Analysis of 17,576 Potentially Functional SNPs in Three Case–Control Studies of Myocardial Infarction

Myocardial infarction (MI) is a common complex disease with a genetic component. While several single nucleotide polymorphisms (SNPs) have been reported to be associated with risk of MI, they do not fully explain the observed genetic component of MI. We have been investigating the association between MI and SNPs that are located in genes and have the potential to affect gene function or expression. We have previously published studies that tested about 12,000 SNPs for association with risk of MI, early-onset MI, or coronary stenosis. In the current study we tested 17,576 SNPs that could affect gene function or expression. In order to use genotyping resources efficiently, we staged the testing of these SNPs in three case–control studies of MI. In the first study (762 cases, 857 controls) we tested 17,576 SNPs and found 1,949 SNPs that were associated with MI (P<0.05). We tested these 1,949 SNPs in a second study (579 cases and 1159 controls) and found that 24 SNPs were associated with MI (1-sided P<0.05) and had the same risk alleles in the first and second study. Finally, we tested these 24 SNPs in a third study (475 cases and 619 controls) and found that 5 SNPs in 4 genes (ENO1, FXN (2 SNPs), HLA-DPB2, and LPA) were associated with MI in the third study (1-sided P<0.05), and had the same risk alleles in all three studies. The false discovery rate for this group of 5 SNPs was 0.23. Thus, we have identified 5 SNPs that merit further examination for their potential association with MI. One of these SNPs (in LPA), has been previously shown to be associated with risk of cardiovascular disease in other studies

Altered Gene Expression by Low-Dose Arsenic Exposure in Humans and Cultured Cardiomyocytes: Assessment by Real-Time PCR Arrays

Chronic arsenic exposure results in higher risk of skin, lung, and bladder cancer, as well as cardiovascular disease and diabetes. The purpose of this study was to investigate the effects on expression of selected genes in the blood lymphocytes from 159 people exposed chronically to arsenic in their drinking water using a novel RT-PCR TaqMan low-density array (TLDA). We found that expression of tumor necrosis factor-α (TNF-α), which activates both inflammation and NF-κB-dependent survival pathways, was strongly associated with water and urinary arsenic levels. Expression of KCNA5, which encodes a potassium ion channel protein, was positively associated with water and toe nail arsenic levels. Expression of 2 and 11 genes were positively associated with nail and urinary arsenic, respectively. Because arsenic exposure has been reported to be associated with long QT intervals and vascular disease in humans, we also used this TLDA for analysis of gene expression in human cardiomyocytes exposed to arsenic in vitro. Expression of the ion-channel genes CACNA1, KCNH2, KCNQ1 and KCNE1 were down-regulated by 1-μM arsenic. Alteration of some common pathways, including those involved in oxidative stress, inflammatory signaling, and ion-channel function, may underlay the seemingly disparate array of arsenic-associated diseases, such as cancer, cardiovascular disease, and diabetes

Changing Epidemiology of Clostridium difficile–Associated Disease during Stem Cell Transplantation

AbstractThe incidence and severity of Clostridium difficile–associated disease (CDAD) within the general population has risen dramatically over the past decade, yet little data are available from hematopoietic stem cell transplantation (HSCT) centers. In the present study, we performed a chart review of 822 consecutive autologous and allogeneic HCST recipients treated at Northwestern Memorial Hospital between 2004 and 2008 to determine the incidence of CDAD at our institution. Variables including age, sex, diagnosis, chemotherapy regimen, transplantation type, microbial colonization, coinfections, diet, antibiotic use, neutropenic fever, comorbid conditions, time to engraftment, growth factor administration, and occurrence of graft-versus-host disease were assessed as potential risk factors for the development of CDAD. Eighty-five CDAD cases (10.3%) were identified. Bivariate analysis revealed a significant association between CDAD and neutropenic fever, administration of a neutropenic diet, ciprofloxacin and aztreonam use and duration of therapy, vancomycin and aztreonam use and duration of therapy, receipt of an allogeneic transplantation, bacterial coinfection, and vancomycin-resistant Entereococcus faecium (VRE) colonization. Cox regression analysis identified the following as factors associated with the development of CDAD: age >60 years, allogeneic transplantation, and prior VRE colonization. Allogeneic recipients with CDAD experienced increased higher rates of grades II to IV gastrointestinal graft-versus-host disease and nonrelapse mortality. A risk stratification model was developed to identify HSCT recipients at different levels of risk. With an incidence >10%, CDAD is a significant infectious complication of stem cell transplantation

A review in the treatment of oncologic emergencies

Aim Oncologic emergencies are often categorized as a group of metabolic abnormalities associated with the diagnosis of cancer or the initiation of chemotherapy for treatment. These syndromes often arise in the acute setting, demanding an accurate knowledge of the associated condition and current treatment. In this review, we evaluate five oncologic emergencies: tumor lysis syndrome, hypercalcemia, hyponatremia, spinal cord compression, and disseminated intravascular coagulation. Summary Oncologic emergencies are often diverse in etiology and are often associated with the initiation of chemotherapy. Tumor lysis syndrome presents as severe electrolyte abnormalities that need to be addressed urgently, sometimes prior to initiation of chemotherapy. Hypercalcemia of malignancy is treated with aggressive rehydration, furosemide, and intravenous bisphosphonates. If a patient with cancer presents with normovolemic hyponatremia, syndrome of inappropriate antidiuretic hormone should be suspected. Malignant spinal cord compression happens when cancer cells grow in, or near to, the spine and press on the spinal cord and nerves. This causes swelling and a reduction in the blood supply to the spinal cord and nerve roots. Disseminated intravascular coagulation is characterized by systemic activation of blood coagulation, which results in generation and deposition of fibrin, leading to microvascular thrombi in various organs and contributing to multiple organ dysfunction syndrome. Conclusion Knowledge of oncology emergencies is critical to the understanding of these emergent syndromes in oncology patients. Each of these disease states requires careful evaluation of the patient’s symptoms, monitoring parameters for conditions and supportive care measures and interventions. </jats:sec

Questioning the Role of a Neutropenic Diet following Hematopoetic Stem Cell Transplantation

The use of a neutropenic diet (ND) after hematopoietic stem cell transplantation (HSCT) was instituted more than 30 years ago as a means of preventing infection from organisms colonizing the gastrointestinal tract. Evidence supporting this practice is lacking, however, and the actual efficacy of the ND remains unknown. Institutional policy at Northwestern Memorial Hospital discontinued the use of ND in 2006. We conducted a retrospective study of 726 consecutive HSCT recipients, 363 who received an ND and 363 who received a general hospital diet, to determine the incidence of microbiologically confirmed infections during and after transplantation. Our findings indicate a higher rate of infections in the HSCT recipients who received an ND

Idarubicin Appears Equivalent to Dose-Intense daunorubicin for AML Induction

Abstract Abstract 3581 Worldwide cancer drug shortages have recently required the substitution of daunorubicin, the “gold standard” anthracycline for idarubicin for induction therapy in acute myeloid leukemia(AML). Previously published randomized trials have shown idarubicin (12/m2) to be equal to, or better than daunorubicin (45–50mg/m2) for achieving complete remission(Blood. 1991 Apr 15;77(8):1666–74). It is currently unknown whether these results can be extrapolated when compared to intensified doses of daunorubicin(90mg/m2), shown to improve the CR rate when compared to 45 mg/m2 (N Engl J Med. 2009 Sep 24;361(13):1249–59). We therefore conducted an observational study to compare CR rates in AML patients who received either daunorubicin 90mg/m2 or idarubicin 12mg/m2 for the treatment of newly diagnosed AML. Methods: Medical records were used to identify newly diagnosed patients with AML who received daunorubicin 90mg/m2(Dau-90) or idarubicin 12mg/m2(Ida-12) between 1/2007 and 6/2012. Patients with APL were excluded. MDS patients who evolved to AML were included. AML was diagnosed by WHO criteria. Patients received daunorubin 90mg/m2 IV bolus or idarubicin 12mg/m2 IV bolus on days 1–3. Cytarabine 100mg/m2 by continuous infusion was given concomitantly on day 1–7 to both groups. All patients underwent marrow biopsy on day 14 after initiation of therapy. If residual disease was found, patients were considered treatment failure. Patients without residual disease were re-biopsied around the time of WBC recovery to assess CR. CR rates are reported after a single induction course. Results: 28 Ida-12 and 37 Dau-90 patients were identified. Table 1 shows patient demographics and outcomes. There was no significant baseline difference between the 2 study arms for gender, age, weight, maximum WBC prior to therapy, cytogenetic risk group, percent of patients with FLT-3 ITD or NPM mutations, or combined risk factors. A non-significant trend was observed in the percent of marrow blasts prior to therapy and in the number of patients&gt;60years(but not for age &gt;55) within the Ida-12 study arm. Overall CR was similar between the Ida-12 and Dau- 90 treatment groups(p&lt;0.1072) Subset analysis shows CR rates were significantly higher in Ida-12 treated patients who had an unfavorable karyotype(p&lt;0.0359) or unfavorable combined cytogenetic risk(0.0388) or for age &gt; 55 years(p&lt;.0063). Overall morbidity and mortality was similar between groups. Conclusion: Ida-12 appears to be as effective as Dau-90 for achieving CR after a single induction course. Thus, Thus, substitution of Ida-12 for Dau-90 during times of drug shortages appears acceptable. Ida-12 may potentially be superior for patients &gt;55 years or for those with unfavorable cytogenetics. These results warrant validation from a randomized clinical trial. Disclosures: No relevant conflicts of interest to declare. </jats:sec

Tacrolimus Dosing in Allogeneic Hematopoietic Stem Cell Transplant (HSCT) Recipients Receiving Concomitant Voriconazole.

Abstract Tacrolimus is an effective immunosuppressive agent for allogeneic HSCT. It is primarily metabolized by the CYP450 3A4 isoenzyme. Voriconazole is often used to prevent fungal infections after allogeneic HSCT. It is metabolized by the CYP450 3A4, 2C9 and 2C19 isosenzymes. Studies in healthy volunteers and case reports in HSCT recipients have shown significant drug interaction between the two requiring reduction of tacrolimus dose. Ordinarily, tacrolimus prophylaxis is initiated at the dose of 0.03 mg/kg IV daily on day -1. After starting tacrolimus at this dose and having to reduce the dose substantially within 2–3 days in all patients receiving concomitant voriconazole 200 mg twice daily orally from day 0, we implemented a simple, pre-emptive tacrolimus dose reduction strategy to maintain steady-state levels between 5 and 15 ng/mL in patients on IV tacrolimus. As a first step, IV tacrolimus was initiated at the reduced dose of 0.022 mg/kg adjusted body weight per day. As a second step, tacrolimus dose was reduced by 30–40% if the steady-state level 48 h after initiation of tacrolimus (day +1) was between 7 and 10 ng/mL, and by 40–50% if the level was between 10 and 15 ng/mL. No change was made if the level was &lt;7 ng/mL. Subsequently, tacrolimus levels were monitored 2–3 times a week and the dose adjusted as needed. In this report, we evaluate the pharmacokinetic effects of concomitant voriconazole administration on blood tacrolimus levels in 27 consecutive allogeneic HSCT recipients (28–64 years; median 55) in whom the pre-emptive dose-modification strategy was used during the first 2 weeks after HSCT while they were receiving IV tacrolimus. A total of 170 levels (3–12 per patient; median 5) were checked between day +1 and day +16. None of the levels was subtherapeutic (&lt;5 ng/mL), and 34 (20%) were &gt;15 ng/mL. 24 of 27 patients required dose-reduction from day 0 to day +1 based on levels. Every single patient required dose-reduction at least twice. An increase in the dose was needed in only 2 patients after initial dose-reduction. The figure below shows the minimum, maximum, and median tacrolimus doses; depicting a steady decline in the median dose. Figure Figure The figure below illustrates that the median tacrolimus levels remained fairly steady as the median absolute tacrolimus dose, the median tacrolimus dose on a mg/kg basis, and the median per cent tacrolimus dose (100% being the baseline mg/kg dose) declined substantially. Figure Figure It is clear from the above figure that lack of pre-emptive dose-reduction would have resulted in tacrolimus levels climbing steadily. Based on these findings, we recommend starting tacrolimus at 0.02–0.022 mg/kg rather than at 0.03 mg/kg if patients are getting concomitant voriconazole, checking levels regularly, and reducing the drug dose by 30–40% if the level is between 7 amd 10, and by 40–50% if the level is between 10 and 15.</jats:p