Intratumor heterogeneity mediated through chromosome instability was associated with an increased risk of recurrence or death, a finding that supports the potential value of chromosome instability as a prognostic predictor. (Funded by Cancer Research UK and others; TRACERx ClinicalTrials.gov number, NCT01888601 .).

SummaryThe early detection of relapse following primary surgery for non-small cell lung cancer and the characterization of emerging subclones seeding metastatic sites might offer new therapeutic approaches to limit tumor recurrence. The potential to non-invasively track tumor evolutionary dynamics in ctDNA of early-stage lung cancer is not established. Here we conduct a tumour-specific phylogenetic approach to ctDNA profiling in the first 100 TRACERx (TRAcking non-small cell lung Cancer Evolution through therapy (Rx)) study participants, including one patient co-recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and perform tumor volume limit of detection analyses. Through blinded profiling of post-operative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients destined to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastases, providing a new approach for ctDNA driven therapeutic studies

SummaryImmune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens.Video Abstract

Zephyr EBV provides clinically meaningful benefits in lung function, exercise tolerance, dyspnea, and quality of life out to at least 12 months, with an acceptable safety profile in patients with little or no collateral ventilation in the target lobe. Clinical trial registered with www.clinicaltrials.gov (NCT 01796392).

Since 1984, we have used a circular patch to reconstruct the left ventricle ("endoventricular circular plasty") in order to maintain a more physiologic cavity. This technique has three theoretical advantages over standard linear closure of the left ventricle (LV). First, it allows exclusion of the septal akinetic segment of the LV. Secondly, circular reorganization of the remaining LV muscle avoids the restraint caused by the linear suture closure and achieves a more physiologic LV cavity. Thirdly, circular plasty using the patch allows a complete resection of aneurysmal segments including resection of extensive subendocardial scar tissue, when appropriate, without critically compromising the cavity size. The technique involves the following steps: --Resection of dyskinetic or akinetic LV free wall and thrombectomy when indicated. --A dacron patch lined with pericardium is secured at the junction of the endocardial muscle and scarred tissue, thereby excluding non contractile portions of the LV and septum. --Myocardial revascularization is performed as indicated with particular attention paid to revascularizing the proximal left anterior descending segment. The group of patients forming this study includes 130 cases of LV reconstruction since 1984. The three main indications for surgery were angina (40%), cardiac failure (35%), arrhythmias (10%). There have been 8 hospital deaths, 4 late mortalities related to recurrence of cardiac failure in this group.(ABSTRACT TRUNCATED AT 250 WORDS)