To screen or not to screen for breast cancer? How do modelling studies answer the question?

Breast cancer screening is a topic of hot debate, and currently no general consensus has been reached on starting and ending ages and screening intervals, in part because of a lack of precise estimations of the benefit-harm ratio. Simulation models are often applied to account for the expected benefits and harms of regular screening; however, the degree to which the model outcomes are reliable is not clear. In a recent systematic review, we therefore aimed to assess the quality of published simulation models for breast cancer screening of the general population. The models were scored according to a framework for qualitative assessment. We distinguished seven original models that utilized a common model type, modelling approach, and input parameters. The models predicted the benefit of regular screening in terms of mortality reduction; and overall, their estimates compared well to estimates of mortality reduction from randomized controlled trials. However, the models did not report on the expected harms associated with regular screening. We found that current simulation models for population breast cancer screening are prone to many pitfalls; their outcomes bear a high overall risk of bias, mainly because of a lack of systematic evaluation of evidence to calibrate the input parameters and a lack of external validation. Our recommendations concerning future modelling are therefore to use systematically evaluated data for the calibration of input parameters, to perform external validation of model outcomes, and to account for both the expected benefits and the expected harms so as to provide a clear balance and cost-effectiveness estimation and to adequately inform decision-makers.

The value of PET/CT with FES or FDG tracers in metastatic breast cancer: a computer simulation study in ER-positive patients.

BACKGROUND: The aim of this study was to evaluate the effect on the number of performed biopsies and costs associated with implementing positron emission tomography (PET) and computed tomography (PET/CT) with 16α-[(18)F]fluoro-17ß-oestradiol (FES) or 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG) as an upfront imaging test for diagnosing metastatic breast cancer (MBC) in comparison with the standard work-up in oestrogen receptor-positive women with symptoms. METHODS: A published computer simulation model was adapted and validated. Three follow-up strategies were evaluated in a simulated cohort of women with primary breast cancer over a 5-year-time horizon: (1) the standard work-up, (2) upfront FES-PET/CT and (3) upfront FDG-PET/CT. The main outcome was the number of avoided biopsies to assess MBC. The costs for all three strategies were calculated based on the number of imaging tests and biopsies. The incremental cost-effectiveness ratio (ICER) to avoid a biopsy was calculated only based on the costs of initial imaging and staging tests. RESULTS: The FES-PET/CT strategy decreased the number of biopsies by 39 ± 9%, while upfront FDG-PET/CT increased the number of biopsies by 38 ± 15% when compared with the standard work-up. Both PET/CT strategies reduced the number of imaging tests and false positives when compared with the standard work-up. The number of false negatives decreased only in the FES-PET/CT strategy. The ICER in the FES-PET/CT strategy per avoided biopsy was 12.1 ± 3.4 thousand Euro. In the FDG-PET/CT strategy, the costs were higher and there were no avoided biopsies as compared with the standard work-up, hence this was an inferior strategy in terms of cost effectiveness. CONCLUSIONS: The number of performed biopsies was lower in the FES-PET/CT strategy at an ICER of 12.1 ± 3.4 thousand Euro per biopsy avoided, whereas the application of the FDG-PET/CT did not reduce the number of biopsies and was more expensive. Whether the FES-PET/CT strategy has additional benefits for patients in terms of therapy management has to be evaluated in clinical studies.

[Course and delivery outcomes of 34 pregnancies complicated by HELLP syndrom]. / Prubeh a výsledky 34 tehotenství komplikovaných syndromem HELLP.

OBJECTIVE: To analyze the course and delivery outcomes of pregnancies complicated by HELLP syndrom and compare them to previously published data. DESIGN: Retrospective cohort study. SUBJECT AND METHOD: We analyzed pregnancy outcomes of 34 pregnancies complicated by HELLP syndrom of women who delivered at our hospital between years 2004 and 2009. SETTING: Department of Obstetrics and Gynecology, University Hospital Ostrava. RESULTS: There were 34 pregnancies and deliveries complicated by HELLP syndrom between the years 2004 and 2009 (64 months). The average age of mothers was 28.5 years, the average gestational age at delivery time was 33 weeks and 4 days. Only 2 women delivered vaginaly, the other 32 delivered by cesarean section and the average weight of the newborn was 1930 g. There were 3 twin pregnacies. Twenty two (65%) patients had laboratory abnormalities in coagulation parameters but clinical signs of coagulation disorder were noted in 8 patients only (23.5%). Six patients recevied blood transfusions (18 units in total) and 9 patients received plasma transfusions (20 units in total). The average length of stay of mothers at intensive care unit was 3.2 days. There was no maternal mortality. One fetus was stillborn and 12 newborns (33.3%) had their early postnatal period complicated by severe morbidity. CONCLUSION: Early diagnosis and active management is a major factor for the prevention of severe forms of HELLP syndrom which still remains one of the most severe complications of pregnancy.

[Disordered cardiac electrical stability in beta-adrenergic damage and antioxidant protection]. / Narushenie élektricheskoi stabil'nosti serdtsa pri beta-adrenergicheskom povrezhdenii i antioksidantnaia zashchita.

The electrical threshold of ventricular fibrillation induced by premature single impulses and the ectopic activity and also an abnormal conduction during vagus inhibition of sinus node were estimated 24 hours after the administration of isoproterenol (10 mg/kg, s/c, on time) in rats. In addition the cardiac contractile function of the left ventricle was studied. The study was performed on male Wistar rats, 250-300 body weight, under nembutal anesthesia. Isoproterenol had no effect on the contractile function in the rest and during maximal isometric load, induced by coarctation of ascending aorta. But in the treated animals the threshold of fibrillation fell more than 2-fold and the vagal bradycardia was more 2-fold then in the untreated animals. The AB-block, idioventricular rhythm and extrasystoles appeared during vagal bradycardia in treated animals, while in the untreated ones there were no any disturbances. The preliminary administration of the antioxidant ionol (BMT, 30 mg/kg, per os, in sun oil) prevented the enumerated shifts.

[Dynamic biochemical, metrometric and histomorphological studies in isoproterenol-induced myocardial hypertrophy and its regression in rats]. / Dinamichni biokhimichni, metrometrichni i khistomorfologichni prouchvaniia pri izoproterenolova miokardna khipertrofiia (MKh) i regresiiata i u plukhove.

Isoproterenol, administered intraperitoneally in rats in a dose of 2 mg/kg of body mass for a period of 20 days, induced myocardial hypertrophy. After its stoppage a period of regression occurred, during which the myocardium recovered practically to its initial state. Complex studies of connective-tissue components (collagen, glycosaminoglycans, total nonfibrillary protein, total protein, structural, glycoproteins), metrometric data-the coefficient R (1 g of myocardium/199 g of body mass) and histomorphological investigations were performed. The same studies were done on rats of a control nontreated group and of experimental groups-on the 0 day. 7th, 14th and 42 day. It was established there was a gradual recovery to normal values of collagen, total nonfibrillary protein and the coefficient R, which were highest on the day 0. Progressive diminution, e.g., normalization of both the connective tissue components and of the volume of myocardial cells was found histomorphologically, in which the changes were mostly manifested on the day 0, as well. The complex studies of the connective tissue with isoproterenol MH proved that the changes of MH in this tissue correlated with the stages of MH respectively its regression.

Changes in the enzyme activity of the myocardium and participation of the alpha-adrenergic and M-cholinergic systems in experimental isoprenaline myocardial hypertrophy.

With a view to clarifying the mechanisms of haemodynamic stress, as well as the role of some neurotransmitter systems in the pathogenesis of myocardial hypertrophy (MH), a complex of experiments was carried out with an MH model induced in rats by isoprenaline treatment and by applying the M-cholinolytic agent atropine and the alpha-adrenergic blocker phentolamine in a part of the experimental groups. The changes in the activity of some enzymes of myocardial metabolism, namely: glucose-6-phosphate dehydrogenase, pyruvate kinase, alpha-hydroxy-butyrate dehydrogenase, isocitrate dehydrogenase, malate dehydrogenase and creatine phosphokinase, were traced in 33 male Wistar rats. Considerable activation of glucose-6-phosphate dehydrogenase was found in the different experimental groups, suggesting the adaptive "anti-stress" character of this change. The results of the pathobiochemical studies presuppose the substantial participation of the alpha-adrenergic and of the M-cholinergic systems in the stage of compensated isoprenaline-induced myocardial hypertrophy.

[Action of the antihypertensive effect of captopril on manifestations of hypertrophy and several parameters of myocardial metabolism]. / Vliianie antigipertenzivnogo éffekta kaptoprila na vyrazhennost' gipertrofii i nekotorye parametry metabolizma serdechnoi myshtsy.

The administration of captopril (CP, 30 mg/kg) limited the arterial hypertension induced by the coarctation of the renal arteria and cardiac hypertrophy in rats. CP prevented the activation of MB-KK and glucoso-6-phosphate dehydrogenase. Besides CP decreased the activity of pyruvate kinase and increased that of malate dehydrogenase. These data demonstrate, that CP prevents both the cardiac hypertrophy and metabolic changes in animals with the renal hypertension.

Changes in ECG, plasma and myocardial lipids in experimental myocardial hypertrophy in rats.

ECG, systolic blood pressure (BP), the ratio (R) of grams of myocardial mass/100 g of body mass, total lipids, cholesterol, triglycerides and phospholipids in blood plasma and the left ventricular myocardium, as well as the plasma free fatty acids, were investigated in 58 male Wistar rats 3, 30 and 180 days after operation, in a model of myocardial hypertrophy (MH) induced by experimental coarctation hypertension, after the method of Selye. An attempt was made to correlate some functional and metabolic indices which characterize the development of this type of MH. On a background of progressively rising BP and parallel increasing R, ECG changes were recorded. They were typical of the respective stage of arterial hypertension and MH and expressed mostly in a shifting of the electrical axis of the heart to the left and in essential repolarization disturbances. The most significant changes in the studied lipid fractions were found 30 days after the induction of hypertension. The pathological changes manifested on the 180th day are discussed in relation to age, the stage of hypertension and especially in relation to the developing hypoxic and ischaemic myocardial damage.

Preventive effect of captopril on the development of experimental hypertension in rats.

The arterial blood pressure (BP), the ratio between gram myocardial mass per 100 g body mass (R), the plasma renin activity (PRA) and the aldosteron content in the blood plasma (PA) were investigated in a model of renal hypertension, 30 days after the operation, in the following groups of male Wistar rats: operated and treated throughout the entire experimental period with captopril Pharmachim in a dose of 30 mg/kg body mass twice daily orally, and two control groups--operated and treated with saline, and non-operated animals of the same age, treated only with saline. BP, R and PA increase significantly in the control group with experimental hypertension. In the group treated with captopril PRA was more than doubled compared with the two control groups, with a considerable decrease in PA compared with the control group with hypertension. The results obtained for the captopril-treated experimental group (with the exception of PRA) are identical and close to the data for the control non-operated animals, i.e. the treatment of the experimental animals with captopril prevents the development of arterial hypertension and of myocardial hypertrophy with the coarctation hypertension model used.

Content of prostaglandins E and F in the blood plasma and kidneys in arterial hypertension (clinical-experimental study).

A dynamic study is made of the content of PGE and PGF2 alpha in the kidneys of rats with experimental coarctation hypertension, as well as the PGF2 alpha-metabolite in the blood plasma of the same experimental model in rats and in patients with arterial hypertension. The level of the PGF2 alpha-metabolite tends to decrease both in the animals with experimental hypertension and in hypertonic patients. In rats with 30-day hypertension low values are established in 55 per cent, while in 45 per cent there are high values of the PGE level in the kidney homogenate compared with the control group. The concentration of PGF2 alpha in the left ("endocrine") kidney (whose artery originates distally from the place of aortic coarctation) is higher than the concentration of the same PG in the right kidney. Our findings give grounds for the following assumptions: 1. The PGF2 alpha-metabolite as hormone and partly PGE in the kidneys seem to be involved in the pathogenesis of arterial hypertension as compensatory factors. 2. PGF2 alpha in the kidneys probably participates directly as one of the elements of the complex pathogenesis of arterial hypertension.

[Electrocardiographic and histomorphological changes in the myocardium of rats with Selye's experimental hypertension]. / Elektrokardiografski i khisto-morfologichni promeni v miokarda na plukhove pri eksperimentalna khipertoniia po Selie.

The authors described electrocardiographic and histomorphological changes in white rats with coarctation hypertention, induced by the method of Selye. The electrocardiographic changes were manifested as prologation of preauricular-ventricular conduction time, dislocation of the intermediate part ST to the isoelectrical line, low, negative or biphasic T-wave at the initial stages of the experiment, but after the thirthieth day there was a pathologic Q-wave, a reduced voltage of the steap curves and manifested left type of ECG in the majority of the experimental animals. Histomorphological and histochemical study on thmyocardium revealed in the beginning of the experiment mainly lesion changes, but sign of myocardial hypertrophy and manifested difuse and/or focal myocardial fibrosis on the 30th to the 90th day of the experiment.

Quantitative determination of drugs by means of densitometry of thin-layer chromatograms. Part 6 Determination of 1-benzhydril-4-allypiperazine dihydrochloride in biological media.

A quantitative method for determination of 1-benzhydril-4-allypiperazine dihydrochloride (As-2) in blood is proposed, based on direct densitometry of t.l.c. plates. The main advantage of the method consists in the fact that it can be applied for determination of As-2 in biological samples in the presence of its metabolites and other components of the investigated samples. The statistical treatment of results obtained from ten analyses shows that the method has no systematic error and the relative percentage error is +/- 8.5%. The lowest concentration which can be determined is 5 microng/1 ml plasma. It has been established that As-2 administered intravenously in the maximally tolerable dose of 22 mg/kg can be detected in the blood after the first min (RF = 0.45). Ten min after application one major metabolite (RF = 0.35) is observed under UV-light. When administered per os in the maximally tolerable dose of 100 mg/kg, As-2 is established in the blood after 15 min while the metabolite mentioned above is detected by the thirtieth min.

[Experimental hypertension in rats and their adrenal activity]. / Eksperimentalna khipertoniia u plukhove i nadbubrechna aktivnost.

The authors examined dynamically the arterial pressure and plasma activity of 11-hydroxycorticosteroids in two groups of rats with pure hypertension and with hypertension on the background of beta-adrenergic activity. There was an elevation of arterial pressure in both groups, less manifested in the rats, treated with beta blocker. The values after six months were equally high in both groups. The content of 11-hydroxycorticosteroids was increased with a maximum at the sixth month. The authors make an inference that beta blocker-obsidan lowers blood pressure, but does not affect the level of 11-hydroxycorticosteroidids in plasma.

[Participation of cyclic-3',5'-adenosine monophosphate in the pathogenesis of myocardial hypertrophy in experimental hypertension]. / Uchastie na tsiklichniia 3', 5', adenozinomonofosfat v patogenezata na miokardnata khipertrofiia pri eksperimentalnata khipertoniia.

The authors examined the concentration of cAMP in the myocardium of rats with experimental hypertension during various periods after modeling of the process. The changes in the values of cyclic nucleotide corresponded to the dynamics of the development of the arterial hypertension. There was na increase of the level of cAMP in the myocardium on the third day after modeling of hypertension, accompanying the initial elevation of the arterial pressure. The maximal values of cAMP were established on the 30th day, which corresponded to the maximal development of hypertension. Cyclic 3,5-adenomonophosphate began to diminish parallel to the lowering of the arterial pressure during the chronic phase 90th day. The obtained results give a possibility to discuss the participation of cAMP in the pathogenesis of myocardial hypertension, occurring in experimental hypertension.

[Changes in renal enzyme activity in rats with experimental hypertension]. / Promeni v enzimnata aktivnost na bubretsite pri eksperimentalna khipertoniia u plukhove

The study was carried out on rats of the Wistar strain with experiments hypertension by the method of Selye, modified by Kolarova. These authors examined the activity of the enzymes of protein metabolism (GOT, GPT, AP), of glycolysis (ALD, LDH, alpha-HBDH) and of the citric cycle (MDH) in the left and right kidney at various intervals after modeling the process (3th, 15th, 30th and 90th day). The activity of the enzymes of the glycolytic chain and the cycle of Krebs in the left kidney was lowered at all stages of the experiment. Transaminase activity diminished progressively. Such a dynamics revealed the activity of adenosine phosphate as well. The activity of all examined enzymes of the right kidney showed phase changes-after initial elevation on the third day there was a lowering at the later stages of the experiment. The altered activity off the left kidney was connected with the disturbed vascularization with subsequent metabolic changes. The changes in the enzymic activity in the right kidney were assumed as a consequence of the occurred adaptive hyperfunction.