Tumor tissue levels of tissue inhibitor of metalloproteinase-1 as a prognostic marker in primary breast cancer.

PURPOSE: In the present study, we investigated the association between tumor tissue levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) and prognosis in patients with primary breast cancer and analyzed whether TIMP-1 may be useful as a prognostic marker in combination with urokinase plasminogen activator (uPA) and plasminogen activator inhibitor type-1 (PAI-1). EXPERIMENTAL DESIGN: In cytosolic extracts of 2984 primary breast tumors, total levels of TIMP-1 were determined using an established, validated ELISA. Levels of uPA and PAI-1 have previously been determined in the extracts. RESULTS: Univariate survival analysis showed a significant relationship between higher levels of TIMP-1 (continuous log-transformed variable) and poor prognosis [recurrence-free survival (RFS), overall survival (OS); P < 0.001]. Performing isotonic regression analysis, we identified a cut point to classify tumors as TIMP-1-low or TIMP-1-high. Using this cut point, high levels of TIMP-1 were significantly associated with shorter survival in univariate analysis, both in the total patient group (RFS, OS; P < 0.001), in the node-negative subgroup (RFS, hazard ratio = 1.28, P = 0.006), and in the node-positive subgroup (RFS, hazard ratio = 1.43, P < 0.001). In multivariate analysis, including uPA and PAI-1, TIMP-1 was significantly associated with shorter RFS, both when included as a continuous log-transformed (P = 0.03) and as a dichotomized variable (P = 0.002). CONCLUSIONS: This study validates previous findings that tumor tissue levels of TIMP-1 are associated with prognosis in patients with primary breast cancer. It confirms that TIMP-1 may be useful as a prognostic marker in combination with uPA/PAI-1 and adds substantial positive information on the use of TIMP-1 as a prognostic marker in breast cancer.     

Change in quality of life of medically hospitalized patients – A one-year follow-up study

Objectives: To examine changes in quality of life (QOL) among elderly medically hospitalized patients one year after hospitalization, and to explore factors associated with the changes.

Methods: A one-year follow-up study included 363 (175 men) medical inpatients with age range 65–98 (mean 80.2, SD 7.5) years. Information was collected at baseline and follow-up using the WHOQOL-BREF questionnaire assessing the physical, psychological, social and environment domain of QOL as the dependent variable, and the Mini-Mental State Examination, Lawton and Brody's scales for physical self-maintenance and instrumental activities of daily living, the Hospital Anxiety and Depression scale and assistance in living as the independent variables.

Results: The mean score of the physical domain of QOL had increased (mean change 0.6, SD 2.5; p?p? Conclusion: Good cognitive, physical and emotional health at baseline and follow-up were associated with improved QOL in previously hospitalized elderly patients independent of their need for assistance in living.     

The Association Between Serum Calcium Levels and Short-Term Mortality in Patients with Chronic Heart Failure

Background

Patients with chronic heart failure have vulnerable myocardial function and are susceptible to electrolyte disturbances. In these patients, diuretic treatment is frequently prescribed, though it is known to cause electrolyte disturbances. Therefore, we investigated the association between altered calcium homeostasis and the risk of all-cause mortality in chronic heart failure patients.

A single topical dose of erythropoietin applied on a collagen carrier enhances calvarial bone healing in pigs

Background and purpose

The osteogenic potency of erythropoietin (EPO) has been documented. However, its efficacy in a large-animal model has not yet been investigated; nor has a clinically safe dosage. The purpose of this study was to overcome such limitations of previous studies and thereby pave the way for possible clinical application. Our hypothesis was that EPO increases calvarial bone healing compared to a saline control in the same subject.

Methods

We used a porcine calvarial defect model. In each of 18 pigs, 6 cylindrical defects (diameter: 1 cm; height: 1 cm) were drilled, allowing 3 pairwise comparisons. Treatment consisted of either 900 IU/mL EPO or an equal volume of saline in combination with either autograft, a collagen carrier, or a polycaprolactone (PCL) scaffold. After an observation time of 5 weeks, the primary outcome (bone volume fraction (BV/TV)) was assessed with high-resolution quantitative computed tomography. Secondary outcome measures were histomorphometry and blood samples.

Results

The median BV/TV ratio of the EPO-treated collagen group was 1.06 (CI: 1.02–1.11) relative to the saline-treated collagen group. Histomorphometry showed a similar median effect size, but it did not reach statistical significance. Autograft treatment had excellent healing potential and was able to completely regenerate the bone defect independently of EPO treatment. Bony ingrowth into the PCL scaffold was sparse, both with and without EPO. Neither a substantial systemic effect nor adverse events were observed. The number of blood vessels was similar in EPO-treated defects and saline-treated defects.

Interpretation

Topical administration of EPO on a collagen carrier moderately increased bone healing. The dosing regime was safe, and could have possible application in the clinical setting. However, in order to increase the clinical relevance, a more potent but still clinically safe dose should be investigated.Erythropoietin (EPO) is a hematopoietic growth factor that stimulates the formation of red blood cells. In recent years, the non-hematopoietic effects of EPO have been investigated. Of interest for skeletal tissue engineering, the pleiotropic capabilities of EPO include osteogenic and angiogenic potencies (Rölfing et al. 2012). Subcutaneous injections of 250 IU/kg EPO were found to enhance bone formation 6 weeks after operation in a spinal fusion model in rabbits (Rölfing et al. 2012). The validity of the methodology of this study was confirmed in a recently published meta-analysis (Riordan et al. 2013, Rölfing and Bünger 2013). Other independent research groups have reported increased bone formation in mice and rats after daily treatment with 200–6,000 IU/kg EPO (Bozlar et al. 2006, Holstein et al. 2007, 2011, Shiozawa et al. 2010, Garcia et al. 2011, Kim et al. 2012). Furthermore, vascularization of 3-dimensional scaffolds for bone tissue regeneration remains a challenge. The described pleiotropic functions of EPO may overcome this limitation of skeletal tissue engineering in the future. EPO could possibly facilitate angiogenesis directed into the core of the scaffold, thereby facilitating bony ingrowth. Moreover, EPO promotes a direct and indirect osteogenic stimulation of mesenchymal stromal cells (Shiozawa et al. 2010, Rölfing et al. 2013).Translation of these promising in vitro and in vivo data into clinical trials requires a physiological dosage of EPO in order to avoid its known complications, such as thromboembolism (Ehrenreich et al. 2009, Shiozawa et al. 2010, Kim et al. 2012, Rölfing et al. 2012). Notably, we observed an extremely high hematocrit level after 250 IU/kg EPO for 20 days in a rabbit model (Rölfing et al. 2012). In other in vivo studies, repetitive EPO injections ranging from 500 to 6,000 IU/kg were administered. These treatment regimes have a systemic effect, and thus hold the risk of adverse events. Testing of the efficacy of a clinically safe dose of EPO is therefore necessary before clinical trials can be considered. Aiming for clinical progress and feasibility, the present study was carried out with a view to evaluating the efficacy of a single, low-dose EPO to stimulate bone healing in a large-animal study. The dose of EPO was chosen based on the following considerations. The translation of the minimally effective dose in cell studies into large-animal models is difficult (Rölfing et al. 2013). The rather low dosage of 2,700 IU/animal, equivalent to 18.5 ± 2.0 IU/kg, was chosen in order to minimize the systemic effect of EPO due to safety concerns and in order to minimize the potential effect on the within-subject controls. In anemic patients, 20–240 IU/kg are injected subcutaneously or intravenously 3 times a week. The hypothesis was that 900 IU site-specifically applied EPO would increase bony ingrowth compared to a saline-treated control in a porcine calvarial defect model.     

Immunisation against PCV2 structural protein by DNA vaccination of mice

Porcine circovirus type 2 (PCV2) is the causative agent of an emerging swine disease, postweaning multisystemic wasting syndrome (PMWS). The disease affects primarily 5-12-weeks-old pigs which might suggest that infection with PCV2 occurs when the level of maternal antibodies have declined to sub-protective levels around weaning at 3-5-weeks of age. If immunoprophylaxis is to be effective, an immunisation method capable of breaking through maternal immunity must be employed. In this study, we have developed and investigated the potential of a DNA vaccination approach to be one such method. The gene encoding the capsid protein of PCV2 was cloned in a DNA vaccination plasmid and expression of capsid protein was demonstrated in vitro. Mice were gene gun vaccinated three timesand all mice responded serologically by raising antibodies against PCV2. The results suggest, that DNA based vaccination might offer opportunities for vaccination of piglets against PCV2.     

Metabolic abnormalities (hypertension,hyperglycemia and overweight), lifestyle (high energy intake and physical inactivity) and endometrial cancer risk in a Norwegian cohort

Since high energy intake, inactivity, hypertension and diabetes are linked to obesity and an unfavorable hormonal profile, we wanted to test whether energy intake, physical activity, blood pressure and serum glucose are related to the risk of endometrial cancer independent of the body mass index (BMI). A cohort of 24,460 women, aged 20-49 years, attended a Norwegian health screening twice during 1974-1981; they answered questions about diet, physical activity and chronic diseases, and their height, weight, blood pressure and non-fasting serum glucose were measured. By the end of 1996, during 15.7 years of follow-up, 130 cases of endometrial carcinomas were identified. The relative risks (RRs) for endometrial cancer were estimated in proportional hazards models including potentially confounding factors. Obese women (BMI > or = 30 kg/m(2)) were at 2.6 times increased risk of endometrial cancer compared to normal weight women (BMI < 25 kg/m(2)) (RR = 2.57, 95%CI = 1.61-4.10). Among overweight women (BMI > or = 25 kg/m(2)), non-fasting serum glucose in the upper quartile vs. in the lower quartile was associated with a 2.4 times increase in risk (RR = 2.41, 95%CI = 1.08-5.37), whereas among obese women, blood pressure above 140/90 mmHg vs. below 140/90 mmHg in both surveys was associated with a 3.5 times increase in risk (RR = 3.47, 95%CI = 1.24-9.70). Especially in women younger than 50 years, high energy intake (5,044-6,401 kJ/day) conferred higher risk compared to low energy intake (< 4266 kJ/day) (RR = 3.40, 95%CI = 1.52-7.60). Increasing recreational activity tended to be protective. Among obese women with non-sedentary jobs at both screenings, RR declined to 0.18 (95%CI = 0.05-0.62) as the level of sustained occupational activity increased (p(trend) = 0.03). Our results suggest that inactivity and high energy intake are major risk factors for endometrial cancer independent of BMI, and that hypertension and relative hyperglycemia are significant markers of risk, especially among the heaviest women.     

Influence of birth weight and adult body composition on 17β-estradiol levels in young women

Background  Estrogens induce cellular proliferation and are associated with an increased risk of breast cancer. Birth weight and adult body weight have independently been associated with both estrogen levels and breast cancer risk. Thus, we hypothesize that low birth weight, in combination with adult overweight, may influence premenopausal 17β-estradiol over an entire menstrual cycle of possible importance for breast cancer. Methods  Among 204 healthy women, aged 25–35 years, who participated in the Norwegian EBBA-I Study, birth weight and age at menarche were assessed. Levels of 17β-estradiol were measured in daily saliva samples over one menstrual cycle using radioimmunoassay (RIA). Measurements of body composition; waist circumference (cm), body mass index (BMI, kg/m²), and total fat percentage (DEXA, %) were assessed. Fasting blood samples were drawn, and serum concentrations of lipids and hormones were determined. Results  The participating women had mean birth weight of 3,389 g and age at menarche 13.1 years. Women within the highest tertile of birth weight had the lowest 17β-estradiol throughout the menstrual cycle (p = 0.03), and they tended to have a later age at menarche (p = 0.06). When we looked into birth weight in combination with adult-attained weight, we found that women with lower birth weights, combined with excess weight during adulthood, had higher levels of free 17β-estradiol over an entire menstrual cycle compared with women with high birth weights and adult overweight. Women with birth weights <3,530 g, who later developed excess body weight (waist ≥ 84 cm), showed 33% higher 17β-estradiol concentrations over a menstrual cycle compared with women with higher birth weights (≥3,530 g) and adult excess body weight (p = 0.03). The association was even more pronounced in women with birth weights <3,220 g, early age at menarche (<12 years), and adult overweight. Conclusion  Our findings support variation of premenopausal levels of 17β-estradiol in response to birth weight and energy status in adult life, suggesting that women with low birth weight in combination with adult overweight are put at risk for higher estradiol levels throughout menstrual cycles, which is of possible importance for breast cancer risk.     

Psychometric evaluation of a Norwegian version of the Communication Strategies Scale of the Communication Profile for the Hearing Impaired

Aim. To evaluate the Communication Strategies Scale (CSS) in an adult Norwegian sample with hearing loss.

Subjects and methods. Of 474 invited patients, a total of 337 consecutive adults admitted to the outpatient Unit of Audiology, ENT Department of a university hospital answered the CSS of the Communication Profile for the Hearing Impaired. The inventory assesses the use of three specific coping strategies; Maladaptive Behaviour, Verbal and Nonverbal Communication Strategies. The psychometric evaluation included construct validity by corrected item-total correlation, the internal consistency reliability by coefficient alpha (Cronbach's) and standard error of the measurement (SEM). Internal structure was evaluated by factor analyses using principal factors followed by a varimax rotation.

Results. CSS showed good psychometric properties with acceptable and good internal consistency reliability for the subscales. The internal structure of the entire scale gave main loadings at 24 of 25 items at the same factor as the original one.

Conclusion. CSS may well be used as a clinical tool in the routine assessment of maladaptive and adaptive communication strategies in an unselected adult population of hearing impaired outpatients.