Abstract The role of adjuvant chemotherapy in patients with stage IB non–small-cell lung cancer (NSCLC) is controversial. Identifying patient subgroups with the greatest risk of relapse and, consequently, most likely to benefit from adjuvant treatment thus remains an important clinical challenge. Here, we hypothesized that recurrent patterns of genomic amplifications and deletions in lung tumors could be integrated with gene expression information to establish a robust predictor of clinical outcome in stage IB NSCLC. Using high-resolution microarrays, we generated tandem DNA copy number and gene expression profiles for 85 stage IB lung adenocarcinomas/large cell carcinomas. We identified specific copy number alterations linked to relapse-free survival and selected genes within these regions exhibiting copy number–driven expression to construct a novel integrated signature (IS) capable of predicting clinical outcome in this series (P = 0.02). Importantly, the IS also significantly predicted clinical outcome in two other independent stage I NSCLC cohorts (P = 0.003 and P = 0.025), showing its robustness. In contrast, a more conventional molecular predictor based solely on gene expression, while capable of predicting outcome in the initial series, failed to significantly predict outcome in the two independent data sets. Our results suggest that recurrent copy number alterations, when combined with gene expression information, can be successfully used to create robust predictors of clinical outcome in early-stage NSCLC. The utility of the IS in identifying early-stage NSCLC patients as candidates for adjuvant treatment should be further evaluated in a clinical trial. [Cancer Res 2009;69(3):1055–62]
Abstract Objective The objective of this study was to ascertain whether wearable technology coupled with action planning was effective in increasing physical activity (PA) in colorectal and endometrial cancer survivors at cardiovascular risk. Methods Sixty‐eight survivors who had cardiovascular risk factors and were insufficiently active were randomized to intervention and control arms. Intervention participants were given a wearable tracker for 12 weeks, two group sessions, and a support phone call. Participants in the control arm received print materials describing PA guidelines. Assessments at baseline and 12 weeks measured triaxial and uniaxial estimates of moderate‐vigorous physical activity (MVPA), sedentary behaviour, blood pressure, and body mass index (BMI). Results The intervention group significantly increased MVPA by 45 min/wk compared with a reduction of 21 min/wk in the control group. Group by time interactions were significant for minutes of MVPA ( F 1,126 = 5.14, P = 0.025). For those with diastolic hypertension, there was a significant group by time interaction ( F 1,66 = 4.89, P = 0.031) with a net reduction of 9.89 mm Hg in the intervention group. Conclusions Significant improvements in MVPA were observed following the intervention. The results display promise for the use of pragmatic, low‐intensity interventions using wearable technology.
4203 Aneuploidy is common in gastric cancer while little is known of structurally rearranged chromosomes that may drive carcinogenesis. Pan-genomic copy number profiles of gastric cancer currently lack utility. We studied (a) copy number aberrations as genomic classifiers and prognostic markers; (b) highly expressed genes of gastric cancer amplicons; and (c) gene expression changes in recurrent translocation breakpoint loci. Analysis of 203 primary gastric adenocarcinomas (Progenetix CGH database, July 2004) using a neural network (Self Organising Tree Algorithm, EBI) segregated 2 genomic subclasses of 89 and 114 tumors. Supervised class prediction (GeneCluster 2.0) was performed on training (203 gastric cancers) and test (44 gastric cancers and 18 human gastric cancer cell lines) datasets. Models were built from the training set using a S2N similarity metric, median values for class estimate and 10 4 random permutations. Genomic classifiers (17q and 20q) were evaluated on the test set by weighted voting and leave-one-out cross-validation with 73% accuracy (45/62 correctly assigned). Genomic subclasses correlated significantly with clinical stage (p=0.011, Fisher’s exact test). The cell lines were almost equally distributed between the genomic subclasses, indicating that they were true biological representations of primary gastric cancers. 16p copy number gains were more prevalent in stage 3 and 4 gastric cancers (p=0.047, Fisher’s test) than in stages 1 and 2. 16p gains were associated with shorter survival (p=0.01, log rank rest). Overexpression of a 16p gene, SLC9A3R2, in 56% of gastric cancers was however associated with longer survival (p=0.038, log rank test). Forty-eight recurrent translocation breakpoints e.g. 2p22 and 8q22, were identified from parallel CGH and spectral karyotyping of 18 gastric cancer cell lines (AGS, NCIN87, Hs746T, Kato III, SNU1, SNU5, SNU16, IM95, MKN7, FU97, YCC-1, YCC-2, YCC-3, YCC-6, YCC-9, YCC-10, YCC-11 and YCC-16). Copy number gains among 247 primary gastric cancers were more frequent in recurrent breakpoint regions than in cytobands unaffected by translocations (p≤0.001, Mann-Whitney test). We ascertained the expression status of breakpoint genes in 55 primary gastric cancers. Eighty-two breakpoint genes were overexpressed (> 2-fold) in 20-96% of gastric cancers, while 83 were underexpressed (
Abstract Background Within the tumor microenvironment (TME), the association of B lymphocytes (B cells) with prognosis and therapy response in gastric cancer (GC) remains poorly characterized. We investigated the predictive and prognostic value of B cells, including their spatial organization within the TME, in one of the largest multi-cohort studies to date. Methods Using CD20 immunohistochemistry, we evaluated B cell density in resection specimens from 977 patients with resectable GC across three cohorts, including the randomized phase III Korean CLASSIC trial. The relationship between CD20 density, clinicopathological characteristics, and overall survival (OS) was analyzed. Digital spatial profiling of 1063 regions of interest from 15 patients was performed to characterize B cell distribution within different regions of interest (ROIs) using the NanoString GeoMx platform. Results CD20 density was significantly higher in diffuse-type GC compared to intestinal-type ( p = 0.000012). Patients with CD20-low diffuse-type GC had the shortest OS in the CLASSIC trial (median OS: 49 vs 62 months, HR: 1.9, 95% CI: 1.2–3.0, p = 0.003) and in a Japanese cohort (median OS: 49 vs 67 months, HR: 2.2, 95% CI: 1.2–4.0, p = 0.011). This survival difference was not seen in patients treated with adjuvant chemotherapy (median OS: 62 vs 63 months, HR: 1.8, 95% CI: 0.88–3.5, p = 0.108). Spatial profiling revealed significant B cell enrichment within tumor ROIs compared to the stroma, particularly in diffuse-type GC. Conclusions Low CD20 positivity, especially in diffuse-type GC, is linked to poor prognosis and may identify patients who could benefit from chemotherapy. These findings underscore the role of B cells in GC.
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