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Adam Bass, Gad Getz, Scott Carter and colleagues report the whole-exome sequences of 25 pairs of esophageal adenocarcinoma and Barrett's esophagus. They identify two pathways by which Barrett's esophagus can develop into esophageal adenocarcinoma. Barrett's esophagus is thought to progress to esophageal adenocarcinoma (EAC) through a stepwise progression with loss of CDKN2A followed by TP53 inactivation and aneuploidy. Here we present whole-exome sequencing from 25 pairs of EAC and Barrett's esophagus and from 5 patients whose Barrett's esophagus and tumor were extensively sampled. Our analysis showed that oncogene amplification typically occurred as a late event and that TP53 mutations often occurred early in Barrett's esophagus progression, including in non-dysplastic epithelium. Reanalysis of additional EAC exome data showed that the majority (62.5%) of EACs emerged following genome doubling and that tumors with genomic doubling had different patterns of genomic alterations, with more frequent oncogenic amplification and less frequent inactivation of tumor suppressors, including CDKN2A . These data suggest that many EACs emerge not through the gradual accumulation of tumor-suppressor alterations but rather through a more direct path whereby a TP53 -mutant cell undergoes genome doubling, followed by the acquisition of oncogenic amplifications.

The aim of this study was to identify differentially-expressed miRNAs in the serum of non-small cell lung cancer (NSCLC) patients that might be a clinically-useful tool for lung cancer early detection. We performed miRNA expression profile analysis using TaqMan OpenArray Human panel in a discovery set of 70 serum samples obtained at lung tumor resection and 22 non-cancer subjects (NC). Selected serum miRNAs were then validated by quantitative PCR using an independent validation set of serum samples from LC patients (n = 84) and NC (n = 23). Sixty miRNAs were significantly up-regulated and 31 were down-regulated in the serum from NSCLC patients versus NC (adjusted p  < 0.001). Four miRNAs (miR-193b, miR-301, miR-141 and miR-200b) were selected for validating their diagnostic value in an independent cohort. In the discovery set, the ROC plot derived from the combination of these miRNAs yielded an area under the curve (AUC) of 0.985 (95% CI 0.961–1.000, p  < 0.001). In the test set, this miRNA signature exhibited an AUC of 0.993 (95% CI 0.979–1.000, p  < 0.001). In conclusion, we identified a serum 4-miRNA signature that discriminated with high accuracy lung cancer patients from NC. Further prospective validation of this miRNA signature is warranted.

Lung cancer is emerging as a paradigm for disease molecular subtyping, facilitating targeted therapy based on driving somatic alterations. Here we perform transcriptome analysis of 153 samples representing lung adenocarcinomas, squamous cell carcinomas, large cell lung cancer, adenoid cystic carcinomas and cell lines. By integrating our data with The Cancer Genome Atlas and published sources, we analyse 753 lung cancer samples for gene fusions and other transcriptomic alterations. We show that higher numbers of gene fusions is an independent prognostic factor for poor survival in lung cancer. Our analysis confirms the recently reported CD74-NRG1 fusion and suggests that NRG1 , NF1 and Hippo pathway fusions may play important roles in tumours without known driver mutations. In addition, we observe exon-skipping events in c-MET, which are attributable to splice site mutations. These classes of genetic aberrations may play a significant role in the genesis of lung cancers lacking known driver mutations. Targeted cancer therapy requires knowledge of driver aberrations. Here the authors perform large-scale transcriptome analysis, and show that gene fusions in NRG1 , NF1 and Hippo pathway genes are recurrent mostly among lung cancers lacking known driver mutations.

After lung transplantation, spirometric values are routinely followed to assess graft function. FEV1 is used to characterize chronic allograft dysfunction, whereas the course of FVC change has been less acknowledged and rarely used. To better understand the temporal relationship and prognostic ability of FEV1 and FVC decline after lung transplantation. Serial FEV1 and FVC values were studied among 205 bilateral lung transplant recipients. Different decline patterns were characterized and evaluated for prognostic value via restricted mean modeling of mortality and times to other pertinent events. Baseline FEV1 was achieved earlier than baseline FVC (median, 296 vs. 378 d; P < 0.0001). Decline in FEV1 or FVC from their respective post-transplant baselines occurred in 85 patients (41%). Fifty-nine of 85 (69%) had an isolated FEV1 decline, with 80% later meeting the FVC decline criterion. This subsequent FVC decline was associated with worsening FEV1 and lower median survival. Twenty-five of 85 patients (29%) demonstrated concurrent FEV1 and FVC decline. Patients with concurrent decline had higher 1- and 5-year mortality rates (1-yr, 53% vs. 18%, P < 0.0001; 5-yr, 61% vs. 48%, P = 0.001). These patients were more likely to have rapid-onset of spirometry decline (P = 0.05) and lower FEV1% predicted (P = 0.04) at presentation. FVC decline from its post-transplant baseline provides valuable prognostic information. Concurrent FEV1 and FVC decline identifies patients with fulminant, rapid deterioration and is the strongest clinical predictor of poor survival. Subsequent FVC decline in patients with an initial isolated FEV1 decline identifies disease progression and portends poor prognosis.

Gene amplification is a tumor-specific event during malignant transformation. Recent studies have proposed a lineage-dependency (addiction) model of human cancer whereby amplification of certain lineage transcription factors predisposes a survival mechanism in tumor cells. These tumor cells are derived from tissues where the lineage factors play essential developmental and maintenance roles. Here, we show that recurrent amplification at 18q11.2 occurs in 21% of esophageal adenocarcinomas (EAC). Utilization of an integrative genomic strategy reveals a single gene, the embryonic endoderm transcription factor GATA6, as the selected target of the amplification. Overexpression of GATA6 is found in EACs that contain gene amplification. We find that EAC patients whose tumors carry GATA6 amplification have a poorer survival. We show that ectopic expression of GATA6, together with FGFR2 isoform IIIb, increases anchorage-independent growth in immortalized Barrett's esophageal cells. Conversely, siRNA-mediated silencing of GATA6 significantly reduces both cell proliferation and anchorage-independent growth in EAC cells. We further demonstrate that induction of apoptotic/anoikis pathways is triggered upon silencing of GATA6 in EAC cells but not in esophageal squamous cells. We show that activation of p38α signaling and up-regulation of TNF-related apoptosis-inducing ligand are detected in apoptotic EAC cells upon GATA6 deprivation. We conclude that selective gene amplification of GATA6 during EAC development sustains oncogenic lineage-survival of esophageal adenocarcinoma.

We employed RNA sequencing analysis to reveal dysregulated lncRNAs in lung cancer utilizing 461 lung adenocarcinomas and 156 normal lung tissues from 3 separate cohorts. We found that LINC00152 was highly overexpressed in lung tumors as compared to their adjacent normal tissues. Patients with high LINC00152 expression demonstrate a significantly poorer survival than those with low expression. We verified the diagnostic/prognostic potential of LINC00152 expression in an independent cohort of lung tumor tissues using quantitative RT-PCR. After knockdown of LINC00152 using siRNAs in lung cancer cell lines, both cell proliferation and colony formation were decreased. Cell fractionation and qRT-PCR analysis indicated that LINC00152 is found mainly in the cytoplasm. Treatment with Trichostatin A in cell lines having low LINC00152 expression indicated that histone acetylation may be one mechanism underlying LINC00152 overexpression in NSCLC. Western blot analyses indicated that p38a, STAT1, STAT3, CREB1, CCNE1 and c-MYC proteins were decreased after LINC00152 siRNA treatment. Our study indicates LINC00152 plays an important role in lung tumor growth and is potentially a diagnostic/prognostic marker. Further characterization of LINC00152 in regulating its target proteins may provide a novel therapeutic target of lung cancer.

18F-fluorodeoxyglucose positron emission tomography (FDG-PET) is critical for staging non-small-cell lung cancer (NSCLC). While PET intensity carries prognostic significance, the genetic abnormalities associated with increased intensity remain unspecified. NSCLC samples (N = 34) from 1999 to 2011 for which PET data were available were identified from a prospectively collected tumor bank. PET intensity was classified as mild, moderate, or intense based on SUVmax measurement or radiology report. Associations between genome-wide expression (RNAseq) and PET intensity were determined. Associations with overall survival were then validated in two external NSCLC cohorts. Overall survival was significantly worse in patients with PET-intense (N = 11) versus mild (N = 10) tumors (p = 0.039). Glycolytic gene expression patterns were markedly similar between intense and mild tumors. Gene ontology analysis demonstrated significant enhancement of cell-cycle and proliferative processes in FDG-intense tumors (p<0.001). Gene set enrichment analysis (GSEA) suggested associations between PET-intensity and canonical oncogenic signaling pathways including MYC, NF-κB, and HIF-1. Using an external cohort of 25 tumors with PET and genomic profiling data, common genes and gene sets were validated for additional study (P<0.05). Of these common gene sets, 20% were associated with hypoxia or HIF-1 signaling. While HIF-1 expression did not correlate with poor survival in the NSCLC validation cohort (N = 442), established targets of hypoxia signaling (PLAUR, ADM, CA9) were significantly associated with poor overall survival. PET-intensity is associated with a variety of oncogenic alterations in operable NSCLC. Adjuvant targeting of these pathways may improve survival among patients with PET-intense tumors.

Esophageal adenocarcinoma (EAC) develops from Barrett's esophagus (BE), a chronic inflammatory state that can progress through a series of transformative dysplastic states before tumor development. While molecular and genetic changes of EAC tumors have been studied, immune microenvironment changes during Barrett's progression to EAC remain poorly understood. In this study, we identify potential immunologic changes that can occur during BE-to-EAC progression. RNA sequencing (RNA-Seq) analysis on tissue samples from EAC patients undergoing surgical resection demonstrated that a subset of chemokines and cytokines, most notably IL6 and CXCL8, increased during BE progression to EAC. xCell deconvolution analysis investigating immune cell population changes demonstrated that the largest changes in expression during BE progression occurred in M2 macrophages, pro-B cells, and eosinophils. Multiplex immunohistochemical staining of tissue microarrays showed increased immune cell populations during Barrett's progression to high-grade dysplasia. In contrast, EAC tumor sections were relatively immune poor, with a rise in PD-L1 expression and loss of CD8+ T cells. These data demonstrate that the EAC microenvironment is characterized by poor cytotoxic effector cell infiltration and increased immune inhibitory signaling. These findings suggest an immunosuppressive microenvironment, highlighting the need for further studies to explore immune modulatory therapy in EAC.

An operative anatomy course was developed within the construct of a surgical internship preparatory curriculum. This course provided fourth-year medical students matching into a surgical residency the opportunity to perform intern-level procedures on cadavers under the guidance of surgical faculty members. Senior medical students performed intern-level procedures on cadavers with the assistance of faculty surgeons. Students' confidence, anxiety, and procedural knowledge were evaluated both preoperatively and postoperatively. Preoperative and postoperative data were compared both collectively and based on individual procedures. Student confidence and procedural knowledge significantly increased and anxiety significantly decreased when preoperative and postoperative data were compared (P < .05). Students reported moderate to significant improvement in their ability to perform a variety of surgical tasks. The consistent improvement in confidence, knowledge, and anxiety justifies further development of an operative anatomy course, with future assessment of the impact on performance in surgical residency.

The spread of cancer throughout the body is driven by circulating tumour cells (CTCs) 1 . These cells detach from the primary tumour and move from the bloodstream to a new site of subsequent tumour growth. They also carry information about the primary tumour and have the potential to be valuable biomarkers for disease diagnosis and progression, and for the molecular characterization of certain biological properties of the tumour. However, the limited sensitivity and specificity of current methods for measuring and studying these cells in patient blood samples prevents the realization of their full clinical potential. The use of microfluidic devices is a promising method for isolating CTCs 2 , 3 . However, the devices are reliant on three-dimensional structures, which limits further characterization and expansion of cells on the chip. Here we demonstrate an effective approach to isolating CTCs from blood samples of pancreatic, breast and lung cancer patients, by using functionalized graphene oxide nanosheets on a patterned gold surface. CTCs were captured with high sensitivity at a low concentration of target cells (73 ± 32.4% at 3–5 cells per ml blood). Circulating tumour cells from patients with early-stage cancers have now been captured and characterized by using functionalized graphene oxide nanosheets.