Monitoring of treatment with L-asparaginase in children with acute lymphoblastic leukaemia, with a focus on silent inactivation and its influence on the treatment outcome.

Introduction: The aim of the study was to analyse the frequency of silent inactivation and allergic reaction to asparaginase (ASP) and its impact on treatment results in patients with lymphoblastic leukaemia. Material and methods: Seventy patients with acute lymphoblastic leukaemia treated with ASP were enrolled in the study. Asparaginase activity was monitored. The patients were switched to another ASP formulation after allergy or inactivation. The treatment results were analysed. Results: Silent inactivation of native E. coli ASP was diagnosed in 5 patients (7%) and allergy in 34 patients (49%), and these patients were switched to pegylated ASP (PEG-ASP). Silent inactivation of PEG-ASP occurred in 8 patients (23%) and allergy in 6 patients (17%). Eight children continued therapy with Erwinase, and 4 did not switch to Erwinase after inactivation of PEG-ASP. Allergy to Erwinase occurred in 2 patients (22%); there was no inactivation. No significant differences in outcome were found between the groups of patients with and without allergy or silent inactivation of ASP. Due to regular monitoring and switching to other ASP preparations after allergy or silent inactivation, therapeutic activity was ensured in almost all patients. Conclusions: Monitoring of ASP activity is crucial to recognize silent inactivation and to guarantee treatment effectiveness by switching to other ASP preparations.

Simplification of intradermal skin testing in Hymenoptera venom allergic children.

BACKGROUND: The direct comparison between children and adults with Hymenoptera venom anaphylaxis (HVA) has never been extensively reported. Severe HVA with IgE-documented mechanism is the recommendation for venom immunotherapy, regardless of age. OBJECTIVE: To determine the differences in the basic diagnostic profile between children and adults with severe HVA and its practical implications. METHODS: We reviewed the medical records of 91 children and 121 adults. RESULTS: Bee venom allergy was exposure dependent, regardless of age (P < .001). Atopy was more common in children (P = .01), whereas cardiovascular comorbidities were present almost exclusively in adults (P = .001). In the bee venom allergic group, specific IgE levels were significantly higher in children (29.5 kUA/L; interquartile range, 11.30-66.30 kUA/L) compared with adults (5.10 kUA/L; interquartile range, 2.03-8.30 kUA/L) (P < .001). Specific IgE levels for culprit insect venom were higher in bee venom allergic children compared with the wasp venom allergic children (P < .001). In adults, intradermal tests revealed higher sensitivity, accompanied by larger area of skin reactions, regardless of type of venom. At concentrations lower than 0.1 µg/mL, 16% of wasp venom allergic children and 39% of bee venom allergic children had positive intradermal test results. The median tryptase level was significantly higher in adults than in children for the entire study group (P = .002), as well as in bee (P = .002) and wasp venom allergic groups (P = .049). CONCLUSION: The basic diagnostic profile in severe HVA reactors is age dependent. Lower skin test reactivity to culprit venom in children may have practical application in starting the intradermal test procedure with higher venom concentrations.

Antithrombin III as the Indicator of L-Asparaginase Activity in Children Treated for Acute Lymphoblastic Leukemia.

L-asparaginase (ASP) is widely used in the treatment of acute lymphoblastic leukemia (ALL) in children. Monitoring its activity is necessary because of the risk of drug inactivation as the result of an immune reaction. Besides allergic reactions, another frequent side effect of ASP treatment is coagulopathy, especially deficiency of antithrombin III (ATIII). The aim of this study was to analyze the relationship between ASP and ATIII activities and the possibility of ATIII activity use in an indirect ASP activity assessment. ASP and ATIII activity was measured in 76 children with ALL treated according to the ALL IC BFM 2002 protocol. A correlation between ASP and ATIII activities was found (R=-0.43, P=0.0001). ROC curve analysis revealed some utility regarding the determination of ATIII in identifying patients with low or undetectable ASP activity (area under the curve=0.87 [95% confidence interval, 0.77-0.96], P<0.0001 and 0.93 [95% confidence interval, 0.85-1.0], P<0.0001, respectively). Higher ATIII activity is associated with a higher probability of a decline in ASP activity. Examination of ATIII activity cannot replace a direct determination of ASP activity, but in the case of unavailability of the direct test, it can be a helpful surrogate parameter of drug activity.

Peptides from adipose tissue in monitoring energy balance in infants.

BACKGROUND/AIM: Overnutrition as well as undernutrition is a serious problem in hospitalized patients, especially in infants. Routine laboratory tests detecting disturbances in energy balance are not specific or accurate. The aim of this study was to evaluate adiponectin and leptin as markers of short-time energy malnutrition. METHODS: Forty-five infants fed orally and parenterally were included in the study. Plasma glucose, leptin and adiponectin were measured in a fasting state and postprandially (1 h after the meal), after a minimum of 24 h of total parenteral nutrition (TPN) and after a minimum of 8 h of intravenous infusion of glucose and crystalloids. RESULTS: Postprandial glucose levels in children fed orally was similar to that observed in children who received intravenous infusion of glucose. The TPN children had slightly higher glucose concentration in contrast to leptin levels which were significantly lower in this group (1.08 mg/mL +/- 0.43) as compared to the others (p < 0.05 in both cases). The mean postprandial levels of the adiponectin in orally fed children were significantly higher (10.7 microg/mL +/- 2.4) than in children with TPN (5.8 microg/mL +/- 2.4; p < 0.001) and in children hydrated intravenously (3.3 microg/mL +/- 2.3; p < 0.001). The concentration of adiponectin correlated significantly with calorie intake. CONCLUSIONS: Oral meal does not affect the plasma concentrations of leptin and adiponectin in infants. Adiponectin is a good short-time marker of energy malnutrition in infants.

Bimodal influence of plasma estradiol on relation between insulin-like growth factor-I (IGF-I) and estradiol in women.

OBJECTIVE: To compare the influence of low and normal endogenous estradiol concentration on circulating hGH, IGF-I and IGFBP-3 levels as well as on mutual correlations of these parameters. PATIENTS: 45 women (age 30.7 ± 9.0 years, BMI 25.7 ± 8.0) divided into group A - 15 hypoestrogenic women and group B - 30 normoestrogenic controls. Neither of the women was menopausal nor hyperprolactinemic. METHODS: Blood sample was taken at the standard conditions prior to the initiation of hormonal supplementation therapy in group A and at the day 3-5 of menstrual cycle in group B. Serum hGH, IGF-I, IGFBP-3, insulin, testosterone, sex hormone binding globulin (SHBG) dihydroepiandrosterone sulphate (DHEAS) and LH as well as prolactin (PRL), FSH and estradiol levels were measured by standard RIA kits. RESULTS: Mean IGF-1, LH, FSH, testosterone and estradiol and PRL plasma levels were lower in group A compared to group B. There were no significant differences in mean SHBG, insulin and DHEAS levels. There were also no differences in mean: age, body mass, BMI as well as percentage of each BMI range between groups. Regardless the estradiol level the IGF-I/age link was found in both groups. A IGF-I/IGFBP-3 relation was found in both groups. IGF-I/estradiol link was seen only in group A. In group B hGH/SHBG link was found, in group A this relation was indirect. A link between hGH and testosterone levels was found only in group B. SHBG was related in group B to IGFBP-3, testosterone and to DHEAS. Insulin/IGFBP-3 link was seen in group B. The stepwise multiple regression revealed DHEAS and LH as predictors of IGF-I level in group A, while in group B none of the parameters predicted IGF-I level. The results of the same analysis in case of hGH are as follows: in group A hGH level was predicted by estradiol and SHBG. In group B none of factors predicted hGH levels. CONCLUSION: Estradiol plasma level is correlated to circulating IGF-I, albeit the relation seems to be biphasic.

The somatotropic axis in postmenopausal women during six month of transdermal continuous 17beta-estradiol administration combined with oral medroxyprogesterone.

AIM: The evaluation of the influence of continuous transdermal estradiol supplementation combined with oral medroxyprogesterone on the somatotropic axis in postmenopausal women. MATERIAL AND METHODS: 25 women completed the study Group A--13 women received transdermal 17beta-estradiol (Oesclim 50 - Fournier-Solvay) combined with oral 5 mg daily medroxyprogesterone (Gestomikron - Adamed). Group B--12 women without treatment. Basic plasma FSH, estradiol, glucose, insulin, SHBG, hGH, total and free IGF-I, IGFBP-1 as well as IGFBP-3 were measured initially and at the 12th and 24th week of the study. RESULTS: The mean plasma FSH level was reduced and mean plasma estradiol level was increased in group A during estradiol supplementation. Mean plasma level of free IGF-I and free to total IGF-I ratio were increased in group A during 24 weeks of hormone therapy. In the control group (group B) there was the significant increase in mean plasma IGFBP-3 level. Other parameters showed no significant changes in the control group. CONCLUSION: The administration of transdermal 17beta-estradiol combined with oral medroxyprogesterone increases the IGF-I bioavailability. However this influence do not exceed the physiologial level of IGF-I bioavailability.

[Influence of estradiol administration mode on plasma insulin-like growth factor-I (IGF-I) and its binding proteins 1 and 3 concentration in postmenopausal women treated with norethisterone acetate]. / Wplyw drogi podania 17beta-estradiolu na stezenie insulinopodobnego czynnika wzrostu-I (IGF-I) i jego bialek wiazacych 1 i 3 w surowicy krwi u kobiet po menopauzie stosujacych octan norethisteronu.

AIM: The aim of the present work was to assess the influence of estradiol administration mode on the plasma IGF-I, IGFBP-1, IGFBP-3 levels in postmenopausal women treated with norethisterone acetate. MATERIAL AND METHODS: 39 women were enrolled into the study Group A--14 women received transdermal 17beta-estradiol (Oesclim 50--Fournier-Solvay) combined with oral norethisterone 2.5 mg daily (Primolut-Nor--Schering), Group B--10 women on oral 2 mg 17beta-estradiol combined with oral 1 mg daily norethisterone (Kliogest--Novo-Nordisk). Control group (group C) consisted of 15 postmenopausal women who received no treatment. Basic plasma FSH, estradiol and total IGF-I, IGFBP-1 as well as IGFBP-3 levels were measured initially and at the 52nd week of the study. RESULTS: The mean plasma FSH level was reduced and mean plasma estradiol level was increased in groups A and B during hormone therapy. Mean plasma levels of total IGF-I, IGFBP-1, IGFBP-3 as well as IGFBP-3/IGF-I ratio did not changed significantly during 52 weeks of observation in groups A, B and C. The comparison of plasma IGF-I, IGFBP-1, IGFBP-3 between groups at the initial visit and after 52 weeks showed the lowest concentration f IGBP-3 in group B. Other parameters showed no differences among the three groups. CONCLUSION: Mode of administration of estradiol did not influenced the plasma levels of IGF-I, IGFBP-1, IGFBP-3 in postmenopausal women treated with norethisterone acetate.

[Plasma levels of total cholesterol, LDL-cholesterol, and HDL-cholesterol in postmenopausal women during 12 months' oral administration of dydrogesterone or medroxyprogesterone combined with continuous transdermal supplementation of 17beta-estradiol]. / Stezenia cholesterolu calkowitego, frakcji LDL cholesterolu i frakcji HDL-cholesterolu w surowicy u kobiet po menopauzie w trakcie 12 miesiecznej doustnej podazy dydrogesteronu lub medroxyprogesteronu lacznie z przezskórna suplementacja 17beta-estradiolu.

AIM: To compare the effect on total cholesterol and LDL and HDL cholesterol of oral dydrogesterone and medroxyprogesterone administration combined with continuous transdermal supplementation of 17beta-estradiol in postmenopausal women. MATERIAL & METHODS. The prospective study was carried out in 59 healthy postmenopausal women (mean age 54.5 +/- 3.34 years). They were randomized and treated either with continuous transdermal hormonal therapy (HT) (Group A; n=25; 17beta-estradiol at a dose of 0.05 mg/24 hours combined with oral dydrogesterone at a daily dose of 5 mg or group B, n=24; 17beta-estradiol at a dose of 0.05 mg/24 hours combined with oral medroxyprogesterone at a daily dose of 5 mg) or observed as a control group C (n=10). Basal plasma levels of total cholesterol, HDL-cholesterol and LDL-cholesterol as well as basal estrogen and FSH levels were measured before HT and after 6 and 12 months of treatment. At the same time intervals, all the studied parameters were measured for group C. RESULTS: After 6 months of continuous transdermal supplementation of 17beta-estradiol with oral dydrogesterone the plasma level of total cholesterol decreased (6.23 +/- 1.02 mmol/l vs 5.65 +/- 0.96 mmol/l; p < 0.05). The effect was also maintained after 12 months of HT (5.46 +/- 1.0 mmol/l). The plasma level of LDL-cholesterol was also decreased after 6 months of HT (3.87 +/- 0.83 mmol/ I vs 3.42 +/- 0.58 mmol/l; p < 0.05). The effect was also maintained after 12 months of HT (3.48 +/- 0.73 mmol/l). HDL-cholesterol plasma level was increased after 6 months of HT (1.52 +/- 0.45 mmol/l vs 1.76 +/- 0.45 mmol/l; p < 0.05) and was maintained after 12 months. The beneficial changes of plasma levels of total cholesterol, HDL-cholesterol and LDL-cholesterol in group B did not reach the statistical significance. The lipid and lipoproteins mean plasma levels remained unchanged in the control group during 12 months of observation. CONCLUSION: Adding dydrogestrone or medroxyprogesterone to the continuous transdermal supplementation of 17beta-estradiol did not deteriorate the modificable atherosclerotic risk factors.

Pressure pain threshold and ß-endorphins plasma level are higher in lean polycystic ovary syndrome women.

BACKGROUND: Despite some evidence that indicates that the evolution of polycystic ovary syndrome (PCOS) is related to the activity of the endogenous opioid system, and that concentration of plasma ß-endorphin levels can increase pain threshold, there are no studies which evaluate pressure pain threshold in the PCOS women population. METHODS: In 48 lean women with PCOS and 38 lean women without this disorder plasma ß-endorphins and PPT were measured. RESULTS: The ß-endorphins level was higher in the PCOS group compared to the controls (15.28±2.49 pg/mL vs. 6.33±1.71 pg/mL, P<0.001). In PCOS group PPTs measured on deltoid and trapezius muscles were higher compared to the controls (9.33±1.3 kg/cm² vs. 5.19±0.57 kg/cm², P<0.001; 8.23±1.04 kg/cm² vs. 4.79±0.55 kg/cm², P<0.001). The ß-endorphin levels positively correlated with PPTs in PCOS group. Increase in ß-endorphin level of 1 pg/mL was associated with increase of PPT value on deltoid muscle of 0.23 kg/cm² (R=0.632, P=0.011) and of 0.18 kg/cm² on trapezius muscle (R=0.588, P=0.037). There were no correlations between testosterone level and PPT in PCOS group. CONCLUSIONS: ß-endorphin serum level as well as PPT are higher in lean PCOS group than in controls. We found correlations between ß-endorphin levels and PPT in the PCOS group. It may suggest the role of endogenous opioids in the pathogenesis of PCOS and also that the increases in circulating plasma ß-endorphins concentration can increases PPT in this group.

Metformin increases pressure pain threshold in lean women with polycystic ovary syndrome.

BACKGROUND: Despite the strong preclinical rationale, there are only very few data considering the utility of metformin as a potential pain therapeutic in humans. The aim of this study was to determine the association between metformin therapy and pressure pain threshold (PPT) in lean women with polycystic ovary syndrome (PCOS). We hypothesized that metformin therapy in lean PCOS women increases PPT. MATERIALS AND METHODS: Twenty-seven lean PCOS women with free androgen index phenotype >5 and 18 lean healthy controls were enrolled in the study. Fifteen of the PCOS women were randomly assigned to be treated with metformin 1,500 mg daily for 6 months. PPT and plasma ß-endorphin levels were measured in all women at the beginning of the study and after 6 months of observation. RESULTS: We observed an increase in PPT values measured on deltoid and trapezius muscle in the PCOS with metformin group after 6 months of metformin administration (4.81±0.88 kg/cm(2), P<0.001 on deltoid muscle, and 5.71±1.16 kg/cm(2) on trapezius muscle). We did not observe any significant changes in PPT values in the PCOS without treatment group and in controls. We did not observe any significant changes in serum ß-endorphin levels in any studied groups during the 6-month observation. CONCLUSION: We conclude that metformin therapy increases PPT in lean PCOS women, without affecting plasma ß-endorphin concentration. Our results may suggest the potential role of metformin in pain therapy. We propose that larger, randomized studies on metformin impact on pain perception should be performed.

Entero-insular axis in children with anorexia nervosa.

UNLABELLED: Entero-insular axis plays an important role in generating satiety signal. Thus disturbances in this axis may influence the course of anorexia nervosa. The aim of the study was analysis of the function of the hormonal part of the entero-insular axis in girls with anorexia nervosa. Thirteen girls with anorexia nervosa and in 10 healthy girls were studied. Each girl was subjected to oral glucose tolerance test and standard meal test. Blood was collected before stimulation and within 15, 30, 60, and 120 min thereafter. The concentrations of all peptides were determined by radioimmunoassay commercial kits. Fasted and postprandial levels of these peptides as well as integrated outputs were measured. Fasting insulin concentration was significantly higher in the group of girls with anorexia nervosa than in the control group (p<0.03). What more in girls with anorexia the integrated output of insulin was significantly lower in oral glucose tolerance test than after the meal (p<0.001). Also the integrated output of glucagon in both tests was higher in the group of girls with anorexia than in the control group. The mean output of pancreatic polypeptide and cholecystokinin in anorexia group was significantly higher (p<0.001 in both cases) than that in the control group but only after the test meal. The integrated outputs of gastric inhibitory peptide in both tests were significantly higher in anorectic girls than those in the control group (oral glucose tolerance test, p<0.02; meal test, p<0.001), However, mean values of the integrated output of glucagon-like peptide 1 in both tests were significantly higher in the control group than in the girls with anorexia (p<0.001 in each case). Highly significant correlation was found between glucose concentration and the concentrations of insulin, cholecystokinin, and gastric inhibitory peptide in both tests and for the both groups. In the anorectic girls, significant correlation between insulin concentration and the concentration of gastric inhibitory peptide was found after both stimulation tests and between insulin and cholecystokinin after oral glucose only. CONCLUSION: the disturbed secretion of the hormones of entero-insular axis after the meal in anorectic girls may have negative influence on the course of anorexia nervosa. This disease has no effect on the incretin function of cholecystokinin, gastric inhibitory peptide and glucagon-like peptide 1.

Effect of hormone therapy on the enteroinsular axis.

OBJECTIVE: Menopause is associated with a decline in insulin response to glucose and with insulin resistance. It has been proven that hormone therapy (HT) improves carbohydrate metabolism in postmenopausal women. However, it is known that gastrointestinal hormones play a key role in the coordination of digestion and absorption of ingested nutrients and in the regulation of pancreatic endocrine function. Therefore, the aim of this study was to investigate the effect of HT on gastrointestinal hormones and carbohydrate metabolism in postmenopausal women. DESIGN: The prospective study was performed in 90 healthy postmenopausal women (mean age 54.5 years, standard deviation 3.34 years), of whom 49 completed the study. They were randomized and treated either with continuous transdermal HT (0.05 mg 17[beta]-estradiol every 24 hours) combined with 5 mg oral dydrogesterone daily (group A, n = 25), or with oral HT (2 mg 17[beta]-estradiol semihydrate every 24 hours) combined with 10 mg dydrogesterone as a continuous therapy (group B, n = 8). The control group (group C, n = 16) received no HT. Both basal and meal-stimulated plasma concentrations of glucose, insulin, glucose-dependent insulinotropic peptide (GIP), glucagon-like peptide-1 (GLP-1), and cholecystokinin (CCK), as well as basal estrogen levels, were measured before HT and after 6 and 12 months of treatment. At the same time intervals, all the studied parameters were measured for group C. RESULTS: After 12 months of the transdermal HT, a decrease in both fasting (P < 0.002) and postprandial (P < 0.05) plasma glucose levels was observed. Oral HT reduced only the fasting plasma glucose level in the 12th month of treatment (P < 0.05). Regardless of the route of administration, HT reduced postprandial plasma levels of insulin (oral HT: P < 0.05; transdermal HT: P < 0.02). Fasting plasma levels of GIP were reduced after 6 and 12 months of transdermal HT (P < 0.002 and P < 0.001, respectively). Moreover, levels of postprandial GIP were reduced after 6 and 12 months of transdermal HT (P < 0.002 in both cases). Fasting and postprandial GLP-1 levels were reduced by transdermal HT after 12 months of supplementation. Oral HT also decreased these levels, but not significantly. The observed differences may, however, be related not only to the route of administration, but also to the difference in the dose of estradiol. Regardless of the route of administration, HT did not influence plasma levels of CCK. CONCLUSIONS: Hormone therapy significantly influences the enteroinsular axis in postmenopausal women and contributes to the normalization of plasma glucose levels.

Clinical utility of ammonia concentration as a diagnostic test in monitoring of the treatment with L-asparaginase in children with acute lymphoblastic leukemia.

L-asparaginase (ASP) is an enzyme used as one of the basic regimens in the acute lymphoblastic leukemia (ALL) therapy. Because of the possibility of the enzyme inactivation by antibodies, monitoring of ASP activity is essential. The aim of the study was to examine if plasma concentration of ammonia, a direct product of the reaction catalyzed by ASP, can be used in the assessment of ASP activity. A group of 87 patients with acute lymphoblastic leukemia treated in the Department of Pediatric Oncology and Hematology in Krakow was enrolled to the study. ASP activity and ammonia concentration were measured after ASP administrations during induction. A positive correlation was found between the ammonia concentration and ASP activity (R = 0.44; P < 0.0001) and between the medium values of ammonia concentration and ASP activity (R = 0.56; P < 0.0001). The analysis of ROC curves revealed the moderate accuracy of the ammonia concentration values in the ASP activity assessment. It was also found that the medium value of ammonia concentrations can be useful in identification of the patients with low (<100 IU/L) and undetectable (<30 IU/L) ASP activity. The plasma ammonia concentration may reflect ASP activity and can be useful when a direct measurement of the activity is unavailable.

Gastric lipase secretion in children with gastritis.

Gastric lipase is one of the prepancreatic lipases found in some mammalian species and in humans. Our knowledge of the hormonal regulation of gastric lipase secretion in children and adolescents is still very limited. The aim of this study was to compare the activity of human gastric lipase (HGL) in gastric juice in healthy adolescents and in patients with gastritis. The adolescents were allocated to three groups: the first including patients with Helicobacter pylori gastritis (HPG; n = 10), the second including patients with superficial gastritis caused by pathogens other than H. pylori (non-HPG; n = 14) and the control group including healthy adolescents (n = 14). Activity of HGL was measured in gastric juice collected during endoscopy. Plasma concentrations of cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) were measured in all adolescents. Activity of HGL in the non-HPG group was significantly lower than in the HPG group (p < 0.005) and the control group (p < 0.005). Mean plasma GIP levels in the control group were lower than in the non-HPG group (p < 0.003) and the HPG group (p < 0.01). We conclude that the regulation of HGL secretion by GLP-1 and CCK is altered in patients with gastritis. Moreover, GIP is a potent controller of HGL activity, both in healthy subjects and in patients with gastritis.