bims-mesote 2023-12-10 papers

Issue of 2023–12–10
five papers selected by
Laura Mannarino, Humanitas Research

Cancer Res Commun. 2023 Dec 06.

Combined inhibition of EZH2 and FGFR is synergistic in BAP1- deficient malignant mesothelioma.

Jitendra Badhai, Nick Landman, Gaurav Kumar Pandey, Ji-Ying Song, Danielle Hulsman, Oscar Krijgsman, Gayathri Chandrasekaran, Anton Berns, Maarten van Lohuizen.

Malignant mesothelioma is a highly aggressive tumour with a survival of only 4-18 months after diagnosis. Treatment options for this disease are limited. Immune checkpoint blockade using Ipilimumab and Nivolumab has recently been approved as a frontline therapy, but this led to only a small improvement in overall patient survival. As more than half of mesothelioma patients have alterations in the gene encoding for BAP1 this could be a potential marker for targeted therapies. In this study, we investigated the synergistic potential of combining EZH2 inhibition together with FGFR inhibition for treatment of BAP1-deficient malignancies. The efficacy of the combination was evaluated using human and murine preclinical models of mesothelioma and uveal melanoma in vitro. The efficacy of the combination was further validated in vivo by using BAP1-deficient mesothelioma xenografts and autochthonous mouse models. In vitro data showed sensitivity to the combined inhibition in BAP1-deficient mesothelioma and uveal melanoma tumour cell lines but not for BAP1-proficient subtypes. In vivo data showed susceptibility to the combination of BAP1-deficient xenografts and demonstrated an increase of survival in autochthonous models of mesothelioma. These results highlight the potential of this novel drug combination for the treatment of mesothelioma using BAP1 as a biomarker. Given these encouraging preclinical results, it will be important to clinically explore dual EZH2/FGFR inhibition in BAP1-deficient malignant mesothelioma patients and justifies further exploration in other BAP1-loss-associated tumours.

DOI: https://doi.org/10.1158/2767-9764.CRC-23-0276

Cancer Sci. 2023 Dec 04.

Nationwide prospective registry database of patients with newly diagnosed untreated pleural mesothelioma in Japan.

Seiki Hasegawa, Yasushi Shintani, Teruhisa Takuwa, Keisuke Aoe, Katsuya Kato, Nobukazu Fujimoto, Yasuhiro Hida, Masahiro Morise, Yasumitsu Moriya, Takao Morohoshi, Hidemi Suzuki, Masayuki Chida, Shunsuke Endo, Mitsutaka Kadokura, Meinoshin Okumura, Satoshi Hattori, Hiroshi Date, Ichiro Yoshino.

Due to the scarcity of large-sized prospective databases, the Japanese Joint Committee for Lung Cancer Registry conducted a nationwide prospective registry for newly diagnosed and untreated pleural mesothelioma. All new cases diagnosed pathologically as any subtype of pleural mesothelioma in Japan during the period between April 1, 2017, to March 31, 2019, were included before treatment. Data on survival were collected in April 2021. The eligible 346 patients (285 men [82.3%]; 61 women [17.7%]; median age, 71.0 years [range, 44-88]) were included for analysis. Among these patients, 138 (39.9%) underwent surgery, 164 (47.4%) underwent non-surgical therapy, and the remaining 44 (12.7%) underwent best supportive care. The median overall survival for all 346 patients was 19.0 months. Survival rates at 1, 2, and 3 years for all patients were, 62.8%, 42.3%, and 26.5%, respectively. Median overall survival was significantly different among patients undergoing surgery, non-surgical treatment, and best supportive care (32.2 months vs. 14.0 months vs. 3.8 months, p < 0.001). The median overall survival of patients undergoing pleurectomy/decortication and extrapleural pneumonectomy was 41.8 months and 25.0 months, respectively. Macroscopic complete resection resulted in longer overall survival than R2 resection and partial pleurectomy/exploratory thoracotomy (41.8 months vs. 32.2 months vs. 16.8 months, p < 0.001). Tumor shape, maximum tumor thickness, and sum of three level thickness were significant prognostic factors. The data in the prospective database would serve as a valuable reference for clinical practice and further studies for pleural mesothelioma.

Keywords: chemotherapy; database; pleural mesothelioma; staging system; surgery

DOI: https://doi.org/10.1111/cas.16021

Med Lav. 2023 Dec 07. 114(6): e2023048

Quantitative Assessment of Asbestos Fibers in Abdominal Organs: A Scoping Review.

Yohama Caraballo-Arias, Francesco Roccuzzo, Francesca Graziosi, Nataliia Danilevskaia, Samantha Rota, Carlotta Zunarellli, Paola Caffaro, Paolo Boffetta, Mattia Bonetti, Francesco Saverio Violante.

BACKGROUND: Quantification of asbestos fibers has been mainly performed in the lung but rarely in other organs. However, this may be relevant to understanding better translocation pathways and the oncogenic effects of asbestos on the human body. Electron microscopy is the best technology available to assess the type of fiber, dimensions, and distribution of asbestos fibers in different tissues and as a biomarker of cumulative dose.
OBJECTIVES: This scoping review aims to summarize the findings of the studies in which asbestos fibers have been quantified by electron microscopy, occasionally associated with X-ray microanalysis, in normal and pathological tissue of ten abdominal organs.
METHODS: A scoping review has been performed by searching articles that quantified asbestos fibers in abdominal organs by electron microscopy (Scanning- SEM or Transmission- TEM).
RESULTS: The 12 selected studies included 204 cases, and 325 samples were analyzed. The colon and rectum, kidney, bladder, and abdominal lymph nodes were the organs with at least ten samples available with quantification of asbestos fibers. Asbestos fibers were detected in all the abdominal organs considered: the highest value (152,32 million fibers per gram of dry tissue) was found in the colon and was identified using STEM with EDS.
CONCLUSION: The studies included were heterogeneous in terms of exposure and cases, type of samples, as well as analytical techniques, therefore we cannot confirm a specific pattern of distribution in any organ, based on the low homogeneity of the exposure status. The colon is the organ in which the number of fibers is the highest, probably because of exposure arising from both internal distribution of inhaled fibers and ingestion. Additional studies of the number of asbestos fibers in abdominal organs should be made to achieve better representativity.

DOI: https://doi.org/10.23749/mdl.v114i6.14946

bioRxiv. 2023 Nov 21. pii: 2023.11.21.568094. [Epub ahead of print]

Expanded detection of BAP1 alterations in cancer and tumor type-specific expression score comparison.

Ian R Sturgill, Jesse R Raab, Katherine A Hoadley.

BAP1 is a tumor suppressor gene that was originally studied in uveal melanoma (UVM), kidney renal cell clear cell carcinoma (KIRC), and malignant mesothelioma (MESO). Early analyses focused on single-nucleotide variants, but other alteration types such as larger indels and gene-level copy number (CN) loss can also lead to loss of BAP1 expression. We performed integrated multi-omic analyses using data from The Cancer Genome Atlas (TCGA) for 33 cancer types and more than 10,000 individuals. We combined and manually reviewed existing variant calls and new calls derived from a de novo local realignment pipeline across multiple independent variant callers including indel callers, increasing detection of high-quality somatic variant calls by 30% from 91 to 130, including 7 indels ≥40bp. Including CN loss alterations, 1561 samples from 32 cancer types were BAP1 -altered, with alterations being predominantly CN-driven. Differential expression and survival analyses revealed both shared and tissue-specific consequences associated with BAP1 alteration. Our findings broadly emphasize the improvements that are gained by using new computational approaches in large cancer-genome studies such as TCGA.

DOI: https://doi.org/10.1101/2023.11.21.568094

JTO Clin Res Rep. 2023 Dec;4(12): 100584

Phase 2 Trial of Nivolumab and Ramucirumab for Relapsed Mesothelioma: HCRN-LUN15-299.

Arkadiusz Z Dudek, Min X Xi, Katherine A Scilla, Hirva Mamdani, Benjamin C Creelan, Andreas Saltos, Tawee Tanvetyanon, Alberto Chiappori.

Introduction: We hypothesized that ramucirumab could increase previously reported objective response rate (ORR) of 11% of single-agent nivolumab in the second-line therapy of unresectable mesothelioma.
Methods: This was a cooperative group, single-arm, phase 2 trial enrolling patients with unresectable mesothelioma after progression on more than or equal to one pemetrexed-containing regimen. Ramucirumab and nivolumab were given intravenously every 14 days for up to 24 months. The primary end point was ORR; secondary end points were progression-free survival (PFS) rate at 24 weeks and overall survival (OS).
Results: Between April 2018 and October 2021, 34 patients were recruited. Median age was 72 (range: 40-89) years, 12% were women, and 79% of tumors had epithelial histology. Median follow-up was 10.2 months (interquartile range 19.6 mo [4.3-23.8]). ORR was 22.6% (95% confidence interval [CI]: 9.6%-41.1%) in all population and 43% (95% CI: 10%-82%) in patients with nonepithelioid histology. Of all patients, 45.2% (95% CI: 27.3%-64.0%) had stable disease. PFS rate at 24 weeks was 32% (95% CI: 17%-51%). Median PFS was 4.2 months (95% CI: 1.9-6.4 mo). Median OS was 12.5 months (95% CI: 6.3-23.5 mo). There was no grade greater than or equal to four toxicity. Programmed death-ligand 1 expression in the tumor did not correlate with benefit from treatment. Activation of tumor-infiltrating lymphocytes in response to treatment was associated with a trend toward improvement in PFS.
Conclusions: Nivolumab and ramucirumab combination was safe and generated PFS and OS rates and ORR that compare favorably with single-agent nivolumab in a similar patient population. The primary end point of 40% ORR was not reached. Further investigation of this regimen in mesothelioma with nonepithelioid histology may be warranted. Clinical Trial Information: NCT03502746.

Keywords: Mesothelioma; Nivolumab; Overall response rate; Progression-free survival; Ramucirumab

DOI: https://doi.org/10.1016/j.jtocrr.2023.100584