bims-mesote 2022-09-11 papers

bims-mesote

Biomed News

on Mesothelioma

Issue of 2022–09–11
eight papers selected by
Laura Mannarino, Humanitas Research

Cytology of malignant pleural mesothelioma: Diagnostic criteria, WHO classification updates, and immunohistochemical staining markers diagnostic value.
ER Stress Response and Induction of Apoptosis in Malignant Pleural Mesothelioma: The Achilles Heel Targeted by the Anticancer Ruthenium Drug BOLD-100.
KRAS Pathway Alterations in Malignant Pleural Mesothelioma: An Underestimated Player.
Proposal for a new local recurrence score in patients with recurrent malignant pleural mesothelioma.
Survival Effect of Complete Multimodal Therapy in Malignant Pleural Mesothelioma.
A trial of intra-pleural bacterial immunotherapy in malignant pleural mesothelioma (TILT) - a randomised feasibility study using the trial within a cohort (TwiC) methodology.
Brief Report: Multimodality Therapy in Patients with Primary Pericardial Mesothelioma.
Role of 3'-Deoxy-3'-[18F] Fluorothymidine Positron Emission Tomography-Computed Tomography as a Predictive Biomarker in Argininosuccinate Synthetase 1-Deficient Thoracic Cancers Treated With Pegargiminase.

Diagn Cytopathol. 2022 Sep 07.

Cytology of malignant pleural mesothelioma: Diagnostic criteria, WHO classification updates, and immunohistochemical staining markers diagnostic value.

Nada Shaker, Douglas Wu, Abdul Majeed Abid.

  Malignant pleural mesothelioma (MPM) is a rare but aggressive malignancy with a poor prognosis. Because of this tumor rarity and overlapping histologic features with other malignancy types, the histopathological findings and diagnostic immunohistochemical workup are essential in establishing the final diagnosis of MPMs. We aimed to review the diagnostic criteria, WHO tumor classification updates, and immunohistochemical staining markers diagnostic value to achieve an appropriate clinical diagnosis.

Keywords:  classification; cytopathology; epithelioid; lung; mesothelioma; pleural effusion; reactive mesothelial proliferation; sarcomatoid

DOI:  https://doi.org/10.1002/dc.25053
Cancers (Basel). 2022 Aug 26. pii: 4126. [Epub ahead of print]14(17):

ER Stress Response and Induction of Apoptosis in Malignant Pleural Mesothelioma: The Achilles Heel Targeted by the Anticancer Ruthenium Drug BOLD-100.

Elia Ranzato, Gregorio Bonsignore, Simona Martinotti.

  Malignant mesothelioma is a rare cancer arising from the serosal surfaces of the body, mainly from the pleural layer. This cancer is strongly related to asbestos exposure and shows a very inauspicious prognosis, because there are scarce therapeutic options for this rare disease. Thus, there is an urgent need to develop novel therapeutic approaches to treat this form of cancer. To explore the biology of malignant pleural mesothelioma (MPM), we previously observed that MPM cell lines show high expression of the GRP78 protein, which is a chaperone protein and the master regulator of the unfolded protein response (UPR) that resides in the endoplasmic reticulum (ER). Based on our previous studies showing the importance of GRP78 in MPM, we observed that BOLD-100, a specific modulator of GRP78 and the UPR, shows cytotoxicity against MPM cells. Our studies demonstrated that BOLD-100 increases ROS production and Ca2+ release from the ER, leading to ER stress activation and, ultimately, to cell death. Our in vitro data strongly suggest that BOLD-100 inhibits the growth of MPM cell lines, proposing the application as a single agent, or in combination with other standard-of-care drugs, to treat MPM.

Keywords:  GRP78; ROS; apoptosis; calcium; endoplasmic reticulum; malignant pleural mesothelioma; mitochondria; unfolded protein response (UPR)

DOI:  https://doi.org/10.3390/cancers14174126
Cancers (Basel). 2022 Sep 02. pii: 4303. [Epub ahead of print]14(17):

KRAS Pathway Alterations in Malignant Pleural Mesothelioma: An Underestimated Player.

Lilith Trassl, Georgios T Stathopoulos.

  Malignant pleural mesothelioma (MPM) is a rare, incurable cancer of the mesothelial cells lining the lungs and the chest wall that is mainly caused by asbestos inhalation. The molecular mechanisms of mesothelial carcinogenesis are still unclear despite comprehensive studies of the mutational landscape of MPM, and the most frequently mutated genes BAP1, NF2, CDKN2A, TP53, and TSC1 cannot cause MPM in mice in a standalone fashion. Although KRAS pathway alterations were sporadically detected in older studies employing targeted sequencing, they have been largely undetected by next generation sequencing. We recently identified KRAS mutations and copy number alterations in a significant proportion of MPM patients. Here, we review and analyze multiple human datasets and the published literature to show that, in addition to KRAS, multiple other genes of the KRAS pathway are perturbed in a significant proportion of patients with MPM.

Keywords:  MAPK; PI3K; RAS; TP53; mutations; receptor tyrosine kinase pathway

DOI:  https://doi.org/10.3390/cancers14174303
J Thorac Dis. 2022 Aug;14(8): 2835-2844

Proposal for a new local recurrence score in patients with recurrent malignant pleural mesothelioma.

Olivia Lauk, Thomas Neuer, Bianca Battilana, Ilhan Inci, Katarzyna Furrer, Walter Weder, Masaki Hashimoto, Isabelle Opitz.

   Background: Malignant pleural mesothelioma (MPM) is associated with high rates of local recurrence (LR) up to 75%. Second line treatment should be applied tailored to relapse pattern. We aimed to establish a new score for LR pattern with prognostic impact in this observational study of retrospective nature.
Methods: MPM patients with LR after surgery, verified by serial imaging during follow-up visits or biopsy were included in a retrospective analysis using a new local recurrence score (LRS). We divided the thoracic cavity into six sections and calculated the LRS according to the tumor burden. We assessed the impact on survival after recurrence using cox regression model.
Results: From 2001 until 2017, 128 consecutive MPM patients with LR who underwent macroscopic complete resection (MCR) by extrapleural pneumonectomy (EPP, n=61) or by (extended) pleurectomy/decortication [(E)PD, n=67], were included in the present analysis; 104 patients received second line therapy. Patients with chest wall (CW) recurrence had the shortest survival after recurrence (9 vs. 16 months, P=0.05) as well as patients with affected lymph nodes (LN) (9 vs. 17 months, P=0.02). In subgroup analysis, the (E)PD group had a significantly higher LRS (P≤0.001) despite a longer survival time after recurrence of 12.4 months (IQR, 6.45-20.32) compared to 9.3 months (IQR, 2.93-17.40, EPP group) (P=0.04). Patients with LRS ≤4 had a longer survival undergoing radiotherapy or local surgery for second line treatment whereas patients with LRS >4 only if they underwent chemotherapy.
Conclusions: LRS might be a useful prognostic tool in MPM patients with LR after multimodality therapy to guide second line treatment allocation.

Keywords:  Malignant pleural mesothelioma (MPM); local recurrence (LR); overall survival; score; second line therapy

DOI:  https://doi.org/10.21037/jtd-21-1628
J Chest Surg. 2022 Sep 07.

Survival Effect of Complete Multimodal Therapy in Malignant Pleural Mesothelioma.

Muhammet Sayan, Aynur Bas, Merve Satir Turk, Dilvin Ozkan, Ali Celik, İsmail Cuneyt Kurul, Abdullah Irfan Tastepe.

   Background: Malignant pleural mesothelioma (MPM) is an aggressive pleural malignancy, and despite all multimodal treatment modalities, the 5-year overall survival rate of patients with MPM is less than 20%. In the present study, we aimed to analyze the surgical and prognostic outcomes of patients with MPM who received multimodal treatment.
Methods: In this retrospective, single-center study, the records of patients who underwent surgery for MPM between January 2010 and December 2020 at our department were reviewed retrospectively.
Results: Sixty-four patients were included in the study, of whom 23 (35.9%) were women and 41 (64.1%) were men. Extrapleural pneumonectomy, pleurectomy/decortication, and extended pleurectomy/decortication procedures were performed in 34.4%, 45.3%, and 20.3% of patients, respectively. The median survival of patients was 21 months, and the 5-year survival rate was 20.2%. Advanced tumor stage (hazard ratio [HR], 1.8; p=0.04), right-sided extrapleural pneumonectomy (HR, 3.1; p=0.02), lymph node metastasis (HR, 1.8; p=0.04), and incomplete multimodal therapy (HR, 1.9; p=0.03) were poor prognostic factors. There was no significant survival difference according to surgical type or histopathological subtype.
Conclusion: Multimodal therapy can offer an acceptable survival rate in patients with MPM. Despite its poor reputation in the literature, the survival rate after extrapleural pneumonectomy, especially left-sided, was not as poor as might be expected.

Keywords:  Extrapleural pneumonectomy; Mesothelioma; Pleura; Pneumonectomy

DOI:  https://doi.org/10.5090/jcs.22.037
Pilot Feasibility Stud. 2022 Sep 03. 8(1): 196

A trial of intra-pleural bacterial immunotherapy in malignant pleural mesothelioma (TILT) - a randomised feasibility study using the trial within a cohort (TwiC) methodology.

Anna C Bibby, Natalie Zahan-Evans, Emma Keenan, Charles Comins, John E Harvey, Helen Day, Najib M Rahman, Janet E Fallon, Rachael Gooberman-Hill, Nick A Maskell.

   BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive thoracic malignancy with a poor prognosis. Systemic immunotherapy is an effective frontline treatment for MPM, and there is a scientific rationale supporting the possible efficacy of local, i.e. intra-pleural immune modulators. Trial of intra-pleural bacterial immunotherapy (TILT) investigated the feasibility of performing a randomised trial of intra-pleural bacterial immunotherapy in people with MPM, using the trials within cohorts (TwiC) methodology.
METHODS: TILT was a multicentre, three-armed, randomised, feasibility TwiC of intra-pleural OK432, BCG, or usual care in people with MPM. Eligible participants were identified from within the ASSESS-meso study, a prospective, longitudinal, observational cohort study, and were randomly selected to be offered a single dose of OK432 or BCG, via an indwelling pleural catheter. The primary outcome was feasibility, evaluated against prespecified recruitment, attrition and data completeness targets. The acceptability of trial processes and interventions was assessed during qualitative interviews with participants and family members at the end of the trial. TILT was registered prospectively on the European Clinical Trials Registry (EudraCT number 2016-004,727-23) and the ISRCTN Register on 04 December 2017.
RESULTS: Seven participants were randomised from a planned sample size of 12; thus, the 66% recruitment rate target was not met. Two participants withdrew after randomisation, breaching the pre-stated attrition threshold of 10%. It was not possible to maintain blinding of control participants, which negated a fundamental tenet of the TwiC design. The trial processes and methodology were generally acceptable to participants and relatives, despite several recipients of intra-pleural bacterial agents experiencing significant local and systemic inflammatory responses.
CONCLUSION: It was possible to design a clinical trial of an investigational medicinal product based on the TwiC design and to obtain the necessary regulatory approvals. However, whilst acceptable to participants and relatives, the TwiC design was not a feasible method of investigating intra-pleural bacterial immunotherapy in people with MPM. Future trials investigating this topic should consider the eligibility constraints and recruitment difficulties encountered.
TRIAL REGISTRATION: TILT was registered prospectively on the European Clinical Trials Registry (EudraCT number 2016-004727-23 ) and the ISRCTN Register ( 10432197 ) on 04 December 2017.

Keywords:  Feasibility; Immunotherapy; Intra-pleural therapy; Mesothelioma; Trials within cohorts

DOI:  https://doi.org/10.1186/s40814-022-01156-3
J Thorac Oncol. 2022 Sep 05. pii: S1556-0864(22)01561-1. [Epub ahead of print]

Brief Report: Multimodality Therapy in Patients with Primary Pericardial Mesothelioma.

Michael Offin, Dilanka De Silva, Jennifer L Sauter, Jacklynn V Egger, Ellen Yorke, Prasad S Adusumilli, Andreas Rimner, Valerie W Rusch, Marjorie G Zauderer.

   BACKGROUND: Primary pericardial mesothelioma (PPM) has no accepted standard of care treatment options with management and outcomes often extrapolated from diffuse pleural mesothelioma (DPM). Disease specific research is needed to better define PPM. We report our institutional experience with PPM highlighting the potential role for multimodality therapy.
METHODS: Patients with PPM diagnosed by a multidisciplinary team of medical oncologists, thoracic surgeons, thoracic pathologists, and radiologists between January 2011 and January 2022 were followed through February 2022. Clinicopathologic features and treatment outcomes were annotated. Overall survival (OS) was defined from the date of pathologic diagnosis.
RESULTS: The median age at diagnosis of the 12 patients identified with PPM was 51 (range 21-71) years old. Most patients were female (n=8; 67%), 75% of samples were epithelioid (n=9), and 25% were non-epithelioid (2 sarcomatoid and 1 biphasic). Most (92%, 11/12) cases demonstrated expression of at least two mesothelial markers on immunohistochemistry. The median OS of the cohort was 25.9 months. Five patients had an OS greater than 12 months; four of whom received pericardial radiation. Three of the patients who received radiation did so as part of a trimodality approach (surgical resection, adjuvant chemotherapy, and radiation); the OS for patients who received trimodality therapy was 70.3 months vs. 8.2 months for those who did not.
CONCLUSION: PPM represents a distinct disease with no universally accepted treatment options. Our findings suggest trimodality therapy may improve outcomes in selected patients with PPM.

Keywords:  multimodality therapy; primary pericardial mesothelioma; trimodality therapy

DOI:  https://doi.org/10.1016/j.jtho.2022.08.017
JTO Clin Res Rep. 2022 Sep;3(9): 100382

Role of 3'-Deoxy-3'-[18F] Fluorothymidine Positron Emission Tomography-Computed Tomography as a Predictive Biomarker in Argininosuccinate Synthetase 1-Deficient Thoracic Cancers Treated With Pegargiminase.

Teresa A Szyszko, Joel T Dunn, Melissa M Phillips, John Bomalaski, Michael T Sheaff, Steve Ellis, Lucy Pike, Vicky Goh, Gary J R Cook, Peter W Szlosarek.

   Introduction: Pegargiminase (ADI-PEG 20I) degrades arginine in patients with argininosuccinate synthetase 1-deficient malignant pleural mesothelioma (MPM) and NSCLC. Imaging with proliferation biomarker 3'-deoxy-3'-[18F] fluorothymidine (18F-FLT) positron emission tomography (PET)-computed tomography (CT) was performed in a phase 1 study of pegargiminase with pemetrexed and cisplatin (ADIPemCis). The aim was to determine whether FLT PET-CT predicts treatment response earlier than CT.
Methods: A total of 18 patients with thoracic malignancies (10 MPM; eight NSCLC) underwent imaging. FLT PET-CT was performed at baseline (PET1), 24 hours post-pegargiminase monotherapy (PET2), post one cycle of ADIPemCis (PET3), and at end of treatment (EOT, PET4). CT was performed at baseline (CT1) and EOT (CT4). CT4 (modified) Response Evaluation Criteria in Solid Tumors (RECIST) response was compared with treatment response on PET (changes in maximum standardized uptake value [SUVmax] on European Organisation for Research and Treatment of Cancer-based criteria). Categorical responses (progression, partial response, and stable disease) for PET2, PET3, and PET4 were compared against CT using Cohen's kappa.
Results: ADIPemCis treatment response resulted in 22% mean decrease in size between CT1 and CT4 and 37% mean decrease in SUVmax between PET1 and PET4. PET2 agreed with CT4 response in 62% (8 of 13) of patients (p = 0.043), although decrease in proliferation (SUVmax) did not precede decrease in size (RECIST). Partial responses on FLT PET-CT were detected in 20% (3 of 15) of participants at PET2 and 69% (9 of 13) at PET4 with good agreement between modalities in MPM at EOT.
Conclusions: Early FLT imaging (PET2) agrees with EOT CT results in nearly two-thirds of patients. Both early and late FLT PET-CT provide evidence of response to ADIPemCis therapy in MPM and NSCLC. We provide first-in-human FLT PET-CT data in MPM, indicating it is comparable with modified RECIST.

Keywords:  ASS1; Arginine; FLT PET-CT; Pegargiminase; Thoracic cancers

DOI:  https://doi.org/10.1016/j.jtocrr.2022.100382