bims-mesote 2021-03-21 papers

bims-mesote

Biomed News

on Mesothelioma

Issue of 2021–03–21
seven papers selected by
Laura Mannarino, Humanitas Research

The expression patterns and prognostic significance of pleckstrin homology-like domain family A (PHLDA) in lung cancer and malignant mesothelioma.
The role of volumetric method in the assessment of chemotherapy response and predicting survival in malignant pleural mesothelioma.
Accuracy of pleural biopsy for the diagnosis of histologic subtype of malignant pleural mesothelioma: Necropsy-based study of 134 cases.
Clonal architecture in mesothelioma is prognostic and shapes the tumour microenvironment.
CD146 immunohistochemical staining for the separation of benign from malignant mesothelial proliferations.
Metastasis of Sarcomatoid Malignant Mesothelioma With p16/CDKN2A Deletion Manifested as a Subcutaneous Mass in the Back: A Case Report and Review of Literature.
Pembrolizumab-induced myocarditis in a patient with malignant mesothelioma: plasma exchange as a successful emerging therapy-case report.

J Thorac Dis. 2021 Feb;13(2): 689-707

The expression patterns and prognostic significance of pleckstrin homology-like domain family A (PHLDA) in lung cancer and malignant mesothelioma.

Camila M Baldavira, Juliana Machado-Rugolo, Tabatha G Prieto, Daniel R Bastos, Marcelo Balancin, Alexandre M Ab'Saber, Lygia B Yaegashi, Paola C Souza, Cecilia Farhat, Teresa Y Takagaki, Maria Ap Nagai, Vera L Capelozzi.

   Background: Pleckstrin homology domain family A (PHLDA) genes play important roles in cancer cellular processes, including inhibiting Akt activation, repressing growth factor signaling, inhibiting the negative feedback of EGFR/ErbB2 signaling cells, and inducing apoptosis. However, the prognostic significance of PHLDA in non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MM) remains unclear. The present study investigates the associations between PHLDA expression patterns and their prognostic value in lung adenocarcinoma (LUAD) and MM.
Methods: We analyzed PHLDA family members at the genomic level in silico to explore their mRNA expression pattern and predictive significance in LUAD and MM. We then created a PHLDA-drug interaction network and a protein-protein interaction (PPI) network using different databases. Finally, we immunohistochemically assessed the protein expression of each PHLDA family member on tissue microarrays (TMAs) in both LUAD and MM cohorts with long-term follow-up.
Results: While PHLDA1 mRNA expression in both LUAD and MM was lower than that of normal tissue, PHLDA2 mRNA was significantly overexpressed in LUAD, and PHLDA3 mRNA was overexpressed in MM. In NSCLC, both low PHLDA1 mRNA expression and high PHLDA3 mRNA expression correlated with worse overall survival (OS) (P<0.01), whereas high PHLDA2 mRNA expression was associated with better OS (P<0.01). In MM, patients presenting high PHLDA1 and PHLDA2 mRNA expression had poor OS (P=0.01 and P<0.01, respectively). In addition, the PHLDA-drug interaction network indicated that several common drugs could potentially modulate PHLDA expression, and the PPI network suggested that PHLDA1 interacts with Notch family members, whereas PHLDA3 interacts with TP53. Our results also showed that the expression of PHLDA2 and PHLDA3 was significantly higher in LUAD and MM than that of PHLDA1 (P<0.05) and was associated with the risk of death. While patients with PHLDA2 >85.09 cells/mm2 had a low risk of death (P=0.01) and a median survival time of 48 months, those with PHLDA3 <70.38 cells/mm2 had a high risk of death (P=0.03) and a median survival time of 34 months.
Conclusions: We shed light on the role of the PHLDA family as promising predictive biomarkers and potential therapeutic targets in LUAD and MM.

Keywords:  Morphometry; data mining; lung adenocarcinoma; malignant mesothelioma; pleckstrin homology-like domain family A (PHLDA)

DOI:  https://doi.org/10.21037/jtd-20-2909
J Cancer Res Ther. 2021 Jan-Mar;17(1):17(1): 69-74

The role of volumetric method in the assessment of chemotherapy response and predicting survival in malignant pleural mesothelioma.

Furkan Erturk Urfali, Selma Metintas, Atila Gurgen, A K Guntulu, Ragip Ozkan, Muzaffer Metintas.

   Background: Malignant pleural mesothelioma (MPM) is a pleural tumor with high mortality rate and short-term survival expectancy after diagnosis. Assessment of the response to chemotherapy, which is the first choice in treatment of MPM, is important for the transition to alternative chemotherapy protocols and immunotherapy. There is no clarity in the response to chemotherapy treatment.
Objective: Our study aims to compare the assessment of chemotherapy response using the Modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria and volumetric measurements and to correlate with median survival.
Materials and Methods: Thirty-two patients (16 females and 16 males) were included in the study, and their ages ranged from 28 to 78 years. Chemotherapy response was determined by both mRECIST and volumetric approach. Tumor volume was measured by linear interpolation and semi-automatic segmentation. Log-rank multiple cutoff analysis was used to determine appropriate cutoff values of volumetric response criteria.
Results: According to both mRECIST and volumetric approach, median survival times in partial response, stable disease, and progressive disease groups were 24, 15, and 9 months, respectively. The survival times of the three groups were different (logrank: 17.76; P < 0.001) by mRECIST. The survival of the progressive disease group was shorter than that of the other groups (logrank: 18.91; P < 0.001) by volumetric approach.
Conclusions: In the assessment of chemotherapy response, even though classifications obtained according to the mRECIST criteria and volumetric measurements are statistically compatible, we think that the measurement of the volumetric values will increase the standardization. In our study, threshold values for volumetric measurements were determined; however, these values should be supported by large-scale multicenter studies.

Keywords:  Chemotherapy response evaluation; Modified Response Evaluation Criteria in Solid Tumor; computed tomography; malignant pleural mesothelioma; volumetric tumor measurement

DOI:  https://doi.org/10.4103/jcrt.JCRT_217_19
Tumori. 2021 Mar 15. 300891620988354

Accuracy of pleural biopsy for the diagnosis of histologic subtype of malignant pleural mesothelioma: Necropsy-based study of 134 cases.

Pietro Gino Barbieri, Dario Consonni, Manuela Schneider.

   BACKGROUND: Definition of histologic subtype of malignant pleural mesothelioma (MPM) is important for management of patients, because surgical treatment improves prognosis for patients with epithelioid but not biphasic or sarcomatoid MPM. In a series of necropsies performed in a hospital specialized for MPM diagnosis, we retrospectively investigated the accuracy of histologic diagnosis performed on pathologic specimens collected through pleural biopsies obtained at video-assisted thoracoscopic surgery (VATS) or surgery.
METHODS: We reviewed histologic records of an unselected series of autopsies performed in patients with MPM employed in the Monfalcone shipyards (Northeast Italy) or living with shipyard workers from 1999 through 2017. Using necropsy results as a gold standard, we calculated sensitivity, specificity, and positive and negative predictive values of histology from VATS or surgery after combining nonepithelioid subtypes.
RESULTS: We retrieved necropsy records for 134 patients: 62 (46.3%) with epithelioid, 51 (38.1%) with biphasic, and 21 (15.7%) with sarcomatoid MPM. We observed good sensitivity of VATS (0.94) and surgery (0.89) in diagnosing epithelioid MPM. Conversely, specificity was low (VATS: 0.46; surgery: 0.32). Therefore, positive predictive values were also low (VATS: 0.58; surgery: 0.60). Misclassification was particularly high for biphasic MPM (three-fourths of biphasic MPM at necropsy had been classified as epithelioid at VATS or surgery).
CONCLUSIONS: We observed a substantial degree of misclassification between epithelioid and biphasic MPM for pleural biopsies performed during VATS. Our results suggest caution should be taken in using histologic subtype obtained from VATS in selecting patients with MPM for surgical treatment. We also observed substantial misclassification of biospecimens collected during MPM surgery.

Keywords:  Pleural mesothelioma; accurate histologic diagnosis; necropsy

DOI:  https://doi.org/10.1177/0300891620988354
Nat Commun. 2021 Mar 19. 12(1): 1751

Clonal architecture in mesothelioma is prognostic and shapes the tumour microenvironment.

Min Zhang, Jin-Li Luo, Qianqian Sun, James Harber, Alan G Dawson, Apostolos Nakas, Sara Busacca, Annabel J Sharkey, David Waller, Michael T Sheaff, Cathy Richards, Peter Wells-Jordan, Aarti Gaba, Charlotte Poile, Essa Y Baitei, Aleksandra Bzura, Joanna Dzialo, Maymun Jama, John Le Quesne, Amrita Bajaj, Luke Martison, Jacqui A Shaw, Catrin Pritchard, Tamihiro Kamata, Nathaniel Kuse, Lee Brannan, Pan De Philip Zhang, Hongji Yang, Gareth Griffiths, Gareth Wilson, Charles Swanton, Frank Dudbridge, Edward J Hollox, Dean A Fennell.

Malignant Pleural Mesothelioma (MPM) is typically diagnosed 20-50 years after exposure to asbestos and evolves along an unknown evolutionary trajectory. To elucidate this path, we conducted multi-regional exome sequencing of 90 tumour samples from 22 MPMs acquired at surgery. Here we show that exomic intratumour heterogeneity varies widely across the cohort. Phylogenetic tree topology ranges from linear to highly branched, reflecting a steep gradient of genomic instability. Using transfer learning, we detect repeated evolution, resolving 5 clusters that are prognostic, with temporally ordered clonal drivers. BAP1/-3p21 and FBXW7/-chr4 events are always early clonal. In contrast, NF2/-22q events, leading to Hippo pathway inactivation are predominantly late clonal, positively selected, and when subclonal, exhibit parallel evolution indicating an evolutionary constraint. Very late somatic alteration of NF2/22q occurred in one patient 12 years after surgery. Clonal architecture and evolutionary clusters dictate MPM inflammation and immune evasion. These results reveal potentially drugable evolutionary bottlenecking in MPM, and an impact of clonal architecture on shaping the immune landscape, with potential to dictate the clinical response to immune checkpoint inhibition.

DOI: https://doi.org/10.1038/s41467-021-21798-w
Virchows Arch. 2021 Mar 15.

CD146 immunohistochemical staining for the separation of benign from malignant mesothelial proliferations.

Taylor Salisbury, Andrew Churg.

  The separation of benign from malignant mesothelial cells is often a challenging problem. Some studies have suggested that immunohistochemical staining of CD146 can be used to make this distinction, but there are marked differences in the reported results. Here, we assessed CD146 expression in tissue microarray specimens of 32 epithelioid reactive mesothelial hyperplasias, 17 spindle cell reactive mesothelial proliferations, 43 epithelioid mesotheliomas, and 31 sarcomatoid mesotheliomas. We found that, although the specificity of CD146 for epithelioid mesotheliomas versus reactive epithelial mesothelial proliferations was high (94%), staining intensity and extent was usually low and sensitivity was poor (23%). For sarcomatoid mesotheliomas versus reactive spindle cell mesothelial processes, both measures (33% sensitivity, 76% specificity) were inadequate. Furthermore, strong staining of endothelial cells and fibroblasts often created difficulties in interpretation. In comparison, BAP1 was lost in 21/43 (49%) epithelioid and 9/31 (29%) sarcomatoid mesotheliomas and methylthioadenosine phosphorylase (MTAP) was lost in 9/40 (23%) epithelioid and 7/29 (24%) sarcomatoid mesotheliomas from these TMAs. There was no association between CD146 staining and BAP1 or MTAP retention/loss. We conclude that CD146 staining is probably not useful for separating malignant from benign mesothelial proliferations.

Keywords:  Benign mesothelial reactions; CD146; Malignant mesothelioma

DOI:  https://doi.org/10.1007/s00428-021-03077-7
Int J Surg Pathol. 2021 Mar 17. 10668969211005094

Metastasis of Sarcomatoid Malignant Mesothelioma With p16/CDKN2A Deletion Manifested as a Subcutaneous Mass in the Back: A Case Report and Review of Literature.

Kai-Bo Chen, Ya-Jing Huang, Yi Huang, Zhi-Wei Wu, Xiao-Li Jin, Hang Zhang, Xue-Ping Xiang, Lin Chen, Li Chen.

  Sarcomatoid malignant mesothelioma (MM) is a rare and aggressive disease, and its diagnosis is challenging. A 60-year-old man presented with a recurrent subcutaneous mass in his right back after the initial resection. A chest computed tomography (CT) scan found right pleural thickening, nodular pleural thickening, pleural effusion, mediastinal, and right infraclavicular lymph nodes enlargement, which indicated a right pleura MM. Immunohistochemical stains of the resected mass showed sarcomatous atypical spindle cells, which were positive for pan-CKs (clone Anti-cytokeratin cocktail AE1/AE3), cytokeratin 5/6 (CK5/6), Wilm's tumor 1, podoplanin, vimentin and programmed death-ligand 1 (PD-L1), and negative for Napsin A, thyroid transcription factor 1, CDX 2, calretinin and desmin, and fluorescent in situ hybridization detected homozygous p16/cyclin-dependent kinase inhibitor 2A (p16/CDKN2A) deletion. The association of the chest CT features and the pathological assessment confirmed metastatic MM in the subcutaneous layer of the back. Moreover, positron emission tomography-CT showed multiple metastases in his brain. He developed massive right pleural effusion and chest tightness soon, and the mass kept growing despite local and systemic treatments. The patient die of pulmonary failure in 3 months.

Keywords:  case report; malignant mesothelioma; p16/CDKN2A; sarcomatoid; subcutaneous

DOI:  https://doi.org/10.1177/10668969211005094
Transl Lung Cancer Res. 2021 Feb;10(2): 1039-1046

Pembrolizumab-induced myocarditis in a patient with malignant mesothelioma: plasma exchange as a successful emerging therapy-case report.

Sanziana R I Schiopu, Lukas Käsmann, Ulf Schönermarck, Michael Fischereder, Ulrich Grabmaier, Farkhad Manapov, Josefine Rauch, Martin Orban.

  Malignant mesothelioma is an aggressive cancer associated with prior exposure to asbestos and dismal prognosis. Immune checkpoint inhibitor therapy is currently approved by the Food and Drug Administration for pre-treated malignant pleural mesothelioma. We describe a 75-year-old patient with disseminated, progressive malignant mesothelioma receiving 2 cycles of pembrolizumab who presented with generalized muscle weakness, shortness of breath, double vision and ptosis. There was no previous history of cardiovascular disease. The clinical picture, supported by the detection of anti-titin autoantibodies suggested myasthenia gravis (MG). Also, cardiac biomarkers were elevated. Echocardiography showed new severely reduced ejection fraction. A 12-lead resting electrocardiogram (ECG) revealed ST segment elevation in the posterior leads with polymorphic ventricular extrasystoles. Because cardiac catheterization revealed no relevant coronary lesions, immune checkpoint inhibitor-associated myocarditis and MG were suspected. Management and Outcome: The patient was started on steroids. Within a few days of presentation respiratory failure set in and the patient was intubated. Recurrent arrhythmias followed, which were treated by repeated emergency electrical cardioversion. In order to relieve myasthenic symptoms, plasma exchange was initiated and 10 cycles were carried out. This consequently also led to an improvement of myocarditis. Upon discharge, the ejection fraction recovered. The patient recovered and was alive at 1-year follow-up, without relevant limitations to his quality of life. Discussion and Conclusion: The article further discusses the use of plasma exchange for immune checkpoint inhibitor-associated myocarditis based on a review of literature. We conclude that patients showing no improvement after steroid therapy for immune checkpoint inhibitor-related myocarditis should be evaluated for plasma exchange, which appears to be an effective treatment option.

Keywords:  Mesothelioma; immune check inhibition; myocarditis; plasma exchange; treatment related toxicity

DOI:  https://doi.org/10.21037/tlcr-20-1095