Rihong Zhai

Clinical Characteristics and Outcomes of Sepsis-Related vs Non-Sepsis-Related ARDS

BACKGROUND ARDS may occur after either septic or nonseptic injuries. Sepsis is the major cause of ARDS, but little is known about the differences between sepsis-related and non-sepsis-related ARDS. METHODS A total of 2,786 patients with ARDS-predisposing conditions were enrolled consecutively into a prospective cohort, of which 736 patients developed ARDS. We defined sepsis-related ARDS as ARDS developing in patients with sepsis and non-sepsis-related ARDS as ARDS developing after nonseptic injuries, such as trauma, aspiration, and multiple transfusions. Patients with both septic and nonseptic risks were excluded from analysis. RESULTS Compared with patients with non-sepsis-related ARDS (n = 62), patients with sepsis-related ARDS (n = 524) were more likely to be women and to have diabetes, less likely to have preceding surgery, and had longer pre-ICU hospital stays and higher APACHE III (Acute Physiology and Chronic Health Evaluation III) scores (median, 78 vs 65, P < .0001). There were no differences in lung injury score, blood pH, Pao(2)/Fio(2) ratio, and Paco(2) on ARDS diagnosis. However, patients with sepsis-related ARDS had significantly lower Pao(2)/Fio(2) ratios than patients with non-sepsis-related ARDS patients on ARDS day 3 (P = .018), day 7 (P = .004), and day 14 (P = .004) (repeated-measures analysis, P = .011). Compared with patients with non-sepsis-related ARDS, those with sepsis-related had a higher 60-day mortality (38.2% vs 22.6%; P = .016), a lower successful extubation rate (53.6% vs 72.6%; P = .005), and fewer ICU-free days (P = .0001) and ventilator-free days (P = .003). In multivariate analysis, age, APACHE III score, liver cirrhosis, metastatic cancer, admission serum bilirubin and glucose levels, and treatment with activated protein C were independently associated with 60-day ARDS mortality. After adjustment, sepsis-related ARDS was no longer associated with higher 60-day mortality (hazard ratio, 1.26; 95% CI, 0.71-2.22). CONCLUSION Sepsis-related ARDS has a higher overall disease severity, poorer recovery from lung injury, lower successful extubation rate, and higher mortality than non-sepsis-related ARDS. Worse clinical outcomes in sepsis-related ARDS appear to be driven by disease severity and comorbidities.

VEGF Polymorphisms and Survival in Early-Stage Non–Small-Cell Lung Cancer

PURPOSE Polymorphisms in the VEGF gene have been identified that are believed to have functional activity. We hypothesized that such polymorphisms may affect survival outcomes among early-stage non-small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS We evaluated the relationship between VEGF polymorphisms and overall survival (OS) among patients with early-stage NSCLC treated with surgical resection at Massachusetts General Hospital from 1992 to 2001. We specifically investigated the VEGF polymorphisms +936C>T (rs3025039), -460T>C (rs833061), and +405G>C (rs2010963). Analyses of genotype associations with survival outcomes were performed using Cox proportional hazards models, Kaplan-Meier methods, and the log-rank test. RESULTS There were 462 patients and 237 deaths. Patients carrying the variant C allele of the VEGF +405G>C polymorphism had significantly improved survival (crude hazard ratio [HR] = 0.70; 95% CI, 0.54 to 0.90; P = .006; adjusted HR = 0.70; 95% CI, 0.54 to 0.91; P = .008). Five-year OS for patients carrying the variant C allele of the VEGF +405G>C polymorphism was 61% (95% CI, 54% to 67%) versus 51% (95% CI, 43% to 59%) for those who had the wild-type variant. There was a trend toward improved survival among patients carrying the variant T allele of the VEGF +936C>T polymorphism (crude HR = 0.74; 95% CI, 0.53 to 1.03; P = .07; adjusted HR = 0.73; 95% CI, 0.52 to 1.03; P = .07). Moreover, patients with higher number of variant alleles of the +405G>C and +936C>T polymorphisms had better survival. There was no association found with the -460T>C polymorphism. CONCLUSION Polymorphisms in VEGF may affect survival in early-stage lung cancer.

A Functional Epidermal Growth Factor (EGF) Polymorphism, EGF Serum Levels, and Esophageal Adenocarcinoma Risk and Outcome

Purpose: The epidermal growth factor (EGF) pathway is important in esophageal adenocarcinoma (EAC) tumorigenesis. We hypothesized that the EGF A61G homozygous variant genotype (GG) is (a) both a risk and poor prognostic factor for EAC and (b) associated with higher EGF serum levels in individuals with gastroesophageal reflux disease (GERD). Experimental Design: Using unconditional logistic regression, we compared EGF A61G in 312 EAC cases and 447 GERD-free controls, adjusting for age, gender, smoking history, and healthy adult body mass index. Using the method of Kaplan and Meier, log-rank tests, and Cox proportional hazard models, we correlated EGF A61G with overall and failure-free survival in the EAC cases. Serum EGF levels and EGF genotype (G/G versus others) were correlated in 144 GERD patients using Wilcoxon rank sum tests. Results: The EGF A61G G/G genotype conferred increased EAC risk, with an adjusted odds ratio of 1.81 (95% confidence interval, 1.2-2.7), and was even higher in the subgroup of EAC patients with concurrent Barretts esophagus (adjusted odds ratio, 2.18; 95% confidence interval, 1.3-3.7). However, EGF A61G was not associated with a more aggressive phenotype or prognosis in EAC patients. Higher serum EGF levels were found in GERD patients carrying G/G compared with A/A or A/G (P = 0.03, Wilcoxon rank sum test). Conclusion: The EGF A61G G/G genotype is associated with a near 2-fold greater risk of EAC. The G/G allele was also associated with higher EGF levels in tumor-free patients with GERD. EGF genotyping can potentially identify high-risk patients with GERD and Barretts metaplasia who might benefit from increased surveillance.

Genotypes and haplotypes of the VEGF gene are associated with higher mortality and lower VEGF plasma levels in patients with ARDS

Background: Endothelial injury is an important prognostic factor in acute respiratory distress syndrome (ARDS). Vascular endothelial growth factor (VEGF) plays a critical role in endothelial destruction and angiogenesis. Genetic variations of the VEGF gene have been associated with VEGF production. A study was undertaken to investigate the impact of VEGF gene polymorphisms on the clinical outcomes of ARDS. Methods: Three VEGF polymorphisms (−460C/T, +405C/G and +936C/T) were determined in 1253 patients in an intensive care unit with risk factors for ARDS, 394 of whom developed ARDS. Patients were followed for assessment of 60 day survival. Plasma VEGF levels were measured in 71 patients with ARDS. Results: The +936TT (OR 4.29, 95% CI 1.12 to 16.40, p = 0.03) and +936CT+TT (OR 1.98, 95% CI 1.14 to 3.42, p = 0.01) genotypes were significantly associated with increased mortality from ARDS. Plasma VEGF levels in patients with ARDS with the +936CT+TT genotype were significantly lower than in subjects with the +936CC genotype (median 49 (IQR 16–98) pg/ml vs 112 (IQR 47–162) pg/ml, p = 0.02). At the haplotype level, haplotype TCT (−460T+405C+936T) was significantly associated with a higher rate of mortality (OR 2.89, 95% CI 1.30 to 6.43, p = 0.009) and haplotype CGT (−460C+405G+936T) was associated less strongly with increased mortality (OR 1.90, 95% CI 0.94 to 3.83, p = 0.07) in patients with ARDS. Lower plasma VEGF levels were correlated with the probability of haplotype CGT (coefficient = −0.26, p<0.05), but the same trend of correlation was not significant to haplotype TCT. Conclusions:VEGF polymorphisms may contribute to the prognosis and inter-individual variations in circulating VEGF levels in patients with ARDS.

Vascular Endothelial Growth Factor Genotypes, Haplotypes, Gender, and the Risk of Non–Small Cell Lung Cancer

Purpose: The vascular endothelial growth factor (VEGF) is a major mediator of angiogenesis involving tumor growth and metastasis. Polymorphisms in the VEGF gene may regulate VEGF production. In this large case-control study, we investigated whether functional polymorphisms (−460C/T, +405C/G, +936C/T) in the VEGF gene are associated with the risk of non–small cell lung cancer (NSCLC). Experimental Design:VEGF genotypes and haplotypes were determined in 1,900 Caucasian patients with NSCLC and 1,458 healthy controls. The results were analyzed using logistic regression models, adjusting for age, gender, smoking status, pack-years of smoking, and years since smoking cessation (for ex-smokers). The false-positive report probability was estimated for the observed odds ratios (OR). Results: There were no overall associations between individual VEGF genotypes and the risk of NSCLC. Stratified analysis suggested that the combined +405CC+CG genotype was significantly associated with increased risk of lung adenocarcinoma in males (adjusted OR, 1.40; 95% confidence interval, 1.03-1.87). In haplotype analysis, haplotypes were globally associated with differences between cases and controls in males (P = 0.03). Specifically, the −460T/+405G/+936C haplotype was significantly (P = 0.02) associated with decreased risk of adenocarcinoma in males when compared with the most common CGC haplotype (adjusted OR, 0.76; 95% confidence interval, 0.50-0.98). None of the VEGF genotypes and haplotypes studied significantly influenced the susceptibility to NSCLC in females. Conclusions: Polymorphisms of −460C/T, +405C/G, and +936C/T in the VEGF gene do not play a major role in NSCLC risk. However, we could not exclude a minor role for the +405CC+CG genotypes and the 460T/+405G/+936C haplotype in lung adenocarcinogenesis in male Caucasians.

Cisplatin pharmacogenetics, DNA repair polymorphisms, and esophageal cancer outcomes

Objectives Genetic variations or polymorphisms within genes of the nucleotide excision repair (NER) pathway alter DNA repair capacity. Reduced DNA repair (NER) capacity may result in tumors that are more susceptible to cisplatin chemotherapy, which functions by causing DNA damage. We investigated the potential predictive significance of functional NER single nucleotide polymorphisms in esophageal cancer patients treated with (n = 262) or without (n = 108) cisplatin. Methods Four NER polymorphisms XPD Asp312Asn; XPD Lys751Gln, ERCC1 8092C/A, and ERCC1 codon 118C/T were each assessed in polymorphism–cisplatin treatment interactions for overall survival (OS), with progression-free survival (PFS) as a secondary endpoint. Results No associations with ERCC1 118 were found. Polymorphism–cisplatin interactions were highly significant in both OS (P = 0.002, P = 0.0001, and P<0.0001) and PFS (P = 0.006, P = 0.008, and P = 0.0007) for XPD 312, XPD 751, and ERCC1 8092, respectively. In cisplatin-treated patients, variant alleles of XPD 312, XPD 751, and ERCC1 8092 were each associated with significantly improved OS (and PFS): adjusted hazard ratios of homozygous variants versus wild-type ranged from 0.22 [95% confidence interval (CI): 0.1–0.5] to 0.31 (95% CI: 0.1–0.7). In contrast, in patients who did not receive cisplatin, variant alleles of XPD 751 and ERCC1 8092 had significantly worse survival, with adjusted hazard ratios of homozygous variants ranging from 2.47 (95% CI: 1.1–5.5) to 3.73 (95% CI: 1.6–8.7). Haplotype analyses affirmed these results. Conclusion DNA repair polymorphisms are associated with OS and PFS, and if validated may predict for benefit from cisplatin therapy in patients with esophageal cancer.

Genetic polymorphisms of VEGF, interactions with cigarette smoking exposure and esophageal adenocarcinoma risk.

Vascular endothelial growth factor (VEGF) is a major regulator of angiogenesis in the process of tumor growth and metastasis in esophageal adenocarcinoma (EA). Polymorphisms in the VEGF gene have been associated with altered VEGF expression and plasma VEGF levels. We hypothesized that polymorphisms of VEGF may contribute to EA risk. Functional polymorphisms in the VEGF gene (-460C/T, +405C/G and +936C/T) were determined in 308 patients with EA and 546 healthy controls. Logistic regression analysis was employed to assess the associations between genotypes, haplotypes of VEGF and EA risk, adjusting for multiple confounding factors. Compared with the +936CC genotype, the combined +936CT+TT genotypes were significantly associated with increased risk of developing EA, with adjusted odds ratio (OR) = 1.49 [95% confidence interval (CI), 1.05-2.12; P = 0.027]. The -460CT+CC were associated with increased risk of EA in smokers (adjusted OR = 1.57; 95% CI, 1.07-2.30; P = 0.021), whereas the -460CT/CC were associated with decreased risk of EA (adjusted OR = 0.47; 95% CI, 0.25-0.91; P = 0.025) in non-smokers. Compared with non-smokers with the +460TT, smokers with the +460CT+CC had significantly higher risk of EA (adjusted OR = 3.32; 95% CI, 1.56-7.10; P = 0.002). No overall or interacting association with EA risk was found for the +405C/G polymorphism. Haplotype CGT (-460C/+405G/+936T) was significantly associated with higher risk of EA (adjusted OR = 1.70; 95% CI, 1.04-2.73; P = 0.034). These results suggested that cigarette smoking modifies the association between VEGF polymorphisms and EA risk among Caucasians.

Myeloperoxidase and superoxide dismutase polymorphisms are associated with an increased risk of developing pancreatic adenocarcinoma

Pancreatic cancer risk has been linked to chronic pancreatitis and periodontitis, suggesting a role for inflammation in disease etiology. Myeloperoxidase (MPO) and superoxide dismutase (SOD2) are enzymes that regulate reactive oxygen species and contain recognized single nucleotide polymorphisms (SNPs) that confer altered enzyme activity.

Apoptosis gene polymorphisms, age, smoking and the risk of non-small cell lung cancer

Apoptosis is important for targeting cancer cells for destruction. Various single-nucleotide polymorphisms (SNPs) in apoptotic genes have been associated with increased risks in lung cancer, particularly FAS -1377 G>A (rs2234767), FASLG -844 C>T (rs763110), IL1B +3954 C>T Phe105Phe (rs1143634) and BAT3 Ser625Pro (rs1052486). We studied the association of these SNPs with non-small cell lung cancer (NSCLC) in a large case-control study (N = 4263: 2644 cases and 1619 controls). No associations with NSCLC were observed in the main effects analysis for all four SNPs, adjusting for age, gender, smoking status, pack-years and years since smoking cessation. In subjects under age 60, for FASLG -844 C>T polymorphism, CT compared with the CC genotype, was significantly associated with increased risk of NSCLC, adjusted odds ratio (aOR) = 1.58 (1.22, 2.05), P = 0.0006 and TT aOR = 1.45 (1.01, 2.04), P = 0.04. In contrast, for those over age 60, the CT aOR = 0.91 (0.73, 1.13), P = 0.37 and TT aOR = 0.86 (0.64, 1.16), P = 0.32. The P-value for the age-genotype interaction was 0.004. For the IL1B +3954 C>T polymorphism, compared with the CC genotype, TT showed significant associations in former smokers and in men but tests of interaction were not significant (P(smoking) = 0.24, P(gender) = 0.17). No interactions were observed for FAS -1377 G>A and BAT3 Ser625Pro polymorphisms. Our findings indicate that age and smoking may modify the association of the FASLG -844 and IL1B + 3954 SNPs with the risk of NSCLC.

Serum bilirubin levels on ICU admission are associated with ARDS development and mortality in sepsis

Background: Hyperbilirubinaemia is a common complication of sepsis. Elevated bilirubin may induce inflammation and apoptosis. It was hypothesised that increased serum bilirubin on Intensive Care Unit (ICU) admission contributes to sepsis-related acute respiratory distress syndrome (ARDS). Methods: Serum bilirubin on ICU admission was measured in 1006 patients with sepsis. Serial serum bilirubin was analysed prospectively in patients with sepsis who had ARDS for a period of 28 days. The effects of clinical factors and variants of the UGT1A1 gene on serum bilirubin levels were determined. Outcomes were ARDS risk and mortality. Results: During 60-day follow-up, 326 patients with sepsis developed ARDS, of whom 144 died from ARDS. The hyperbilirubinaemia (⩾2.0 mg/dl) rate in patients with ARDS (22.4%) was higher than in those without ARDS (14.1%, p = 0.002). For each 1.0 mg/dl increase in admission bilirubin, ARDS risk and 28- and 60-day ARDS mortalities were increased by 7% (OR = 1.07; p = 0.003), 20% (OR = 1.20; p = 0.002) and 18% (OR = 1.18; p = 0.004), respectively. Compared with subjects with bilirubin levels <2.0 mg/dl, patients with hyperbilirubinaemia had higher risks of ARDS (OR = 2.12; p = 0.0007) and 28-day (OR = 2.24; p = 0.020) and 60-day ARDS mortalities (OR = 2.09; p = 0.020). In sepsis-related ARDS, serial bilirubin levels in non-survivors were consistently higher than in survivors (p<0.0001). Clinical variables explained 29.5% of the interindividual variation in bilirubin levels, whereas genetic variants of UGT1A1 contributed 7.5%. Conclusion: In sepsis, a higher serum bilirubin level on ICU admission is associated with subsequent ARDS development and mortality.