Immunohistochemical evaluation of human epidermal growth factor receptor 2 and estrogen and progesterone receptors in invasive breast cancer in women

Introduction

Estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER-2) expression are crucial in the biology of breast carcinoma. HER-2/neu gene is amplified and overexpressed in 15-30% of invasive breast cancers. HER-2-positive breast cancers have worse prognosis than HER-2 negative tumors and possess distinctive clinical features. The aim of this study was to assess the expression of HER2 in cancer tissue of patients with invasive breast cancer in correlation with tumor type, histological grade, tumor size, lymph node status, and expression of estrogen receptor and progesterone receptor.

Material and methods

Formalin-fixed, paraffin-embedded tissues from 40 patients with invasive HER-2-positive breast cancer and from 191 patients with HER-2-negative breast cancer were used in this study. HER2 expression was determined using the test HerceptTest™ DAKO.

Results

Among 231 cases of breast cancer, 18 invasive lobular carcinomas and 213 invasive ductal carcinomas were diagnosed. Sixty percent of HER-2-positive breast cancers were ER-positive compared with 77% in the HER-2-negative group (p = 0.002). The expression of PR was observed in 43% of HER-2-positive breast cancers and in 72% of HER2-negative tumors (p = 0.003). Excessive expression of HER2 protein was detected in 60% of patients positive for estrogen receptors, which may worsen prognosis in these patients.

Conclusions

Determination of HER2 overexpression in breast cancer patients, allows for a determination of a group of patients with a worse prognosis.     

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.     

A framework for discussion on how to improve prevention, management, and control of hypertension in Canada

Increased blood pressure is a leading risk for premature death and disability. The causes of increased blood pressure are intuitive and well known. However, the fundamental basis and means for improving blood pressure control are highly integrated into our complex societal structure both inside and outside our health system and hence require a comprehensive discussion of the pathway forward. A group of Canadian experts was appointed by Hypertension Canada with funding from Public Health Agency of Canada and the Heart and Stroke Foundation of Canada, Canadian Institute for Health Research (HSFC-CIHR) Chair in Hypertension Prevention and Control to draft a discussion Framework for prevention and control of hypertension. The report includes an environmental scan of past and current activities, proposals for key indicators, and targets to be achieved by 2020, and what changes are likely to be required in Canada to achieve the proposed targets. The key targets are to reduce the prevalence of hypertension to 13% of adults and improve control to 78% of those with hypertension. Broad changes in government policy, research, and health services delivery are required for these changes to occur. The Hypertension Framework process is designed to have 3 phases. The first includes the experts' report which is summarized in this report. The second phase is to gather input and priorities for action from individuals and organizations for revision of the Framework. It is hoped the Framework will stimulate discussion and input for its full intended lifespan 2011-2020. The third phase is to work with individuals and organizations on the priorities set in phase 2.     

Complete surgical resection of lung tumor decreases exhalation of mutated KRAS oncogene

Exhaled breath condensate (EBC) contains extracellular DNA that may originate from pathological lesions of the respiratory tract and can be a genetic marker of pulmonary malignancy. We tested whether complete surgical excision of lung cancer will decrease exhalation of mutated KRAS oncogene. Fifty seven patients with clinical diagnosis of lung cancer and detectable KRAS mutations in pre-surgery EBC-DNA were qualified for surgical treatment. Point mutations at codon 12 of KRAS oncogene were detected using mutant-enriched PCR technique in DNA from pre-surgery blood, EBC collected before, 7 and 30 days after surgery and from specimens of resected tumor and normal pulmonary parenchyma. The ratio of mutated to wild type KRAS DNA (R mut/wild KRAS) was calculated for each specimen after electrophoresis and densitometry of the final amplification and digestion product. In 46 patients non-small cell lung cancer (NSCLC) and in 11 benign lesion (BL) were confirmed. All blood and tumor specimens were positive for KRAS mutations, while 41 specimens of normal pulmonary parenchyma were negative. In NSCLC patients pre-surgery EBC R mut/wild KRAS of 0.20?±?0.03 decreased by 1.3- and 3.7-times (p?相似文献   

Major liver resection results in early exacerbation of insulin resistance, and may be a risk factor of developing overt diabetes in the future

Purpose

This single center prospective cohort study evaluated the influence of hemihepatectomy on glucose homeostasis.

Methods

The study included 30 patients undergoing hemihepatectomy. All patients underwent an oral 75 g glucose tolerance test before (baseline), 1 week and 1 month after the surgery. Plasma glucose, insulin and glucagon were measured in the OGTT samples, and the HOMA index was calculated. The fasting levels of interleukin 6 and 1β, tumor necrosis factor and adiponectin were assessed.

Results

The fasting plasma and 120-min post-challenge mean glucose level increased during the study from 89.6 to 103.5 mg/dl (by 15.5 %) and from 136.4 to 162.2 (by 18.9 %; p = 0.51), respectively, accompanied by an increase in fasting glucagon (from 3.2 to 5.9 ng/mL; p = 0.043) and insulin (from 14.6 to 19.3 IU/mL) and by a decrease in plasma insulin at 60 min of OGTT (p = 0.34). An increase of IL-6 (p = 0.015) and TNF (from 49.7 to 53 pg/mL), and decrease of plasma APO (7658 to 5152 ng/mL) and exacerbation of insulin resistance (p = 0.007) were noted.

Conclusion

Hemihepatectomy resulted in moderate disturbances in glucose homeostasis, in a majority of patients that was likely to be of minor clinical relevance. However, the patients might be at higher risk of developing overt diabetes following long-term survival.     

Should mean arterial pressure be included in the definition of ambulatory hypertension in children?

Background

The diagnosis of hypertension (HTN)/normotension (NT) on ambulatory blood pressure monitoring (ABPM) is usually based on systolic (SBP) or diastolic blood pressure (DBP). The goal of this study was to analyze whether inclusion of mean arterial pressure (MAP) improves the detection of HTN on ABPM.

Methods

We retrospectively studied ABPM records in 229 children (116 boys, median age?=?15.3 years) who were referred for evaluation of HTN. A diagnosis of HTN was made if: (A) MAP or SBP or DBP was ≥1.65 SDS (95th percentile); (B) SBP or DBP was ≥1.65 SDS (95th percentile), during 24-h or daytime or night-time in both definitions.

Results

Using definition A, 46/229 patients had HTN compared to definition B by which only 37/229 patients had HTN (p?=?0.001). The level of agreement between the two definitions was very good (kappa?=?0.86?±?0.04), however nine patients (19.5 %) were missed by not using MAP in the definition of HTN. These nine patients had only mild HTN with a median Z score of 1.69.

Conclusions

The inclusion of MAP in the definition of ambulatory HTN significantly increased the number of hypertensive patients. MAP may be very helpful in detecting mild HTN in patients with normal/borderline SBP and DBP.     

Disturbed Lipids,Lipoproteins and Triglyceride-Rich Lipoproteins as Well as Fasting and Nonfasting Non-High–Density Lipoprotein Cholesterol in Post-Renal Transplant Patients

Serum levels of lipids and lipoproteins were determined in 98 post-renal transplant fasting patients, and lipids and non-high density lipoprotein-cholesterol (non-HDL-C) and lipid ratios in the same post-renal transplant non-fasting patients were compared. The reference group was 87 healthy subjects. All patients were divided into two groups: patients with dyslipidemia (n?=?69) and patients with normolipidemic (n?=?29). The post-renal transplant patients (TX) with dyslipidemia had a significantly increased concentration of triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C), non-HDL-C, apoB, and TRL and lipid ratios, and decreased HDL-C level and lipoprotein ratios. The lipids, lipoproteins, and lipoprotein ratios were significantly beneficial in TX patients with normolipidemic than in those with dyslipidemia. However, TRL concentration and lipid ratios were significantly increased and apoAI/apoCIII significantly decreased as compared to the reference group. The TX patients with dyslipidemia showed a significant correlation between TG and apoB:CIII (r?=?0.562, p < 0.001) and apoCIII (r?=?0.380, p < 0.004), but those with normolipidemic showed a significant correlation only between TG and apoCIII (r?=?0.564, p < 0.008). Regression and Bland-Altman analyses showed excellent correlation between fasting and nonfasting non-HDL-C levels (r?=?0.987, R² + 0.987) in TX patients both with dyslipidemia and normolipidemic. We think the finding that nonfasting labs that are reliable for non-HDL-C as well as total cholesterol is important, as fasting labs are not always available. Disturbances of lipids, lipoproteins, and TRLs depend not only on the kind of treatment, but due to multiple factors can accelerate cardiovascular complications in post-renal transplant patients with dyslipidemia and also with normolipidemic. Further studies concerning this problem should be completed.     

Transcranial Magnetic Stimulation: Use of Motor Evoked Potentials in the Evaluation of Surgically Induced Spinal Cord Ischemia

Abstract

We evaluated transcranial magnetic stimulation producing motor evoked potentials (TMS MEP) as a method to detect spinal cord ischemia during surgery for thoracoabdominal aneurysms. Four groups of swine were subjected to different types of surgically-induced ischemia. TMS MEP and neurological function were assessed at baseline, immediately after the ischemic insult and after four hours of reperfusion/post-ligation. Cross-clamping of the aorta in groups A & B resulted in the disappearance and subsequent reappearance of TMS MEP with significantly prolonged latencies in most animals and variable neurological function. Ligation of intercostal arteries produced no changes in TMS MEP or neurological function (group C). However, after ligation of intercostal and lumbar arteries, group D demonstrated no reappearance of TMS MEP and severe neurological deficits. TMS MEP can provide rapid detection of global spinal cord ischemia and can also predict local devascularization injury. (J Spinal Cord Med 1997; 20:395-401)     

Impact of genetic variants of selected cytochrome P450 isoenzymes on pharmacokinetics and pharmacodynamics of clopidogrel in patients co-treated with atorvastatin or rosuvastatin

Impaired antiplatelet effect of clopidogrel (CLP) can result from drug-drug interactions and genetic polymorphisms of drug-metabolizing enzymes. The aim of the study was to evaluate the effect of genetic polymorphisms of ABCB1 and the selected cytochrome P450 isoenzymes on the pharmacodynamics and pharmacokinetics of CLP and its metabolites in patients co-treated with atorvastatin or rosuvastatin. The study involved 50 patients after coronary angiography/angioplasty treated with CLP and atorvastatin (n = 25) or rosuvastatin (n = 25) for at least 6 months. Plasma concentrations of CLP, diastereoisomers of thiol metabolite (inactive H3 and active H4), and inactive CLP carboxylic acid metabolite were measured by UPLC-MS/MS method. Identification of the CYP2C19*2, CYP2C19*17, CYP3A4*1G, CYP1A2*1F, and ABCB1 C3435T genetic polymorphisms was performed by PCR-RFLP, while platelet reactivity units (PRU) were tested using the VerifyNow P2Y12 assay. There were significant differences in the pharmacokinetic parameters of the H4 active metabolite of CLP in the atorvastatin and rosuvastatin group divided according to their CYP2C19 genotype. There were no significant associations between CYP3A4, CYP1A2, and ABCB1 genotypes and pharmacokinetic parameters in either statin groups. In the multivariate analysis, CYP2C19*2 genotype and non-genetic factors including BMI, age, and diabetes significantly affected platelet reactivity in the studied groups of patients (P < 0.01). In the atorvastatin group, CYP2C19*2, CYP3A4*1G, and ABCB1 C3435T TT genotypes were independent determinants of PRU values (P < 0.01). The CYP2C19*2 allele is the primary determinant of the exposition to the H4 active metabolite of clopidogrel and platelet reactivity in patients co-treated with atorvastatin or rosuvastatin.     

Synthesis and biological evaluation of N‐acylated tyramine sulfamates containing C–F bonds as steroid sulfatase inhibitors

Steroid sulfatase (STS) is responsible for the hydrolysis of biologically inactive sulfated steroids into their active un‐sulfated forms and promotes the growth of various hormone‐dependent cancers (e.g., breast cancer). Therefore, the STS enzyme is a promising therapeutic target for the treatment of steroid‐sensitive cancers. Herein, we report the synthesis and biological evaluation of sulfamate analogs as potential STS inhibitors based on N‐acylated tyramines that contain C–F bonds. The inhibitory effects of the analogs were tested using STS isolated from human placenta. Of the analogs tested, 4‐(2‐perfluoroundecanoylaminoethyl)‐phenyl sulfamate, 5r , demonstrated the greatest inhibitory effect, with an IC₅₀ value of 2.18 μm (IC₅₀ value of 2.13 μm for coumarin‐7‐O‐sulfamate was used as a reference). These findings were supported by the results our computational analyses performed using molecular docking techniques.