Novel methylation biomarker panel for the early detection of pancreatic cancer.

PURPOSE: Pancreatic cancer is the fourth leading cause of cancer deaths and there currently is no reliable modality for the early detection of this disease. Here, we identify cancer-specific promoter DNA methylation of BNC1 and ADAMTS1 as a promising biomarker detection strategy meriting investigation in pancreatic cancer. EXPERIMENTAL DESIGN: We used a genome-wide pharmacologic transcriptome approach to identify novel cancer-specific DNA methylation alterations in pancreatic cancer cell lines. Of eight promising genes, we focused our studies on BNC1 and ADAMTS1 for further downstream analysis, including methylation and expression. We used a nanoparticle-enabled methylation on beads (MOB) technology to detect early-stage pancreatic cancers by analyzing DNA methylation in patient serum. RESULTS: We identified two novel genes, BNC1 (92%) and ADAMTS1 (68%), that showed a high frequency of methylation in pancreatic cancers (n = 143), up to 100% in PanIN-3 and 97% in stage I invasive cancers. Using the nanoparticle-enabled MOB technology, these alterations could be detected in serum samples (n = 42) from patients with pancreatic cancer, with a sensitivity for BNC1 of 79% [95% confidence interval (CI), 66%-91%] and for ADAMTS1 of 48% (95% CI, 33%-63%), whereas specificity was 89% for BNC1 (95% CI, 76%-100%) and 92% for ADAMTS1 (95% CI, 82%-100%). Overall sensitivity using both markers is 81% (95% CI, 69%-93%) and specificity is 85% (95% CI, 71%-99%). CONCLUSIONS: Promoter DNA methylation of BNC1 and ADAMTS1 is a potential biomarker to detect early-stage pancreatic cancers. Assaying the promoter methylation status of these genes in circulating DNA from serum is a promising strategy for early detection of pancreatic cancer and has the potential to improve mortality from this disease.

Is laparoscopy a risk factor for bile duct injury during cholecystectomy?

BACKGROUND AND OBJECTIVES: Previously, risk factors for bile duct injury have been identified as acute cholecystitis, male gender, older age, aberrant biliary anatomy, and laparoscopic cholecystectomy. METHODS: A retrospective analysis of the Nationwide Inpatient Sample from 1998 to 2006 was performed with an inclusion criterion of cholecystectomy performed on hospital day 0 or 1. Patient- and hospital-level factors potentially associated with bile duct injury were examined by logistic regression. RESULTS: A total of 377,424 cholecystectomy patients were identified. There were 1124 bile duct injuries (0.30%), with 177 (0.06%) in the laparoscopic cholecystectomy group and 947 (1.46%) in the open cholecystectomy group (P < .001). On multivariate analysis, significant risk factors for bile duct injury were male gender (odds ratio [OR], 1.21; 95% confidence interval [CI], 1.06-1.38; P = .006), age >60 years (OR, 2.23; 95% CI, 1.61-3.09; P < .001), and academic hospital status (OR, 1.37; 95% CI, 1.05-1.79; P = .02). Acute cholecystitis was associated with a lower risk of bile duct injury (OR, 0.67; 95% CI, 0.46-0.99; P = .044). CONCLUSION: Independent risk factors for bile duct injury included male gender, age >60 years, and academic hospital status. Laparoscopic cholecystectomy, obesity, insurance status, or hospital volume was not associated with an increased risk of bile duct injury.

Open versus laparoscopic hiatal hernia repair.

BACKGROUND: The literature reports the efficacy of the laparoscopic approach to paraesophageal hiatal hernia repair. However, its adoption as the preferred surgical approach and the risks associated with paraesophageal hiatal hernia repair have not been reviewed in a large database. METHOD: The Nationwide Inpatient Sample dataset was queried from 1998 to 2005 for patients who underwent repair of a complicated (the entire stomach moves into the chest cavity) versus uncomplicated (only the upper part of the stomach protrudes into the chest) paraesophageal hiatal hernia via the laparoscopic, open abdominal, or open thoracic approach. A multivariate analysis was performed controlling for demographics and comorbidities while looking for independent risk factors for mortality. RESULTS: In total, 23,514 patients met the inclusion criteria. By surgical approach, 55% of patients underwent open abdominal, 35% laparoscopic, and 10% open thoracic repairs. Length of stay was significantly reduced for all patients after laparoscopic repair (P < .001). Age ≥60 years and nonwhite ethnicity were associated with significantly higher odds of death. Laparoscopic repair and obesity were associated with lower odds of death in the uncomplicated group. CONCLUSION: Laparoscopic repair of paraesophageal hiatal hernia is associated with a lower mortality in the uncomplicated group. However, older age and Hispanic ethnicity increased the odds of death.

Early-stage gallbladder cancer in the Surveillance, Epidemiology, and End Results database: effect of extended surgical resection.

HYPOTHESIS: Extended surgical resection (ESR) may improve survival in patients with early-stage primary gallbladder cancer. DESIGN: Retrospective analysis of findings in the Surveillance, Epidemiology, and End Results (SEER) database. SETTING: Academic research. PATIENTS: Individuals with potentially surgically curable gallbladder cancer (Tis, T1, or T2) who underwent a surgical procedure. MAIN OUTCOME MEASURES: Overall survival, number of lymph nodes (LNs) excised, and results of simple cholecystectomy vs ESR. RESULTS: We identified 3209 patients with early-stage gallbladder cancer (11.7% Tis, 30.1% T1, and 58.2% T2). On multivariate analysis, decreased survival was noted among patients older than 60 years (hazard ratio, 1.57; 95% confidence interval, 1.30-1.90), among patients with more advanced cancer (1.99; 1.46-2.70 for T1; 3.29; 2.45-4.43 for T2), and among patients with disease-positive LNs (1.65; 1.39-1.95 for regional; 2.58; 1.54-4.34 for distant) (P < .001 for all), while increased survival was observed among female patients (0.82; 0.70-0.96; P = .02) and among patients undergoing ESR (0.59; 0.45-0.78; P < .001). The survival advantage of ESR was seen only in patients with T2 lesions (0.49; 0.35-0.68; P < .001). Lymph node excision data were available for a subset of 2507 patients, of whom 68.2% had no LN excised, 28.2% had 1 to 4 LNs excised, and 3.6% had 5 or more LNs excised. On multivariate analysis, patients with 1 to 4 LNs excised had a survival benefit over those with no LN excised (HR, 0.55; 95% CI, 0.46-0.66; P < .001), and patients with 5 or more LNs excised had a survival benefit over patients with 1 to 4 LNs removed (0.63; 0.40-0.96; P = .03). Lymph node excision improved survival in patients with T2 lesions (0.42; 0.33-0.53; P < .001 for patients with 1-4 LNs excised). CONCLUSION: Extended surgical resection, LN excision, or both may improve survival in certain patients with incidentally discovered gallbladder cancer.

Treatment outcomes of injured children at adult level 1 trauma centers: are there benefits from added specialized care?

BACKGROUND: Accidental traumatic injury is the leading cause of morbidity and mortality in children. The authors hypothesized that no mortality difference should exist between children seen at ATC (adult trauma centers) versus ATC with added qualifications in pediatrics (ATC-AQ). METHODS: The National Trauma Data Bank, version 7.1, was analyzed for patients aged <18 years seen at level 1 trauma centers. Bivariate analysis compared patients by ATC versus ATC-AQ using demographic and injury characteristics. Multivariate analysis adjusting for injury and demographic factors was then performed. RESULTS: A total sample of 53,702 children was analyzed, with an overall mortality of 3.9%. The adjusted odds of mortality was 20% lower for children seen at ATC-AQ (odds ratio, .80; 95% confidence interval, .68-.94). Children aged 3 to 12 years, those with injury severity scores > 25, and those with Glasgow Coma Scale scores < 8 all had significant reductions in the odds of death at ATC-AQ. CONCLUSIONS: Improved overall survival is associated with pediatric trauma patients treated at ATC-AQ.

Genomic and epigenomic integration identifies a prognostic signature in colon cancer.

PURPOSE: The importance of genetic and epigenetic alterations maybe in their aggregate role in altering core pathways in tumorigenesis. EXPERIMENTAL DESIGN: Merging genome-wide genomic and epigenomic alterations, we identify key genes and pathways altered in colorectal cancers (CRC). DNA methylation analysis was tested for predicting survival in CRC patients using Cox proportional hazard model. RESULTS: We identified 29 low frequency-mutated genes that are also inactivated by epigenetic mechanisms in CRC. Pathway analysis showed the extracellular matrix (ECM) remodeling pathway is silenced in CRC. Six ECM pathway genes were tested for their prognostic potential in large CRC cohorts (n = 777). DNA methylation of IGFBP3 and EVL predicted for poor survival (IGFBP3: HR = 2.58, 95% CI: 1.37-4.87, P = 0.004; EVL: HR = 2.48, 95% CI: 1.07-5.74, P = 0.034) and simultaneous methylation of multiple genes predicted significantly worse survival (HR = 8.61, 95% CI: 2.16-34.36, P < 0.001 for methylation of IGFBP3, EVL, CD109, and FLNC). DNA methylation of IGFBP3 and EVL was validated as a prognostic marker in an independent contemporary-matched cohort (IGFBP3 HR = 2.06, 95% CI: 1.04-4.09, P = 0.038; EVL HR = 2.23, 95% CI: 1.00-5.0, P = 0.05) and EVL DNA methylation remained significant in a secondary historical validation cohort (HR = 1.41, 95% CI: 1.05-1.89, P = 0.022). Moreover, DNA methylation of selected ECM genes helps to stratify the high-risk stage 2 colon cancers patients who would benefit from adjuvant chemotherapy (HR: 5.85, 95% CI: 2.03-16.83, P = 0.001 for simultaneous methylation of IGFBP3, EVL, and CD109). CONCLUSIONS: CRC that have silenced genes in ECM pathway components show worse survival suggesting that our finding provides novel prognostic biomarkers for CRC and reflects the high importance of integrative analyses linking genetic and epigenetic abnormalities with pathway disruption in cancer.

The impact of insurance status on actuarial survival in hospitalized trauma patients: when do they die?

BACKGROUND: Previous work has suggested that insurance status, gender, and ethnicity all have an independent association with mortality after trauma. The purpose of this study is to investigate whether these factors exerted survival impact that could be observed throughout the hospital stay. METHODS: Using the National Trauma Data Bank (version 7.0), a Cox proportional hazards survival analysis was performed on young (19-30 years old) trauma patients to mitigate the impact of comorbid confounders. Variables included in the model were age, gender, ethnicity, Injury Severity Score, presence of shock at presentation, mechanism of injury, insurance status, year of admission, teaching status of the hospital, diagnosis of substance abuse or psychotic disorders, and complications after admission. Rate ratios (RRs) comparing the slopes of the adjusted survival curves were calculated using the Mantel-Cox method. RESULTS: A total of 192,488 young trauma patients were identified with complete data. Increased hazard of death was seen in patients who were uninsured (hazard ratio [HR]=1.69, 95% confidence interval [CI]=1.59-1.80, p<0.001), of a minority ethnicity (HR=1.08, 95% CI=1.01-1.15, p=0.025) or men (HR=1.14, 95% CI=1.04-1.23, p=0.004). RRs were significantly larger between insurance status (RR=1.75, 95% CI=1.58-1.94, p<0.001) than between race (RR=1.23, 95% CI=1.10-1.37, p<0.001) or between gender (RR=1.16, 95% CI=1.01-1.32, p=0.030). CONCLUSION: Risk of death on the first hospital day after injury differs by insurance status, and this disparity becomes more pronounced throughout the hospital stay. Further study is necessary to determine whether this is a result of additional unmeasured patient covariates with insurance status or a difference in provider behavior in response to patient insurance status.

Asian race/ethnicity as a risk factor for bile duct injury during cholecystectomy.

Iatrogenic bile duct injury (BDI) is an uncommon but serious complication of cholecystectomy, with identified risk factors of acute cholecystitis, male sex, older age, and aberrant biliary anatomy. The Nationwide Inpatient Sample (1998-2006) was queried for cholecystectomy performed on hospital day 0 or 1. Bile duct injury repair procedure codes were used as a surrogate for BDI. We identified 377,424 patients who underwent cholecystectomy, with 1124 BDIs (0.3%). On multivariate logistic regression analysis, Asian race/ethnicity was a significant risk factor for BDI (odds ratio [OR], 2.26; 95% confidence interval [CI], 1.59-3.23; P < .001). This persisted for laparoscopic (OR, 2.62; 95% CI, 1.28-5.39; P = .009) and open (2.21; 1.59-3.07; P < .001) cholecystectomies. No other race/ethnicity was identified as a risk factor for BDI. We report a new finding that Asian race/ethnicity is a significant risk factor for BDI in laparoscopic and open cholecystectomies.

The number of lymph nodes examined debate in colon cancer: how much is enough?

BACKGROUND: Much debate exists over the significance of the number of lymph nodes (LN) examined after colon resection. MATERIALS AND METHODS: The Surveillance, Epidemiology and End Results (SEER) database was queried for patients who presented with colonic adenocarcinoma. Multiple Cox proportional hazard regressions were run using successive LN cut-offs (6-26), first controlling for and then stratifying by T-stage. This was repeated in subsets of patients delineated by LN status. Additional variables controlled for in every regression were age, gender, ethnicity, marital status, number of positive LN, grade, metastases, and extent of surgery. After each regression, a Harrell's C statistic and an Akaike's information criterion (AIC) were performed to test the predictive capacity and fit of the model, respectively. RESULTS: 128,071 patients met selection criteria. The highest Harrell's C statistics among all patients were the cutoffs at 14 LN and 15 LN. Between those, the AIC shows that the cutoff at 15 LN fit the data more closely than the 14 LN cutoff. The models with the best predictive ability and best fit by T-stage were T1, 14 LN; T2, 10 LN; T3, 10 LN; T4, 12 LN. CONCLUSIONS: Using a population-based dataset, we show the optimal number of LN examined is dependent upon the patient's tumor stage. Across all T-stages, the highest optimal number of LN resected was 15. Since it is possible to estimate but not perfectly predict the stage of a patient's tumor preoperatively, we believe the recommendation should be based on the most conservative measure.

Surgical treatment for women with breast cancer: do randomized clinical trials represent current medical practices?

Randomized clinical trials have not shown survival differences between breast cancer patients who undergo breast-conserving surgery and those who undergo modified radical mastectomy (MRM). Recent studies however, have suggested that these randomized clinical trials findings may not be representative of the entire population or the nature of current patient care. A retrospective analysis of female invasive breast cancer patients who underwent surgery in the Surveillance, Epidemiology, and End Results database (1990-2003) was performed. Survival was compared amongst women who underwent partial mastectomy, partial mastectomy plus radiation (PMR), or MRM. Cox proportional hazards regressions were used to investigate the impact of method of treatment upon survival, after adjusting for patient and tumor characteristics. A total of 218,043 patients, mean age 62 years, were identified. MRM accounted for 51.5 per cent of the study population whereas PMR accounted for 34.9 per cent. On multivariate analyses, significant improvement was observed in patient survival associated with PMR when compared with MRM patients (hazard ratio = 0.71, 95% confidence interval = 0.67-0.74, P < 0.001). This population-based study suggests that there is a survival benefit for women undergoing PMR in the treatment of breast cancer.