bims-mesote 2022-02-13 papers

bims-mesote

Biomed News

on Mesothelioma

Issue of 2022–02–13
seven papers selected by
Laura Mannarino, Humanitas Research

Cisplatin-Chelated Iminodiacetic Acid-Conjugated Hyaluronic Acid Nanogels for the Treatment of Malignant Pleural Mesothelioma in Mice.
Small vessel vasculitis and dry gangrene secondary to combined CTLA-4 and PD-1 blockade in malignant mesothelioma.
First-line nivolumab plus ipilimumab versus chemotherapy in patients with unresectable malignant pleural mesothelioma: 3-year outcomes from CheckMate 743.
Survey of malignant pleural mesothelioma treatment in Japan: Patterns of practice and clinical outcomes in tomotherapy facilities.
Analysis of early pleural fluid samples in patients with mesothelioma: A case series exploration of morphology, BAP1, and CDKN2A status with implications for the concept of mesothelioma in situ in cytology.
Incidence, treatment and survival of malignant pleural and peritoneal mesothelioma: a population-based study.
Insulin-Like Growth Factor 2 mRNA Binding Protein 3 Promotes Cell Proliferation of Malignant Mesothelioma Cells by Downregulating p27Kip1.

Mol Pharm. 2022 Feb 10.

Cisplatin-Chelated Iminodiacetic Acid-Conjugated Hyaluronic Acid Nanogels for the Treatment of Malignant Pleural Mesothelioma in Mice.

Yuki Amano, Kazuma L Sakura, Seiichi Ohta, Taichi Ito.

  Malignant pleural mesothelioma (MPM) is one of the intractable cancers that require a more effective therapeutic strategy for clinical practice. Hyaluronic acid (HA) nanogels were prepared by the chelation of cisplatin (CDDP) with different molecular weights of iminodiacetic acid-conjugated hyaluronic acid (HA-IDA). The sizes of the 100, 850, and 2000 kDa HA nanogels were 33, 43, and 44 nm, respectively. MSTO-211H, a human MPM cell line, was more effective in taking up all three HA nanogels compared to AB22, a mouse MPM cell line. In addition, the 850 kDa HA nanogel showed higher anticancer activity against AB22 and MSTO-211H than 100 and 2000 kDa HA nanogels. Furthermore, all the HA nanogels showed a milder cytotoxic effect on normal Met-5A mesothelial cells compared to that exhibited by free CDDP. Finally, the 850 kDa HA nanogel was administrated intrapleurally into both the MSTO-211H xenograft and AB22 allograft mouse models of MPM using an injectable HA-based hydrogel. HA nanogels showed a significant therapeutic effect in both the xenograft and allograft models.

Keywords:  cisplatin; hyaluronic acid; injectable hydrogel; malignant pleural mesothelioma; nanogel

DOI:  https://doi.org/10.1021/acs.molpharmaceut.1c00797
BMC Rheumatol. 2022 Feb 08. 6(1): 10

Small vessel vasculitis and dry gangrene secondary to combined CTLA-4 and PD-1 blockade in malignant mesothelioma.

Joanna Kefas, Catherine Harwood, Myles J Lewis, Peter Szlosarek.

   BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare and aggressive tumour with an overall poor prognosis. In October 2020, first line treatment with the PD-1 antagonist nivolumab and the CTLA-4 antagonist ipilimumab for unresectable disease was FDA approved-the first approved treatment regime since 2004. Interim analyses from the phase 3 CHECKMATE-743 study shows improvements in overall survival. Skin-related toxicities are the most commonly reported any-grade treatment-related adverse event from combined nivolumab and ipilimumab therapy.
CASE PRESENTATION: Here we report a case of a 35-year-old white male who developed digital ischaemia secondary to small vessel vasculitis after receiving PD-1 and CTLA-4 blockade therapy for MPM. His progressive ischaemia became gangrenous, and he required multi-speciality input and treatment with prednisolone, prostacyclin, mycophenolate mofetil and hydroxychloroquine.
CONCLUSIONS: Our case highlights the importance of early detection, intervention, and a multispecialty approach to managing such complications in order to minimise the associated morbidity and mortality.

Keywords:  Case report; Immune related adverse events; Immunotherapy; Mesothelioma; Vasculitis

DOI:  https://doi.org/10.1186/s41927-021-00238-8
Ann Oncol. 2022 Feb 03. pii: S0923-7534(22)00083-7. [Epub ahead of print]

First-line nivolumab plus ipilimumab versus chemotherapy in patients with unresectable malignant pleural mesothelioma: 3-year outcomes from CheckMate 743.

S Peters, A Scherpereel, R Cornelissen, Y Oulkhouir, L Greillier, M A Kaplan, T Talbot, I Monnet, S Hiret, P Baas, A K Nowak, N Fujimoto, A S Tsao, A S Mansfield, S Popat, X Zhang, N Hu, D Balli, T Spires, G Zalcman.

   BACKGROUND: In the phase 3 CheckMate 743 study (NCT02899299), first-line nivolumab plus ipilimumab significantly improved overall survival (OS) versus chemotherapy in patients with unresectable malignant pleural mesothelioma (MPM). We report updated data with 3-year minimum follow-up.
PATIENTS AND METHODS: Adults with previously untreated, histologically confirmed, unresectable MPM and Eastern Cooperative Oncology Group performance status of ≤1 were randomized 1:1 to nivolumab (3 mg/kg every 2 weeks) plus ipilimumab (1 mg/kg every 6 weeks) for up to 2 years, or 6 cycles of platinum plus pemetrexed chemotherapy. This report includes updated efficacy and safety outcomes, exploratory biomarker analyses including 4-gene inflammatory expression signature score, and a post hoc efficacy analysis in patients who discontinued treatment due to treatment-related adverse events (TRAEs).
RESULTS: With median follow-up of 43.1 months, nivolumab plus ipilimumab continued to prolong OS versus chemotherapy. Median OS was 18.1 versus 14.1 months (HR [95% CI], 0.73 [0.61-0.87]), and 3-year OS rates were 23% versus 15%, respectively. Three-year progression-free survival rates were 14% versus 1%, and objective response rates were 40% versus 44%. At 3 years, 28% versus 0% of responders had an ongoing response. Improved survival benefit with nivolumab plus ipilimumab versus chemotherapy was observed across subgroups, including histology. A high score of the 4-gene inflammatory signature appeared to correlate with improved survival benefit with nivolumab plus ipilimumab. No new safety signals were observed with nivolumab plus ipilimumab, despite patients being off therapy for one year. In patients who discontinued nivolumab plus ipilimumab due to TRAEs, median OS was 25.4 months, and 34% of responders maintained their responses for ≥3 years after discontinuation.
CONCLUSIONS: With 3 years' minimum follow-up, nivolumab plus ipilimumab continued to provide long-term survival benefit over chemotherapy and a manageable safety profile, supporting the regimen as standard-of-care treatment for unresectable MPM, regardless of histology.

Keywords:  CTLA-4; PD-L1; dual immunotherapy; first-line; immune checkpoint inhibitors; overall survival

DOI:  https://doi.org/10.1016/j.annonc.2022.01.074
J Radiat Res. 2022 Feb 09. pii: rrab127. [Epub ahead of print]

Survey of malignant pleural mesothelioma treatment in Japan: Patterns of practice and clinical outcomes in tomotherapy facilities.

Mikiko Nakanishi-Imai, Taro Murai, Masahiro Onishi, Atsuto Mouri, Takafumi Komiyama, Motoko Omura, Shigehiro Kudo, Akihiko Miyamoto, Masaru Hoshino, Shinichi Ogawa, Shizuko Ohashi, Masahiko Koizumi, Junichi Omagari, Hiroshi Mayahara, Katsuyuki Karasawa, Toshiyuki Okumura, Yuta Shibamoto.

  We conducted a nationwide survey of tomotherapy for malignant pleural mesothelioma (MPM) in Japan. Fifty-six facilities were surveyed and data on 31 patients treated curatively between 2008 and 2017 were collected from 14 facilities. Twenty patients received hemithorax irradiation after extrapleural pneumonectomy (EPP) (first group). Five patients received irradiation without EPP (second group), while six received salvage radiotherapy for local recurrence (salvage group). Among the seven patients not undergoing EPP, five (four in the second group and one in the salvage group) were treated with lung sparing pleural irradiation (LSPI) and two with irradiation to visible tumors. Two-year overall survival (OS) rates in the first and second groups were 33% and 60%, respectively (median, 13 vs 30 months, P = 0.82). In the first and second groups, 2-year local control (LC) rates were 53 and 67%, respectively (P = 0.54) and 2-year progression-free survival (PFS) rates were 16% and 60%, respectively (P = 0.07). Distant metastases occurred in 15 patients in the first group and three in the second group. In the salvage group, the median OS was 18 months. Recurrence was observed in the irradiated volume in four patients. The contralateral lung dose was higher in LSPI than in hemithorax irradiation plans (mean, 11.0 ± 2.2 vs 6.1 ± 3.1 Gy, P = 0.002). Grade 3 or 5 lung toxicity was observed in two patients receiving EPP and hemithorax irradiation, but not in those undergoing LSPI. In conclusion, outcomes of EPP and hemithorax irradiation were not satisfactory, whereas LSPI appeared promising and encouraging.

Keywords:  hyperthermia; intensity-modulated radiotherapy (IMRT); lung sparing pleural irradiation (LSPI); malignant pleural mesothelioma (MPM); nationwide survey in Japan; tomotherapy; whole hemithorax irradiation (WHI)

DOI:  https://doi.org/10.1093/jrr/rrab127
Cancer Cytopathol. 2022 Feb 10.

Analysis of early pleural fluid samples in patients with mesothelioma: A case series exploration of morphology, BAP1, and CDKN2A status with implications for the concept of mesothelioma in situ in cytology.

Amber Louw, Chris van Vliet, Joanne Peverall, Shane Colkers, Nathan Acott, Jenette Creaney, Y C Gary Lee, Siaw Ming Chai.

   BACKGROUND: The concept of mesothelioma in situ has been revisited and is a new World Health Organization diagnostic entity. The definition centers on ancillary techniques used in pleural mesothelioma (PM) assessment. At the authors' institution, most PM diagnoses are made on cytologic specimens. Effusion samples obtained before definitive PM diagnosis were interrogated using BRCA1-associated protein 1 gene (BAP1), cyclin-dependent kinase inhibitor 2A gene (CDKN2A) and cytologic evaluation to assess whether early or possible in situ disease could be characterized.
METHODS: All cases of PM diagnosed between January 2008 and December 2019 were identified at a tertiary referral center. Patients who had a pleural fluid sample collected 24 months before the diagnosis were selected, numbering 8 in total. The cytomorphology of each sample was reviewed; and, retrospectively, BAP1 immunohistochemistry (IHC) and CDKN2A fluorescence in situ hybridization (FISH) were performed on initial and diagnostic samples.
RESULTS: The initial samples were deemed benign in 5 cases and atypical mesothelial proliferations in 3 cases. A spectrum of apparently normal to atypical cytomorphologic changes was identified. BAP1 loss was present in 6 of 8 initial cases, whereas CDKN2A homozygous deletion was identified in 1 of 7 initial cases. Either abnormality was identified in 7 of 8 initial samples.
CONCLUSIONS: Detectable abnormalities of BAP1 IHC and CDKN2A FISH were present in pleural fluid specimens before the development of cytomorphologic features diagnostic of PM. This is the largest series to date describing cytology samples early in the course of PM development, thereby highlighting a possible cytological equivalent for mesothelioma in situ.

Keywords:  BRCA1-associated protein 1 (BAP1); cyclin-dependent kinase inhibitor 2A gene (CDKN2A); cytology; mesothelioma; mesothelioma in situ

DOI:  https://doi.org/10.1002/cncy.22548
Thorax. 2022 Feb 11. pii: thoraxjnl-2021-217709. [Epub ahead of print]

Incidence, treatment and survival of malignant pleural and peritoneal mesothelioma: a population-based study.

Job P van Kooten, Robert A Belderbos, Jan H von der Thüsen, Mieke J Aarts, Cornelis Verhoef, Jacobus A Burgers, Paul Baas, Arend G J Aalbers, Alexander P W M Maat, Joachim G J V Aerts, Robin Cornelissen, Eva V E Madsen.

   INTRODUCTION: Malignant mesothelioma (MM) is an aggressive cancer that primarily arises from the pleura (MPM) or peritoneum (MPeM), mostly due to asbestos exposure. This study reviewed the Dutch population-based incidence, treatment and survival since the national ban on asbestos in 1993.
MATERIALS AND METHODS: Patients with MPM or MPeM diagnosed from 1993 to 2018 were selected from the Dutch cancer registry. Annual percentage change (APC) was calculated for (age-specific and sex-specific) revised European standardised incidence rates (RESR). Treatment pattern and Kaplan-Meier overall survival analyses were performed.
RESULTS: In total, 12 168 patients were included in the study. For male patients younger than 80 years, the MM incidence significantly decreased in the last decade (APC ranging between -9.4% and -1.8%, p<0.01). Among both male and female patients aged over 80 years, the incidence significantly increased during the entire study period (APC 3.3% and 4.6%, respectively, p<0.01). From 2003 onwards, the use of systemic chemotherapy increased especially for MPM (from 9.3% to 39.4%). Overall, 62.2% of patients received no antitumour treatment. The most common reasons for not undergoing antitumour treatment were patient preference (42%) and performance status (25.6%). The median overall survival improved from 7.3 (1993-2003) to 8.9 (2004-2011) and 9.3 months from 2012 to 2018 (p<0.001).
CONCLUSION: The peak of MM incidence was reached around 2010 in the Netherlands, and currently the incidence is declining in most age groups. The use of systemic chemotherapy increased from 2003, which likely resulted in improved overall survival over time. The majority of patients do not receive treatment though and prognosis is still poor.

Keywords:  asbestos induced lung disease; clinical epidemiology; mesothelioma

DOI:  https://doi.org/10.1136/thoraxjnl-2021-217709
Front Oncol. 2021 ;11 795467

Insulin-Like Growth Factor 2 mRNA Binding Protein 3 Promotes Cell Proliferation of Malignant Mesothelioma Cells by Downregulating p27Kip1.

Ihiro Endo, Vishwa Jeet Amatya, Kei Kushitani, Takahiro Kambara, Tetsuya Nakagiri, Yutaro Fujii, Yukio Takeshima.

  Malignant mesothelioma is a tumor with a poor prognosis, mainly caused by asbestos exposure and with no adequate treatment yet. To develop future therapeutic targets, we analyzed the microarray dataset GSE 29370 of malignant mesothelioma and reactive mesothelial hyperplasia, downloaded from the Gene Expression Omnibus (GEO) database. We identified insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) as one of the significantly upregulated genes in malignant mesothelioma. IGF2BP3 functions as an oncoprotein in many human cancers; however, to our knowledge, this is the first study on the biological function of IGF2BP3 in malignant mesothelioma cells. The knockdown of IGF2BP3 in malignant mesothelioma cells resulted in the suppression of cell proliferation with an increase in the proportion of cells in the G1 phase of the cell cycle. Furthermore, knockdown of IGF2BP3 inhibited cell migration and invasion. We focused on the cell cycle assay to investigate the role of IGF2BP3 in cell proliferation in malignant mesothelioma. Among the various proteins involved in cell cycle regulation, the expression of p27 Kip1 (p27) increased significantly upon IGF2BP3 knockdown. Next, p27 siRNA was added to suppress the increased expression of p27. The results showed that p27 knockdown attenuated the effects of IGF2BP3 knockdown on cell proliferation and G1 phase arrest. In conclusion, we found that IGF2BP3 promotes cell proliferation, a critical step in tumorigenesis, by suppressing the expression of p27 in malignant mesothelioma.

Keywords:  IGF2BP3; cell line; mesothelioma; p27; proliferation; siRNA

DOI:  https://doi.org/10.3389/fonc.2021.795467