Simultaneous colorectal and hepatic procedures for colorectal cancer result in increased morbidity but equivalent mortality compared with colorectal or hepatic procedures alone: outcomes from the National Surgical Quality Improvement Program

AbstractBackgroundSimultaneous colorectal and hepatic surgery for colorectal cancer (CRC) is increasing as surgery becomes safer and less invasive. There is controversy regarding the morbidity associated with simultaneous, compared with separate or staged, resections.MethodsData for 2005–2008 from the National Surgical Quality Improvement Program (NSQIP) were used to compare morbidity after 19 925 colorectal procedures for CRC (CR group), 2295 hepatic resections for metastatic CRC (HEP group), and 314 simultaneous colorectal and hepatic resections (SIM group).ResultsAn increasing number of simultaneous resections were performed per year. Fewer major colorectal and liver resections were performed in the SIM than in the CR and HEP groups. Patients in the SIM group had a longer operative time and postoperative length of stay compared with those in either the CR or HEP groups. Simultaneous procedures resulted in higher rates of postoperative morbidity and major morbidity than CR procedures, but not HEP procedures. This difference was driven by higher rates of wound and organ space infections, and a greater incidence of septic shock. Mortality rates did not differ among the groups.ConclusionsHospitals in the NSQIP are performing more simultaneous colonic and hepatic resections for CRC. These procedures are associated with increases in operative time, length of stay and rate of perioperative complications. Simultaneous procedures do not, however, increase perioperative mortality

Titles versus titles and abstracts for initial screening of articles for systematic reviews

PMC3933432BACKGROUND: There is no consensus on whether screening titles alone or titles and abstracts together is the preferable strategy for inclusion of articles in a systematic review. METHODS: TWO METHODS OF SCREENING ARTICLES FOR INCLUSION IN A SYSTEMATIC REVIEW WERE COMPARED: titles first versus titles and abstracts simultaneously. Each citation found in MEDLINE or Embase was reviewed by two physician reviewers for prespecified criteria: the citation included (1) primary data; (2) the exposure of interest; and (3) the outcome of interest. RESULTS: There were 2965 unique citations. The titles first strategy resulted in an immediate rejection of 2558 (86%) of the records after reading the title alone, requiring review of 239 titles and abstracts, and subsequently 176 full text articles. The simultaneous titles and abstracts review led to rejection of 2782 citations (94%) and review of 183 full text articles. Interreviewer agreement to include an article for full text review using the titles-first screening strategy was 89%-94% (kappa = 0.54) and 96%-97% (kappa = 0.56) for titles and abstracts combined. The final systematic review included 13 articles, all of which were identified by both screening strategies (yield 100%, burden 114%). Precision was higher in the titles and abstracts method (7.1% versus 3.2%) but recall was the same (100% versus 100%), leading to a higher F-measure for the titles and abstracts approach (0.1327 versus 0.0619). CONCLUSION: Screening via a titles-first approach may be more efficient than screening titles and abstracts together.JH Libraries Open Access Fun

Antibodies against endogenous retroviruses promote lung cancer immunotherapy

B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS). Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response

Body composition and lung cancer-associated cachexia in TRACERx

Cancer-associated cachexia (CAC) is a major contributor to morbidity and mortality in individuals with non-small cell lung cancer. Key features of CAC include alterations in body composition and body weight. Here, we explore the association between body composition and body weight with survival and delineate potential biological processes and mediators that contribute to the development of CAC. Computed tomography-based body composition analysis of 651 individuals in the TRACERx (TRAcking non-small cell lung Cancer Evolution through therapy (Rx)) study suggested that individuals in the bottom 20th percentile of the distribution of skeletal muscle or adipose tissue area at the time of lung cancer diagnosis, had significantly shorter lung cancer-specific survival and overall survival. This finding was validated in 420 individuals in the independent Boston Lung Cancer Study. Individuals classified as having developed CAC according to one or more features at relapse encompassing loss of adipose or muscle tissue, or body mass index-adjusted weight loss were found to have distinct tumor genomic and transcriptomic profiles compared with individuals who did not develop such features. Primary non-small cell lung cancers from individuals who developed CAC were characterized by enrichment of inflammatory signaling and epithelial–mesenchymal transitional pathways, and differentially expressed genes upregulated in these tumors included cancer-testis antigen MAGEA6 and matrix metalloproteinases, such as ADAMTS3. In an exploratory proteomic analysis of circulating putative mediators of cachexia performed in a subset of 110 individuals from TRACERx, a significant association between circulating GDF15 and loss of body weight, skeletal muscle and adipose tissue was identified at relapse, supporting the potential therapeutic relevance of targeting GDF15 in the management of CAC

Evolutionary characterization of lung adenocarcinoma morphology in TRACERx

Lung adenocarcinomas (LUADs) display a broad histological spectrum from low-grade lepidic tumors through to mid-grade acinar and papillary and high-grade solid, cribriform and micropapillary tumors. How morphology reflects tumor evolution and disease progression is poorly understood. Whole-exome sequencing data generated from 805 primary tumor regions and 121 paired metastatic samples across 248 LUADs from the TRACERx 421 cohort, together with RNA-sequencing data from 463 primary tumor regions, were integrated with detailed whole-tumor and regional histopathological analysis. Tumors with predominantly high-grade patterns showed increased chromosomal complexity, with higher burden of loss of heterozygosity and subclonal somatic copy number alterations. Individual regions in predominantly high-grade pattern tumors exhibited higher proliferation and lower clonal diversity, potentially reflecting large recent subclonal expansions. Co-occurrence of truncal loss of chromosomes 3p and 3q was enriched in predominantly low-/mid-grade tumors, while purely undifferentiated solid-pattern tumors had a higher frequency of truncal arm or focal 3q gains and SMARCA4 gene alterations compared with mixed-pattern tumors with a solid component, suggesting distinct evolutionary trajectories. Clonal evolution analysis revealed that tumors tend to evolve toward higher-grade patterns. The presence of micropapillary pattern and ‘tumor spread through air spaces’ were associated with intrathoracic recurrence, in contrast to the presence of solid/cribriform patterns, necrosis and preoperative circulating tumor DNA detection, which were associated with extra-thoracic recurrence. These data provide insights into the relationship between LUAD morphology, the underlying evolutionary genomic landscape, and clinical and anatomical relapse risk