Citations

Abstract Purpose: We examined the frequency, tumor characteristics, and prognostic impact of HER2 protein expression and gene amplification in patients with curatively resected esophageal adenocarcinoma (EAC). Experimental Design: HER2 expression was analyzed by immunohistochemistry (IHC) in surgical EAC specimens (n = 713). Gene amplification was examined by FISH in a large subset (n = 344). Most tumors were T3–4 (66%) or node positive (72%); 95% were located in the esophagus or gastroesophageal junction. No patient received neoadjuvant therapy. Cox models were used. Results: Overall, 17% of EACs were HER2 positive (i.e., IHC3+ or IHC2+ with amplification), with strong agreement between HER2 amplification (HER2/CEP17 ratio ≥2) and expression (κ = 0.83). HER2 positivity was significantly associated with lower tumor grade, less invasiveness, fewer malignant nodes, and the presence of adjacent Barrett's esophagus (BE). EACs with BE had higher odds of HER2 positivity than EACs without BE, independent of pathologic features [OR = 1.8 (95% CI: 1.1–2.8), P = 0.014]. Among all cases, HER2 positivity was significantly associated with disease-specific survival (DSS) in a manner that differed by the presence or absence of BE (Pinteraction = 0.0047). In EACs with BE, HER2 positivity was significantly associated with improved DSS [HR = 0.54 (95% CI: 0.35–0.84), P = 0.0065] and overall survival (P = 0.0022) independent of pathologic features, but was not prognostic among EACs without BE. Conclusions: HER2 positivity was shown in 17% of resected EACs and associated with reduced tumor aggressiveness. EACs with BE had nearly twice the odds of being HER2 positive and, within this subgroup, HER2 positivity was independently associated with improved survival. Clin Cancer Res; 18(2); 546–54. ©2012 AACR.

Purpose Symptoms and complications of metastatic colorectal cancer (mCRC) differ by metastatic sites. There is a paucity of prospective survival data for patients with peritoneal carcinomatosis colorectal cancer (pcCRC). We characterized outcomes of patients with pcCRC enrolled onto two prospective randomized trials of chemotherapy and contrasted that with other manifestations of mCRC (non-pcCRC). Methods A total of 2,095 patients enrolled onto two prospective randomized trials were evaluated for overall survival (OS) and progression-free survival (PFS). A Cox proportional hazard model was used to assess the adjusted associations. Results The characteristics of the pcCRC group (n = 364) were similar to those of the non-pcCRC patients in median age (63 v 61 years, P = .23), sex (57% males v 61%, P = .23), and performance status (Eastern Cooperative Oncology Group performance status 0 or 1 94% v 96%, P = .06), but differed in frequency of liver (63% v 82%, P < .001) and lung metastases (27% v 34%, P = .01). Median OS (12.7 v 17.6 months, hazard ratio [HR] = 1.3; 95% CI, 1.2 to 1.5; P < .001) and PFS (5.8 v 7.2 months, HR = 1.2; 95% CI, 1.1 to 1.3; P = .001) were shorter for pcCRC versus non-pcCRC. The unfavorable prognostic influence of pcCRC remained after adjusting for age, PS, liver metastases, and other factors (OS: HR = 1.3, P < .001; PFS: HR = 1.1, P = .02). Infusional fluorouracil, leucovorin, and oxaliplatin was superior to irinotecan, leucovorin, and fluorouracil as a first-line treatment among pcCRC (HR for OS = 0.62, P = .005) and non-pcCRC patients (HR = 0.66, P < .001). Conclusion pcCRC is associated with a significantly shorter OS and PFS as compared with other manifestations of mCRC. Future trials for mCRC should consider stratifying on the basis of pcCRC status.

A two‐stage model for evaluating both trial‐level and patient‐level surrogacy of correlated time‐to‐event endpoints has been introduced, using patient‐level data when multiple clinical trials are available. However, the associated maximum likelihood approach often suffers from numerical problems when different baseline hazards among trials and imperfect estimation of treatment effects are assumed. To address this issue, we propose performing the second‐stage, trial‐level evaluation of potential surrogates within a Bayesian framework, where we may naturally borrow information across trials while maintaining these realistic assumptions. Posterior distributions on surrogacy measures of interest may then be used to compare measures or make decisions regarding the candidacy of a specific endpoint. We perform a simulation study to investigate differences in estimation performance between traditional maximum likelihood and new Bayesian representations of common meta‐analytic surrogacy measures, while assessing sensitivity to data characteristics such as number of trials, trial size, and amount of censoring. Furthermore, we present both frequentist and Bayesian trial‐level surrogacy evaluations of time to recurrence for overall survival in two meta‐analyses of adjuvant therapy trials in colon cancer. With these results, we recommend Bayesian evaluation as an attractive and numerically stable alternative in the multitrial assessment of potential surrogate endpoints. Copyright © 2011 John Wiley & Sons, Ltd.

Purpose Given that smoking affects body mass index (BMI) and survival, stratification by smoking status may be required to determine the true prognostic impact of BMI. Although obesity increases risk for developing esophageal adenocarcinoma (EAC), the prognostic influence of obesity and its potential modification by smoking status is unknown in this disease. Patients and Methods All patients (N = 778) underwent potentially curative esophagectomy. BMI was calculated using measured height and weight at surgery and categorized as obese (≥ 30 kg/m 2 ), overweight (25 to 29.9 kg/m 2 ), or normal (18.5 to 24.9 kg/m 2 ). Cigarette smoking was categorized as never or ever. The association of BMI with disease-specific survival (DSS), disease-free survival (DFS), and overall survival (OS) was determined by Cox regression. Results Excess BMI was significantly associated with DSS in a manner that differed substantially by smoking status (P for interaction = .023). Among never smokers, obesity was significantly associated with adverse DSS (hazard ratio [HR] = 2.11; 95% CI, 1.31 to 3.43; P = .002), DFS (HR = 2.03; 95% CI, 1.30 to 3.18; P = .002), and OS (HR = 1.97; 95% CI, 1.24 to 3.14; P = .004), as compared with normal weight, after adjusting for covariates. By contrast, among ever smokers, obesity was not prognostic, and overweight status was significantly associated with favorable survival in univariate, but not multivariate, analysis. Conclusion Obesity among never smokers was independently associated with two-fold worsening of DSS, DFS, and OS after surgery for EAC, after adjusting for known prognostic factors. These data, in one of the largest reported resected EAC cohorts, are the first to show an adverse prognostic impact of obesity in EAC.

PurposeProgression-free survival (PFS) is not an optimal end point to evaluate therapeutic strategies in advanced colorectal cancer (ACRC). Therefore, composite end points have been proposed to evaluate a chemotherapy strategy when sequential treatments are available: duration of disease control (DDC) and time to failure of strategy (TFS). The goal of this study was to evaluate these alternative end points and their potential surrogacy for overall survival (OS).MethodsWe pooled individual patient data from three randomized trials evaluating chemotherapy strategy, which accrued 1,042 patients with previously untreated ACRC. In these trials, first-line treatment was either oxaliplatin- or irinotecan-based chemotherapy. Compared with TFS, DDC included neither time interval between progression and next sequence of treatment nor time to progression if the best result of the next sequence of treatment was progression.ResultsThere was good correlation between DDC and OS (correlation of median: r, 0.62; correlation of hazard ratio [HR]: adjusted copula R2, 0.72) and between TFS and OS (correlation of median: r, 0.59; correlation of HR: adjusted copula R2, 0.67). There was no correlation between PFS and OS (correlation of median: r, 0.45; correlation of HR: adjusted copula R2, 0.47).ConclusionDDC and TFS roughly achieved the same results. Both are acceptable new end points to evaluate a therapeutic strategy in ACRC. Although TFS achieved a pragmatic evaluation of a multiline strategy, DDC captured the effect of a specific sequence in a therapeutic strategy.

Abstract The CXCR4 chemokine receptor is a G protein-coupled receptor that signals in T lymphocytes by forming a heterodimer with the TCR. CXCR4 and TCR functions are consequently highly cross regulated, affecting T cell immune activation, cytokine secretion, and T cell migration. The CXCR4-TCR heterodimer stimulates T cell migration and activation of the ERK MAPK and downstream AP-1–dependent cytokine transcription in response to stromal cell-derived factor-1 (SDF-1), the sole chemokine ligand of CXCR4. These responses require Gi-type G proteins as well as TCR ITAM domains and the ZAP70 tyrosine kinase, thus indicating that the CXCR4-TCR heterodimer signals to integrate G protein-coupled receptor-associated and TCR-associated signaling molecules in response to SDF-1. Yet, the phospholipase C (PLC) isozymes responsible for coupling the CXCR4-TCR heterodimer to distinct downstream cellular responses are incompletely characterized. In this study, we demonstrate that PLC activity is required for SDF-1 to induce ERK activation, migration, and CXCR4 endocytosis in human T cells. SDF-1 signaling via the CXCR4-TCR heterodimer uses PLC-β3 to activate the Ras-ERK pathway and increase intracellular calcium ion concentrations, whereas PLC-γ1 is dispensable for these outcomes. In contrast, PLC-γ1, but not PLC-β3, is required for SDF-1–mediated migration via a mechanism independent of LAT. These results increase understanding of the signaling mechanisms employed by the CXCR4-TCR heterodimer, characterize new roles for PLC-β3 and PLC-γ1 in T cells, and suggest that multiple PLCs may also be activated downstream of other chemokine receptors to distinctly regulate migration versus other signaling functions.

Although renal failure is one of the known comorbidities associated with rapid progression of aortic stenosis, it is unclear whether hemodialysis alters the progression of prosthetic aortic valve stenosis. We describe a 79-year-old female who underwent bioprosthetic aortic valve replacement 8 years ago with stable prosthetic valve area for the initial 6 years. In the last two years, coinciding with the initiation of maintenance hemodialysis, she developed progressive prosthetic valve stenosis to the point of clinical decompensation. She underwent a second prosthetic aortic valve replacement with symptom resolution. This case suggests that circulating milieu in end-stage renal failure and dialysis can accelerate the progression of prosthetic aortic valve stenosis. More frequent clinical followup and surveillance echocardiogram for dialysis patients with bioprosthetic aortic valve may facilitate timely management of valvular stenosis.

Background— Heart failure (HF) care constitutes an increasing economic burden on the health care system, and has become a key focus in the health care debate. However, there are limited data on the lifetime health care costs for individuals with HF after initial diagnosis. Methods and Results— Olmsted County residents with incident HF from 1987 to 2006 were identified. Direct medical costs incurred from the time of HF diagnosis until death or last follow-up were obtained using population-based administrative data through 2007. Costs were inflated to 2008 US dollars using the general Consumer Price Index. Inpatient, outpatient, and total costs were estimated using a 2-part model with adjustment for right censoring of data. Predictors of total costs were examined using a similar model. A total of 1054 incident HF patients were identified (mean age, 76.8 years; 46.1% men). After a mean follow-up of 4.6 years, 765 (72.6%) patients had died. The estimated total lifetime costs were $109 541 (95% confidence interval, $100 335 to 118 946) per person, with the majority accumulated during hospitalizations (mean, $83 980 per person). After adjustment for age, year of diagnosis, and comorbidity, diabetes mellitus and preserved ejection fraction (≥50%) were associated with 24.8% ( P =0.003) and 23.6% ( P =0.041) higher lifetime costs, respectively. Higher costs were observed at initial HF diagnosis and in the months immediately before death in those surviving >12 months after diagnosis. Conclusions— HF imposes a significant economic burden, primarily related to hospitalizations. Variations in cost over a lifetime can help identify strategies for efficient management of patients, particularly at the end of life.

Background Data collection and review were identified as major contributors to the cost of randomized clinical trials (RCTs). Purpose We proposed and assessed a novel alternative for long-term clinical trial follow-up based on the data captured through an accredited Cancer Registry (CR) that is part of the National Cancer Database (NCDB). Methods Patients from Mayo Clinic, Rochester, enrolled in the North Central Cancer Treatment Group N934653 (COST) trial (98 patients) and the American College of Surgeons Oncology Group Z0030 trial (55 patients) were included in the study. Demographic, treatment, and long-term outcome data were compared between the hospital-based CR and the RCTs’ databases. Concordances were used to estimate the agreement between two databases. Kaplan—Meier curves were plotted to examine the consistency of time-to-event long-term outcomes of the CR and RCT databases. Results High concordances (>95%) were observed for most demographic and treatment variables between the CR data and RCT data. The vital status concordances were 100% and 94.5% between the CR and COST and Z0030 databases, respectively. Three discrepant death dates were observed, one in the COST trial and two in the Z0030 trial. The concordances of disease-free status between the CR and RCT databases were 99.0% and 87.3%, and 15 discrepant disease recurrence cases were identified: 4 for COST and 11 for Z0030. Limitations The analysis has been focused on patients from a single site, Mayo Clinic, Rochester, enrolled in two large RCT evaluating surgical treatments. The findings herein need to be confirmed in a broader setting, such as multi-center, multi-registry including nonsurgical trials. Conclusions CR data were nearly identical to data from two randomized phase III trials in different disease types and conducted by two different cooperative groups. The NCDB Cancer Registries represent a feasible alternative for obtaining long-term follow-up data for large clinical trials. Clinical Trials 2010; 7: 686—695. http:// ctj.sagepub.com