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

Efficacy and Mechanism Evaluation Programme, funded by the Medical Research Council (MRC) and managed by the National Institute for Health Research (NIHR) on behalf of the MRC-NIHR partnership.

Postpneumonectomy pulmonary oedema (PPO) develops in~5% of patients undergoing pneumonectomy or lobectomy, and has a high associated mortality (>50%). In its extreme form, PPO follows a clinical and histopathological course indistinguishable from acute respiratory distress syndrome.Perioperative fluid overload, impaired lymphatic drainage following node dissection and trauma caused by surgical manipulation have been implicated in the pathogenesis of PPO. However, PPO more probably represents the pulmonary manifestation of a panendothelial injury consequent upon inflammatory processes induced by the surgical procedure, which involves collapse and re-expansion of the operative lung to permit hilar dissection and pulmonary resection.High inspired oxygen concentrations are required to overcome the effects of shunt. Animal studies have shown that pulmonary ischaemia/reperfusion can result in oedema formation, possibly due to the generation of pro-oxidant forces. Moreover, plasma taken from patients undergoing lobectomy or pneumonectomy (but not lesser resections) shows evidence of oxidative damage.Such evidence suggests either that the high inspired oxygen concentrations associated with one-lung ventilation, or ischaemia/reperfusion injury, may modulate postpneumonectomy pulmonary oedema. Mechanisms by which redox imbalance may result in tissue damage and postpneumonectomy pulmonary oedema are discussed. Eur Respir J 2000; 15: 790±799.

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Lung volume reduction surgery (LVRS) for chronic obstructive pulmonary disease (COPD) is recommended in both British and international guidelines because trials have shown improvement in survival in selected patients with poor baseline exercise capacity and upper lobe-predominant emphysema. Despite this, few procedures are carried out, possibly because of historical concerns about high levels of morbidity and mortality associated with the operation. The authors reviewed data on lung volume reduction procedures at their institution between January 2000 and September 2012. There were no deaths within 90 days of unilateral LVRS (n=81), bullectomy (n=20) or intracavity drainage procedures (n=14). These data suggest that concerns about surgical mortality should not discourage LVRS in selected patients with COPD, provided that it is undertaken within a multidisciplinary team environment involving appropriate patient selection.

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Although lung volume reduction surgery improves survival in selected patients with emphysema, there has been ongoing interest in developing and evaluating bronchoscopic approaches to try to reduce lung volumes with less morbidity and mortality. The placement of endobronchial valves is one such technique, and although some patients have had a significant improvement, responses have been inconsistent because collateral ventilation prevents lobar atelectasis. We describe the protocol of a trial (ISRCTN04761234) aimed to show that a responder phenotype, patients with heterogeneous emphysema and intact interlobar fissures on CT scanning, can be identified prospectively, leading to a consistent benefit in clinical practice.

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