bims-mesote 2023-09-10 papers

bims-mesote

Biomed News

on Mesothelioma

Issue of 2023–09–10
twelve papers selected by
Laura Mannarino, Humanitas Research

En bloc resection of the recurrent pleural mesothelioma and reconstruction of the chest wall after immunotherapy: A case report.
A review of tumor treating fields (TTFields): advancements in clinical applications and mechanistic insights.
Survival of pleurectomy-decortication and hyperthermic chemotherapy in mesothelioma.
Epithelioid Mesothelioma Patients with Very Long Survival Display Defects in DNA Repair.
Cullin 4B Ubiquitin Ligase Is Important for Cell Survival and Regulates TGF-β1 Expression in Pleural Mesothelioma.
ONCOS-102 plus pemetrexed and platinum chemotherapy in malignant pleural mesothelioma: a randomized phase 2 study investigating clinical outcomes and the tumor microenvironment.
An overview on multimodal imaging for the diagnostic workup of pleural mesothelioma.
Curcumin potentiates the ErbB receptors inhibitor Afatinib for enhanced antitumor activity in malignant mesothelioma.
Extrathoracic Metastases in Pleural Mesothelioma.
Malignant Mesothelioma subtyping via sampling driven multiple instance prediction on tissue image and cell morphology data.
Determining the clinical utility of a breath test for screening an asbestos-exposed population for Pleural Mesothelioma: Baseline results.
Mesothelioma: Peritoneal, Version 2.2023, NCCN Clinical Practice Guidelines in Oncology.

Thorac Cancer. 2023 Sep 02.

En bloc resection of the recurrent pleural mesothelioma and reconstruction of the chest wall after immunotherapy: A case report.

Changlong Qin, Qinghong Xia, Zi-Jia Chen, Qinghua Zhou, Xi Zheng.

  Malignant pleural mesothelioma (MPM) is associated with previous asbestos exposure, while more clinical insights into this disease have come from other case studies. Maximal cytoreduction is critical in disease control and might help to improve the prognosis. Here, a 41-year-old female presented with a 6-month history of a mass detected in the chest wall following resection of a right pleural mesothelioma 2 years previously. A fluorodeoxyglucose positron emission tomography/computed tomography scan showed a right chest wall mass with a blurred boundary 8.9 cm × 3.7 cm in size. The patient had received one cycle of bevacizumab, carboplatin, and pemetrexed, and two cycles of nivolumab, ipilimumab, and gemcitabine 5 months before admission. We subsequently resected the tumor, the involved diaphragm, and the fifth and sixth ribs, and titanium mesh and continuous suture were used to close the thoracic cage. The fixed paraffin-embedded tissues showed epithelioid pleural mesothelioma. The patient received nivolumab and ipilimumab postoperatively, and no recurrence was detected 16 months after surgery. En bloc resection with reconstructive surgery effectively removed the locally advanced malignancy and restored the biological function of the thorax with a favorable prognosis. Neoadjuvant immunotherapy might therefore be conducive to radical resection and perioperative immunotherapy might improve the prognosis.

Keywords:  case report; chest wall defect; reconstructive surgery; recurrent malignant pleural mesothelioma

DOI:  https://doi.org/10.1111/1759-7714.15095
Radiol Oncol. 2023 Sep 01. 57(3): 279-291

A review of tumor treating fields (TTFields): advancements in clinical applications and mechanistic insights.

Xing Li, Kaida Liu, Lidong Xing, Boris Rubinsky.

   BACKGROUND: Tumor Treating Fields (TTFields) is a non-invasive modality for cancer treatment that utilizes a specific sinusoidal electric field ranging from 100 kHz to 300 kHz, with an intensity of 1 V/cm to 3 V/cm. Its purpose is to inhibit cancer cell proliferation and induce cell death. Despite promising outcomes from clinical trials, TTFields have received FDA approval for the treatment of glioblastoma multiforme (GBM) and malignant pleural mesothelioma (MPM). Nevertheless, global acceptance of TTFields remains limited. To enhance its clinical application in other types of cancer and gain a better understanding of its mechanisms of action, this review aims to summarize the current research status by examining existing literature on TTFields' clinical trials and mechanism studies.
CONCLUSIONS: Through this comprehensive review, we seek to stimulate novel ideas and provide physicians, patients, and researchers with a better comprehension of the development of TTFields and its potential applications in cancer treatment.

Keywords:  clinical applications of TTFields; mechanisms of action of TTFields; tumor treating fields

DOI:  https://doi.org/10.2478/raon-2023-0044
Turk Gogus Kalp Damar Cerrahisi Derg. 2023 Jul;31(3): 381-387

Survival of pleurectomy-decortication and hyperthermic chemotherapy in mesothelioma.

Ayşe Gül Ergönül, Sercan Aydın, Seda Kahraman Aydın, Tevfik İlker Akçam, Ali Özdil, Kutsal Turhan, Alpaslan Çakan, Ufuk Çağırıcı.

   Background: This study aims to evaluate overall survival, diseasefree survival, and prognostic factors in patients undergoing pleurectomy-decortication and hyperthermic intrathoracic chemotherapy with the diagnosis of malignant pleural mesothelioma.
Methods: Between January 2020 and November 2021, a total of 53 patients (27 males, 26 females; mean age: 58.1±1.3 years; range, 39 to 81 years) who underwent pleurectomy-decortication and hyperthermic intrathoracic chemotherapy with the diagnosis of malignant pleural mesothelioma were retrospectively analyzed. Data including characteristics, comorbidities, postoperative complications, recurrence and mortality status of the patients were recorded. Overall survival and disease-free survival and prognostic factors were evaluated.
Results: The median disease-free survival was 11.67 months and the median overall survival was 24.60 months. The median disease-free survival was 8.80 months in men and 13.17 months in women, indicating a statistically significant difference as it showed that recurrence was detected earlier in male patients (p=0.037). The median disease-free survival and overall survival was 6.13 months and 11.70 in cases diagnosed with biphasic mesothelioma, respectively, while it was 11.67 months and 25.46 months in cases with epithelial mesothelioma, respectively. Pathological subtype was found to be an effective prognostic factor for both survival (p=0.049 and p<0.001, respectively).
Conclusion: Hyperthermic intrathoracic chemotherapy following cytoreductive surgery is a preferable and tolerable method in the treatment of malignant pleural mesothelioma. While evaluating surgical indications, it should be kept in mind that cases with epithelial mesothelioma may benefit more from surgical treatment.

Keywords:  Chemotherapy; chest; mesothelioma; pleural disease; survival.

DOI:  https://doi.org/10.5606/tgkdc.dergisi.2023.24329
Cancers (Basel). 2023 Aug 29. pii: 4309. [Epub ahead of print]15(17):

Epithelioid Mesothelioma Patients with Very Long Survival Display Defects in DNA Repair.

Monica Ganzinelli, Federica Guffanti, Anna Ianza, Navid Sobhani, Sergio Crovella, Fabrizio Zanconati, Cristina Bottin, Marco Confalonieri, Stefano Fumagalli, Alessandra Guglielmi, Daniele Generali, Giovanna Damia.

   AIM: DNA repair has an important role in malignant pleural mesothelioma (MPM) tumorigenesis and progression. Prognostic/predictive biomarkers for better management of MPM patients are needed. In the present manuscript, we analyzed the expression of more than 700 genes in a cohort of MPM patients to possibly find biomarkers correlated with survival.
METHODS: A total of 54 MPM patients, all with epithelioid histology, whose survival follow-up and formalin-fixed paraffin-embedded tumors were available, were included in the study. Gene expression profiles were evaluated using a Nanostring platform analyzing 760 genes involved in different cellular pathways. The percentages of proliferating tumor cells positive for RAD51 and BRCA1 foci were evaluated using an immunofluorescence assay, as a readout of homologous recombination repair status.
RESULTS: Patient median survival time was 16.9 months, and based on this value, they were classified as long and short survivors (LS/SS) with, respectively, an overall survival ≥ and <16.9 months as well as very long and very short survivors (VLS/VSS) with an overall survival ≥ than 33.8 and < than 8.45 months. A down-regulation in the DNA damage/repair expression score was observed in LS and VLS as compared to SS and VSS. These findings were validated by the lower number of both RAD51 and BRCA1-positive tumor cells in VLS as compared to VSS.
CONCLUSIONS: The down-regulation of DNA repair signature in VLS was functionally validated by a lower % of RAD51 and BRCA1-positive tumor cells. If these data can be corroborated in a prospective trial, an easy, cost-effective test could be routinely used to better manage treatment in MPM patients.

Keywords:  BRCA foci; DNA repair; RAD51 foci; mesothelioma

DOI:  https://doi.org/10.3390/cancers15174309
Int J Mol Sci. 2023 Aug 29. pii: 13410. [Epub ahead of print]24(17):

Cullin 4B Ubiquitin Ligase Is Important for Cell Survival and Regulates TGF-β1 Expression in Pleural Mesothelioma.

Jessica Kreienbühl, Sakunthip Changkhong, Vanessa Orlowski, Michaela B Kirschner, Isabelle Opitz, Mayura Meerang.

  We previously demonstrated that cullin 4B (CUL4B) upregulation was associated with worse outcomes of pleural mesothelioma (PM) patients, while the overexpression of its paralog CUL4A was not associated with clinical outcomes. Here, we aimed to identify the distinct roles of CUL4B and CUL4A in PM using an siRNA approach in PM cell lines (ACC Meso-1 and Mero82) and primary culture. The knockdown of CUL4B and CUL4A resulted in significantly reduced colony formation, increased cell death, and delayed cell proliferation. Furthermore, similar to the effect of CUL4A knockdown, downregulation of CUL4B led to reduced expression of Hippo pathway genes including YAP1, CTGF, and survivin. Interestingly, CUL4B and not CUL4A knockdown reduced TGF-β1 and MMP2 expression, suggesting a unique association of CUL4B with this pathway. However, the treatment of PM cells with exogenous TGF-β1 following CUL4B knockdown did not rescue PM cell growth. We further analyzed ACC Meso-1 xenograft tumor tissues treated with the cullin inhibitor, pevonedistat, which targets protein neddylation, and observed the downregulation of human TGF-β1 and MMP2. In summary, our data suggest that CUL4B overexpression is important for tumor cell growth and survival and may drive PM aggressiveness via the regulation of TGF-β1 expression and, furthermore, reveal a new mechanism of action of pevonedistat.

Keywords:  CTGF; MMP2; TGFβ; YAP; cullin 4A; cullin 4B; pevonedistat; pleural mesothelioma

DOI:  https://doi.org/10.3390/ijms241713410
J Immunother Cancer. 2023 Sep;pii: e007552. [Epub ahead of print]11(9):

ONCOS-102 plus pemetrexed and platinum chemotherapy in malignant pleural mesothelioma: a randomized phase 2 study investigating clinical outcomes and the tumor microenvironment.

Santiago Ponce, Susana Cedrés, Charles Ricordel, Nicolas Isambert, Santiago Viteri, Mercedes Herrera-Juarez, Alex Martinez-Marti, Alejandro Navarro, Mathieu Lederlin, Xavier Serres, Jon Zugazagoitia, Sylvia Vetrhus, Magnus Jaderberg, Thomas Birkballe Hansen, Victor Levitsky, Luis Paz-Ares.

   BACKGROUND: ONCOS-102, an oncolytic adenovirus expressing granulocyte-macrophage colony-stimulating factor, can alter the tumor microenvironment to an immunostimulatory state. Combining ONCOS-102 with standard-of-care chemotherapy for malignant pleural mesothelioma (MPM) may improve treatment outcomes.
METHODS: In this open-label, randomized study, patients with unresectable MPM received intratumoral ONCOS-102 (3×1011 virus particles on days 1, 4, 8, 36, 78, and 120) and pemetrexed plus cisplatin/carboplatin (from day 22), or pemetrexed plus cisplatin/carboplatin alone. The primary endpoint was safety. Overall survival (OS), progression-free survival, objective response rate, and tumor immunologic activation (baseline and day 36 biopsies) were also assessed.
RESULTS: In total, 31 patients (safety lead-in: n=6, randomized: n=25) were enrolled. Anemia (15.0% and 27.3%) and neutropenia (40.0% and 45.5%) were the most frequent grade ≥3 adverse events (AEs) in the ONCOS-102 (n=20) and chemotherapy-alone (n=11) cohorts. No patients discontinued ONCOS-102 due to AEs. No statistically significant difference in efficacy endpoints was observed. There was a numerical improvement in OS (30-month OS rate 34.1% vs 0; median OS 20.3 vs 13.5 months) with ONCOS-102 versus chemotherapy alone in chemotherapy-naïve patients (n=17). By day 36, ONCOS-102 was associated with increased T-cell infiltration and immune-related gene expression that was not observed in the control cohort. Substantial immune activation in the tumor microenvironment was associated with survival at month 18 in the ONCOS-102 cohort.
CONCLUSIONS: ONCOS-102 plus pemetrexed and cisplatin/carboplatin was well tolerated by patients with MPM. In injected tumors, ONCOS-102 promoted a proinflammatory environment, including T-cell infiltration, which showed association with survival at month 18.

Keywords:  T-lymphocytes; immunomodulation; oncolytic viruses; therapies, investigational; tumor microenvironment

DOI:  https://doi.org/10.1136/jitc-2023-007552
Jpn J Radiol. 2023 Sep 07.

An overview on multimodal imaging for the diagnostic workup of pleural mesothelioma.

Michela Gabelloni, Lorenzo Faggioni, Maria Chiara Brunese, Carmine Picone, Roberta Fusco, Giovanni Donato Aquaro, Dania Cioni, Emanuele Neri, Nicoletta Gandolfo, Andrea Giovagnoni, Vincenza Granata.

  Pleural mesothelioma (PM) is an aggressive disease that has a strong causal relationship with asbestos exposure and represents a major challenge from both a diagnostic and therapeutic viewpoint. Despite recent improvements in patient care, PM typically carries a poor outcome, especially in advanced stages. Therefore, a timely and effective diagnosis taking advantage of currently available imaging techniques is essential to perform an accurate staging and dictate the most appropriate treatment strategy. Our aim is to provide a brief, but exhaustive and up-to-date overview of the role of multimodal medical imaging in the management of PM.

Keywords:  Multimodal imaging; Pleural mesothelioma; Radiomics; Staging

DOI:  https://doi.org/10.1007/s11604-023-01480-5
Int J Food Sci Nutr. 2023 Sep 03. 1-14

Curcumin potentiates the ErbB receptors inhibitor Afatinib for enhanced antitumor activity in malignant mesothelioma.

Monica Benvenuto, Daniela Nardozi, Camilla Palumbo, Chiara Focaccetti, Raffaele Carrano, Valentina Angiolini, Loredana Cifaldi, Valeria Lucarini, Patrizia Mancini, Bora Kërpi, Walter Currenti, Roberto Bei, Laura Masuelli.

  Several attempts have been made to develop targeted therapies for malignant mesothelioma (MM), an aggressive tumour with a poor prognosis. In this study we evaluated whether Curcumin (CUR) potentiated the antitumor activity of the ErbB receptors inhibitor Afatinib (AFA) on MM, employing cell lines cultured in vitro and mice bearing intraperitoneally transplanted, syngeneic MM cells. The rationale behind this hypothesis was that CUR could counteract mechanisms of acquired resistance to AFA. We analysed CUR and AFA effects on MM cell growth, cell cycle, autophagy, and on the modulation of tumour-supporting signalling pathways.This study demonstrated that, as compared to the individual compounds, the combination of AFA + CUR had a stronger effect on MM progression which can be ascribed either to increased tumour cell growth inhibition or to an enhanced pro-apoptotic effect. These results warrant future studies aimed at further exploring the therapeutic potential of AFA + CUR-based combination regimens for MM treatment.

Keywords:  EGFR/ErbB receptors; Malignant mesothelioma; afatinib; curcumin; polyphenols

DOI:  https://doi.org/10.1080/09637486.2023.2251723
JTO Clin Res Rep. 2023 Sep;4(9): 100557

Extrathoracic Metastases in Pleural Mesothelioma.

Ibiayi Dagogo-Jack, Beow Y Yeap, Mari Mino-Kenudson, Subba R Digumarthy.

   Introduction: Guidelines recommend obtaining a computed tomography scan of the chest for the staging of pleural mesothelioma and for assessing response to treatment. Consensus is lacking regarding the necessity of serial imaging of distant extrathoracic sites. In this study, we determined the prevalence of extrathoracic metastases in patients with pleural mesothelioma.
Methods: We conducted a retrospective review of patients with pleural mesothelioma treated at Massachusetts General Hospital between 1999 and 2022 who were referred for extrathoracic imaging during their disease course. Imaging reports were reviewed to determine sites of metastasis and calculate the time to development of extrathoracic metastasis. Overall survival and prevalence of extrathoracic metastasis were compared for patients with epithelioid versus nonepithelioid mesothelioma.
Results: The study included 148 patients, 69 (47%) of whom had undergone cytoreductive surgery. Histologic types included epithelioid (n = 82, 55%), biphasic (n = 49, 33%), and sarcomatoid (n = 10, 7%) mesothelioma. The median overall survival for the cohort was 24.0 months, specifically 34.7 months and 16.7 months for patients with epithelioid and nonepithelioid tumors, respectively (p < 0.001). There were 65 (44%) patients who developed extrathoracic metastases, with a median time to extrathoracic metastasis of 11.5 months. The most common sites of involvement were extrathoracic nodes (22%), peritoneum (20%), bone (11%), and liver (11%). Of the 76 patients referred for brain imaging, seven (9%) had brain metastases. The frequency of extrathoracic metastasis was identical for epithelioid and nonepithelioid mesothelioma (44%). Overall survival was shorter for patients who developed extrathoracic metastases (hazard ratio 5.9, p < 0.001).
Conclusions: Patients with pleural mesothelioma often develop extrathoracic metastases, providing a rationale for routinely obtaining imaging that encompasses sites outside of the thoracic cavity.

Keywords:  Bone metastases; Brain metastases; Mesothelioma; Metastases

DOI:  https://doi.org/10.1016/j.jtocrr.2023.100557
Artif Intell Med. 2023 09;pii: S0933-3657(23)00142-2. [Epub ahead of print]143 102628

Malignant Mesothelioma subtyping via sampling driven multiple instance prediction on tissue image and cell morphology data.

Mark Eastwood, Silviu Tudor Marc, Xiaohong Gao, Heba Sailem, Judith Offman, Emmanouil Karteris, Angeles Montero Fernandez, Danny Jonigk, William Cookson, Miriam Moffatt, Sanjay Popat, Fayyaz Minhas, Jan Lukas Robertus.

  Malignant Mesothelioma is a difficult to diagnose and highly lethal cancer usually associated with asbestos exposure. It can be broadly classified into three subtypes: Epithelioid, Sarcomatoid, and a hybrid Biphasic subtype in which significant components of both of the previous subtypes are present. Early diagnosis and identification of the subtype informs treatment and can help improve patient outcome. However, the subtyping of malignant mesothelioma, and specifically the recognition of transitional features from routine histology slides has a high level of inter-observer variability. In this work, we propose an end-to-end multiple instance learning (MIL) approach for malignant mesothelioma subtyping. This uses an adaptive instance-based sampling scheme for training deep convolutional neural networks on bags of image patches that allows learning on a wider range of relevant instances compared to max or top-N based MIL approaches. We also investigate augmenting the instance representation to include aggregate cellular morphology features from cell segmentation. The proposed MIL approach enables identification of malignant mesothelial subtypes of specific tissue regions. From this a continuous characterisation of a sample according to predominance of sarcomatoid vs epithelioid regions is possible, thus avoiding the arbitrary and highly subjective categorisation by currently used subtypes. Instance scoring also enables studying tumor heterogeneity and identifying patterns associated with different subtypes. We have evaluated the proposed method on a dataset of 234 tissue micro-array cores with an AUROC of 0.89±0.05 for this task. The dataset and developed methodology is available for the community at: https://github.com/measty/PINS.

Keywords:  Cancer subtyping; Computational pathology; Deep learning; Malignant Mesothelioma; Multiple instance learning

DOI:  https://doi.org/10.1016/j.artmed.2023.102628
J Breath Res. 2023 Sep 08.

Determining the clinical utility of a breath test for screening an asbestos-exposed population for Pleural Mesothelioma: Baseline results.

Kathleen Zwijsen, Eline Schillebeeckx, Eline Janssens, Joris Van Cleemput, Tom Richart, Veerle Surmont, Kristiaan Nackaerts, Elly Marcq, Jan P van Meerbeeck, Kevin Lamote.

   BACKGROUND: Pleural mesothelioma (PM) is an aggressive cancer of the serosal lining of the thoracic cavity, predominantly caused by asbestos exposure. Due to nonspecific symptoms, PM is characterized by an advanced-stage diagnosis, resulting in a dismal prognosis. However, early diagnosis improves patient outcome. Currently, no diagnostic biomarkers or screening tools are available. Therefore, exhaled breath was explored as this can easily be obtained and contains volatile organic compounds (VOCs), which are considered biomarkers for multiple (patho)physiological processes. A breath test, which differentiates asbestos-exposed (AEx) individuals from PM patients with 87% accuracy, was developed. However, before being implemented as a screening tool, the clinical utility of the test must be determined.Methods: Occupational AEx individuals underwent annual breath tests using multicapillary column/ion mobility spectrometry (MCC/IMS). A baseline breath test was taken and their individual risk of PM was estimated. PM patients were included as controls.Results: In total, 112 AEx individuals and 6 PM patients were included in the first of 4 screening rounds. All 6 PM patients were correctly classified as having mesothelioma (100% sensitivity) and out of 112 AEx individuals 78 were classified by the breath-based model as PM patients (30% specificity).Discussion: Given the large false positive outcome, the breath test will be repeated annually for 3 more consecutive years to adhere to the 'test, re-test' principle and improve the false positivity rate. A low-dose computed tomography (CT) scan in those with 2 consecutive positive tests will correlate test positives with radiological findings and the possible growth of a pleural tumor. Finally, the evaluation of the clinical value of a breath-based prediction model may lead to the initiation of a screening program for early detection of PM in Aex individuals, which is currently lacking.This clinical study received approval from the Antwerp University Hospital Ethics Committee (B300201837007).

Keywords:  Asbestos; Biomarker; Breathomics; Early detection; Pleural mesothelioma; Screening; Volatomics

DOI:  https://doi.org/10.1088/1752-7163/acf7e3
J Natl Compr Canc Netw. 2023 Sep;21(9): 961-979

Mesothelioma: Peritoneal, Version 2.2023, NCCN Clinical Practice Guidelines in Oncology.

David S Ettinger, Douglas E Wood, James Stevenson, Dara L Aisner, Wallace Akerley, Jessica R Bauman, Ankit Bharat, Debora S Bruno, Joe Y Chang, Lucian R Chirieac, Malcolm DeCamp, Thomas J Dilling, Jonathan Dowell, Gregory A Durm, Scott Gettinger, Travis E Grotz, Matthew A Gubens, Aparna Hegde, Rudy P Lackner, Michael Lanuti, Jules Lin, Billy W Loo, Christine M Lovly, Fabien Maldonado, Erminia Massarelli, Daniel Morgensztern, Trey C Mullikin, Thomas Ng, Gregory A Otterson, Sandip P Patel, Tejas Patil, Patricio M Polanco, Gregory J Riely, Jonathan Riess, Theresa A Shapiro, Aditi P Singh, Alda Tam, Tawee Tanvetyanon, Jane Yanagawa, Stephen C Yang, Edwin Yau, Kristina M Gregory, Miranda Hughes.

Mesothelioma is a rare cancer originating in mesothelial surfaces of the peritoneum, pleura, and other sites. These NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) focus on peritoneal mesothelioma (PeM). The NCCN Guidelines for PeM provide recommendations for workup, diagnosis, and treatment of primary as well as previously treated PeM. The diagnosis of PeM may be delayed because PeM mimics other diseases and conditions and because the disease is so rare. The pathology section was recently updated to include new information about markers used to identify mesothelioma, which is difficult to diagnose. The term "malignant" is no longer used to classify mesotheliomas, because all mesotheliomas are now defined as malignant.

DOI: https://doi.org/10.6004/jnccn.2023.0045