Integrative molecular characterization of malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is a highly lethal cancer of the lining of the chest cavity. To expand our understanding of MPM, we conducted a comprehensive integrated genomic study, including the most detailed analysis of BAP1 alterations to date. We identified histology-independent molecular prognostic subsets, and defined a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity. We also report strong expression of the immune-checkpoint gene VISTA in epithelioid MPM, strikingly higher than in other solid cancers, with implications for the immune response to MPM and for its immunotherapy. Our findings highlight new avenues for further investigation of MPM biology and novel therapeutic options. SIGNIFICANCE: Through a comprehensive integrated genomic study of 74 MPMs, we provide a deeper understanding of histology-independent determinants of aggressive behavior, define a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity, and discovered strong expresssion of the immune-checkpoint gene VISTA in epithelioid MPM

Surveillance testing for SARS-COV-2 infection in an asymptomatic athlete population: A prospective cohort study with 123 362 tests and 23 463 paired RT-PCR/antigen samples

Objective To assess the diagnostic accuracy of antigen compared with reverse transcriptase (RT)-PCR testing in an asymptomatic athlete screening programme and to monitor infection in college athletes. Methods Quidel Sofia-2 SARS-CoV-2 Antigen Tests were performed daily before sports participation for football, basketball, wrestling and water polo from 29 September 2020 to 28 February 2021. Paired RT-PCR and antigen tests were performed at least once a week. Positive antigen tests were confirmed with RT-PCR. Results 81 175 antigen and 42 187 RT-PCR tests were performed, including 23 462 weekly paired antigen/RT-PCR screening tests in 1931 athletes. One hundred and seventy-two athletes had a positive screening RT-PCR (0.4%), of which 83 (48%) occurred on paired testing days. The sensitivity of antigen tests varied with the frequency of RT-PCR testing and prevalence of COVID-19. The sensitivity of antigen testing was 35.7% (95% CI: 17% to 60%) and specificity 99.8% (95% CI: 99.7% to 99.9%) with once-a-week RT-PCR testing after adjusting for school prevalence. Daily antigen testing was similar to RT-PCR testing two to three times a week in identifying infection. Antigen testing identified infection before the next scheduled PCR on 89 occasions and resulted in 234 days where potentially infectious athletes were isolated before they would have been isolated with RT-PCR testing alone. Two athletic-related outbreaks occurred; 86% of total infections were community acquired. Conclusion Antigen testing has high specificity with a short turnaround time but is not as sensitive as RT-PCR. Daily antigen testing or RT-PCR testing two to three times a week is similar. There are benefits and drawbacks to each testing approach. © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

LONG-TERM RESULTS OF LUNG METASTASECTOMY: PROGNOSTIC ANALYSES BASED ON 5206 CASES

Objectives: The International Registry of Lung Metastases was established in 1991 to assess the long-term results of pulmonary lnetastasectomy. Methods: The Registry has accrued 5206 cases of lung metastasectomy, from 18 departments of thoracic surgery in Europe (n = 13), the United States (n = 4) and Canada (n = 1). Of these patients, 4572 (88%) underwent complete surgical resection. The primary tumor was epithelial in 2260 cases, sarcoma in 2173, germ cell in 363, and melanoma in 328. The disease-free interval was 0 to 11 months in 2199 cases, 12 to 35 months in 1857, and more than 36 months in 1620. Single metastases accounted for 2383 cases and multiple lesions for 2726. Mean follow-up was 46 months. Analysis was performed by Kaplan- Meier estimates of survival, relative risks of death, and multivariate Cox model. Results: The actuarial survival after complete metastasectomy was 36% at 5 years, 26% at 10 years, and 22% at 15 years (median 35 months); the corresponding values for incomplete resection were 113% at 5 years and 7% at 10 years (median 15 months). Among complete resections, the 5-year survival was 33% for patients with a disease-free interval of 0 to 11 months and 45% for those with a disease-free interval of more than 36 months; 43% for single lesions and 27% for four or more lesions. Multivariate analysis showed a better prognosis for patients with germ cell tumors, disease-free intervals of 36 months or more, and single metastases. Conclusions: These results confirm that lung metastasectomy is a safe and potentially curative procedure. Resectability, disease-free interval, and number of metastases enabled us to design a simple system of classification valid for different tumor types

LONG-TERM RESULTS OF LUNG METASTASECTOMY: PROGNOSTIC ANALYSES BASED ON 5206 CASES

Objectives: The International Registry of Lung Metastases was established in 1991 to assess the long-term results of pulmonary lnetastasectomy. Methods: The Registry has accrued 5206 cases of lung metastasectomy, from 18 departments of thoracic surgery in Europe (n = 13), the United States (n = 4) and Canada (n = 1). Of these patients, 4572 (88%) underwent complete surgical resection. The primary tumor was epithelial in 2260 cases, sarcoma in 2173, germ cell in 363, and melanoma in 328. The disease-free interval was 0 to 11 months in 2199 cases, 12 to 35 months in 1857, and more than 36 months in 1620. Single metastases accounted for 2383 cases and multiple lesions for 2726. Mean follow-up was 46 months. Analysis was performed by Kaplan- Meier estimates of survival, relative risks of death, and multivariate Cox model. Results: The actuarial survival after complete metastasectomy was 36% at 5 years, 26% at 10 years, and 22% at 15 years (median 35 months); the corresponding values for incomplete resection were 113% at 5 years and 7% at 10 years (median 15 months). Among complete resections, the 5-year survival was 33% for patients with a disease-free interval of 0 to 11 months and 45% for those with a disease-free interval of more than 36 months; 43% for single lesions and 27% for four or more lesions. Multivariate analysis showed a better prognosis for patients with germ cell tumors, disease-free intervals of 36 months or more, and single metastases. Conclusions: These results confirm that lung metastasectomy is a safe and potentially curative procedure. Resectability, disease-free interval, and number of metastases enabled us to design a simple system of classification valid for different tumor types

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation; analyses timings and patterns of tumour evolution; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity; and evaluates a range of more-specialized features of cancer genomes