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

SummaryCD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology.

• Magnetic resonance imaging is increasingly used to assess Crohn's disease. • MRI measurements can provide a quantitative assessment of small bowel motility. • MR enterography can grade Crohn's disease. • Small bowel motility can be used as a marker of inflammatory activity.

SummarySuperior mesenteric artery syndrome is a rare and controversial form of upper intestinal obstruction in which the third part of the duodenum is compressed by the overlying superior mesenteric artery. Any disease process decreasing the angle between the superior mesenteric artery and the abdominal aorta can result in the external compression of the duodenum and subsequent intestinal obstruction. The aetiology, presentation, investigation and management of this unusual condition are discussed.

Evaluation of small bowel motility from two-dimensional dynamic MRI is of increasing interest for the assessment of segmental diseases such as Crohn's disease. We propose to use nonrigid image registration for automated motility analysis. Registration is particularly difficult when localized intensity changes occur (e.g., due to intraluminal flow or throughplane motion). Therefore, displacements were extracted using a joint registration and modeling of intensity changes. Results were analyzed in 10 patients with known or suspected Crohn's disease. Bowel wall displacements were assessed by tracking bowel cross-sectional markers over time. Automated tracking with the proposed technique was in good agreement with manual tracking (similar bias, improved standard deviations). The ability to quantify different grades of bowel motility was investigated by comparing direct motion measures (i.e., changes in bowel cross-sectional diameter or area) and various parametric maps, e.g., based on the Jacobian of the measured displacements with expert grading. Among these measures, the standard deviation over time of the Jacobian was the best at predicting grades from 1 (moving normally) to 4 (not moving at all) in 50 bowel regions with normal and pathologically reduced motility, yielding 93% correct classification with a 1-class tolerance (i.e., same score as the expert 6 1). Magn Reson Med 68:783-793, 2012. V C 2012 Wiley Periodicals, Inc.

http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13130151/-/DC1.