bims-mesote 2021-04-18 papers

Issue of 2021–04–18
nine papers selected by
Laura Mannarino, Humanitas Research

Sci Transl Med. 2021 Apr 14. pii: eabd9882. [Epub ahead of print]13(589):

Triple-modality therapy maximizes antitumor immune responses in a mouse model of mesothelioma.

Junichi Murakami, Licun Wu, Mikihiro Kohno, Mei-Lin Chan, Yidan Zhao, Zhihong Yun, B C John Cho, Marc de Perrot.

Malignant pleural mesothelioma (MPM) is an intractable disease with an extremely poor prognosis. Our clinical protocol for MPM of subablative radiotherapy (RT) followed by radical surgery achieved better survival compared to other multimodal treatments, but local relapse and metastasis remain a problem. This subablative RT elicits an antitumoral immune response that is limited by the immunosuppressive microenvironment generated by regulatory T (Treg) cells. The antitumor effect of immunotherapy to simultaneously modulate the immune activation and the immune suppression after subablative RT has not been investigated in MPM. Herein, we demonstrated a rationale to combine interleukin-15 (IL-15) superagonist (IL-15SA) and glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) agonist (DTA-1) with subablative RT in mesothelioma. IL-15SA boosted the systemic expansion of specific antitumoral memory CD8+ T cells that were induced by RT in mice. Their effect, however, was limited by the up-regulation and activation of Treg cells in the radiated tumor microenvironment. Hence, selective depletion of intratumoral Treg cells through DTA-1 enhanced the benefit of subablative RT in combination with IL-15SA. The addition of surgical resection of the radiated tumor in combination with IL-15SA and DTA-1 maximized the benefit of RT and was accompanied by a reproducible abscopal response in a concomitant tumor model. These data support the development of clinical trials in MPM to test such treatment options for patients with locally advanced or metastatic tumors.

DOI: https://doi.org/10.1126/scitranslmed.abd9882

BMC Med Genomics. 2021 Apr 13. 14(1): 104

Identification of genes and pathways involved in malignant pleural mesothelioma using bioinformatics methods.

Xingsheng Liu, Kun Qian, Gaojun Lu, Peng Chen, Yi Zhang.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare tumor in the pleura. This study was carried out to identify key genes and pathways that may be involved in MPM.
METHODS: Microarray datasets GSE51024 and GSE2549 were analyzed for differentially expressed genes (DEGs) between normal and MPM tissues. The identified DEGs were subjected to functional analyses using bioinformatics tools.
RESULTS: A total of 276 DEGs were identified, consisting of 187 downregulated and 79 upregulated genes. Gene ontology and Kyoto encyclopedia of genes and genomes pathway enrichment analysis indicated that the DEGs were enriched in extracellular structure organization, extracellular matrix, and ECM-receptor interaction. Due to high degree of connectivity among 24 hub genes, EZH2 and HMMR are likely to play roles in the carcinogenesis and progression of MPM. The two genes were found over-expressed in MPM tissues. Patients with elevated EZH2 and HMMR expressions had poor overall survival.
CONCLUSIONS: EZH2 and HMMR are identified to be the hub genes for MPM and they may be further characterized to better understand the molecular mechanisms underlying the carcinogenesis of MPM.

Keywords: Bioinformatics; Cancer; Differentially expressed genes; Gene expression profile; Microarray; Protein–protein interaction

DOI: https://doi.org/10.1186/s12920-021-00954-7

Cell Death Dis. 2021 Apr 15. 12(4): 406

Malignant pleural mesothelioma co-opts BCL-XL and autophagy to escape apoptosis.

Duo Xu, Shun-Qing Liang, Zhang Yang, Haitang Yang, Rémy Bruggmann, Simone Oberhaensli, Sabina Berezowska, Thomas M Marti, Sean R R Hall, Patrick Dorn, Gregor J Kocher, Ralph A Schmid, Ren-Wang Peng.

Escape from programmed cell death is a hallmark of cancer. In this study, we investigated the anti-apoptotic mechanisms and explored the therapeutic potential of BCL-2 homology domain-3 (BH3) mimetics in malignant pleural mesothelioma (MPM), a lethal thoracic malignancy with an extreme dearth of treatment options. By implementing integrated analysis of functional genomic data of MPM cells and quantitative proteomics of patients' tumors, we identified BCL-XL as an anti-apoptotic driver that is overexpressed and confers an oncogenic dependency in MPM. MPM cells harboring genetic alterations that inactivate the NF2/LATS1/2 signaling are associated with increased sensitivity to A-1155463, a BCL-XL-selective BH3 mimetic. Importantly, BCL-XL inhibition elicits protective autophagy, and concomitant blockade of BCL-XL and autophagic machinery with A-1155463 and hydroxychloroquine (HCQ), the US Food and Drug Administration (FDA)-approved autophagy inhibitor, synergistically enhances anti-MPM effects in vitro and in vivo. Together, our work delineates the molecular basis underlying resistance to apoptosis and uncovers an evasive mechanism that limits response to BH3 mimetics in MPM, suggesting a novel strategy to target this aggressive disease.

DOI: https://doi.org/10.1038/s41419-021-03668-x

BMJ Case Rep. 2021 Apr 12. pii: e241166. [Epub ahead of print]14(4):

Tongue: the unusual site in malignant pleural mesothelioma.

Iskandar Zulqarnain Bin Mohamed, Matthew Idle, Timothy Bates, Sundus Yahya.

Malignant mesotheliomas (MMs) are malignancies of the mesothelium, with primary deposits originating in the pleura, peritoneum, pericardium and the tunica vaginalis (ie, testicular). Metastatic spread is commonly reported to affect the liver, adrenal glands, kidney and contralateral lung (in cases of malignant pleural mesothelioma). Metastases to distant sites are uncommon. Spread to the oral cavity in particular is very rare. A total of 23 cases of metastatic spread to the oral cavity have been reported in the literature to date; of those, 9 cases have been to the tongue. Given the rarity of the site of metastasis, the management remains challenging. This case highlights a rare site of metastasis in MM, discusses treatment options available and briefly talks about technical limitations in treating a mobile structure such as the tongue. Good palliative and supportive care is crucial in managing cases where no curative treatment is possible.

Keywords: lung cancer (oncology); mouth; oral and maxillofacial surgery

DOI: https://doi.org/10.1136/bcr-2020-241166

Histopathology. 2021 Apr 13.

L1CAM expression in cystic mesothelial lesions: a comparison with adenomatoid tumors, well-differentiated papillary mesothelial tumors and malignant mesotheliomas.

Georgia Karpathiou, Francois Casteillo, Maroa Dridi, Alexandra Papoudou-Bai, Jean Marc Dumollard, Michel Peoc'h.

Malignant mesothelioma (MM), the primary cancer of the mesothelium, is characterized by dismal prognosis. However, there are other forms of primary mesothelial tumors, which are benign, the adenomatoid tumors (AT) and the well-differentiated papillary mesothelial tumor (WDPMT, formerly called well-differentiated papillary mesothelioma) (1). Interestingly, two recent studies showed that both ATs and WDPMTs harbor mutations in the TRAF7 (2,3), suggesting a possible pathogenetic link between them (1). The authors further proposed that as a possible consequence of this mutation, the L1 cell adhesion molecule (L1CAM), should be expressed in these lesions (2,3). Indeed, after performing immunohistochemistry for this marker, they showed L1CAM expression in both ATs and WDPMTs. Another lesion that could enter the family of benign mesothelial lesions, is the so-called "multicystic mesothelioma" (4). The exact nature of this lesion, reactional or neoplastic, has been a matter of debate since decades, and their varied terminology does prove the uncertainty (4). Given their common mesothelial origin, we aimed to explore the possible expression of L1CAM in a large series of cystic mesothelial lesions.

Keywords: TRAF7 ; cystic mesothelioma; multicystic mesothelioma; pericardial cyst; peritoneal cyst

DOI: https://doi.org/10.1111/his.14387

Eur Radiol. 2021 Apr 15.

Tract metastasis in patients with long-term pleural catheter-computed tomography diagnosis and longitudinal assessment.

Faisal Hamad, Carolina Souza, Michael Mitchell, Kayvan Amjadi.

OBJECTIVES: Long-term indwelling pleural catheters (IPC), used for the management of malignant pleural mesothelioma (MPM), may lead to catheter tract metastasis (CTM). While computed tomography (CT) is valuable for diagnosis, no studies have assessed CT manifestations of CTM. Our goal is to describe the incidence, CT appearances, and temporal evolution of CTM in MPM.
METHODS: A retrospective review of CT of 90 consecutive patients with MPM and IPC. In patients with CTM, a longitudinal assessment was performed for CT appearance at diagnosis and over time, interval from insertion to diagnosis and rate of progression.
RESULTS: The incidence of CTM was 26% (23/90), in 22 men (54-83 years, mean 73 years). CTM manifested with focal lesion (3 to 60 mm, mean 25 mm) in the subcutaneous tissue at the insertion site. Abnormalities of sub-adjacent skin and fat stranding were present in 16/24 (66%) and 11/24 (46%), respectively, enlargement of chest wall musculature in 11/24 (46%), and dilated subcutaneous vessels in 4/24 (17%) patients. On follow-up, 53% had enlargement of focal lesion. The average rate of progression was 3.5 mm/month, compared to 0.79 mm/month for pleural thickening (p = 0.03). The time between IPC insertion and CTM diagnosis varied from 58 to 1375 days (median 408 days); 83% occurred after IPC removal. Reporting radiologists described focal abnormality at the insertion site in only 9/23 (39%) patients.
CONCLUSIONS: CTM is commonly overlooked and underreported by radiologists. CT invariably demonstrates focal subcutaneous lesion in the procedure tract, most commonly after IPC removal. Ancillary findings, notably serratus or latissimus dorsi muscle enlargement, are novel finding that can assist in CT detection and diagnosis.
KEY POINTS: • Catheter tract metastasis (CTM), resulting from indwelling pleural catheter to manage malignant pleural mesothelioma, invariably manifested on CT as a focal subcutaneous lesion at the site of insertion, more commonly after catheter removal. • Ipsilateral muscle enlargement is a newly described CT finding that can assist in the detection and diagnosis. • Catheter tract metastasis was commonly overlooked by radiologists, reported in only 39% of cases.

Keywords: Mesothelioma; Metastasis, thoracic wall; Tomography

DOI: https://doi.org/10.1007/s00330-021-07867-0

Indian J Pathol Microbiol. 2021 Apr-Jun;64(2):64(2): 277-281

Histological and immunohistochemical characteristics and p16 status studied by FISH in six incidentally detected cases of well-differentiated papillary mesothelioma of the peritoneum.

Fumiyoshi Fujishima, Sachiko Konosu-Fukaya, Kazuki Nabeshima, Keely M McNamara, Kazuhiro Sakamoto, Junko Sakurada, Hironobu Sasano, Yasuhiro Nakamura.

Well-differentiated papillary mesothelioma (WDPM) is an uncommon mesothelial neoplasm, which is generally regarded as benign or indolent in terms of its clinical behavior. However, details about WDPM have remained relatively unknown. Therefore, in this study, we examined six incidentally detected cases of WDPM of the peritoneum. All six cases were surgically excised, without any additional therapeutic measures. None of the cases showed recurrence. All six cases presented single lesions and the tumor sizes ranged from 2 to 10 mm. Histologically, all six cases exhibited papillary proliferation of cytologically bland mesothelial cells with a fibroconnective tissue core. One of the cases (Case 6) presented small invasive foci in the stalk. The tumor cells were immunohistochemically positive for mesothelial markers and negative for GLUT-1, p53, and CD146. The Ki-67 labeling index of the tumor cells was lower than 5% at the hot spots. All samples were BAP1-positive. None of the samples presented p16 homozygous deletion, as assessed by fluorescence in situ hybridization (FISH). None of the patients deceased due to WDPM. However, in Case 3, death occurred due to pancreatic cancer. The results of this study indicate the importance of analyzing immunohistochemical markers and p16 status to diagnose WDPM accurately.

Keywords: Immunohistochemistry; malignant mesothelioma; peritoneum; well-differentiated papillary mesothelioma

DOI: https://doi.org/10.4103/IJPM.IJPM_111_20

Virchows Arch. 2021 Apr 14.

Tertiary lymphoid structures in epithelioid malignant peritoneal mesothelioma are associated with neoadjuvant chemotherapy, but not with prognosis.

RENAPE Network

Epithelioid mesothelioma is the most prevalent subtype of diffuse malignant peritoneal mesothelioma. The relationship between a strong adaptive immune response and a better prognosis in malignant solid tumors is widely known. Due to the low incidence of epithelioid malignant peritoneal mesothelioma (EMPM), very little is known about their immune micro-environment. We encountered several cases of tertiary lymphoid structures in EMPM in a previous study and aimed to investigate in the same series the prevalence, clinicopathological features, and the prognostic impact associated with tertiary lymphoid structures in EMPM (TLS-EMPM). Cases of EMPM, from 1995 to 2018, were retrieved from 7 French institutions from the RENAPE Network. The predictions in terms of overall survival (OS) and progression-free survival (PFS) of TLS-EMPM were analyzed. We report 52 cases of TLS-EMPM among a series of 138 cases of EMPM. TLS-EMPM was significantly associated with neoadjuvant chemotherapy, and was not a prognostic indicator for OS (p = 0.652) and PFS (p = 0.804) in our series. TLS is a component of the host immune response to EMPM significantly associated with neoadjuvant chemotherapy, but was not a predictor of prognosis for overall and progression-free survivals in this series. These findings provide another possible etiology for tertiary lymphoid structures.

Keywords: Biomarker; Malignant epithelioid peritoneal mesothelioma; Mesothelioma; Tertiary lymphoid structures

DOI: https://doi.org/10.1007/s00428-021-03099-1

Lancet Respir Med. 2021 Apr 09. pii: S2213-2600(21)00043-6. [Epub ahead of print]

Tremelimumab plus durvalumab retreatment and 4-year outcomes in patients with mesothelioma: a follow-up of the open label, non-randomised, phase 2 NIBIT-MESO-1 study.

Luana Calabrò, Giulia Rossi, Aldo Morra, Claudio Rosati, Ornella Cutaia, Maria Grazia Daffinà, Maresa Altomonte, Anna Maria Di Giacomo, Milena Casula, Carolina Fazio, Giuseppe Palmieri, Diana Giannarelli, Alessia Covre, Michele Maio.

BACKGROUND: The NIBIT-MESO-1 study demonstrated the efficacy and safety of tremelimumab combined with durvalumab in patient with unresectable mesothelioma followed up for a median of 52 months [IQR 49-53]. Here, we report 4-year survival and outcomes after retreatment, and the role of tumour mutational burden (TMB) in identifying patients who might have a better outcome in response to combined therapy.
METHODS: NIBIT-MESO-1 was an open-label, non-randomised, phase 2 trial of patients with unresectable pleural or peritoneal mesothelioma who received intravenous tremelimumab (1 mg/kg bodyweight) and durvalumab (20 mg/kg bodyweight) every 4 weeks for four doses, followed by maintenance intravenous durvalumab at the same dose and schedule for nine doses. In this follow-up study, patients with disease progression following initial clinical benefit-ie, a partial repsonse or stable disease-were eligible for retreatment and with the same doses and schedules for tremelimumab and durvalumab as used in the NIBIT-MESO-1 trial. The primary endpoint, immune-related objective response rate, was evaluated per immune-related modified Response Evaluation Criteria in Solid Tumors (RECIST) or immune-related RECIST 1.1 criteria for patients with pleural or peritoneal malignant mesothelioma, respectively. Key secondary endpoints were overall survival and safety, and TMB was also evaluated post hoc in patients who had tumour tissue available before treatment. The intention-to-treat population was used for analysis of all efficacy endpoints. This study is registered with ClinicalTrials.gov, number NCT02588131.
FINDINGS: 40 patients were enrolled in the NIBIT-MESO-1 study between Oct 30, 2015, and Oct 12, 2016. At data cut-off, April 30, 2020, five (13%) of 40 patients were alive, and 35 (88%) patients had died of progressive disease. At a median follow-up of 52 months (IQR 49-53), median overall survival was 16·5 months (95% CI 13·7-19·2). Survival was 20% (eight of 40 patients) at 36 months and 15% (six of 40 patients) and 48 months. 17 (43%) of 40 patients met the criteria for enrolment in the retreatment study and were retreated with at least one dose of tremelimumab and durvalumab. No immune-related objective responses were observed in the 17 retreated patients. Seven (41%) of 17 patients achieved immune-related stable disease. From the start of retreatment to a median follow-up of 24 months (22·0-25·0), median overall survival was 12·5 months (95% CI 0·0-25·8), and survival at 12 months was 52·9%, at 18 months was 35·3%, and at 24 months was 23·5%. There were no grade 3-4 immune-related adverse events in the retreatment cohort. In a post-hoc analysis of 28 patients for whom tumour tissue before treatment was available, patients with a TMB higher than the median value of 8·3 mutations per Mb had a higher median overall survival compared with patients with TMB below the median value, but this difference was non-significant. Moreover, when patients were additionally stratified for ICI retreatment (n=13), there was a significant difference in survival between those with a TMB higher than the median of 8·3 mutations per Mb and those with TMB lower than the median in the retreated cohort (41·3 months vs 17·4 months; p=0·02).
INTERPRETATION: Tremelimumab combined with durvalumab was associated with long-term survival in patients with mesothelioma. Retreatment was safe and resulted in clinically meaningful outcomes, thus suggesting its potential application in the clinical practice of mesothalioma patients.
FUNDING: NIBIT Foundation, Fondazione AIRC, AstraZeneca.

DOI: https://doi.org/10.1016/S2213-2600(21)00043-6