Investigation of DPYD, MTHFR and TYMS polymorphisms on 5-fluorouracil related toxicities in colorectal cancer.

Aim: To investigate the association of DPYD, MTHFR and TYMS polymorphisms on 5-fluorouracil (5-FU) related toxicities and patient survival. Materials & methods: A total of 103 colorectal cancer patients prescribed 5-FU were included in the study. Genotyping was conducted for several DPYD, MTHFR and TYMS polymorphisms using a microarray analyzer. Results: DPYD 496A>G polymorphism was found to be significantly associated with 5-FU related grade 0-2, but not severe toxicities (p = 0.02). Furthermore, patients with DPYD 85TC and CC genotypes had longer progression and overall survival times compared to TT genotypes in our study group (log rank = 6.60; p = 0.01 and log rank = 4.40; p = 0.04, respectively). Conclusion: According to our results, DPYD 496AG and GG genotypes might be protective against severe adverse events compared to the AA genotype. Another DPYD polymorphism, 85T>C, may be useful in colorectal cancer prognosis. Further studies for both polymorphisms should be conducted in larger populations to achieve accurate results.

5-fluorouracil (5-FU) is a widely used drug for chemotherapy in colorectal cancer. In this study, we investigated the relationship between the severity of 5-FU induced adverse events and several variations in DPYD, MTHFR and TYMS genes, which encode the enzymes involved in 5-FU metabolism in a total of 103 colorectal patients. We also examined the relationship between the polymorphisms and progression-free and overall survival times of the patients in our study group. Among the variations, DPDY 496A>G polymorphism was found to be associated with 5-FU induced adverse events. Also, the DPYD 85T>C polymorphism was detected to be associated with longer progression-free and overall survival times.

Investigation of Vascular Endothelial Growth Factor Polymorphisms on Risk, Metastasis, Laterality, and Prognosis of Colorectal Cancer in Turkish Subjects.

Objectives: Tumor angiogenesis is known to support the spread and invasion of tumor cells, allow distant organ metastasis and to result in poorer prognoses and increased mortality. Since vascular endothelial growth factor-A (VEGF-A) is the major regulator of angiogenesis, in the present study the associations of the VEGF-A +405G>C and -460C>T polymorphisms with risk, primary tumor location, prognosis and metastasis of colorectal cancer (CRC) were investigated in Turkish subjects. Material and Methods: A total of 153 subjects consist of 74 controls and 79 CRC diagnosed patients were included in the study. VEGF-A +405G>C and -460C>T polymorphisms were analyzed using the Agena MassARRAY platform. Results: The VEGF +405GC+CC genotypes were found to be significantly associated with left colon cancer (unadjusted OR = 5.208 95% CI: 1.064-25.496, p = 0.04). The VEGF -460TT and CT+TT genotypes were associated with reduced liver metastasis risk (OR = 0.080 95% CI: 0.009-0.689 p = 0.02 and OR = 0.191 95% CI: 0.039-0.925, p = 0.04, respectively). Patients with the VEGF +405GG genotype showed longer progression-free survival in response to bevacizumab treatment (Log rank = 6.92, p = 0.03). Conclusion: According to our results, the VEGF +405G>C and -460C>T polymorphisms were found to be associated with CRC prognosis, sidedness and metastases. Our findings need to be replicated in further studies.

Association of PD-1 and PDL-1 gene polymorphisms with colorectal cancer risk and prognosis.

BACKGROUND: Programmed Cell Death-1 (PD-1) together with Programmed Death Ligand 1 (PDL-1) have crucial roles in anti-tumor immune response, cancer susceptibility and prognosis. Since PD-1 and PDL-1 have been considered as important genetic risk factors in cancer development and their functions can be affected by polymorphic sites, we investigated the effects of PD-1 rs2227981, rs2227982, rs36084323 and PDL-1 rs2282055, rs822336 gene polymorphisms on colorectal cancer (CRC) risk and prognosis in Turkish subjects. METHODS AND RESULTS: Our study group consisted of 5-FU or Capacitabine prescribed CRC diagnosed patients and healthy controls. Genotype analyses of PD1 and PDL-1 polymorphisms were performed with Agena MassARRAY platform. rs36084323 CT genotype frequency was found to be higher in controls compared to cases (p < 0.001). rs36084323 CT genotype was highly associated with reduced CRC risk compared to CC genotype (OR 0.068, 95% CI 0.022-0.211, p < 0.001). In adjusted analysis, rs2282055 GG genotype was found to be associated with reduced CRC risk (OR 0.271, 95% CI 0.078-0.940, p = 0.040). rs2282055 TT genotype was found to be related to longer progression-free (Bonferroni corrected Log rank p = 0.013) and overall survival (Bonferroni corrected Log rank p = 0.009) to that of GG genotypes. Patients with rs822336 GC+CC genotypes showed longer overall survival times compared to GG (Log rank p = 0.044). CONCLUSIONS: According to our results, PD-1 rs822336 G > C polymorphism might be useful in predicting CRC prognosis. PDL-1 rs2282055 T > G polymorphism might be useful in predicting both CRC risk and prognosis. Further studies should be conducted in larger and different populations to clear the roles of PD-1 and PDL-1 polymorphisms in CRC risk and prognosis.

The effects of CYP2C9 and VKORC1 gene polymorphisms on warfarin maintenance dose in Turkish cardiac patients.

Aim: Our aim was to examine the effect of CYP2C9 and VKORC1 polymorphisms on warfarin dose requirements in Turkish patients. Materials & methods: 24 warfarin prescribed patients were included and analyzed for eight VKORC1 and 6 CYP2C9 polymorphisms in the study. Results: Patients with CYP2C9 *1/*1 and VKORC1 -1639 GG and GA genotypes required higher warfarin doses in comparison to wild type VKORC1 genotype. Patients with CYP2C9 *1/*3 and VKORC1 -1639 GG genotypes simultaneously, required the lowest dose of warfarin (4.64 mg/day). Patients with CYP2C9 *1/*1 and VKORC1 9041 AA genotype were found to require higher warfarin doses. Conclusion: Our results provide additional evidence to support the hypothesis that CYP2C9 *2, *3, VKORC1 9041 G > A polymorphisms explain considerable proportion of inter-individual variability in warfarin dose requirement.

The association between aspirin resistance and extent and severity of coronary atherosclerosis.

OBJECTIVE: Uncontrolled inflammatory responses could contribute to the pathogenesis of many leading causes of human morbidity and mortality. Aspirin is an anti-inflammatory and antithrombotic drug that is used in the primary and secondary protection in atherothrombotic diseases and complications. The aim of the present study was to analyze the effect of aspirin resistance on the extent and severity of atherosclerosis. METHODS: One hundred patients who underwent coronary angiography with suspected or known coronary artery disease and were using aspirin were enrolled in the study. RESULTS: Of these 100 patients, 30 (8 female and 22 male) formed the aspirin-resistant group (ARG), and 70 (22 female and 48 male) formed the control group. Gensini scoring system (GSS) was significantly higher in the ARG than in the control group (80.5 (36-166) vs. 45 (2-209); p<0.001). The number of percutaneous coronary intervention (PCI) patients was significantly higher in the ARG (13 of 30 (43.3%) ARG vs. 13 of 70 (18.6%) control group; p=0.01). Furthermore, when we evaluate the 16 reintervention patients, stent restenosis was significantly higher in the ARG (11 of 16 (68.75%) ARG vs. 5 of 16 (31.25%) control group; p=0.016). Multivariate logistic regression analysis revealed that GSS (p=0.038; 95% CI: 1.001-1.026) and PCI history (p=0.017; 95% CI: 1.182-89.804) were independent risk factors for aspirin resistance. CONCLUSION: In conclusion, atherosclerotic burden as calculated by the GSS is significantly higher in aspirin-resistant patients. According to this result, we suggest that aspirin treatment can be prescribed in higher doses in aspirin resistance patients with coronary events. Furthermore, GSS and PCI history could be independent predictors of aspirin resistance.

Effect of obesity and serum leptin level on clopidogrel resistance.

OBJECTIVE: Clopidogrel inhibits platelet aggregation by blockade of platelet adenosine diphosphate (ADP) P2Y12 receptor. Leptin is the obesity gene product, and its serum level increases with obesity. Platelets have leptin receptors on their surfaces. Hyperleptinemia may induce ADP-mediated platelet aggregation. It has been proposed that clopidogrel effect could be diminished with high serum leptin levels. The aim of the present trial was to further investigate the relationship between serum leptin level and clopidogrel resistance. METHODS: A total of 100 subjects who underwent percutaneous coronary intervention were enrolled. Two groups were organized according to presence of clopidogrel resistance, and serum leptin levels were compared. Threshold for clopidogrel resistance and hyperleptinemia were accepted as ≥P2Y12 reaction unit (PRU) 240 and ≥15 ng/mL leptin, respectively. Body mass index (BMI) of 30 kg/m2 or greater was considered obese. RESULTS: A total of 37% of patients were considered clopidogrel-resistant. Comparison of groups revealed significantly higher clopidogrel resistance (p=0.017) and PRU levels (p=0.001) in hyperleptinemic patients. No significant difference in serum leptin levels (p=0.116) was found. Increased clopidogrel resistance was observed in patients with BMI >30 kg/m2 (p=0.015). CONCLUSION: Clopidogrel resistance is more common in obese and hyperleptinemic patients. Dosage should be individualized in these populations.

The Relationship between P & QT Dispersions and Presence & Severity of Stable Coronary Artery Disease.

BACKGROUND AND OBJECTIVES: The study aimed to evaluate the correlation between electrocardiographic (ECG) parameters and presence and extent of coronary artery disease (CAD) to indicate the usefulness of these parameters as predictors of severity in patients with stable CAD. SUBJECTS AND METHODS: Two hundred fifty patients, without a history of any cardiovascular event were included in the study. The ECG parameters were measured manually by a cardiologist before coronary angiography. The patients were allocated into five groups: those with normal coronary arteries (Group 1), non-critical coronary lesions (Group 2), one, two and three vessel disease (Group 3, Group 4 and Group 5, respectively. RESULTS: Group 1 had the lowest P wave dispersion (PWD) and P wave (Pmax), QT interval (QTmax), QT dispersion (QTd), corrected QT dispersion (QTcd) and QT dispersion ratio (QTdR), while the patients in group 5 had the highest values of these parameters. Gensini score and QTmax, QTd, QTcmax, QTcd, QTdR, Pmax, and PWD were positively correlated. QTdR was the best ECG parameter to differentiate group 1 and 2 from groups with significant stenosis (groups 3, 4, and 5) (area under curve [AUC] 0.846). QTdR was the best ECG parameter to detect coronary arterial narrowing lesser than 50% and greater than 50%, respectively (AUC 0.858). CONCLUSION: Presence and severity of CAD can be determined by using ECG in patients with stable CAD and normal left ventricular function.

Leptin and leptin receptor polymorphisms are related to body mass index in a Turkish population.

BACKGROUND/AIM: Leptin is a hormone that is known to be related to weight gain and obesity. The soluble leptin receptor has been found in plasma as an important determinant of leptin sensitivity. In this study, our goal was to investigate the association between leptin levels and leptin receptor polymorphisms in a Turkish population. MATERIALS AND METHODS: The sample pool of this study consisted of 202 subjects. G2548A variant in the promoter region of the leptin gene and Q223R polymorphism of the leptin receptor gene were evaluated by using PCR-RFLP. Leptin levels were determined by ELISA. RESULTS: Leptin levels were significantly higher in subjects with the A allele than in subjects without the A allele. Leptin receptor levels were lower in subjects with the AA genotype than in those with the AG genotype. There was a higher prevalence of the leptin-2548 AA genotype among subjects with a BMI ≥ 25 kg/m2 than in those with a BMI < 25 kg/m2. CONCLUSION: The leptin-2548A allele might be a predisposing factor for obesity.

The association between coronary atherosclerotic burden and asymmetric dimethylarginine, carotis intima media thickness and endothelial function.

OBJECTIVES: Detection of extent and severity of atherosclerosis using easy, non-invasive methods is of great importance. Atherosclerotic burden may be evaluated with the Gensini scoring system (GSS). Carotis intima media thickness (CIMT), plasma asymmetric dimethyl arginine (ADMA) level, and endothelial dysfunction are well known surrogate markers of atherosclerosis. The aim of this study was to evaluate the relationship between atherosclerotic burden determined by the GSS, and ADMA, CIMT and endothelial function. STUDY DESIGN: Consecutive patients who had undergone coronary angiography were evaluated. 50 patients with acute coronary syndrome (ACS), 50 patients with stable coronary artery disease (SCA), and 50 patients with normal coronary arteries (NCA) were included. All subjects' GSS, ADMA, CIMT and endothelial functions were evaluated and compared. RESULTS: GSS was higher in ACS than SCA (75.4 vs 54.9; p<0.001). CIMT was higher in ACS and SCA in compared to NCA (0.98, 0.96, 0.78 mm respectively; p<0.001). Endothelium derived vasodilatory response (EDVR) was decreased in ACS and SCA in compared to NCA (3.5±2.1%, 3.3±1.8%, 7.2±3.5% respectively; p<0.001). Plasma ADMA concentration was higher in ACS and SCA in compared to NCA (0.928, 0.992, 0.475 µmol/l respectively; p<0.001). There was a weak positive correlation between GSS and plasma ADMA levels (r=0.293; p=0.002), an intermediate positive correlation between GSS and CIMT (r=0.508; p<0.001), and an intermediate negative correlations between GSS and EDVR (r= -0.662; p<0.001). CONCLUSION: This study showed that CIMT, ADMA concentration and endothelial dysfunction were significantly associated with CAD. However, only the GSS was significantly different between ACS and SCA groups.

Remote monitoring of left ventricular assist device parameters after HeartAssist-5 implantation.

Although several left ventricular assist devices (LVADs) have been used widely, remote monitoring of LVAD parameters has been available only recently. We present our remote monitoring experience with an axial-flow LVAD (HeartAssist-5, MicroMed Cardiovascular, Inc., Houston, TX, USA). Five consecutive patients who were implanted a HeartAssist-5 LVAD because of end-stage heart failure due to ischemic (n=4) or idiopathic (n=1) cardiomyopathy, and discharged from hospital between December 2011 and January 2013 were analyzed. The data (pump speed, pump flow, power consumption) obtained from clinical visits and remote monitoring were studied. During a median follow-up of 253 (range: 80-394) days, fine tuning of LVADs was performed at clinical visits. All patients are doing well and are in New York Heart Association Class-I/II. A total of 39 alarms were received from three patients. One patient was hospitalized for suspected thrombosis and was subjected to physical examinations as well as laboratory and echocardiographic evaluations; however, no evidence of thrombus washout or pump thrombus was found. The patient was treated conservatively. Remaining alarms were due to insufficient water intake and were resolved by increased water consumption at night and summer times, and fine tuning of pump speed. No alarms were received from the remaining two patients. We believe that remote monitoring is a useful technology for early detection and treatment of serious problems occurring out of hospital thereby improving patient care. Future developments may ease troubleshooting, provide more data from the patient and the pump, and eventually increase physician and patient satisfaction. Despite all potential clinical benefits, remote monitoring should be taken as a supplement to rather than a substitute for routine clinical visits for patient follow-up.

Prevalence of endothelial nitric oxide synthase E298D polymorphism in Turkish patients with essential hypertension.

AIMS: Our aim was to evaluate the effects of endothelial nitric oxide synthase (eNOS) E298D polymorphism in obesity variables and essential hypertension (eHT) development risk. The genotype frequencies of E298D polymorphism in eHT patients and non-hypertensive (non-HT) controls (proven to have normal coronaries angiographically) were analyzed for their association with demographic and obesity related data of the eHT patients and controls. MATERIALS AND METHODS: eNOS gene E298D genotypes were determined with qPCR. RESULTS: The eNOS E298D polymorphism frequencies for 298E/E, 298E/D and 298D/D genotypes were respectively as 41.1%, 44.6%, 14.3% in subjects eHT and 52.8%, 38.9%, 8.3% in the non-HT groups. The combined E298D homozygous polymorphic and heterozygous genotypes were found to have a decreasing effect on serum total-cholesterol levels in comparison to wild-type genotypes in eHT patients but not controls. CONCLUSIONS: Our results support the idea that, the eNOS E298D polymorphism, which is not associated with hypertension, may increase the risk of hypertension when associated with high serum total-cholesterol levels.

Management of a rare case of arrhythmogenic right ventricular dysplasia in pregnancy: a case report.

INTRODUCTION: Arrhythmogenic right ventricular dysplasia is a heritable disease of the heart muscle characterized by fibrofatty degeneration of cardiomyocytes. Patients present with ventricular arrhythmias or congestive heart failure, and sometimes sudden cardiac death occurs. Prenatal diagnosis has become possible with the detection of mutations, but, to the best of our knowledge, no case of prenatal diagnosis has been reported previously. There is little information about the management of arrhythmogenic right ventricular dysplasia in pregnancy, and the preferred mode of delivery is not certain; therefore, we present the case of a patient with arrhythmogenic right ventricular dysplasia and discuss the prenatal diagnosis, patient management and prognosis in pregnancy. CASE PRESENTATION: A 26-year-old Caucasian woman who presented to our hospital with heart palpitations was diagnosed with arrhythmogenic right ventricular dysplasia, and, after three years of follow up with anti-arrhythmic drugs, she wanted to conceive. During pregnancy, she ceased taking her medication. She tolerated pregnancy very well but her cardiac symptoms recurred after her 30th week of pregnancy. She delivered a baby via cesarean section under general anesthesia in her 38th week of pregnancy. She was discharged without any medications and continued lactation for six months. CONCLUSION: Patients with mild to moderate arrhythmogenic right ventricular dysplasia tolerate pregnancy and breastfeeding very well, but patients with end-stage arrhythmogenic right ventricular dysplasia should be discouraged from conception.

Presence of fatty-acid-binding protein 4 expression in human epicardial adipose tissue in metabolic syndrome.

BACKGROUND: Metabolic syndrome is a cluster of different clinical manifestations that are risk factors for atherothrombotic cardiovascular disorders. Fatty-acid-binding protein 4 (FABP4/aP2), which is highly expressed in adipocytes, specifically exerts intracellular lipid trafficking. A high level of fatty-acid-binding protein 4 expression present in obese subjects has also been found in mice and humans, especially in macrophages at atherosclerotic lesions. An in vivo study demonstrated that the inhibitor of aP2 would be a new therapeutic agent for treating metabolic diseases in mice. We have investigated the mRNA expression of fatty-acid-binding protein 4 in human epicardial adipose and ascending aorta tissues of metabolic syndrome and nonmetabolic syndrome patients. METHODS: Paired epicardial adipose and ascending aorta tissue samples were obtained from 10 metabolic syndrome patients and 4 nonmetabolic syndrome patients during coronary bypass grafting and aortic valve replacement therapy, respectively. Fatty-acid-binding protein 4 gene expression was determined by quantitative real-time polymerase chain reaction. RESULTS AND CONCLUSIONS: Fatty-acid-binding protein 4 expression of epicardial adipose tissue was significantly higher in metabolic syndrome patients than in nonmetabolic syndrome controls (P<.05). In metabolic syndrome patients, fatty-acid-binding protein 4 expression in epicardial adipose tissue was 66 times higher than fatty-acid-binding protein 4 expression in ascending aorta tissue. The expression level of fatty-acid-binding protein 4 in epicardial adipose tissue was found to be significantly correlated with waist circumference in all subjects (r=.535, P<.05). Our data showed for the first time that human epicardial adipose and ascending aorta tissues express fatty-acid-binding protein 4 and that its level of expression in epicardial adipose tissues of metabolic syndrome patients is elevated. Increased fatty-acid-binding protein 4 gene expression in epicardial adipose tissues of metabolic syndrome patients led us think that fatty-acid-binding protein 4 might be an important factor in metabolic syndrome.

Lipoprotein lipase gene PvuII polymorphism serum lipids and risk for coronary artery disease: meta-analysis.

Our aim was to determine whether lipoprotein lipase gene PvuII polymorphism can be considered as an independent risk factor for coronary artery disease (CAD) by conducting a meta-analysis of all available published trials, including our own study. In 7 seperate studies, 3289 subjects were screened for this substitution; meta-analysis included only some of these individuals. Among the 7 studies, 6 were performed on white subjects, whereas 1 was on patients with Saudi Arabic descent.Subgroup analysis indicated that individuals with PvuII substitution does not have an increased risk for CAD. The LPL-PvuII genotype and allele frequency distributions did not differ significantly between CAD patients and healthy controls. There was no difference in the distribution of LPL-PvuII genotypes between the healthy subjects and the patients with CAD. However, no significant differences in lipid variables (triglyceride and HDL-cholesterol) were determined for the PvuII polymorphisms in the patients with CAD. No significant differences were found in serum triglyceride and HDL-cholesterol levels for LPL-PvuII genotypes when the control and CAD groups were pooled. In conclusion, LPL-Pvu II polymorphism cannot be used as independent genetic risk factor for CAD.

[The effects of phase II cardiac rehabilitation programme on patients undergone coronary bypass surgery]. / Koroner baypas geçiren olgularda faz II kardiyak rehabilitasyon programinin etkileri.

OBJECTIVE: To investigate the effects of phase II cardiac rehabilitation in 52 patients undergone coronary artery bypass surgery. METHODS: Gradual walking tests, cardio-pulmonary capacity tests and lipid profile were administered to patients selected for phase II cardiac rehabilitation before and after the programme. Training was started on 12-channel electrocardiogram controlled running bands 3 times a week for 20 min periods for 12 weeks fitting the programme. Low or intermediate level exercise programme was applied to patients. Cleveland Clinic Chronotropic Assessment exercise protocol was used during rehabilitation. RESULTS: As a result of phase II cardiac rehabilitation administered to 52 patients undergone coronary bypass operation, exercise capacity, oxygen consumption, anaerobic threshold, cardiac output mean values (p<0.001) and mean HDL cholesterol level (p<0.05) were found to increase, whereas body mass index, total cholesterol, LDL cholesterol and triglyceride mean levels reduced (p<0.001) significantly. CONCLUSION: In patients who have undergone coronary bypass surgery, phase II cardiac rehabilitation is a very useful programme in improvement of life quality and secondary prevention.