The effects of an intentional transition from extrapleural pneumonectomy to extended pleurectomy/decortication

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Women in thoracic surgery: European perspectives

During the last decades, women have been discouraged from entering the medical career and in particular in the surgical specialties. This situation is changing across continents and national and international initiatives are supporting aspiring female surgeons in pursuing the surgical career through mentorship and fellowship programmes. Due to the differences in training programmes, Health Care systems and cultural backgrounds, it's not easy to describe unanimously the pathways and obstacles that junior female thoracic surgeons are experiencing in Europe. The development of female surgical associations, mentorship programmes and national initiatives will further champion the gender equality in this specialty across Europe. During the recent years, the European Society of Thoracic Surgeons (ESTS) has established initiatives like the first ESTS Women in Thoracic Surgery Scientific Session or the annual Women in Thoracic ESTS Reception during the Annual Conference, which are done in an effort to encourage all female colleagues to join this specialty and increase the opportunity to share their experience and meet potential mentors. In this article we will depict the situation in some of the European countries whose female thoracic surgeons have led their way. We aim to give the next generation the examples that can influence women's choice of surgical career, and the possible strategies and initiatives to reduce the gender discrimination within healthcare

Case Report: Spontaneous lung intercostal hernia series and literature review

Spontaneous lung intercostal hernia (SLIH) is a rare condition potentially carrying severe morbidity. About 120 cases have been described so far, with an apparently increasing number of reports in recent years. The main presenting findings are chest pain and bulging, with ecchymosis in the affected area, hemoptysis, respiratory distress, and signs of infection or incarceration being described as well. The gold standard treatment has not been established, and conservative management has been advocated as first-line treatment for asymptomatic patients. Here, we report a case series of five patients, and surgical repair was deemed necessary for four of them either at first evaluation or after failure of conservative management. One patient remains under surveillance and conservative management. We believe that SLIH surgical repair should be considered as first-line treatment for fit patients, due to the uncertainty of its mid- and long-term impact and described pejorative trend/defect enlargement. A proposed algorithm for SLIH management is also presented

Ganetespib in combination with pemetrexed-platinum chemotherapy in patients with pleural Mesothelioma (MESO-02) : a phase Ib trial

Purpose: Ganetespib, a highly potent, small molecule Heatshock protein 90 inhibitor, has potential efficacy in malignant pleural mesothelioma (MPM) via activity on critical survival pathways and known synergies with antifolates and platinum chemotherapy. We conducted a dose-escalation study to identify the Maximum Tolerated Dose (MTD) of ganetespib in chemotherapy-naïve MPM patients. Experimental Design: MESO-02 (ClinicalTrials.gov: NCT01590160) was a non-randomized, multicentre, phase Ib trial of 3-weekly ganetespib (100 mg/m2, 150 mg/m2, 200 mg/m2; days 1 and 15) with pemetrexed (500 mg/m2; day 1) and cisplatin (75 mg/m2; day 1) or carboplatin (area under concentration-time curve 5; day 1) in MPM patients. Dose-escalation was performed using the 3+3 design (cisplatin) and accelerated titration design (carboplatin). Secondary endpoints included best response, progression-free survival (PFS) and pharmacogenomic analyses. Results: Of 27 patients enroled (cisplatin, n=16; carboplatin, n=11), 3 experienced dose-limiting toxicities: grade 3 nausea (cisplatin, n=1; carboplatin, n=1); grade 2 infusion-related reaction (carboplatin, n=1). Ganetespib's MTD was 200 mg/m2. Partial response was observed in 14/27 patients (52%; 61% in 23 response-evaluable patients) and 13/21 (62%) with epithelioid histology. At the MTD, 10/18 patients (56%) had partial response, 15/18 (83%) had disease control, and median PFS was 6.3 months (95% CI 5.0-10.0). One responder exhibited disease control beyond 50 months. Global Loss of Heterozygosity was associated with shorter time to progression (Hazard Ratio 1.12, 95% CI 1.02-1.24; p=0.018). Conclusions: Ganetespib can be combined safely with pemetrexed and platinum chemotherapy to treat patients with MPM. This class of agent should be investigated in larger randomized studies

Transcriptional perturbation of protein arginine methyltransferase-5 exhibits MTAP-selective oncosuppression.

We hypothesized that small molecule transcriptional perturbation could be harnessed to target a cellular dependency involving protein arginine methyltransferase 5 (PRMT5) in the context of methylthioadenosine phosphorylase (MTAP) deletion, seen frequently in malignant pleural mesothelioma (MPM). Here we show, that MTAP deletion is negatively prognostic in MPM. In vitro, the off-patent antibiotic Quinacrine efficiently suppressed PRMT5 transcription, causing chromatin remodelling with reduced global histone H4 symmetrical demethylation. Quinacrine phenocopied PRMT5 RNA interference and small molecule PRMT5 inhibition, reducing clonogenicity in an MTAP-dependent manner. This activity required a functional PRMT5 methyltransferase as MTAP negative cells were rescued by exogenous wild type PRMT5, but not a PRMT5E444Q methyltransferase-dead mutant. We identified c-jun as an essential PRMT5 transcription factor and a probable target for Quinacrine. Our results therefore suggest that small molecule-based transcriptional perturbation of PRMT5 can leverage a mutation-selective vulnerability, that is therapeutically tractable, and has relevance to 9p21 deleted cancers including MPM

Clonal architecture in mesothelioma is prognostic and shapes the tumour microenvironment.

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

Interrogating inter- and intratumour genomic heterogeneity in mesothelioma

BackgroundDespite recent advances, treatment options for patients with malignant pleural mesothelioma (MPM) are limited and prognosis remains poor. The aims of this work were to better understand the somatic copy number alteration (SCNA) landscape of MPM and to identify potential therapeutic targets, to determine genetic factors predicting outcome following radical surgery, and to develop an evolutionary study of MPM.MethodsThe Affymetrix Oncoscan array was used to evaluate SCNAs from 94 tumour samples. Common SCNAs were evaluated as potential therapeutic targets, including PRMT5 as a synthetic lethal target for MTAP in vitro. SCNA profiles of patients with extremes of outcome following radical surgery were compared to determine any genetic predictors of outcome. A second set of tumours was analysed in an attempt to validate these findings. A pilot of the Medusa study (NCT03654833) was carried out to evaluate the genomic spatial heterogeneity within 6 MPM tumours by whole exome sequencing.ResultsDeletion of 9p21.3 was the most prevalent SCNA. MTAP was shown to have potentially synthetic lethal interaction with PRMT5 in vitro. Deletion of CDKN2A was a truncal event in 67% of cases. BAP1 and NF2 were commonly heterozygously deleted, with mutation of the remaining allele a truncal event on phylogenetic analysis. A group of 47 SCNAs were exclusive to patients with a short time to progression, and having one or more of these predicted outcome.Conclusions Several potential therapeutic targets have been identified. The presence of one or more specific SCNAs could give a measure of prognosis for patients from routinely obtained tumour tissue samples.</div