Malignant Pleural Mesothelioma (MPM) is typically diagnosed 20–50 years after exposure to asbestos and evolves along an unknown evolutionary trajectory. To elucidate this path, we conducted multi-regional exome sequencing of 90 tumour samples from 22 MPMs acquired at surgery. Here we show that exomic intratumour heterogeneity varies widely across the cohort. Phylogenetic tree topology ranges from linear to highly branched, reflecting a steep gradient of genomic instability. Using transfer learning, we detect repeated evolution, resolving 5 clusters that are prognostic, with temporally ordered clonal drivers. BAP1/−3p21 and FBXW7/-chr4 events are always early clonal. In contrast, NF2/−22q events, leading to Hippo pathway inactivation are predominantly late clonal, positively selected, and when subclonal, exhibit parallel evolution indicating an evolutionary constraint. Very late somatic alteration of NF2/22q occurred in one patient 12 years after surgery. Clonal architecture and evolutionary clusters dictate MPM inflammation and immune evasion. These results reveal potentially drugable evolutionary bottlenecking in MPM, and an impact of clonal architecture on shaping the immune landscape, with potential to dictate the clinical response to immune checkpoint inhibition.

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CD40L/interleukin-4 (IL-4) stimulation occurs in vivo in the tumor microenvironment and induces global translation to varying degrees in individuals with chronic lymphocytic leukemia (CLL) in vitro. However, the implications of CD40L/IL-4 for the translation of specific genes is not known. To determine the most highly translationally regulated genes in response to CD40L/IL-4, we carried out ribosome profiling, a next-generation sequencing method. Significant differences in the translational efficiency of DNA damage response genes, specifically ataxia-telangiectasia-mutated kinase (ATM) and the MRE11/RAD50/NBN (MRN) complex, were observed between patients, suggesting different patterns of translational regulation. We confirmed associations between CD40L/IL-4 response and baseline ATM levels, induction of ATM, and phosphorylation of the ATM targets, p53 and H2AX. X-irradiation was used to demonstrate that CD40L/IL-4 stimulation tended to improve DNA damage repair. Baseline ATM levels, independent of the presence of 11q deletion, correlated with overall survival (OS). Overall, we suggest that there are individual differences in translation of specific genes, including ATM, in response to CD40L/IL-4 and that these interpatient differences might be clinically important.

Malignant pleural mesotheliomas (MPMs) are characterised by their wide variation in natural history, ranging from minimally to highly aggressive, associated with both interpatient and intra-tumour genomic heterogeneity. Recent insights into the nature of this genetic variation, the identification of drivers, and the emergence of novel strategies capable of targeting vulnerabilities that result from the inactivation of key tumour suppressors suggest that new approaches to molecularly strategy therapy for mesothelioma may be feasible.

Background: Dumon silicone Y-stent is useful for releasing the tracheobronchial stenosis. We often encounter patients with tumors involving the carina between the bronchus to the right upper lobe and bronchus intermedius. However, there has not been ideal stenting for such cases, especially to maintain the patency of the right upper lobe bronchus. We investigated the clinical outcome in patients with malignant tracheobronchial stenosis, especially focused on the patency of right upper lobe bronchus after Y-stent placement. Method: From January 2012 until December 2018, 102 patients who had placed Y-stent on malignant tracheobronchial stenosis in our department were examined retrospectively. This study involved 73 male and 29 female. The mean age was 64 years (range, 30-91 years). Fifty-nine patients had lung cancer, 29 had esophageal cancer, and 14 had other carcinomas. All procedures were carried out in the operating room under general anesthesia, and the stents were implanted via rigid bronchoscopy. The patients were divided into two groups based on the patency of right upper bronchus: patency group (P group, n¼73) and stenosis /occlusion group (S group, n¼29). The clinicopathological features, clinical course, and the survival after stenting of the groups were compared. Result: Stents were implanted and symptoms were resolved in all cases. No operative death occurred. Stent indwelling types were only Y-stent in 69 patients and Y-stent with additional self-expanding metallic stent (SEMS) in 33. Although there was no difference between the two groups in age, gender, preoperative Hugh-Jones classification, hospitalization days, and size of Y-stent, esophageal cancer was significantly more frequent in P group. The total length of placed stent was significantly longer in S group (median 10.5cm) compared to P group (8cm) (p<0.01) and the postoperative Hugh-Jones classification (I or II) in S group (47%) was inferior compared to the P group (72%). After stent placement, 67% of the P group could be treated chemotherapy/radiotherapy to primary disease, while only 43% of the S group was received these because of their poor general condition (p ¼ 0.03).The median survival time (MST) and 1-year survival rate of the two groups was 7 months and 32% (P group), and 2 months and 17% (S group), respectively (p<0.01). Conclusion: The patency of right upper lobe bronchus after Y-stent placement affects not only the improvement of postoperative Hugh-Jones classification but also the administration of subsequent treatment to primary disease and associated to their clinical outcome.