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Introduction: Pleural mesothelioma (PM) is an aggressive malignancy with no identified predictive biomarkers. We assessed whether tumor BAP1 status is a predictive biomarker for survival in patients receiving first-line combination platinum and pemetrexed therapy., Methods: PM cases (n = 114) from Aalborg, Denmark, were stained for BAP1 on tissue microarrays. Demographic, clinical, and survival data were extracted from registries and medical records. Surgical cases were excluded. BAP1 status was associated with overall survival (OS) by Cox regression and Kaplan-Meier methods. Results were validated in an independent cohort from Perth, Australia (n = 234)., Results: BAP1 loss was found in 62% and 60.3% of all Danish and Australian samples, respectively. BAP1 loss was an independent predictor of OS in multivariate analyses corrected for histological subtype, performance status, age, sex, and treatment (hazard ratio = 2.49, p < 0.001, and 1.48, p = 0.01, respectively). First-line platinum and pemetrexed-treated patients with BAP1 loss had significantly longer median survival than those with retained BAP1 in both the Danish (20.1 versus 7.3 mo, p < 0.001) and Australian cohorts (19.6 versus 11.1 mo, p < 0.01). Survival in patients with BAP1 retained and treated with platinum and pemetrexed was similar as in those with best supportive care. There was a higher OS in patients with best supportive care with BAP1 loss, but it was significant only in the Australian cohort (16.8 versus 8.3 mo, p < 0.01)., Conclusions: BAP1 is a predictive biomarker for survival after first-line combination platinum and pemetrexed chemotherapy and a potential prognostic marker in PM. BAP1 in tumor is a promising clinical tool for treatment stratification., (Copyright © 2022 International Association for the Study of Lung Cancer. All rights reserved.)

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., (© 2022 American Cancer Society.)

Objective: To assess the utility of BRCA1-associated protein 1 (BAP1) immunohistochemistry (IHC) for the diagnosis of malignant pleural mesothelioma (MPM) in fluid samples with atypical cytology., Methods: Pleural fluid samples with an atypical mesothelial proliferation (diagnostic categories: 'atypical' and 'suspicious') received between January 2015 and March 2018 at a tertiary referral centre were identified. Results of routine IHC testing were recorded for each case. BAP1 by IHC was performed and a final diagnosis sought from subsequent pathology specimens, medical records, or consensus clinical diagnosis., Results: Of 50 cases identified, 41 were reported as atypical and 9 as suspicious. Seven (14%) demonstrated loss of BAP1 staining, 40 retained BAP1 staining, 1 had heterogeneous staining, and 2 had insufficient cells for analysis. All seven cases with BAP1 loss were diagnosed with MPM on follow-up. Of those with retained BAP1, 52.5% (21) were subsequently diagnosed with MPM, while 40% (16) had non-MPM diagnoses after a median follow-up of 24 months. Three cases were not further investigated based on patient and clinician decision. The case with heterogeneous staining was diagnosed as mesothelioma by clinical consensus., Conclusions: BAP1 IHC loss is highly specific for malignancy and has value as a rule-in test. Even in a tertiary centre with clinical interest in the cytological diagnosis of MPM this investigation was able to increase diagnostic accuracy beyond routine IHC studies. Cytological criteria remain valuable, as retained BAP1 in an atypical or suspicious mesothelial proliferation cannot exclude malignancy., (© 2021 John Wiley & Sons Ltd.)

Aims: Accurate assessment of anaplastic lymphoma kinase (ALK) gene rearrangement in non-small-cell lung cancers (NSCLCs) is critical to identify patients who are likely to respond to crizotinib. The aim of this study was to evaluate the ALK/EML4 TriCheck FISH probe in a series of NSCLCs enriched for tumours with equivocal ALK status., Methods and Results: ALK FISH was prospectively performed on 45 NSCLCs with the ALK/EML4 TriCheck probe (ZytoVision) and the Vysis ALK break-apart probe (Abbott Molecular). ALK immunohistochemistry was performed with 5A4 and D5F3 antibodies. Fourteen cases had equivocal ALK status, based on borderline or focal FISH positivity, an atypical FISH pattern, or discrepancy between ALK FISH and immunohistochemistry. Four of the 14 equivocal cases showed discordance between the two FISH probes. All other cases were concordant. The TriCheck probe showed that, of 31 unequivocal cases, 15 were ALK-rearranged, and 60% of these had EML4 as the translocation partner. Within the group of 14 equivocal cases, 12 showed rearrangement with the Tricheck probe; only one of these showed EML4 rearrangement. Of the six equivocal cases that received crizotinib, four showed clinical benefit., Conclusions: The ALK/EML4 TriCheck FISH probe may be useful for the detection of ALK rearrangements, especially in borderline or atypical cases, where an additional unique ALK FISH probe may provide further confirmation of rearrangement., (© 2015 John Wiley & Sons Ltd.)

A case-control study was conducted in the southern part of The Netherlands to investigate the risk of lung cancer in coal miners; 381 age-matched pairs of primary lung cancer cases and controls, diagnosed between 1972 and 1988, were selected from the pathology department of the University Hospital in the region. Information about past employment in coal mines was obtained through the registers of the collaborative pension fund for Dutch miners. 20% of the cases were (at some time) employed in coal mining, compared with 21% of the controls (odds ratio 0.95; 95% confidence interval: 0.65-1.38). 9% of both cases and controls had an underground work history (odds ratio 0.96; 95% confidence interval: 0.56-1.65). The duration of underground coal mining did not differ substantially between cases and referents (average duration: respectively 117 and 108 months). No relation between specific histologic tumor cell types and coal mining could be demonstrated. The study gives no indication that workers in Dutch coal mines have an increased risk of developing lung malignancies.