Long-term results and tolerability of tandem peptide receptor radionuclide therapy with 90Y/177Lu-DOTATATE in neuroendocrine tumors with respect to the primary location: a 10-year study.

INTRODUCTION: The peptide receptor radionuclide therapy (PRRT) with 90Y and 177Lu is a form of molecular targeted therapy for inoperable or disseminated neuroendocrine tumors (NET). AIM: The aim of the study was to evaluate clinical results and long-term side effects of tandem 90Y /177Lu-DOTATATE therapy in patients with NET. Additionally, we evaluated clinical results with reference to the primary site. MATERIALS AND METHODS: 59 patients with disseminated NET were included in the study prospectively. 3-5 cycles of combined 1:1 90Y/177Lu-DOTATATE (total injected activity 11.1-16.65 GBq) with mixed amino acids for kidney protection were performed. RESULTS: During a median follow-up of 75.8 months, the PFS was 32.2 months, and the OS was 82 months; 25 patients died. Depending on primary tumor's site, the PFS and the OS for pancreatic NET vs. small bowel, NET vs. large bowel, NET were 30.4 vs. 29.5 vs. 40.3 and 78.9 vs. 58.1 vs. 82.5, respectively. The observed 5-year overall survival was 63%, and a 2-year risk of progression was 39.4%. The following imaging response was observed: CR in 2%, PR in 22%, SD in 65%, and PD in 6% patients. The disease control rate was 89%. The objective response rate was 24%. The PRRT was well tolerated by all patients. One patient (2%) revealed MDS, and one patient (2%) grade 3 nephrotoxicity. No other grade 3 and 4 hematological or renal toxicity was observed. CONCLUSIONS: These results indicated the tandem 90Y/177Lu-DOTATATE therapy for patients with disseminated/inoperable NET as highly effective and safe, considering long-term side effects. In the majority of patients, clinical improvement was observed.

Simplified protocol of cardiac 18F-fluorodeoxyglucose positron emission tomography viability study in normoglycemic patients with known coronary artery disease.

PURPOSE: The purpose was to evaluate quality of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) myocardial scans and its correlation with background glucose (BG) after simplified 5% intravenous glucose load protocol. METHODS: An intravenous glucose load protocol was applied in 69 normoglycemic patients with confirmed coronary artery disease. The blood glucose level was measured every 15 min. RESULTS: Eighty-four percent of images were optimal, 8.7% suboptimal, and 7.3% uninterpretable. The quality of 18F-FDG-PET was BG independent and body mass index dependent (P=.0007). CONCLUSIONS: Simplified glucose load protocol is a safe and efficient method of preparation for FDG cardiac viability study in patients with normoglycemia.

Validation of a hemoglobin A1c model in patients with type 1 and type 2 diabetes and its use to go beyond the averaged relationship of hemoglobin A1c and mean glucose level.

BACKGROUND: Glycated hemoglobin A1c (HbA1c) has been used as an index of glycemic control in the management, guidance, and clinical trials of diabetic patients for the past 35 years. The aim of this study was to validate the HbA1c model in patients with type 1 and type 2 diabetes and to use it to support interpretation of HbA1c in different clinical situations. METHODS: The HbA1c model was identified in 30 patients (15 with type 1 diabetes and 15 with type 2 diabetes) by estimating the overall glycation rate constant (k), based on results of continuous glucose monitoring. The model was validated by assessing its ability to predict HbA1c changes in cultures of erythrocytes in vitro and to reproduce results of the A1C-Derived Average Glucose (ADAG) study. The model was used to simulate the influence of different glucose profiles on HbA1c. RESULTS: The mean k was equal to 1.296 ± 0.216 × 10(-9) l mmol(-1) s(-1) with no difference between type 1 and type 2 diabetes. The mean coefficient of variation of k was equal to 16.7%. The model predicted HbA1c levels in vitro with a mean absolute difference less than 0.3% (3.3 mmol/mol). It reproduced the linear relationship of HbA1c and mean glucose levels established in the ADAG study. The simulation experiments demonstrated that during periods of unstable glycemic control, glycemic profiles with the same mean glucose might result in much different HbA1c levels. CONCLUSIONS: Patients with type 1 and type 2 diabetes are characterized by the same mean value of k, but there is considerable interindividual variation in the relationship of HbA1c and mean glucose level. Results suggest that reciprocal changes in glycation rate and the life span of erythrocytes exist in a wide range of HbA1c values. Thus, for an average patient with diabetes, no modifications of parameters of the glycation model are required to obtain meaningful HbA1c predictions. Interpreting HbA1c as a measure of the mean glucose is fully justified only in the case of stable glycemia. The model and more frequent tests of HbA1c might be used to decrease ambiguity of interpreting HbA1c in terms of glycemic control.

Lithium carbonate pre-treatment in 131-I therapy of hyperthyroidism.

BACKGROUND: The aim of the present work was to investigate the influence of lithium carbonate on the kinetics of radioiodine in the thyroid gland, and the long-lasting effect of radioiodine therapy pre-treated with lithium carbonate in patients with different types of hyperthyreosis and low baseline 24-h thyroidal radioactive iodine uptake (RAIU). MATERIAL AND METHODS: The examinations were performed in two groups of patients: in a control group with RAIU 〉 30% and in patients with RAIU 〈 30%. All groups were comparable with regard to age, sex, duration and type of disease (Graves' disease, autonomous node, multinodular goitre). The control group was treated (without lithium) according to described protocol. The second group was pre-treated with lithium carbonate in a dose of 1.0 g/day for 6 days before radioiodine and 3 days thereafter. RESULTS: A significant increase in iodide uptake in the thyroid gland was observed during intake of lithium carbonate in 106 out of 128 patients. A decrease of T(3), FT(3), T(4), and FT(4) levels and no significant changes in concentration of TSH were observed as an effect of lithium carbonate treatment. Three years of follow-up show that the results of radioiodine therapy with short lasting lithium carbonate intake are better in the first year and are similar in the second and third years in comparison to the control group. CONCLUSIONS: Lithium pre-treatment in hyperthyroid patients with low baseline uptake of radioiodine can increase iodine retention in the thyroid gland independently of the primary disease and permits the use of lower doses of radiation in the therapy.

Hemoglobin glycation rate constant in non-diabetic Individuals.

The objectives were as follows: (1) estimating mean value of the overall hemoglobin glycation rate constant (k); (2) analyzing inter-individual variability of k; (3) verifying ability of the hemoglobin A1c (HbA1c) formation model to predict changes of HbA1c during red blood cells cultivation in vitro and to reproduce the clinical data. The mean k estimated in a group of 10 non-diabetic subjects was equal to 1.257 ± 0.114 × 10(-9) L mmol(-1) s(-1). The mean k was not affected by a way of estimation of glycemia. The mean k differed less than 20% from values reported earlier and it was almost identical to the mean values calculated on basis of the selected published data. Analysis of variability of k suggests that inter-individual heterogeneity of HbA1c formation is limited or rare. The HbA1c mathematical model was able to predict changes of HbA1c in vitro resulting from different glucose levels and to reproduce a linear relationship of HbA1c and average glucose obtained in the A1C-Derived Average Glucose Study. This study demonstrates that the glycation model with the same k value might be used in majority of individuals as a tool supporting interpretation of HbA1c in different clinical situations.

Leptin in acute myocardial infarction and period of convalescence in patients with type 2 diabetes mellitus.

BACKGROUND: Leptin is a protein produced in adipose tissue and takes part in angiogenesis and atherogenesis. Leptin is associated with development of type 2 diabetes and cardiovascular disease. AIM: To evaluate leptin concentrations in acute myocardial infarction and in the period of convalescence in patients with type 2 diabetes mellitus. METHODS: Coronary angiography was performed in 58 patients with acute myocardial infarction. The study group comprised 35 patients with type 2 diabetes mellitus (DM) (25 men, 10 women, mean age 63.8 + or - 11.5 years) and 23 non-diabetic subjects (17 men, 6 women, mean age 58.6 + or - 9.9 years) - the control group. All patients underwent medical examination and body mass indices (BMI) as well as waist/hip ratios (WHR) were calculated. Venous blood was collected after 24 hours of admission (second day), on day 5 and three weeks after admission. RESULTS: Leptin level was significantly associated with BMI (DM: r = 0.46, p = 0.005; control group: r = 0.67, p < 0.01), and hip circumference (DM: r = 0.28, p = 0.09; control group: r = 0.41, p = 0.04). Plasma leptin levels in women with type 2 diabetes were higher than in men (32.1 + or - 11.7 microg/mL vs 12.7 + or - 11.2 microg/mL, p < 0.01). Plasma leptin levels were significantly lower in non-diabetics compared to diabetic patients. Plasma leptin levels in diabetic patients were significantly higher in the acute phase of myocardial infarction than in the period of convalescence (18.3 + or - 14.3 microg/mL, 16.1 + or - 12.8 microg/mL, 14.8 + or - + or - 11.2 microg/mL, p = 0.02) but not in the control group (10.6 + or - 8.2 microg/mL, 10.0 + or - 7.3 microg/mL, 9.6 + or - 7.0 microg/mL, NS). CONCLUSIONS: Plasma leptin levels in diabetic patients were significantly higher in the acute myocardial infarction than in the period of convalescence. These findings suggests that leptin may play an important role in the metabolic changes taking place during the first days of myocardial infarction.

[Direct and indirect treatment cost of patient with ischaemic heart disease]. / Bezposrednie i posrednie koszty leczenia pacjenta z niestabilna choroba niedokrwienna serca.

Authors of this paper attempted to evaluate the cost of treatment of hypothetical patient with ischaemic heart disease during the period 16 years. The medical costs (costs of medicines, diagnostic procedures, coronary angioplasty and bypass surgery) and indirect costs of lost productivity have been estimated.

Validation of hemoglobin glycation models using glycemia monitoring in vivo and culturing of erythrocytes in vitro.

Glycated hemoglobin A1c (HbA1c) concentration in blood is an index of the glycemic control widely used in diabetology. The aim of the work was to validate two mathematical models of HbA1c formation (assuming irreversible or reversible glycation, respectively) and select a model, which was able to predict changes of HbA1c concentration in response to varying glycemia courses with higher accuracy. The experimental procedure applied consisted of an original combination of: in vivo continuous glucose concentration monitoring, long-term in vitro culturing of the human erythrocytes and mathematical modeling of HbA1c formation in vivo and in vitro with HbA1c values scaled according to the most specific analytical methods. Sixteen experiments were conducted in vitro using blood samples collected from healthy volunteer and stable type 1 diabetic patients whose glycemia was estimated beforehand based on long-term monitoring. The mean absolute difference of the measured and predicted HbA1c concentrations for the in vitro experiments were equal to 0.64 +/- 0.29% and 1.42 +/- 0.16% (p = 0.0007) for irreversible and for reversible model, respectively, meaning that the irreversible model was able to predict the glycation kinetics with a higher accuracy. This model was also more sensitive to a deviation of the erythrocytes life span.

Contribution of Na+/H+ exchange to Na+ overload in the ischemic hypertrophied hyperthyroid rat heart.

OBJECTIVE: The mechanisms responsible for intracellular ion homeostasis in ischemic hypertrophied myocardium are not fully known. Moderately hypertrophied hyperthyroid hearts (T3) are characterized by the bioenergetic changes and increased Na+/H+ exchange (NHE) activity comparable with those observed in humans and experimental models of hypertrophy. Here we test the hypothesis whether NHE inhibition in T3 heart improves ion homeostasis during ischemia and contractile function during recovery. METHODS: We compared intracellular H+ (H+i) and Na+ (Na+i) accumulations during 28 min global ischemia in isolated perfused T3 and euthyroid (EUT) rat hearts with and without NHE inhibition by using 31P and 23Na NMR. Heart function was measured during control perfusion and 30 min following ischemic insult. RESULTS: In T3 hearts ischemia caused: (1) faster and greater Na+i accumulation (534+/-25% of preischemic level versus 316+/-22% in EUT, P<0.001); (2) lower acidification (pH(i) 6.66+/-0.66 versus 6.12+/-0.12 in EUT, P<0.001); and (3) faster hydrolysis of ATP. NHE inhibition (amiloride 1 mM) in T3 hearts lead to: (1) delayed and lower Na+i accumulation by 35+/-5%; (2) faster and greater acidification (pH(i) 6.45+/-0.15, P<0.05); (3) delayed ATP degradation; and (4) improved heart function during recovery. When NHE was inhibited, all T3 hearts (n=11) recovered 68+/-10% of their preischemic rate pressure product (RPP), while only two untreated T3 hearts (from 11) recovered approximately 40% of preischemic RPP. CONCLUSIONS: These data suggest that NHE inhibition could be useful intervention for the prevention of ischemic/reperfusion cell injury and could improve the function of the hypertrophied heart after acute ischemia.

[Pancreastatin secretion stimulation in healthy volunteers]. / Stymulacja wydzielania pankreastatyny u zdrowych ochotników.

According to animal studies pancreastatin (PST), a peptide that is secreted by numerous neroendocrine cells, inhibits insulin secretion and has a hyperglycaemic and glycogenolytic effect. However, physiologic role of PST in carbohydrate metabolism remains unclear. In order to determine the best stimulus of PST secretion, four different stimulations of GI tract were carried out in 10 healthy volunteers: oral glucose loading test, intravenous glucose loading test, intravenous glucagon infusion and standard meal loading test. Serum PST concentration was measured radioimmunologically at established intervals after each stimulation. It was found that either oral or intravenous glucose loading test do not increase serum PST concentration; intravenous glucagon infusion decreases serum PST concentration and a standard meal increases serum PST concentration.