Comparison of Endoscopic Ultrasonography and Multislice Spiral Computed Tomography for the Preoperative Staging of Gastric Cancer - Results of a Single Institution Study of 610 Chinese Patients

Background

This study compared the performance of endoscopic ultrasonography (EUS) and multislice spiral computed tomography (MSCT) in the preoperative staging of gastric cancer.

Methodology/Principal Findings

A total of 610 patients participated in this study, all of whom had undergone surgical resection, had confirmed gastric cancer and were evaluated with EUS and MSCT. Tumor staging was evaluated using the Tumor-Node-Metastasis (TNM) staging and Japanese classification. The results from the imaging modalities were compared with the postoperative histopathological outcomes. The overall accuracies of EUS and MSCT for the T staging category were 76.7% and 78.2% (P=0.537), respectively. Stratified analysis revealed that the accuracy of EUS for T1 and T2 staging was significantly higher than that of MSCT (P<0.001 for both) and that the accuracy of MSCT in T3 and T4 staging was significantly higher than that of EUS (P<0.001 and 0.037, respectively). The overall accuracy of MSCT was 67.2% when using the 13th edition Japanese classification, and this percentage was significantly higher than the accuracy of EUS (49.3%) and MSCT (44.6%) when using the 6th edition UICC classification (P<0.001 for both values).

Conclusions/Significance

Our results demonstrated that the overall accuracies of EUS and MSCT for preoperative staging were not significantly different. We suggest that a combination of EUS and MSCT is required for preoperative evaluation of TNM staging.     

The Association between Two MicroRNA Variants (miR-499, miR-149) and Gastrointestinal Cancer Risk: A Meta-Analysis

Background

MicroRNAs (miRNAs) are small RNA molecules that regulate the expression of corresponding messenger RNAs (mRNAs). Single nucleotide polymorphisms (SNPs) in miRNAs may contribute to cancer susceptibility due to changes in the microRNA’s properties and/or maturation. The present study aimed to investigate the association between two miRNA polymorphisms (miR-499 rs3746444 and miR-149 rs2292832) and gastrointestinal (GI) cancer risk.

Methodology/Principal Findings

We conducted a search of case-control studies in PubMed, Wiley Online Library, Web of Science and the CNKI database. Eleven rs3746444 studies and six rs2292832 studies were included in our meta-analysis. The only obvious association between the miR-499 polymorphism and colorectal cancer susceptibility was found in the homozygote comparison (GG vs. AA: OR = 1.66, 95% CI: 1.02–2.70, P _h = 0.10, P = 0.04). No significant association was found in the subgroup analysis for ethnicity and risk of hepatocellular and gastric cancer. A marginally elevated GI cancer risk was discovered in the recessive model for miR-149 (TT vs. TC+CC: OR = 1.15, 95% CI: 1.03–1.30, P _h = 0.68, P = 0.02). Stratifying the results by ethnicity revealed a slight association between the recessive model and the Asian population (TT vs. TC+CC: OR = 1.14, 95% CI: 1.01–1.29, P _h = 0.79, P = 0.03).

Conclusions/Significance

The present meta-analysis indicates that miR-499 may be associated with the risk to colorectal cancer. MiR-149 may confer a marginally increased risk of susceptibility to gastrointestinal cancer, especially for Asians.     

Interactions between Diet,Lifestyle and IL10, IL1B,and PTGS2/COX-2 Gene Polymorphisms in Relation to Risk of Colorectal Cancer in a Prospective Danish Case-Cohort Study

Background & Aims

Diet contributes to colorectal cancer development and may be potentially modified. We wanted to identify the biological mechanisms underlying colorectal carcinogenesis by assessment of diet-gene interactions.

Methods

The polymorphisms IL10 C-592A (rs1800872), C-rs3024505-T, IL1b C-3737T (rs4848306), G-1464C (rs1143623), T-31C (rs1143627) and PTGS2 (encoding COX-2) A-1195G (rs689466), G-765C (rs20417), and T8473C (rs5275) were assessed in relation to risk of colorectal cancer (CRC) and interaction with diet (red meat, fish, fibre, cereals, fruit and vegetables) and lifestyle (non-steroid-anti-inflammatory drug use and smoking status) was assessed in a nested case-cohort study of nine hundred and seventy CRC cases and 1789 randomly selected participants from a prospective study of 57,053 persons.

Results

IL1b C-3737T, G-1464C and PTGS2 T8473C variant genotypes were associated with risk of CRC compared to the homozygous wildtype genotype (IRR=0.81, 95%CI: 0.68-0.97, p=0.02, and IRR=1.22, 95%CI: 1.04-1.44, p=0.02, IRR=0.75, 95%CI: 0.57-0.99, p=0.04, respectively). Interactions were found between diet and IL10 rs3024505 (P-value for interaction (P_int); meat=0.04, fish=0.007, fibre=0.0008, vegetables=0.0005), C-592A (P_int; fibre=0.025), IL1b C-3737T (P_int; vegetables=0.030, NSAID use=0.040) and PTGS2 genotypes G-765C (P_int; meat=0.006, fibre=0.0003, fruit 0.004), and T8473C (P_int; meat 0.049, fruit=0.03) and A-1195G (P_int; meat 0.038, fibre 0.040, fruit=0.059, vegetables=0.025, and current smoking=0.046).

Conclusions

Genetically determined low COX-2 and high IL-1β activity were associated with increased risk of CRC in this northern Caucasian cohort. Furthermore, interactions were found between IL10, IL1b, and PTGS2 and diet and lifestyle factors in relation to CRC. The present study demonstrates that gene-environment interactions may identify genes and environmental factors involved in colorectal carcinogenesis.     

Detection of Synchronous Cancers by Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography during Primary Staging Workup for Esophageal Squamous Cell Carcinoma in Taiwan

Aim

The aim of this retrospective study was to investigate the ability of fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in the detection of synchronous cancers during staging workup for esophageal squamous cell carcinoma.

Materials and Methods

We performed a retrospective chart review of 426 Taiwanese patients with esophageal cancer who received FDG-PET/CT during their primary staging workup between December 2006 and December 2011. We defined synchronous cancers as those occurring within 6 months of the FDG-PET/CT scan. All of the synchronous lesions were confirmed by histology or imaging follow-up. The study patients were followed for at least 18 months or were censored on the date of last follow-up.

Results

Fifty patients were excluded from analysis because of the presence of distant metastases. Of the remaining 376 patients, 359 were diagnosed with squamous cell carcinoma (SCC). We identified 17 patients with synchronous cancers, and all of them had a diagnosis of SCC. Synchronous head and neck cancers were the most frequent (n=13, 76.4%), followed by gastrointestinal cancers (colon cancer, n=2; hepatocellular carcinoma, n=1), and renal cell carcinoma (n=1). FDG-PET/CT successfully detected 15 synchronous cancers (12 head and neck cancers, 2 colon cancers, and 1 renal cell carcinoma). In contrast, conventional workup detected only 9 synchronous cancers (7 head and neck cancers, 1 hepatocellular carcinoma and 1 renal cell carcinoma). The sensitivity of FDG-PET/CT and conventional workup in detecting synchronous cancers were 88.2% and 52.9% respectively.

Conclusion

The most frequent synchronous lesions in patients with esophageal SCC were head and neck cancers in Taiwan. Our data indicate that FDG-PET/CT is superior to conventional workup in the detection of synchronous tumors during primary staging for esophageal squamous cell carcinoma.     

HIF-1α 1772 C/T and 1790 G/A Polymorphisms Are Significantly Associated with Higher Cancer Risk: An Updated Meta-Analysis from 34 Case-Control Studies

Background

HIF-1 activates various genes in cancer progression and metastasis. HIF-1α 1772 C/T and 1790 G/A polymorphisms are reportedly associated with cancer risk; however, the results are inconclusive.

Methodology/Principal Findings

A meta-analysis of 34 studies that involved 7522 cases and 9847 controls for 1772 C/T and 24 studies that involved 4884 cases and 8154 controls for 1790 G/A was conducted to identify the association of C/T and G/A polymorphisms with cancer risk. Odds ratio (OR) and 95% confidence intervals (95% CI) were used to assess the strength of association.HIF-1α 1772 C/T and 1790 G/A polymorphisms were associated with higher cancer risk in homozygote comparison (1772C/T: TT vs. CC: OR = 2.45, 95% CI: 1.52, 3.96; P _{heterogeneity} = 0.028; 1790G/A: AA vs. GG: OR=4.74, 95% CI: 1.78, 12.6; P _{heterogeneity} < 0.01), dominant model (1772C/T: TT/CT vs. CC: OR = 1.27, 95% CI: 1.04, 1.55; P _{heterogeneity} < 0.01, 1790G/A: AA/GA vs. GG: OR = 1.65, 95% CI: 1.05, 2.60; P _{heterogeneity} < 0.01), T allele versus C allele (T vs. C: OR = 1.42, 95% CI: 1.18, 1.70; P _{heterogeneity} < 0.01), and A allele versus G allele (A vs. G: OR = 1.83, 95% CI: 1.13, 2.96; P _{heterogeneity} < 0.01). On a subgroup analysis, the 1772 C/T polymorphism was significantly linked to higher risks for breast cancer, lung cancer, prostate cancer, and cervical cancer, whereas the 1790 G/A polymorphism was significantly linked to higher risks for lung cancer and prostate cancer. A significantly increased cancer risk was found in both Asians and Caucasians for 1772C/T polymorphism, whereas a significantly increased cancer risk was found in Caucasians in the heterozygote comparison and recessive model for 1790G/A polymorphism.

Conclusions

HIF-1α 1772 C/T and 1790 G/A polymorphisms are significantly associated with higher cancer risk.     

Physical Activity and Sedentary Behavior in Relation to Esophageal and Gastric Cancers in the NIH-AARP Cohort

Introduction

Body mass index is known to be positively associated with an increased risk of adenocarcinomas of the esophagus, yet there is there limited evidence on whether physical activity or sedentary behavior affects risk of histology- and site-specific upper gastrointestinal cancers. We used the NIH-AARP Diet and Health Study to assess these exposures in relation to esophageal adenocarcinoma (EA), esophageal squamous cell carcinoma (ESCC), gastric cardia adenocarcinoma (GCA), and gastric non-cardia adenocarcinoma (GNCA).

Methods

Self-administered questionnaires were used to elicit physical activity and sedentary behavior exposures at various age periods. Cohort members were followed via linkage to the US Postal Service National Change of Address database, the Social Security Administration Death Master File, and the National Death Index. Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95 percent confidence intervals (95%CI)

Results

During 4.8 million person years, there were a total of 215 incident ESCCs, 631 EAs, 453 GCAs, and 501 GNCAs for analysis. Strenuous physical activity in the last 12 months (HR_{>5 times/week vs. never}=0.58, 95%CI: 0.39, 0.88) and typical physical activity and sports during ages 15–18 years (p for trend=0.01) were each inversely associated with GNCA risk. Increased sedentary behavior was inversely associated with EA (HR_{5–6 hrs/day vs. <1 hr}=0.57, 95%CI: 0.36, 0.92). There was no evidence that BMI was a confounder or effect modifier of any relationship. After adjustment for multiple testing, none of these results were deemed to be statistically significant at p<0.05.

Conclusions

We find evidence for an inverse association between physical activity and GNCA risk. Associations between body mass index and adenocarcinomas of the esophagus do not appear to be related to physical activity and sedentary behavior.     

Common Variants Related to Serum Uric Acid Concentrations Are Associated with Glucose Metabolism and Insulin Secretion in a Chinese Population

Background

Elevated serum uric acid concentration is an independent risk factor and predictor of type 2 diabetes (T2D). Whether the uric acid-associated genes have an impact on T2D remains unclear. We aimed to investigate the effects of the uric acid-associated genes on the risk of T2D as well as glucose metabolism and insulin secretion.

Method

We recruited 2,199 normal glucose tolerance subjects from the Shanghai Diabetes Study I and II and 2,999 T2D patients from the inpatient database of Shanghai Diabetes Institute. Fifteen single nucleotide polymorphisms (SNPs) mapped in or near 11 loci (PDZK1, GCKR, LRP2, SLC2A9, ABCG2, LRRC16A, SLC17A1, SLC17A3, SLC22A11, SLC22A12 and SF1) were genotyped and serum biochemical parameters related to uric acid and T2D were determined.

Results

SF1 rs606458 showed strong association to T2D in both males and females (p = 0.034 and 0.0008). In the males, LRRC16A was associated with 2-h insulin and insulin secretion (p = 0.009 and 0.009). SLC22A11 was correlated with HOMA-B and insulin secretion (p = 0.048 and 0.029). SLC2A9 rs3775948 was associated with 2-h glucose (p = 0.043). In the females, LRP2 rs2544390 and rs1333049 showed correlations with fasting insulin, HOMA-IR and insulin secretion (p = 0.028, 0.033 and 0.052 and p = 0.034, 0.047 and 0.038, respectively). SLC2A9 rs11722228 was correlated with 2-h glucose, 2-h insulin and insulin secretion (p = 0.024, 0.049 and 0.049, respectively).

Conclusions

Our results indicated that the uric acid-associated genes have an impact on the risk of T2D, glucose metabolism and insulin secretion in a Chinese population.     

The Association between Hypoxia-Inducible Factor-1 α Gene C1772T Polymorphism and Cancer Risk: A Meta-Analysis of 37 Case-Control Studies

Background

The possible association between HIF-1α C1772T polymorphism and cancer risk has been studied extensively. However, the results were controversial. In order to get a more precise conclusion of this association, a meta-analysis was performed.

Methods

A total of 10186 cases and 10926 controls in 37 case-control studies were included in this meta-analysis. Allele and genotypic differences between cases and controls were evaluated. Subgroup analysis by cancer site, ethnicity, source of controls and gender was performed.

Results

The T allele of HIF-1α gene C1772T was significantly associated with increased cancer risk in three genetic models: TT+CT vs.CC (dominant model OR=1.23, 95%CI=1.03-1.47), TT vs. CT+CC (recessive model OR=2.51, 95%CI=1.54-4.09), TT vs. CC (homozygote comparison OR=2.02, 95%CI=1.21-3.39).In subgroup analysis, the frequency of the T variant was found to be significantly increased in cervical cancer, pancreatic cancer, head and neck cancer, renal cell carcinoma, Asian and female subgroups.

Conclusions

Our meta-analysis suggests that the substitution of C allele with T at HIF-1α gene C1772T polymorphism is a risk factor of cancer, especially for cervical, head and neck cancer, pancreatic cancer and renal cell carcinoma. It is also a risk factor of cancer in Asian group as well as in female group.     

Association of VEGF Gene Polymorphisms with Diabetic Retinopathy: A Meta-Analysis

Background

Studies on the association of vascular endothelial growth factor (VEGF) gene -460T/C and -2578C/A polymorphisms with diabetic retinopathy (DR) have reported conflicting results. The aim of the present study was to assess the association by using meta-analysis.

Methods

A systematic search of electronic databases (PubMed, EMBASE, Elsevier Science Direct, ISI Web of Science, CBM, CNKI and VIP) was carried out until Sept 18, 2013. The pooled odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were used to assess the strength of the association.

Results

Eleven studies (-460T/C: 6 studies including 932 cases and 722 controls; -2578C/A: 6 studies including 1,071 cases and 1,137 controls) were involved in this meta-analysis. Significant association was found for -460T/C polymorphism (C versus T: OR=1.48, 95%CI=1.07–2.05, P=0.02; TC+CC versus TT: OR=1.78, 95%CI=1.02–3.12, P=0.04; CC versus TT+TC: OR=1.76, 95%CI=1.10–2.81, P=0.02), but not for -2578C/A polymorphism (P>0.05). Similar results were found in the subgroup analysis.

Conclusions

This meta-analysis demonstrates that DR is associated with VEGF gene -460T/C polymorphism, but not -2578C/A polymorphism. Further case-control studies based on larger sample size are still needed, especially for -2578C/A polymorphism.     

Association between Tumor Necrosis Factor-α 308G/A Gene Polymorphism and Silicosis Susceptibility: A Meta-Analysis

Background

Tumor necrosis factor-α (TNF-α) 308 G/A gene polymorphism has been reported to be associated with susceptibility to silicosis. However, the relevant study results are still inconsistent.

Objective and Methods

A meta-analysis was performed in order to drive a more precise estimation of the relationship between TNF-α-308 G/A gene polymorphism and susceptibility to silicosis. Electronic databases were searched and nine separate studies were included. The pooled odds ratios (ORs) and the corresponding 95% confidence internal (CI) were calculated by a fixed effect model.

Results

A total of 1267 cases and 1214 controls were included. In the overall analysis, significantly increased silicosis risk was found (for GA+AA vs. GG OR=1.45, 95%CI: 1.20-1.760, P=1.58E4; for GA vs. GG: OR=1.53, 95%CI=1.25-1.86, P=3.11E5; for A allele vs. G allele: OR=1.27, 95%CI=1.08-1.50, P= 0.004). In the subgroup analysis, significantly increased silicosis risk was also found among Asians (for GA+AA vs. GG: OR=1.63, 95%CI=1.27-2.08, P=1.01E4), for GA vs. GG: OR=1.71, 95%CI=1.33-2.20, P=3.44E5), for A allele vs. G allele: OR=1.45, 95%CI=1.17-1.80, P=0.001). However, no significantly increased risk was found among non-Asians for all genetic models.

Conclusions

TNF-α-308 G/A polymorphism might lead to an increased risk of silicosis susceptibility, especially for Asians. However, further studies with large sample sizes should be conducted to confirm the association.     

The -607C/A Polymorphisms in Interleukin-18 Gene Promoter Contributes to Cancer Risk: Evidence from A Meta-Analysis of 22 Case-Control Studies

Background

Several observational studies have investigated the association between -607 C/A polymorphism of IL-18 gene and cancer risk; however, the results were inconsistent. Therefore, we performed a meta-analysis to derive a more precise estimation of the association to help us better understand the relationship between -607 C/A polymorphism of IL-18 gene promoter and risk of cancer.

Methods

A literature search was carried out using PubMed, EMBASE, and China National Knowledge Infrastructure (CNKI) database between January 1966 and February 2013. Fixed-effect and random-effect models were used to estimate the pooled odds ratio (OR) and the corresponding 95% confidence intervals (CIs).

Results

A total of 22 case-control studies including 4100 cancer cases and 4327 controls contributed to the analysis. Significant association between -607C/A polymorphism in IL-18 gene promoter and cancer risk was observed (CA vs CC:OR =1.221, 95% CI: 1.096, 1.360; P_{heterogeneity}=0.219; AA/CA vs. CC:OR =1.203, 95% CI: 1.057, 1.369; P_{heterogeneity}=0.064). In the subgroup analysis by ethnicity, -607C/A polymorphism significantly increased risk of cancer among Asian population (AA/CA vs. CC:OR =1.197, 95% CI: 1.023,1.401; P_{heterogeneity}=0.088); however, no significant association was found in Caucasian or African population. The -607C/A polymorphism was associated with a significantly increased risk of nasopharyngeal carcinoma (CA vs CC:OR =1.330, 95% CI: 1.029,1.719; P_{heterogeneity}=0.704; AA/CA vs. CC:OR =1.323, 95% CI: 1.037,1.687; P_{heterogeneity}=0.823) and esophageal cancer (AA/CA vs. CC:OR =1.289, 95% CI: 1.002,1.658; P_{heterogeneity}=0.700).

Conclusions

The present meta-analysis suggests that the -607C/A polymorphisms in IL-18 gene promoter is associated with a significantly increased risk of cancer, especially for nasopharyngeal carcinoma and esophageal cancer and in Asian population. More studies with larger sample size, well controlled confounding factors are warranted to validate this association.     

Dynamics of Immune Reconstitution and Activation Markers in HIV+ Treatment-Na?ve Patients Treated with Raltegravir,Tenofovir Disoproxil Fumarate and Emtricitabine

Background

The dynamics of CD4+ T cell reconstitution and changes in immune activation and inflammation in HIV-1 disease following initiation of antiretroviral therapy (ART) are incompletely defined and their underlying mechanisms poorly understood.

Methods

Thirty-nine treatment-naïve patients were treated with raltegravir, tenofovir DF and emtricitabine. Immunologic and inflammatory indices were examined in persons with sustained virologic control during 48 weeks of therapy.

Results

Initiation of ART increased CD4+ T cell numbers and decreased activation and cell cycle entry among CD4+ and CD8+ T cell subsets, and attenuated markers of coagulation (D-dimer levels) and inflammation (IL-6 and TNFr1). These indices decayed at different rates and almost all remained elevated above levels measured in HIV-seronegatives through 48 weeks of viral control. Greater first and second phase CD4+ T cell restoration was related to lower T cell activation and cell cycling at baseline, to their decay with treatment, and to baseline levels of selected inflammatory indices, but less so to their changes on therapy.

Conclusions

ART initiation results in dynamic changes in viral replication, T cell restoration, and indices of immune activation, inflammation, and coagulation. These findings suggest that determinants of T cell activation/cycling and inflammation/coagulation may have distinguishable impact on immune homeostasis.

Trial Registration

Clinicaltrials.gov NCT00660972     

Novel Single Nucleotide Polymorphism Markers for Low Dose Aspirin-Associated Small Bowel Bleeding

Background

Aspirin-induced enteropathy is now increasingly being recognized although the pathogenesis of small intestinal damage induced by aspirin is not well understood and related risk factors have not been established.

Aim

To investigate pharmacogenomic profile of low dose aspirin (LDA)-induced small bowel bleeding.

Methods

Genome-wide analysis of single nucleotide polymorphisms (SNPs) was performed using the Affymetrix DMET™ Plus Premier Pack. Genotypes of candidate genes associated with small bowel bleeding were determined using TaqMan SNP Genotyping Assay kits and direct sequencing.

Results

In the validation study in overall 37 patients with small bowel bleeding and 400 controls, 4 of 27 identified SNPs: CYP4F11 (rs1060463) GG (p=0.003), CYP2D6 (rs28360521) GG (p=0.02), CYP24A1 (rs4809957) T allele (p=0.04), and GSTP1 (rs1695) G allele (p=0.04) were significantly more frequent in the small bowel bleeding group compared to the controls. After adjustment for significant factors, CYP2D6 (rs28360521) GG (OR 4.11, 95% CI. 1.62 -10.4) was associated with small bowel bleeding.

Conclusions

CYP4F11 and CYP2D6 SNPs may identify patients at increased risk for aspirin-induced small bowel bleeding.     

Genetic Variation in DROSHA 3’UTR Regulated by hsa-miR-27b Is Associated with Bladder Cancer Risk

Purpose

miRNAs can regulate the biological processes, including differentiation, proliferation and apoptosis. DICER and DROSHA are two members of RNase III family, playing pivotal roles in the pathway of miRNAs biogenesis. In this study, we hypothesized that genetic variations of the DICER and DROSHA genes were associated with the bladder cancer risk.

Experimental Design

We performed a case-control study of 685 bladder cancer cases and 730 controls to investigate the association between the seven functional SNPs of DICER and DROSHA genes and bladder cancer risk. We then evaluated the functionality of the important SNPs.

Results

We found that rs10719T>C polymorphism located in 3’ untranslated region (UTR) of DROSHA gene was associated with the increased risk of bladder cancer. Stratified analysis suggested that rs10719TC/CC genotype can increase risk of bladder cancer among male patients (Adjusted OR = 1.34, 95% CI = 1.05-1.70, P = 0.018), and ever smokers (1.56, 1.14-2.14, 0.006), compared with TT genotype. Furthermore, DROSHA rs10719T>C polymorphism was predicted to regulate the binding activity of hsa-miR-27a/b. Luciferase reported gene assay confirmed that rs10719 T to G substitution disrupted the binding site for hsa-miR-27b, resulting the increased levels of DROSHA protein.

Conclusions

Taken together, these findings suggested that DROSHA rs10719T>C polymorphism may be associated with bladder cancer risk in a Chinese population, and hsa-miR-27b can influence the expression of DROSHA protein by binding with 3’UTR.     

High Postoperative Serum Cortisol Level Is Associated with Increased Risk of Cognitive Dysfunction Early after Coronary Artery Bypass Graft Surgery: A Prospective Cohort Study

Context

Stress response induced by surgery is proposed to play an important role in the pathogenesis of postoperative cognitive dysfunction.

Objective

To investigate the association between postoperative serum cortisol level and occurrence of cognitive dysfunction early after coronary artery bypass graft surgery.

Design

Prospective cohort study.

Setting

Two teaching hospitals.

Patients

One hundred and sixth-six adult patients who were referred to elective coronary artery bypass graft surgery from March 2008 to December 2009.

Intervention

None.

Main Outcome Measures

Neuropsychological tests were completed one day before and seven days after surgery. Cognitive dysfunction was defined using the same definition as used in the ISPOCD1-study. Blood samples were obtained in the first postoperative morning for measurement of serum cortisol concentration. Multivariate Logistic regression analyses were performed to assess the relationship between serum cortisol level and occurrence of postoperative cognitive dysfunction.

Results

Cognitive dysfunction occurred in 39.8% (66 of 166) of patients seven days after surgery. Multivariate Logistic regression analysis showed that high serum cortisol level was significantly associated with the occurrence of postoperative cognitive dysfunction (odds ratio [OR] 2.603, 95% confidence interval [CI] 1.371-4.944, P = 0.003). Other independent predictors of early postoperative cognitive dysfunction included high preoperative New York Heart Association functional class (OR 0.402, 95% CI 0.207-0.782, P = 0.007), poor preoperative Grooved Pegboard test score of nondominant hand (OR 1.022, 95% CI 1.003-1.040, P = 0.020), use of penehyclidine as premedication (OR 2.565, 95% CI 1.109-5.933, P = 0.028), and occurrence of complications within seven days after surgery (OR 2.677, 95% CI 1.201-5.963, P = 0.016).

Conclusions

High serum cortisol level in the first postoperative morning was associated with increased risk of cognitive dysfunction seven days after coronary artery bypass graft surgery.     

Post-Mastectomy Radiotherapy for Breast Cancer Patients with T1-T2 and 1-3 Positive Lymph Nodes: a Meta-Analysis

Background

The role of post-mastectomy radiotherapy (PMRT) in patients with T1-2 and 1-3 positive lymph nodes remains controversial. The aim of this study is to investigate the possible benefits of PMRT for this subgroup.

Methods

Three electronic databases were systematically quarried (Cochrane Library, MEDLINE, and EMBASE) for published studies evaluating the effects of PMRT on breast cancer patients with T1-T2 tumors with 1-3 positive lymph nodes. Of the 334 studies identified, information was available for 3432 patients from 10 clinical studies. Pooled relative risk estimates (RR) and overall survival (OS) were calculated using the inverse variance weighted approach, publication bias and chi-square test were also calculated.

Results

From the 10 studies, the pooled RR (RRs) for locoregional recurrence (LRR) with PMRT was 0.348 (95% CI = 0.254 to 0.477), suggesting a significant benefit for PMRT to decrease the risk of LRR in patients with T1-T2 tumors and 1-3 positive nodes (p<0.05). Reporting bias ( Begg’s p = 0.152; Egger’s p = 0.107) or significant heterogeneity (Cochran’s p = 0.380; I² = 6.7%) were not detected. For further subset analysis, the RR for T1, N1-3+ tumors was 0.330 (95% CI = 0.171 to 0.639); for T2, N1-3+ tumors the RR was 0.226 (95% CI = 0.121 to 0.424). The pooled RR for overall survival (OS) was not significantly different between PMRT and no-PMRT group (1.051, 95% CI =1.001 to 1.104).

Conclusions

Our pooled analysis revealed that PMRT significantly reduces the risk of LRR in patients with TI-T2 tumors with 1-3 positive nodes, and the magnitude of the LRR risk reduction is slightly greater for larger tumors. Our results suggest that PMRT should be considered for patients with T1/T2 tumors with 1-3 positive nodes to decrease the relatively high risk of LRR.     

Implications of False Negative and False Positive Diagnosis in Lymph Node Staging of NSCLC by Means of 18F-FDG PET/CT

Background

Integrated ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT) is widely performed in hilar and mediastinal lymph node (HMLN) staging of non-small cell lung cancer (NSCLC). However, the diagnostic efficiency of PET/CT remains controversial. This retrospective study is to evaluate the accuracy of PET/CT and the characteristics of false negatives and false positives to improve specificity and sensitivity.

Methods

219 NSCLC patients with systematic lymph node dissection or sampling underwent preoperative PET/CT scan. Nodal uptake with a maximum standardized uptake value (SUVmax) >2.5 was interpreted as PET/CT positive. The results of PET/CT were compared with the histopathological findings. The receiver operating characteristic (ROC) curve was generated to determine the diagnostic efficiency of PET/CT. Univariate and multivariate analysis were conducted to detect risk factors of false negatives and false positives.

Results

The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of PET/ CT in detecting HMLN metastases were 74.2% (49/66), 73.2% (112/153), 54.4% (49/90), 86.8% (112/129), and 73.5% (161/219). The ROC curve had an area under curve (AUC) of 0.791 (95% CI 0.723-0.860). The incidence of false negative HMLN metastases was 13.2% (17 of 129 patients). Factors that are significantly associated with false negatives are: concurrent lung disease or diabetes (p<0.001), non-adenocarcinoma (p<0.001), and SUVmax of primary tumor >4.0 (p=0.009). Postoperatively, 45.5% (41/90) patients were confirmed as false positive cases. The univariate analysis indicated age > 65 years old (p=0.009), well differentiation (p=0.002), and SUVmax of primary tumor ≦4.0 (p=0.007) as risk factors for false positive uptake.

Conclusion

The SUVmax of HMLN is a predictor of malignancy. Lymph node staging using PET/CT is far from equal to pathological staging account of some risk factors. This study may provide some aids to pre-therapy evaluation and decision-making.     

Inhibiting AKT Phosphorylation Employing Non-Cytotoxic Anthraquinones Ameliorates TH2 Mediated Allergic Airways Disease and Rhinovirus Exacerbation

Background

Severe asthma is associated with T helper (T_H) 2 and 17 cell activation, airway neutrophilia and phosphoinositide-3-kinase (PI3K) activation. Asthma exacerbations are commonly caused by rhinovirus (RV) and also associated with PI3K-driven inflammation. Anthraquinone derivatives have been shown to reduce PI3K-mediated AKT phosphorylation in-vitro.

Objective

To determine the anti-inflammatory potential of anthraquinones in-vivo.

Methods

BALB/c mice were sensitized and challenged with crude house dust mite extract to induce allergic airways disease and treated with mitoxantrone and a novel non-cytotoxic anthraquinone derivative. Allergic mice were also infected with RV1B to induce an exacerbation.

Results

Anthraquinone treatment reduced AKT phosphorylation, hypoxia-inducible factor-1α and vascular endothelial growth factor expression, and ameliorated allergen- and RV-induced airways hyprereactivity, neutrophilic and eosinophilic inflammation, cytokine/chemokine expression, mucus hypersecretion, and expression of T_H2 proteins in the airways. Anthraquinones also boosted type 1 interferon responses and limited RV replication in the lung.

Conclusion

Non-cytotoxic anthraquinone derivatives may be of therapeutic benefit for the treatment of severe and RV-induced asthma by blocking pro-inflammatory pathways regulated by PI3K/AKT.     

Genetic and Non-Genetic Determinants of Raltegravir Penetration into Cerebrospinal Fluid: A Single Arm Pharmacokinetic Study

Background

Antiretroviral drugs vary in their central nervous system penetration, with better penetration possibly conferring neurocognitive benefit during human immunodeficiency virus (HIV) therapy. The efflux transporter gene ABCB1 is expressed in the blood-brain barrier, and an ABCB1 variant (3435C→T) has been reported to affect ABCB1 expression. The integrase inhibitor raltegravir is a substrate for ABCB1. We examined whether ABCB1 3435C→T affects raltegravir disposition into cerebrospinal fluid (CSF), and explored associations with polymorphisms in other membrane transporter genes expressed in the blood-brain barrier.

Methods

Forty healthy, HIV-negative adults of European descent (20 homozygous for ABCB1 3435 C/C, 20 homozygous for 3435 T/T, each group divided equally between males and females) were given raltegravir 400 mg twice daily for 7 days. With the final dose, plasma was collected for pharmacokinetic analysis at 9 timepoints over 12 hours, and CSF collected 4 hours post dose.

Results

The 4-hour CSF concentration correlated more strongly with 2-hour (r²=0.76, P=1.12x10^-11) than 4-hour (r²=0.47, P=6.89x10^-6) single timepoint plasma concentration, and correlated strongly with partial plasma area-under-the-curve values (AUC_0-4h r²=0.86, P=5.15x10^-16). There was no significant association between ABCB1 3435C→T and ratios of CSF-to-plasma AUC or concentration (p>0.05 for each comparison). In exploratory analyses, CSF-to-plasma ratios were not associated with 276 polymorphisms across 16 membrane transporter genes.

Conclusions

Among HIV-negative adults, CSF raltegravir concentrations do not differ by ABCB1 3435C→T genotype but strongly correlate with plasma exposure.

Trial Registration

ClinicalTrials.gov NCT00729924 http://clinicaltrials.gov/show/NCT00729924     

The Prognostic Significance of Pretreatment Serum CEA Levels in Gastric Cancer: A Meta-Analysis Including 14651 Patients

Background

Carcinoembryonic antigen (CEA) is commonly used as a serum tumor marker in clinical practice; however, its prognostic value for gastric cancer patients remains uncertain. This meta-analysis was performed to assess the prognostic value of CEA and investigate CEA as a tumor marker.

Methods

PubMed, EMBASE and other databases were searched for potentially eligible studies. Forty-one studies reporting the prognostic effect of pretreatment serum CEA expression in gastric cancer patients were selected. Data on 14651 eligible patients were retrieved for the meta-analysis. Based on the data extracted from the available literature, the hazard ratio (HR) and 95% confidence interval (CI) for an adverse prognosis were estimated for gastric cancer patients with elevated pretreatment serum levels of CEA (CEA+) relative to patients with normal pretreatment CEA levels (CEA-).

Results

The CEA+ patients had a significantly poorer prognosis than the CEA- patients in terms of overall survival (OS: HR 1.716, 95% CI 1.594 - 1.848, P< 0.001), disease-specific survival (DSS: HR 1.940, 95% CI 1.563 - 2.408, P< 0.001), and disease-free survival (DFS: HR 2.275, 95% CI 1.836 - 2.818, P< 0.001). Publication bias and an influence of different cut-off values were not observed (all P> 0.05). In the pooled analyses of multivariate-adjusted HRs, the results suggested that pretreatment serum CEA may be an independent prognostic factor in gastric cancer (OS: HR 1.681, 95% CI 1.425 - 1.982; DSS: HR 1.900, 95% CI 1.441 - 2.505; DFS: HR 2.579, 95% CI 1.935 - 3.436).

Conclusion/Significance

The meta-analysis based on the available literature supported the association of elevated pretreatment serum CEA levels with a poor prognosis for gastric cancer and a nearly doubled risk of mortality in gastric cancer patients. CEA may be an independent prognostic factor for gastric cancer patients and may aid in determining appropriate treatment which may preferentially benefit the CEA+ patients.