and poor prognosis. A better understanding of mesothelioma genomics and transcriptomics could advance therapies. Here, we present a mesothelioma cohort of 122 patients along with their germline and tumor whole-exome and tumor RNA sequencing data as well as phenotypic and drug response information. We identify a 48-gene prognostic signature that is highly predictive of mesothelioma patient survival, including CCNB1, the expression of which is highly predictive of patient survival on its own. In addition, we analyze the transcriptomics data to study the tumor immune microenvironment and identify synthetic-lethality-based signatures predictive of response to therapy. This germline and somatic whole-exome sequencing as well as transcriptomics data from the same patient are a valuable resource to address important biological questions, including prognostic biomarkers and determinants of treatment response in mesothelioma.

Keywords:  WES; mesothelioma; response to therapy; synthetic lethality; transcriptome

DOI:  https://doi.org/10.1016/j.xcrm.2023.100938
BMJ Case Rep. 2023 Feb 14. pii: e252441. [Epub ahead of print]16(2):

Rare recurrence of malignant mesothelioma spreading to the perineum.

Angelo Alessandro Marra, Andrea Di Giorgio, Carlo Ratto.

  Malignant mesothelioma is a rare aggressive tumour of the mesothelium with a propensity to spread locally and, rarely, to distant organs. The latest advances in its diagnosis and treatment have led to an increase in unusual disease presentations. Although a direct invasion of the perineum has been previously described in a men, a malignant mesothelioma spreading to the perianal region was never reported in a women. We presented a rare case of malignant mesothelioma recurrence spreading from the peritoneal cavity to the perineum through the rectovaginal space.

Keywords:  Carcinogenesis; Chemotherapy; Gastroenterology; Gastrointestinal surgery; Oncology

DOI:  https://doi.org/10.1136/bcr-2022-252441
Sci Rep. 2023 Feb 13. 13(1): 2580

Asbestos exposure as an additional risk factor for small duct intrahepatic cholangiocarcinoma: a pilot study.

Francesco Vasuri, Marzia Deserti, Angelo G Corradini, Simona Tavolari, Valeria Relli, Andrea Palloni, Giorgio Frega, Stefania Curti, Stefano Mattioli, Matteo Cescon, Antonia D'Errico, Giovanni Brandi.

Intrahepatic cholangiocarcinoma (iCCA) is a rare malignancy, recently classified in small duct and large duct morphological subtypes. Growing evidence suggests asbestos as a putative risk factor for iCCA, albeit no correlation between asbestos and iCCA morphology has been investigated so far. The aim of the present study was to assess the relationship between asbestos exposure and iCCA morphological subtype. Forty patients with surgically removed iCCA were prospectively enrolled: asbestos exposure was assessed according to the Italian National Mesothelioma Register questionnaire. From the surgical iCCA specimens the main histopathological variables were collected, including the small duct (sd-iCCA, 32 patients) and large duct subtypes (ld-iCCA, 8 patients). Five sd-iCCA cases had a definite/probable occupational exposure to asbestos, while no cases of ld-iCCA were classified as being occupationally exposed (definite/probable). Other kind of asbestos exposure (i.e. possible occupational, familial, environmental) were recorded in 16 sd-iCCA and 3 ld-iCCA. Cases with unlikely exposure to asbestos were 11 sd-iCCA (35.5%) and 5 ld-iCCA (62.5%). In conclusion, these findings seem to indicate that sd-iCCA might be more frequently associated to asbestos exposure rather than ld-iCCA, suggesting that asbestos fibres might represent a parenchymal, rather than a ductal risk factor for iCCA. This pilot study must be confirmed by further case-control studies or large independent cohorts.

DOI: https://doi.org/10.1038/s41598-023-27791-1
Chest. 2023 Feb 09. pii: S0012-3692(23)00176-9. [Epub ahead of print]

Pleural plaques and the role of exposure to mineral particles in the Asbestos Post-Exposure Survey.

Christophe Paris, Isabelle Thaon, François Laurent, Anastasia Saade, Pascal Andujar, Patrick Brochard, Julia Benoist, Benedicte Clin, Gilbert Ferretti, Antoine Gislard, Cecile Gramond, Pascal Wild, Aude Lacourt, Fleur Delva, Jean-Claude Pairon.

   BACKGROUND: Previous studies have inconsistently reported associations between Refractory Ceramic Fibers (RCF) or Mineral Wool Fibers (MWF) and the presence of pleural plaques (PP). Moreover, all these studies were based on Chest X-Ray, known to be associated with a poor sensitivity for the diagnosis of PP.
RESEARCH QUESTION: Does the risk of pleural plaques increase with cumulative exposure to RCF, MWF and silica ? and if yes, do these dose-response relationships depend on the co-exposure to asbestos or conversely, are the dose-response relationships for asbestos modified by co-exposure to RCF, MWF and silica ?
STUDY DESIGN AND METHODS: Volunteer workers were invited to participate in a CT-scan screening program for asbestos-related diseases in France. Asbestos exposure was assessed by industrial hygienists and exposure to RCF, MWF and silica was determined by using Job-Exposure Matrices. A Cumulative Exposure Index (CEI) was then calculated for each subject and separately for each of the 4 mineral particle exposures. All available CT-scans were submitted to randomized, double reading by a panel of radiologists.
RESULTS: In this cohort of 5,457 subjects, we found a significant dose-response relationships, after adjustment for asbestos exposure between CEI to RCF or MWF and the risk of PP (OR= 1.29 [1.00-1.67] and OR= 1.84 [1.49-2.27] for the highest CEI quartile respectively). Moreover, significant interactions were found between asbestos on one side and respectively MWF or RCF on the other side.
INTERPRETATION: This study suggests the existence of a significant association between exposure to RCF and MWF and the presence of PP in a large population previously exposed to asbestos and screened by CT-scan.

Keywords:  asbestos; epidemiology; exposure; mineral wool fibres; occupational; pleural plaques; refractory ceramic fibres; silica

DOI:  https://doi.org/10.1016/j.chest.2023.02.004
J Thorac Oncol. 2023 Feb 10. pii: S1556-0864(23)00125-9. [Epub ahead of print]

Global Incidence, Risk Factors, and Temporal Trends of Mesothelioma: a population-based study.

Junjie Huang, Sze Chai Chan, Wing Sze Pang, Shui Hang Chow, Veeleah Lok, Lin Zhang, Xu Lin, Don Eliseo Lucero-Prisno, Wanghong Xu, Zhi-Jie Zheng, Edmar Elcarte, Mellissa Withers, Martin Cs Wong.

   INTRODUCTION: Mesothelioma is an uncommon type of cancer which has received little attention. This study aims to evaluate the global disease burden, trends of mesothelioma by age, sex and geographical locations, and investigate its risk factors on the population level.
METHODS: Global Cancer Observatory (GLOBOCAN), Cancer Incidence in Five Continents Plus (CI5 Plus), Global Burden of Disease (GBD) were accessed for mesothelioma incidence and its risk factors worldwide. The associations between mesothelioma incidence and asbestos were examined for each country by multivariable linear regression analysis by sex and age. Average Annual Percentage Change (AAPC) was calculated using Joinpoint regression to examine epidemiological trends of mesothelioma.
RESULTS: The age-standardised rate of mesothelioma was 0.30 per 100,000 persons with Northern Europe reporting the highest incidence rates. The incidence rate of the male population was much higher than females. Countries with higher HDI (β=0.119, CI 0.073 to 0.166, p<0.001), GDP per capita (β=0.133, CI 0.106 to 0.161, p<0.001), and asbestos exposure (β=0.087, CI 0.073 to 0.102, p<0.001; Figure) had higher mesothelioma. The overall trend of mesothelioma incidence was decreasing although an increase was observed in Bulgaria (AAPC: 5.56, 95% CI: 2.94 to 8.24, p=0.001) and Korea (AAPC: 3.24, 95% CI 0.08 to 6.49, p=0.045).
CONCLUSION: There was a significant declining incidence trend of mesothelioma for the past decade possibly related to the restriction of the use of asbestos in some countries. Meanwhile, the increasing trend in mesothelioma incidence observed in females might be indicative of an increase in environmental exposure to mineral fibres.

Keywords:  incidence; mesothelioma; risk factors; temporal trend

DOI:  https://doi.org/10.1016/j.jtho.2023.01.095
Biomed Res Int. 2023 ;2023 3164166

Applications of Neural Network-Based Plan-Cancer Method for Primary Diagnosis of Mesothelioma Cancer.

Dhiraj Kapila, Sarika Panwar, M K Mohan Maruga Raja, Tamal Mondal, Shaik Mohammad Rafi, Suryabhan Pratap Singh, Bhupendra Kumar.

"Malignant mesothelioma (MM)" is an uncommon although fatal form of cancer. The proper MM diagnosis is crucial for efficient therapy and has significant medicolegal implications. Asbestos is a carcinogenic material that poses a health risk to humans. One of the most severe types of cancer induced by asbestos is "malignant mesothelioma." Prolonged shortness of breath and continuous pain are the most typical symptoms of the condition. The importance of early treatment and diagnosis cannot be overstated. The combination "epithelial/mesenchymal appearance of MM," however, makes a definite diagnosis difficult. This study is aimed at developing a deep learning system for medical diagnosis MM automatically. Otherwise, the sickness might cause patients to succumb to death in a short amount of time. Various forms of artificial intelligence algorithms for successful "Malignant Mesothelioma illness" identification are explored in this research. In relation to the concept of traditional machine learning, the techniques support "Vector Machine, Neural Network, and Decision Tree" are chosen. SPSS has been used to analyze the result regarding the applications of Neural Network helps to diagnose MM.

DOI: https://doi.org/10.1155/2023/3164166
bioRxiv. 2023 Feb 06. pii: 2023.02.06.527192. [Epub ahead of print]

Overcoming clinical resistance to EZH2 inhibition using rational epigenetic combination therapy.

Yaniv Kazansky, Daniel Cameron, Phillip Demarest, Nadia Zaffaroni, Noemi Arrighetti, Valentina Zuco, Yasumichi Kuwahara, Rui Qu, Elisa De Stanchina, Filemon Dela Cruz, Andrew Kung, Mrinal Gounder, Alex Kentsis.

Essential epigenetic dependencies have become evident in many cancers. Based on functional antagonism between BAF/SWI/SNF and PRC2 in SMARCB1 -deficient sarcomas, we and colleagues recently completed the clinical trial of the EZH2 inhibitor tazemetostat, leading to its FDA approval. However, the principles of tumor response to epigenetic therapy in general, and tazemetostat in particular, remain unknown. Using functional genomics of patient tumors and diverse experimental models, we define molecular mechanisms of tazemetostat resistance in SMARCB1 -deficient sarcomas and rhabdoid tumors. We found distinct classes of acquired mutations that converge on the RB1/E2F axis and decouple EZH2-dependent differentiation and cell cycle control. This allows tumor cells to escape tazemetostat-induced G1 arrest despite EZH2 inhibition, and suggests a general mechanism for effective EZH2 therapy. Thus, we develop combination strategies to circumvent tazemetostat resistance using cell cycle bypass and synthetic lethal targeting, and provide prospective biomarkers for therapy stratification. This offers a paradigm for rational epigenetic combination therapy suitable for immediate translation to clinical trials for epithelioid sarcomas, rhabdoid tumors, and other epigenetically dysregulated cancers.
Significance: Genomic studies of patient tumors and cell lines identify mutations converging on a common pathway that is essential for response to EZH2 inhibition. Resistance mutations decouple drug-induced differentiation from cell cycle control. We identify complementary epigenetic combination strategies to overcome resistance and improve response, supporting their investigation in clinical trials.

DOI: https://doi.org/10.1101/2023.02.06.527192