Temporal Trends in Difficult and Failed Tracheal Intubation in a Regional Community Anesthetic Practice.

BACKGROUND: When tracheal intubation is difficult or unachievable before surgery or during an emergent resuscitation, this is a critical safety event. Consensus algorithms and airway devices have been introduced in hopes of reducing such occurrences. However, evidence of improved safety in clinical practice related to their introduction is lacking. Therefore, we selected a large perioperative database spanning 2002 to 2015 to look for changes in annual rates of difficult and failed tracheal intubation. METHODS: Difficult (more than three attempts) and failed (unsuccessful, requiring awakening or surgical tracheostomy) intubation rates in patients 18 yr and older were compared between the early and late periods (pre- vs. post-January 2009) and by annual rate join-point analysis. Primary findings from a large, urban hospital were compared with combined observations from 15 smaller facilities. RESULTS: Analysis of 421,581 procedures identified fourfold reductions in both event rates between the early and late periods (difficult: 6.6 of 1,000 vs. 1.6 of 1,000, P < 0.0001; failed: 0.2 of 1,000 vs. 0.06 of 1,000, P < 0.0001), with join-point analysis identifying two significant change points (2006, P = 0.02; 2010, P = 0.03) including a pre-2006 stable period, a steep drop between 2006 and 2010, and gradual decline after 2010. Data from 15 affiliated practices (442,428 procedures) demonstrated similar reductions. CONCLUSIONS: In this retrospective assessment spanning 14 yr (2002 to 2015), difficult and failed intubation rates by skilled providers declined significantly at both an urban hospital and a network of smaller affiliated practices. Further investigations are required to validate these findings in other data sets and more clearly identify factors associated with their occurrence as clues to future airway management advancements. VISUAL ABSTRACT: An online visual overview is available for this article at http://links.lww.com/ALN/B635.

Epsilon Aminocaproic Acid to Reduce Blood Loss and Transfusion After Total Hip and Total Knee Arthroplasty.

BACKGROUND: Total hip and knee arthroplasty (THA and TKA) are associated with significant blood loss and some patients require postoperative blood transfusion. While tranexamic acid has been studied extensively among this population, we tested the hypothesis that epsilon aminocaproic acid (EACA) can reduce blood loss and transfusion after joint arthroplasty. METHODS: In April 2014, our Veterans Affairs Medical Center introduced a protocol to administer EACA during THA and TKA. No antifibrinolytics were used previously. We retrospectively compared blood loss and incidence of transfusion among patients who underwent primary arthroplasty in the year before standardized administration of EACA with patients having the same procedures the following year. Blood loss was measured as delta hemoglobin (preoperative hemoglobin - hemoglobin on postoperative day 1). All patients undergoing primary THA or TKA were included. Patients having revision surgery were excluded. RESULTS: We identified 185 primary arthroplasty patients from the year before and 184 from the year after introducing the EACA protocol. There were no changes in surgical technique or attending surgeons during this period. Delta hemoglobin was significantly lower in the EACA group (2.7 ± 0.8 mg/dL) compared to the control group (3.4 ± 1.1 mg/dL) (P < .0001). The incidence of blood transfusion was also significantly lower in the EACA group (2.7%) compared to the control group (25.4%) (P < .0001). There was no difference in venous thromboembolic complications between groups. CONCLUSION: We demonstrated reductions in hemoglobin loss and transfusion following introduction of the EACA protocol in patients undergoing primary arthroplasty. EACA offers a lower cost alternative to TXA for reducing blood loss and transfusion in this population.

Systemic Anaplastic Lymphoma Kinase-positive Anaplastic Large Cell Lymphoma: A Population-based Analysis of Incidence and Survival.

INTRODUCTION: Systemic ALK-positive anaplastic large cell lymphoma (ALK-positive ALCL) is a T-cell lymphoma. Owing to its rarity, variations in incidence and survival at the population level are not clearly known. MATERIALS AND METHODS: Using the Surveillance Epidemiology and End Results database (SEER 18), we selected patients aged ≥ 20 years with ALK-positive ALCL, diagnosed between 2001 and 2013. Incidence rate, overall survival (OS), and its determinants were analyzed with a significance level of P < .05. RESULTS: We identified 1604 patients with a median age of 54 years. The disease incidence increased significantly with advancing age, with higher incidence in Blacks and lower incidence in American Indians and Asian/Pacific Islanders as compared with Whites. The 5-year OS significantly declined as the age advanced (age 20-40 years, 68.7%; age 41-60 years, 53.8%; age 61-80 years, 28.9%; age > 80 years, 15.2%; P < .01) and varied with race (Whites, 49.7% vs. Blacks, 37.7% vs. Asian/Pacific Islander, 42.8% vs. American Indian, 35.8%; P = .03). On multivariate analysis, treatment with radiation (hazard ratio [HR], 0.72; 95% confidence interval [95% CI], 0.59-0.87; P < .01) and year of diagnosis from 2009 through 2013 (HR, 0.77; 95% CI, 0.65-0.93; P < .01) were associated with lower mortality. Advanced age, Black race (HR, 1.37; 95% CI, 1.14-1.65; P < .01), and advanced disease stage (HR, 1.74; 95% CI, 1.51-2.02; P < .01) were associated with higher mortality. CONCLUSION: Incidence and survival of ALK-positive ALCL varies significantly with patients' demographic characteristics as identified in our study. Treatment strategies need to be tailored accordingly to address these variations and ensure uniform access to care.

Polymorphic Variations Associated With Doxorubicin-Induced Cardiotoxicity in Breast Cancer Patients.

Doxorubicin (DOX) is a commonly used antineoplastic agent for the treatment of various malignancies, and its use is associated with unpredictable cardiotoxicity. Susceptibility to DOX cardiotoxicity is largely patient dependent, suggesting genetic predisposition. We have previously found that individual sensitivity to DOX cardiotoxicity was associated with differential expression of genes implicated in inflammatory response and immune trafficking, which was consistent with the increasing number of reports highlighting the important role of human leukocyte antigen (HLA) complex polymorphism in hypersensitivity to drug toxicity. This pilot study aimed to investigate DNA from patients treated with DOX-based chemotherapy for breast cancer and to correlate the results with the risk for DOX-associated cardiotoxicity. We have identified 18 SNPs in nine genes in the HLA region (NFKBIL1, TNF-α, ATP6V1G2-DDX39B, MSH5, MICA, LTA, BAT1, and NOTCH4) and in the psoriasis susceptibility region of HLA-C as potential candidates for association with DOX cardiotoxicity. These results, albeit preliminary and involving a small number of patients, are consistent with reports showing the presence of susceptibility loci within the HLA gene region for several inflammatory and autoimmune diseases, and with our previous findings indicating that the increased sensitivity to DOX cardiotoxicity was associated with dysregulation of genes implicated both in inflammation and autoimmune disorders.

Germline Genetic Variants in TEK, ANGPT1, ANGPT2, MMP9, FGF2 and VEGFA Are Associated with Pathologic Complete Response to Bevacizumab in Breast Cancer Patients.

BACKGROUND: We previously reported improved pathologic complete response (pCR) in a prospective phase II study using neoadjuvant bevacizumab in combination with chemotherapy compared to chemotherapy alone in breast cancer patients (41% vs. 25%, p = 0.0291). In this study, we queried germline single-nucleotide polymorphisms (SNPs) in angiogenesis-related genes for their impact on pCR and overall survival (OS). METHODS: DNA for genotyping was available from 34 subjects who received bevacizumab in addition to chemotherapy and 29 subjects who did not. Using Illumina® technology, we queried 504 SNPs with a minor allele frequency (MAF) of at least 5%, located in 10 angiogenesis-related genes, for their effect on pCR via logistic regression with an additive-inheritance model while adjusting for race and bevacizumab treatment. SNPs that showed significant associations with pCR were selected for additional characterization. RESULTS: After adjusting for race and tumor type, patients who had bevacizumab added to their neoadjuvant therapy were found to experience a significantly improved rate of pCR compared to patients who did not (adjusted OR 8.40, 95% CI 1.90-37.1). When patients were analyzed for SNP effects via logistic regression with race and bevacizumab treatment included as covariates, two SNPs in angiopoietin 1 (ANGPT1), six in ANGPT2, three in fibroblast growth factor 2 (FGF2), four in matrix metalloproteinase 9 (MMP9), three in tyrosine kinase, endothelial (TEK) and two in vascular endothelial growth factor A (VEGFA) were associated with pCR (P<0.05). However, when overall survival was considered, there was no difference between treatment groups or between genotypes. CONCLUSION: Genetic variability in TEK, ANGPT1, ANGPT2, FGF2, MMP9 and VEGFA is associated with pCR in bevacizumab-treated patients. Consistent with other studies, adding bevacizumab to standard chemotherapy did not impact OS, likely due to other factors and thus, while SNPs in TEK, ANGPT1, ANGPT2, FGF2, MMP9 and VEGFA were associated with pCR, they were not predictive of OS in this patient population. TRIAL REGISTRATION: ClinicalTrials.gov NCT00203502.

Acute Leukemia of Ambiguous Lineage in Elderly Patients - Analysis of Survival Using Surveillance Epidemiology and End Results-Medicare Database.

BACKGROUND: Acute leukemia of ambiguous lineage (ALAL) is a rare leukemia with sparse data availability about the survival and management strategies in elderly patients. METHODS: We used the Surveillance Epidemiology and End Results (SEER)-Medicare database to describe the overall survival (OS) and treatment pattern of elderly patients (age > 65 years) with ALAL. OS analysis was done using the Kaplan-Meier method, and its determinants were analyzed using the Cox proportional hazard regression method with a significant P < .05. RESULTS: We included 705 patients with ALAL and a median age of 80 years. The 2-year OS was 16.4% for patients aged 66 to 70 years, 8.1% for patients aged 71 to 75 years, 5.5% for patients aged 76 to 80 years, and 3.7% for patients aged > 80 years (P < .01). Two-year OS did not significantly vary by race or gender. Among the study cohort, 151 patients received chemotherapy. Two-year OS was 17% in the chemotherapy group and 3% in the no-chemotherapy group (P < .001). On multivariate analysis, age less than 80 years (Age 66-70 years: hazard ratio [HR]; 0.66, 95% confidence interval [CI], 0.52-0.85; age 71-75 years: HR, 0.80; 95% CI, 0.65-0.99; age 76-80 years: HR, 0.80; 95% CI, 0.66-0.98; P = .004) and chemotherapy (HR, 0.51; 95% CI, 0.42-0.62; P = .001) significantly reduced the hazard for mortality. CONCLUSION: Our study suggests that the OS of elderly patients with ALAL remains poor. Although treatment improved the OS, only 21.5% of patients received therapy. The optimal choice of therapy needs to be determined by prospective studies.

Incidence and survival outcomes of chronic myelomonocytic leukemia in the United States.

Chronic myelomonocytic leukemia (CMML) is an aggressive neoplasm with sparse data on outcomes at a population level. Using Surveillance Epidemiology and End Results (SEER) database, we identified 2238 patients with CMML diagnosed in the period 2003-2013. We found that the disease incidence was significantly higher with advancing age and lower in females, Blacks, and Asian/pacific islanders. Median OS declined significantly with increasing age (age 20-39 - 25 months, age 40-59 - 20 months, age 60-79 - 18 months, and age ≥80 - 11 months, p < .01), but did not vary by gender or race. Median OS has improved in the period 2007-2013 as compared with 2003-2006 (17 months vs. 14 months, p < .01). In spite of advances in CMML biology and therapeutics, in general, the survival of CMML patients remains dismal. More effective therapies are needed to improve the outcomes of CMML.

Risk of Cancer among Commercially Insured HIV-Infected Adults on Antiretroviral Therapy.

The objective of this study was to explore the cancer incidence rates among HIV-infected persons with commercial insurance who were on antiretroviral therapy and compare them with those rates in the general population. Paid health insurance claims for 63,221 individuals 18 years or older, with at least one claim with a diagnostic code for HIV and at least one filled prescription for an antiretroviral medication between January 1, 2006, and September 30, 2012, were obtained from the LifeLink® Health Plan Claims Database. The expected number of cancer cases in the general population for each gender-age group (<30, 30-39, 40-49, 50-59, and >60 years) was estimated using incidence rates from the Surveillance Epidemiology and End Results (SEER) program. Standardized incidence ratios (SIRs) were estimated using their 95% confidence intervals (CIs). Compared to the general population, incidence rates for HIV-infected adults were elevated (SIR, 95% CI) for Kaposi sarcoma (46.08; 38.74-48.94), non-Hodgkin lymphoma (4.22; 3.63-4.45), Hodgkin lymphoma (9.83; 7.45-10.84), and anal cancer (30.54; 25.62-32.46) and lower for colorectal cancer (0.69; 0.52-0.76), lung cancer (0.70; 0.54, 0.77), and prostate cancer (0.54; 0.45-0.58). Commercially insured, treated HIV-infected adults had elevated rates for infection-related cancers, but not for common non-AIDS defining cancers.

Reduction in blood transfusion in a cohort of infants having cardiac surgery with cardiopulmonary bypass after instituting a goal-directed transfusion policy.

BACKGROUND: Current trends in pediatric cardiac surgery and anesthesiology include goal-directed allogeneic blood transfusion, but few studies address the transfusion of platelets and cryoprecipitate. We report a quality improvement initiative to reduce the transfusion of platelets and cryoprecipitate in infants having cardiac surgery with cardiopulmonary bypass (CPB). METHODS: Data from 50 consecutive patients weighing four to ten kilograms having cardiac surgery with CPB were prospectively collected after the institution of a policy to obtain each patient's platelet and fibrinogen levels during the rewarming phase of CPB. Data from 48 consecutive patients weighing four to ten kilograms having cardiac surgery with CPB prior to the implementation of the policy change were retrospectively collected. Demographics, laboratory values and blood product transfusion data were compared between the groups, using the Chi-square/Fisher's exact test or the T-Test/Wilcoxon Rank-Sum test, as appropriate. RESULTS: The results showed more total blood product exposures in the control group during the time from bypass through the first twenty-four post-operative hours (median of 2 units versus 1 unit in study group, p=0.012). During the time period from CPB separation through the first post-operative day, 67% of patients in the control group received cryoprecipitate compared to 32% in the study group (p=0.0006). There was no difference in platelet exposures between the groups. CONCLUSION: Checking laboratory results during the rewarming phase of CPB reduced cryoprecipitate transfusion by 50%. This reproducible strategy avoids empiric and potentially unnecessary transfusion in this vulnerable population.

High-circulating Tie2 Is Associated With Pathologic Complete Response to Chemotherapy and Antiangiogenic Therapy in Breast Cancer.

INTRODUCTION: Vascular endothelial growth factor (VEGF) is a central mediator of angiogenesis in breast cancer. Research in antiangiogenic cancer treatment has been marked by the development of the monoclonal antibody bevacizumab, which targets VEGF in many solid tumors. As patients do not equally benefit from bevacizumab, it has become necessary to define the profile of patients who will benefit from the drug. MATERIALS AND METHODS: We have conducted a prospective phase II study in 39 patients using bevacizumab in breast cancer in the neoadjuvant setting, and found improved pathologic complete response (pCR) when bevacizumab was added to chemotherapy in patients with hormone receptor negative and invasive ductal carcinoma. Blood samples were collected at baseline and serially while patients were on treatment. Circulating angiogenesis-related proteins angiopoietin (ANG)1, ANG2, basic fibroblast growth factor, IL-1a, matrix metalloproteinase 9, platelet derived growth factor - BB, platelet endothelial cell adhesion molecule -1, Tie2, VEGF, and vascular endothelial growth factor receptor 2 were measured at baseline and during treatment. This correlative study was conducted to identify specific serum angiogenic factor profiles that might be associated with pCR in the neoadjuvant setting in breast cancer patients receiving bevacizumab and chemotherapy. RESULTS: Elevated baseline serum Tie2 and basic fibroblast growth factor were associated with pCR in response to this combination. Changes in serum levels of these proteins were seen during treatment but were not significantly different between the pCR and non-pCR groups. CONCLUSIONS: Baseline-circulating Tie2 levels may help distinguish patients who will have pCR from those who will not and may form the basis for future development of antiangiogenic therapy in breast cancer. Larger studies are needed to validate these findings. ClinicalTrials.gov Identifier: NCT00203502.

Discordance in Grading Methods of Aortic Stenosis by Pre-Cardiopulmonary Bypass Transesophageal Echocardiography.

BACKGROUND: Current guidelines define severe aortic valve stenosis (AS) as an aortic valve area (AVA) ≤1.0 cm by the continuity equation and mean gradient (ΔPm) ≥ 40 mm Hg. However, these measurements can be discordant when classifying AS severity. Approximately one-third of patients with normal ejection fraction and severe AS by AVA have nonsevere AS by ΔPm when measured by preoperative transthoracic echocardiography (TTE). Given the use of positive pressure ventilation and general anesthesia in the pre-cardiopulmonary bypass (pre-CPB) period, we hypothesized that discordance between ΔPm and AVA during pre-CPB transesophageal echocardiography (TEE) would be higher than previously reported by TTE. METHODS: We retrospectively examined pre-CPB TEE data for patients who had aortic valve replacement, with or without coronary artery bypass grafting, from 2000 to 2012. Patients were excluded if they had ejection fraction <55%, emergency surgery, repeat sternotomy, moderate or severe mitral regurgitation, or severe aortic regurgitation. Only patients with both pre-CPB AVA and ΔPm measurements were included. Patients were grouped according to severity (mild, moderate, and severe) by AVA or ΔPm. Discordance was defined as disagreement between severities based on either parameter. RESULTS: A total of 277 patients met inclusion criteria. There were 227 patients with AVA ≤ 1.0 cm. The proportion of these patients with a ΔPm < 40 mm Hg was 54% (95% confidence interval, 47%-61%). The rate of discordance was significantly higher than the rate (37%; P < 0.001) found in previously reported analyses using TTE. Of the patients with a ΔPm ≥ 40 mm Hg, only 8% (n = 9/113) had a discordant AVA. In contrast, of the patients with ΔPm < 40 mm Hg, 80% (n = 131/164) had a discordant AVA. CONCLUSIONS: We confirmed our hypothesis that grading AS by ΔPm and AVA during pre-CPB TEE exhibits higher discordance than reported for TTE by others. It remains unclear whether these discrepancies reflect the effect of general anesthesia, imaging modality (TTE versus TEE) differences, inaccuracies in AS grading cutoffs when applied to pre-CPB TEE, or selection bias of the surgical population.

Day of surgery cancellation rate after preoperative telephone nurse screening or comprehensive optimization visit.

BACKGROUND: Structured preoperative assessment has been reported to improve operating room efficiency as measured by metrics such as day of surgery cancellations (DOSCs). However, not all patients require comprehensive assessment; routine full assessments can result in unnecessary duplication of tests and investigations. Selective nurse screening under the supervision of anesthesiology may provide adequate information gathering in lower risk patients. This study is undertaken to assess if DOSC rates vary with different assessment processes. METHODS: At a single academic tertiary care hospital, from Jan 2 to May 31, 2013, the consecutive patients undergoing comprehensive preoperative assessment (CPA) and nurse screening (NS), as well as the patients not assessed by the anesthesiology-supervised preoperative process, were followed for the occurrence and reason for DOSC. The operating room schedule of all elective surgery patients was analyzed to allow calculation of rates of DOSCs. Reasons for cancellations were documented as one of ten structured reasons by preoperative holding area clerical staff. RESULTS: Overall, there were 14,893 elective surgery patients in this time period, with 183 DOSCs, giving a rate of 1.23 % (95 % CI 1.06, 1.42). Patients who received CPA numbered 5980; 29 of them had a DOSC, giving a rate of 0.48 % (95 % CI 0.33-0.70) (P < 0.0001 vs. no assessment). Patients receiving NS numbered 1840; 11 of them had a DOSC, giving a rate of 0.60 % (95 % CI 0.30-1.10) (P < 0.0001 vs. no assessment). The most common reason for cancellation was new medical condition. CONCLUSIONS: A very low DOSC rate can be achieved with a comprehensive preoperative process where some patients are selectively telephone screened by nurses, with complete assessment deferred to the anesthesiologist on the day of surgery.

Short- and Long-Term Soy Diet Versus Casein Protects Liver Steatosis Independent of the Arginine Content.

Nonalcoholic fatty liver disease, a major cause of abnormal liver function, is often associated with obesity. Arginine (ARG) plays a role in modulating body weight/fat, but limited data exist as to the role of ARG in soy protein's ability to protect from liver steatosis. We investigated the role of native ARG in the soy protein isolate (SPI) in reducing liver steatosis in male obese Zucker rats. Rats (N=48; 6 weeks old) were randomly assigned to one of three diets for 8 or 16 weeks: the casein (CAS) diet as control (0.6% ARG), CAS diet supplemented to contain 1.3% ARG, or an SPI diet containing isoflavones (1.3% ARG). SPI and ARG rats gained significantly more weight (P<.05) than CAS rats after 16 weeks only. The SPI rats had lower liver steatosis scores after 8 and 16 weeks (P<.05 and P<.001, respectively) compared to CAS and ARG rats. SPI rats had lower serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels (P<.05) compared to CAS after 16 weeks, and AST was lower (P<.05) compared to ARG rats. After 16 weeks, the SPI rats had lower (P<.05) serum ALT and AST levels than at 8 weeks. Our results suggest that a longer period of SPI feeding results in lower liver steatosis and serum ALT and AST levels, while the ARG diet had no effect on steatosis or ALT and AST levels. We found that the SPI diet reduced (P<.001) serum tumor necrosis factor-α (TNF-α) compared to CAS and ARG diets after 8 and 16 weeks. The SPI diet significantly reduced (P<.001) interleukin-6 (IL-6) when compared to the CAS diet at 8 weeks, but there was no significant difference at 16 weeks. Based on the findings of our study, the protective effect of SPI in reducing liver steatosis is not modulated by its native arginine content.

Genotypic and allelic variability in CYP19A1 among populations of African and European ancestry.

CYP19A1 facilitates the bioconversion of estrogens from androgens. CYP19A1 intron single nucleotide polymorphisms (SNPs) may alter mRNA splicing, resulting in altered CYP19A1 activity, and potentially influencing disease susceptibility. Genetic studies of CYP19A1 SNPs have been well documented in populations of European ancestry; however, studies in populations of African ancestry are limited. In the present study, ten 'candidate' intronic SNPs in CYP19A1 from 125 African Americans (AA) and 277 European Americans (EA) were genotyped and their frequencies compared. Allele frequencies were also compared with HapMap and ASW 1000 Genomes populations. We observed significant differences in the minor allele frequencies between AA and EA in six of the ten SNPs including rs10459592 (p<0.0001), rs12908960 (p<0.0001), rs1902584 (p = 0.016), rs2470144 (p<0.0001), rs1961177 (p<0.0001), and rs6493497 (p = 0.003). While there were no significant differences in allele frequencies between EA and CEU in the HapMap population, a 1.2- to 19-fold difference in allele frequency for rs10459592 (p = 0.004), rs12908960 (p = 0.0006), rs1902584 (p<0.0001), rs2470144 (p = 0.0006), rs1961177 (p<0.0001), and rs6493497 (p = 0.0092) was observed between AA and the Yoruba (YRI) population. Linkage disequilibrium (LD) blocks and haplotype clusters that is unique to the EA population but not AA was also observed. In summary, we demonstrate that differences in the allele frequencies of CYP19A1 intron SNPs are not consistent between populations of African and European ancestry. Thus, investigations into whether CYP19A1 intron SNPs contribute to variations in cancer incidence, outcomes and pharmacological response seen in populations of different ancestry may prove beneficial.

Effect of MRP2 and MRP3 Polymorphisms on Anastrozole Glucuronidation and MRP2 and MRP3 Gene Expression in Normal Liver Samples.

Anastrozole is an aromatase inhibitor (AI) used as adjuvant therapy for breast cancer. Anastrozole is subject to direct glucuronidation catalyzed by UDP-glucuronosyltransferase1A4 (UGT1A4). Interindividual variability in anastrozole glucuronidation may be affected by UGT1A4 SNPs. Interplay between drug metabolizing genes such as UGT1A4 and transporter genes may also be affected by genetic variability. Thus, we hypothesize that genetic variability in MRPs could influence anastrozole glucuronidation. The correlation between UGT1A4 and MRP2 or MRP3 transporter gene expressions and the correlation between MRP2 or MRP3 mRNA and anastrozole glucuronidation were analyzed in normal human liver samples. MRP2 and MRP3 mRNA levels were significantly correlated with UGT1A4 mRNA, with anastrozole glucuronidation and with each other (p<0.05). The data also demonstrated that MRP2 SNPs are positively correlated with MRP2 mRNA expression, while there was no association between MRP3 SNPs from this study and MRP3 expression. Significant correlations (p<0.05) between certain MRP2 SNPs (3972C>T, 2366C>T and -24C>T) and anastrozole glucuronidation were observed. There were no observed correlations between MRP3 SNPs and anastrozole glucuronidation. MRP2 polymorphisms have been identified as playing a role in the disposition of other drugs, and the data presented here indicate for the first time that MRP2 SNPs could influence anastrozole metabolism and contribute to interindividual variation in treatment responses.

CYP19A1 single nucleotide polymorphism associations with CYP19A1, NFκB1, and IL6 gene expression in human normal colon and normal liver samples.

BACKGROUND: Estrogen is known to decrease the risk of colon cancer in postmenopausal women, and may exert its actions by decreasing interleukin-6 (IL6) production via stabilization of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB). Estrogens are biosynthesized by CYP19A1 (aromatase), so it is possible that genetic variations in CYP19A1 influences the risk of colon cancer by altering expression of CYP19A1. Further, studies on gene-gene interactions suggest that single nucleotide polymorphisms in one gene may affect expression of other genes. The current study aims to explore the role of CYP19A1 single nucleotide polymorphisms on CYP19A1, NFκB1 and IL6 gene expression. METHODS: Phenotype-genotype associations, cross-associations between genes, and haplotype analyses were performed in both normal human colon (n=82) and liver (n=238) samples. RESULTS: CYP19A1 rs10459592, rs1961177, and rs6493497 were associated with CYP19A1 expression in colon samples (P=0.042, P=0.041, and P=0.013, respectively). CYP19A1 single nucleotide polymorphisms (rs12908960, rs730154, rs8025191, and rs17523880) were correlated with NFκB1 expression (P=0.047, P=0.04, P=0.05, and P=0.03, respectively), and CYP19A1 rs11856927, rs2470152, and rs2470144 (P=0.049, P=0.025, P=0.047, respectively) were associated with IL6 expression in the colon. While rs730154 and rs17523880 could not be analyzed in the liver samples, none of the other associations with the colon were replicated in the liver samples. Haplotype analysis revealed three separate haplotypes of the CYP19A1 single nucleotide polymorphism that were significantly associated with CYP19A1, NFκB1, and IL6 gene expression. CONCLUSION: CYP19A1 single nucleotide polymorphisms are associated not only with CYP19A1 expression but also with NFκB1 and IL6 expression. These data demonstrate the possible functional consequences of genetic variation within the CYP19A1 gene on other genes in a biologically plausible pathway.

A potential role for human UDP-glucuronosyltransferase 1A4 promoter single nucleotide polymorphisms in the pharmacogenomics of tamoxifen and its derivatives.

Tamoxifen (Tam) is a selective estrogen receptor modulator used to inhibit breast tumor growth. Tam can be directly N-glucuronidated via the tertiary amine group or O-glucuronidated after cytochrome P450-mediated hydroxylation. In this study, the glucuronidation of Tam and its hydroxylated and/or chlorinated derivatives [4-hydroxytamoxifen (4OHTam), toremifene (Tor), and 4-hydroxytoremifene (4OHTor)] was examined using recombinant human UDP-glucuronosyltransferases (UGTs) from the 1A subfamily and human hepatic microsomes. Recombinant UGT1A4 catalyzed the formation of N-glucuronides of Tam and its derivatives and was the most active UGT enzyme toward these compounds. Therefore, it was hypothesized that single nucleotide polymorphisms (SNPs) in the promoter region of UGT1A4 have the ability to significantly decrease the glucuronidation rates of Tam metabolites in the human liver. In vitro activity of 64 genotyped human liver microsomes was used to determine the association between the UGT1A4 promoter and coding region SNPs and the glucuronidation rates of Tam, 4OHTam, Tor, and 4OHTor. Significant decreases in enzymatic activity were observed in microsomes for individuals heterozygous for -163G/A and -217T/G. These alterations in glucuronidation may lead to prolonged circulating half-lives and may potentially modify the effectiveness of these drugs in the treatment of breast cancer.

Sulfotransferase 1A1 (SULT1A1) gene expression is regulated by members of the NFI transcription factors in human breast cancer cells.

BACKGROUND: Sulfotransferase 1A1 (SULT1A1) gene expression is tissue specific, with little to no expression in normal breast epithelia. Expression in breast tumors has been documented, but the transcriptional regulation of SULT1A1 in human breast tissue is poorly understood. We identified Nuclear Factor I (NFI) as a transcription factor family involved in the regulation of SULT1A1 expression. METHODS: Transcription Factor Activation Profiling Plate Array assay was used to identify the possible transcription factors that regulate the gene expression of SULT1A1in normal breast MCF-10A cells and breast cancer ZR-75-1 cells. Expression levels of NFI-C and SULT1A1 were determined by real-time RT-PCR using total RNA isolated from 84 human liver samples. Expression levels of SULT1A1, NFI-A, NFI-B, NFI-C, and NFI-X were also determined in different human breast cancer cell lines (MCF-7, T-47D, ZR-75-1, and MDA-MB-231), in the transformed human epithelial cell line MCF-10A, and in ZR-75-1 cells that were transfected with siRNAs directed against NFI-A, NFI-B, NFI-C, or NFI-X for 48 h. The copy numbers of SULT1A1 in cell lines ZR-75-1, MCF-7, T-47D, MDA-MB-231, and MCF-10A were determined using a pre-designed Custom Plus TaqMan® Copy Number kit from Life Technologies. RESULTS: In normal human liver samples, SULT1A1 mRNA level was positively associated with NFI-C. In different human breast cancer and normal epithelial cell lines, SULT1A1 expression was positively correlated with NFI-B and NFI-C. SULT1A1 expression was decreased 41% and 61% in ZR-75-1 cells treated with siRNAs against NFI-A and NFI-C respectively. SULT1A1 gene expression was higher in cells containing more than one SULT1A1 copy numbers. CONCLUSIONS: Our data suggests that SULT1A1 expression is regulated by NFI, as well as SULT1A1 copy number variation in human breast cancer cell lines. These data provide a mechanistic basis for the differential expression of SULT1A1 in different tissues and different physiological states of disease.

Genetic variability in energy balance and pancreatic cancer risk in a population-based case-control study in Minnesota.

OBJECTIVES: Accumulating evidence suggests that energy imbalance plays a role in pancreatic carcinogenesis. However, it remains unclear whether single-nucleotide polymorphisms (SNPs) in genes regulating energy homeostasis influence pancreatic cancer risk. We investigated this question in a case-control study conducted from 1994 to 1998. METHODS: Patients (n = 173) were ascertained from hospitals in the Twin Cities and Mayo Clinic, Minnesota. Control subjects (n = 476) were identified from the general population and frequency matched to patients by age and sex. Seven SNPs were evaluated in relation to pancreatic cancer using unconditional logistic regression. RESULTS: After adjustment for confounders, the leucine/proline or proline/proline genotype of the neuropeptide Y (NPY) gene rs16139 was associated with a lower risk than the leucine/leucine genotype (odds ratio, 0.40 [95% confidence interval, 0.15-0.91]). Conversely, an increased risk was observed for the glycine/arginine or arginine/arginine genotype of the adrenoceptor ß2, surface (ADRB2) gene rs1042713 as compared with the glycine/glycine genotype (odds ratio, 1.52 [95% confidence interval, 1.01-2.31]). CONCLUSIONS: This study first reveals that SNPs in genes modulating energy intake (NPY) and energy expenditure (ADRB2) altered pancreatic cancer risk. If confirmed by other studies, our findings may shed new light on the etiology and prevention of pancreatic cancer.