Variants in the ATM‐CHEK2‐BRCA1 axis determine genetic predisposition and clinical presentation of papillary thyroid carcinoma

The risk of developing papillary thyroid carcinoma (PTC), the most frequent form of thyroid malignancy, is elevated up to 8.6‐fold in first‐degree relatives of PTC patients. The familial risk could be explained by high‐penetrance mutations in yet unidentified genes, or polygenic action of low‐penetrance alleles. Since the DNA‐damaging exposure to ionizing radiation is a known risk factor for thyroid cancer, polymorphisms in DNA repair genes are likely to affect this risk. In a search for low‐penetrance susceptibility alleles we employed Sequenom technology to genotype deleterious polymorphisms in ATM, CHEK2, and BRCA1 in 1,781 PTC patients and 2,081 healthy controls. As a result of the study, we identified CHEK2 rs17879961 (OR = 2.2, P = 2.37e‐10) and BRCA1 rs16941 (odds ratio [OR] = 1.16, P = 0.005) as risk alleles for PTC. The ATM rs1801516 variant modifies the risk associated with the BRCA1 variant by 0.78 (P = 0.02). Both the ATM and BRCA1 variants modify the impact of male gender on clinical variables: T status (P = 0.007), N status (P = 0.05), and stage (P = 0.035). Our findings implicate an important role of variants in the ATM‐ CHEK2‐ BRCA1 axis in modification of the genetic predisposition to PTC and its clinical manifestations. © 2014 Wiley Periodicals, Inc.     

MMP-9 and MMP-2 regulation in patients undergoing non-oncological and non-vascular elective surgery independent of the use of propofol or sevoflurane

BackgroundThere is debate regarding whether inhaled sevoflurane or intravenous propofol used during anesthesia achieves the best outcome. Propofol has been shown to affect expression of matrix metalloproteinases (MMPs). MMPs are enzymes that play a role in extracellular matrix remodeling, with activity balance disturbances during surgery. The goal of this study was to compare MMP-2/9 concentrations, activity, and tissue inhibitors of metalloproteinases (TIMPs) 1/2 concentrations in blood of who had undergone 2 types of anesthesia: based on volatile sevoflurane and intravenous propofol during non-oncological, non-vascular surgery.Methods39 patients were enrolled into analysis, 20 anesthetized with total intravenous anesthesia with propofol (P), 19 with volatile induction/maintenance of anesthesia with sevoflurane (S). Plasma samples collected before and 24 h after surgery were analyzed for MMP-2/9, and TIMP-1/2 concentrations using ELISAs. Additionally, MMP-2/9 activities were assessed by gelatin zymography.ResultsStudy revealed increased MMP-9 concentration (ELISA) (P:p = 0.011; S:p = 0.001) and activity (zymography) (P:p = 0.004; S:p = 0.008) in both groups 24 h after surgery. We noticed decreased (both groups) MMP-2 concentration (P:p = 0.044; S:p = 0.027) with MMP-2 activity increase (P:p = 0.002; S:p = 0.006) 24 h after surgery. We observed decreased TIMP-1 plasma concentrations (P:p = 0.002; S:p = 0.000) 24 h after procedures, while TIMP-2 plasma levels remain unchanged (P:p = 0.097; S:p = 0.172). There were no differences between concentration and activity of MMPs and TIMPs in regard to anesthetic used. Meperidine administration correlated with lower MMP-9 activity (R=-0.430; p = 0.006).ConclusionsConcluding, neither sevoflurane nor propofol used as anesthetics modulate MMP-2 and MMP-9 concentrations and activities during non-oncological, non-vascular elective surgery. Meperidine seems to decrease MMP-9 activity.     

Ulcerated plaques of the aorta as a cause of ischaemic stroke

Stroke is a second cause of mortality worldwide and a leading cause of acquired disability in adults. Approximately 20% of all ischaemic strokes are of cardioembolic origin. We present a case of a 60-year-old man with a history of stroke without changes in carotid and vertebral arteries. Echocardiography exam revealed patent foramen ovale (PFO) and abnormal echos in the aorta that were verified as advanced complex atheromas by computed tomography. Due to small size PFO was deemed insignificant and the source of embolism were most probably aortic atheromas. Patient was put on acenocumarol, aspirin and statin.     

Clinical characteristics, sex hormones, and long-term follow-up in Swiss postmenopausal women presenting with Takotsubo cardiomyopathy

Background:

The overwhelming majority of patients with stress cardiomyopathy (SC) are postmenopausal women, suggesting an important pathophysiologic role of the female sex hormones. Preliminary data suggest that myocardial stunning might be provoked by estrogen deficiency.

Hypothesis:

We hypothesized that, compared with age‐ and gender‐matched patients with myocardial infarction (MI) or patients with normal coronary arteries, patients with SC would exhibit altered levels of sex hormones. Furthermore, we aimed to describe the clinical course and the pattern of sex hormones of the SC patients during long‐term follow‐up.

Methods:

Blood samples obtained on hospital admission were analyzed for estradiol (E2), progesterone (P), luteinizing hormone (LH), and follicle‐stimulating hormone (FSH) in women with SC (n = 17), age‐matched women with acute MI (n = 16), and women with normal coronary arteries (n = 15). Six years after the initial event, SC patients underwent a clinical and echocardiographic follow‐up and reassessment of sex hormones.

Results:

Estrogen concentrations at hospital admission were significantly higher in the SC group compared with the MI and the control groups, with no difference in P, FSH, and LH concentrations. Follow‐up E2 after 6 years in SC patients was lower than during the acute SC episode. Follow‐up P in these patients was lower than P in the MI and control groups during the acute event, with a similar trend for E2. After a median follow‐up of 6.4 years, 1 sudden cardiac death occurred and 2 patients suffered from SC recurrence.

Conclusions:

During the acute event, E2 concentrations are elevated in postmenopausal SC patients compared with women with acute MI or with normal coronary arteries. The higher E2 concentrations might have exerted atheroprotective effects and thus diverted the stress response to SC rather than MI. Recurrence and/or sudden cardiac death remains a potential risk of SC. Clin. Cardiol. 2012 DOI: 10.1002/clc.21986 Roman Brenner, MD, and Daniel Weilenmann, MD, contributed equally to this work and should be considered first authors. The authors have no funding, financial relationships, or conflicts of interest to disclose.     

EGFR mutation testing on cytological and histological samples in non-small cell lung cancer: a Polish,single institution study and systematic review of European incidence

The targeted treatment of advanced non-small-cell lung cancer (NSCLC) depends on confirmation of activating somatic EGFR mutation. The aim of the study was to evaluate the incidence of EGFR mutations in NSCLC detected in cytological and histological material and present literature review on European EGFR mutation incidence. 273 patients with confirmed NSCLC were entered into the study: 189 histological, paraffin-embedded materials, 12 fresh and 72 fixed cytological specimens. DNA was extracted from both types of material and the EGFR mutation in exons 18-21 was analyzed by direct sequencing. In addition the EGFR gene copy number in cases with sufficient histological material (110 patients) was evaluated by fluorescent in situ hybridization (FISH) technique. The percentage of EGFR somatic mutations was 10.62%. FISH positive results (amplification or high polysomy of EGFR gene) were identified in 33 patients (30.0%). The strongest clinicopathological correlation with the EGFR mutation was found for histological type (adenocarcinoma; p < 0.01), gender (females; p < 0.01) and FISH positive result (p < 0.05). This is the first, single institution study that estimates the EGFR mutation incidence in the Polish population. Cytological material recovered from fixed preparations and stained with hematoxylin and eosin showed DNA quality comparable to fresh tumor cells and histological samples.     

Resistant hypertension in visceral obesity

BackgroundVisceral obesity increases the risk of arterial hypertension (78% of cases of hypertension in men and 65% of cases in women). The aim of the study is to assess the role of visceral obesity in causing resistant hypertension (RH).MethodsThe survey was performed on 5065 hypertensive patients with visceral obesity. BP control was analyzed on the basis of office and home BP measurements. Patients reporting non-compliance were excluded from the study.ResultsThe percentage of RH after excluding undertreated patients (receiving less than 3 drugs or on at least 3-drug regimen without diuretic and without reaching target BP goal) was 13.9%. RH was more frequent only in obese with BMI ≥ 35 and < 40 kg/m² (16.2%) and in morbidly obese individuals (26.5%). Patients with BMI ≥ 35 and < 40 kg/m² and with morbid obesity were receiving three-drug therapy more frequently than patients with visceral obesity and BMI < 30 kg/m². A multiple regression analysis revealed that obesity was associated with RH independent from longer than 5-year period of antihypertensive therapy, diabetes, smoking cigarettes, cardiovascular disease and heart failure. The analysis of home BP measurement revealed that in 11.1% of patients RH was in fact “white coat” hypertension.ConclusionsUndertreatment, underuse of diuretics in multidrug regimens, and the “white-coat” effect are the most common reasons for over-diagnosing resistant hypertension in patients with visceral obesity. Obesity is an independent risk factor for the occurrence of RH.