Whole exome and targeted deep sequencing identify genome-wide allelic loss and frequent SETDB1 mutations in malignant pleural mesotheliomas.

Malignant pleural mesothelioma (MPM), a rare malignancy with a poor prognosis, is mainly caused by exposure to asbestos or other organic fibers, but the underlying genetic mechanism is not fully understood. Genetic alterations and causes for multiple primary cancer development including MPM are unknown. We used whole exome sequencing to identify somatic mutations in a patient with MPM and two additional primary cancers who had no evidence of venous, arterial, lymphovascular, or perineural invasion indicating dissemination of a primary lung cancer to the pleura. We found that the MPM had R282W, a key TP53 mutation, and genome-wide allelic loss or loss of heterozygosity, a distinct genomic alteration not previously described in MPM. We identified frequent inactivating SETDB1 mutations in this patient and in 68 additional MPM patients (mutation frequency: 10%, 7/69) by targeted deep sequencing. Our observations suggest the possibility of a new genetic mechanism in the development of either MPM or multiple primary cancers. The frequent SETDB1 inactivating mutations suggest there could be new diagnostic or therapeutic options for MPM

A guide for managing patients with stage I NSCLC: Deciding between lobectomy, segmentectomy, wedge, SBRT and ablation-part 2: Systematic review of evidence regarding resection extent in generally healthy patients

Background: Clinical decision-making for patients with stage I lung cancer is complex. It involves multiple options (lobectomy, segmentectomy, wedge, stereotactic body radiotherapy, thermal ablation), weighing multiple outcomes (e.g., short-, intermediate-, long-term) and multiple aspects of each (e.g., magnitude of a difference, the degree of confidence in the evidence, and the applicability to the patient and setting at hand). A structure is needed to summarize the relevant evidence for an individual patient and to identify which outcomes have the greatest impact on the decision-making. Methods: A PubMed systematic review from 2000-2021 of outcomes after lobectomy, segmentectomy and wedge resection in generally healthy patients is the focus of this paper. Evidence was abstracted from randomized trials and non-randomized comparisons with at least some adjustment for confounders. The analysis involved careful assessment, including characteristics of patients, settings, residual confounding etc. to expose degrees of uncertainty and applicability to individual patients. Evidence is summarized that provides an at-a-glance overall impression as well as the ability to delve into layers of details of the patients, settings and treatments involved. Results: In healthy patients there is no short-term benefit to sublobar resection Conclusions: A systematic, comprehensive summary of evidence regarding resection extent in healthy patients with attention to aspects of applicability, uncertainty and effect modifiers provides a foundation on which to build a framework for individualized clinical decision-making

A guide for managing patients with stage I NSCLC: Deciding between lobectomy, segmentectomy, wedge, SBRT and ablation-part 3: Systematic review of evidence regarding surgery in compromised patients or specific tumors

Background: Clinical decision-making for patients with stage I lung cancer is complex. It involves multiple options [lobectomy, segmentectomy, wedge, stereotactic body radiotherapy (SBRT), thermal ablation], weighing multiple outcomes (e.g., short-, intermediate-, long-term) and multiple aspects of each (e.g., magnitude of a difference, the degree of confidence in the evidence, and the applicability to the patient and setting at hand). A structure is needed to summarize the relevant evidence for an individual patient and to identify which outcomes have the greatest impact on the decision-making. Methods: A PubMed systematic review from 2000-2021 of outcomes after lobectomy, segmentectomy and wedge resection in older patients, patients with limited pulmonary reserve and favorable tumors is the focus of this paper. Evidence was abstracted from randomized trials and non-randomized comparisons (NRCs) with adjustment for confounders. The analysis involved careful assessment, including characteristics of patients, settings, residual confounding etc. to expose degrees of uncertainty and applicability to individual patients. Evidence is summarized that provides an at-a-glance overall impression as well as the ability to delve into layers of details of the patients, settings and treatments involved. Results: In older patients, perioperative mortality is minimally altered by resection extent and only slightly affected by increasing age; sublobar resection may slightly decrease morbidity. Long-term outcomes are worse after lesser resection; the difference is slightly attenuated with increasing age. Reported short-term outcomes are quite acceptable in (selected) patients with severely limited pulmonary reserve, not clearly altered by resection extent but substantially improved by a minimally invasive approach. Quality-of-life (QOL) and impact on pulmonary function hasn\u27t been well studied, but there appears to be little difference by resection extent in older or compromised patients. Patient selection is paramount but not well defined. Ground-glass and screen-detected tumors exhibit favorable long-term outcomes regardless of resection extent; however solid tumors \u3c1 cm are not a reliably favorable group. Conclusions: A systematic, comprehensive summary of evidence regarding resection extent in compromised patients and favorable tumors with attention to aspects of applicability, uncertainty and effect modifiers provides a foundation for a framework for individualized decision-making

A guide for managing patients with stage I NSCLC: Deciding between lobectomy, segmentectomy, wedge, SBRT and ablation-part 4: Systematic review of evidence involving SBRT and ablation

Background: Clinical decision-making for patients with stage I lung cancer is complex. It involves multiple options [lobectomy, segmentectomy, wedge, stereotactic body radiotherapy (SBRT), thermal ablation], weighing multiple outcomes (e.g., short-, intermediate-, long-term) and multiple aspects of each (e.g., magnitude of a difference, the degree of confidence in the evidence, and the applicability to the patient and setting at hand). A structure is needed to summarize the relevant evidence for an individual patient and to identify which outcomes have the greatest impact on the decision-making. Methods: A PubMed systematic review from 2000-2021 of outcomes after SBRT or thermal ablation Results: Short-term outcomes are meaningfully better after SBRT than resection. SBRT doesn\u27t affect quality-of-life (QOL), on average pulmonary function is not altered, but a minority of patients may experience gradual late toxicity. Adjusted non-randomized comparisons demonstrate a clinically relevant detriment in long-term outcomes after SBRT Conclusions: A systematic, comprehensive summary of evidence regarding Stereotactic Body Radiotherapy or thermal ablatio

Consensus Report of the 2015 Weinman International Conference on Mesothelioma.

On November 9 and 10, 2015, the International Conference on Mesothelioma in Populations Exposed to Naturally Occurring Asbestiform Fibers was held at the University of Hawaii Cancer Center in Honolulu, Hawaii. The meeting was cosponsored by the International Association for the Study of Lung Cancer, and the agenda was designed with significant input from staff at the U.S. National Cancer Institute and National Institute of Environmental Health Sciences. A multidisciplinary group of participants presented updates reflecting a range of disciplinary perspectives, including mineralogy, geology, epidemiology, toxicology, biochemistry, molecular biology, genetics, public health, and clinical oncology. The group identified knowledge gaps that are barriers to preventing and treating malignant mesothelioma (MM) and the required next steps to address barriers. This manuscript reports the group's efforts and focus on strategies to limit risk to the population and reduce the incidence of MM. Four main topics were explored: genetic risk, environmental exposure, biomarkers, and clinical interventions. Genetics plays a critical role in MM when the disease occurs in carriers of germline BRCA1 associated protein 1 mutations. Moreover, it appears likely that, in addition to BRCA1 associated protein 1, other yet unknown genetic variants may also influence the individual risk for development of MM, especially after exposure to asbestos and related mineral fibers. MM is an almost entirely preventable malignancy as it is most often caused by exposure to commercial asbestos or mineral fibers with asbestos-like health effects, such as erionite. In the past in North America and in Europe, the most prominent source of exposure was related to occupation. Present regulations have reduced occupational exposure in these countries; however, some people continue to be exposed to previously installed asbestos in older construction and other settings. Moreover, an increasing number of people are being exposed in rural areas that contain noncommercial asbestos, erionite, and other mineral fibers in soil or rock (termed naturally occurring asbestos [NOA]) and are being developed. Public health authorities, scientists, residents, and other affected groups must work together in the areas where exposure to asbestos, including NOA, has been documented in the environment to mitigate or reduce this exposure. Although a blood biomarker validated to be effective for use in screening and identifying MM at an early stage in asbestos/NOA-exposed populations is not currently available, novel biomarkers presented at the meeting, such as high mobility group box 1 and fibulin-3, are promising. There was general agreement that current treatment for MM, which is based on surgery and standard chemotherapy, has a modest effect on the overall survival (OS), which remains dismal. Additionally, although much needed novel therapeutic approaches for MM are being developed and explored in clinical trials, there is a critical need to invest in prevention research, in which there is a great opportunity to reduce the incidence and mortality from MM