Occurrence of additional chromosome aberrations in chronic myeloid leukemia patients treated with imatinib mesylate.
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Antineoplastic Agents↗
Biomedical subjects
W Kern
Publications and source records attributed to W Kern.
[Diagnostics and therapy of acute myeloid leukemia].
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Aged↗
[Diagnosis of leukemia using microarray technology].
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Bone Marrow↗
The effect of experimentally induced insulin resistance on the leptin response to hyperinsulinaemia.
OBJECTIVE: Insulin is thought to be an important regulator of leptin secretion. However, increasing evidence suggests that insulin-mediated glucose uptake rather than insulin per se regulates circulating leptin concentration. Here, we hypothesised that a reduction of insulin sensitivity, ie insulin resistance, will diminish the stimulatory effect of insulin on leptin secretion as a consequence of decreased insulin-mediated glucose uptake. DESIGN: Changes in serum leptin concentration during 30 hyperinsulinaemic-hypoglycaemic clamps were studied after induction of different levels of insulin resistance in normal-weight men. In 15 subjects insulin sensitivity was reduced by exposing them to a 2.5 h antecedent hypoglycaemia (3.1 mmol/l) induced by a high rate of insulin infusion (15.0 mU/min/kg) on the day before the proper experiment ('ante-hypo' condition). In the other 15 subjects no antecedent hypoglycaemia was induced ('control' condition). The proper experiment on both conditions was a 6 h stepwise hypoglycaemic clamp induced by a constant rate of insulin infusion (1.5 mU/min/kg). SUBJECTS: Experiments were carried out in 30 lean healthy subjects (age, mean +/- s.e.m., 26 +/- 1 y; body mass index, 23.1 +/- 0.6 kg/m2). RESULTS: As expected, glucose demand during the clamp was lower in the ante-hypo condition than in the control condition (gram of glucose infused per kilogram body weight, 1.52 +/- 0.16 vs 2.01 +/- 0.17 g/kg; P < 0.05). During the clamp, leptin levels increased by 25.4 +/- 4.3% in the control condition (P < 0.05), but not in the ante-hypo condition (+4.8 +/- 4.5%; P > 0.25). Thus, serum leptin response to the clamp significantly differed between the two conditions (P < 0.01). Across both conditions, the increase of leptin levels during the clamp was correlated with the amount of glucose infused (r = 0.37; P < 0.05). CONCLUSION: Considering that insulin concentrations were identical during both clamp conditions, the data indicate that experimentally-induced insulin resistance diminishes the stimulatory effect of insulin on leptin secretion.
Adult↗
Karyotype instability between diagnosis and relapse in 117 patients with acute myeloid leukemia: implications for resistance against therapy.
The instability of the karyotype may play a role in the development of refractoriness of acute myeloid leukemia (AML) to anti-leukemic therapy. Therefore, in the current study cytogenetic analyses were performed in 117 patients with AML both at diagnosis and at relapse. Changes in karyotype were observed in 38% (36% of initially normal karyotypes, 39% of initially aberrant karyotypes). An evolution of karyotype, ie the acquisition of further aberrations in addition to those present at diagnosis, occurred more frequently in patients with unfavorable karyotypes at diagnosis as compared to all others (60% vs 32%, P = 0.0095). The duration from initial diagnosis to relapse was significantly shorter in cases with an evolution of the aberrant karyotype as compared to cases with no changes in the aberrant karyotype between diagnosis and relapse or with solely regression of aberrations at relapse (9.2 +/- 4.4 vs14.0 +/- 8.5 months, P = 0.0081). In an additional analysis, another cohort of 120 patients with refractory and relapsed AML who were treated uniformly within the respective trial of the German AML Cooperative Group was analyzed cytogenetically at diagnosis and at relapse to further prove the prognostic impact of karyotype aberrations at relapse. Karyotypes were prognostically favorable, intermediate, unfavorable and not available in 8%, 50%, 17% and 25% at diagnosis and in 8%, 49%, 21% and 22% at relapse, respectively. Karyotype aberrations at diagnosis had no impact on response to therapy (P = 0.32) but influenced survival and event-free survival significantly (P = 0.03 and P = 0.02). In contrast, karyotype aberrations at relapse strongly influenced response to therapy (P = 0.05), survival (P = 0.01), and event-free survival (P = 0.002). These data suggest that the instability of the karyotype between diagnosis and relapse and thus karyotype aberrations at relapse in particular contribute to the refractoriness of AML to anti-leukemic therapy.
Acute Disease↗
Dependence of age-specific incidence of acute myeloid leukemia on karyotype.
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Adult↗
Aldehydic lipid peroxidation products derived from linoleic acid.
Lipid peroxidation (LPO) processes observed in diseases connected with inflammation involve mainly linoleic acid. Its primary LPO products, 9-hydroperoxy-10,12-octadecadienoic acid (9-HPODE) and 13-hydroperoxy-9,11-octadecadienoic acid (13-HPODE), decompose in multistep degradation reactions. These reactions were investigated in model studies: decomposition of either 9-HPODE or 13-HPODE by Fe(2+) catalyzed air oxidation generates (with the exception of corresponding hydroxy and oxo derivatives) identical products in often nearly equal amounts, pointing to a common intermediate. Pairs of carbonyl compounds were recognized by reacting the oxidation mixtures with pentafluorobenzylhydroxylamine. Even if a pure lipid hydroperoxide is subjected to decomposition a great variety of products is generated, since primary products suffer further transformations. Therefore pure primarily decomposition products of HPODEs were exposed to stirring in air with or without addition of iron ions. Thus we observed that primary products containing the structural element R-CH=CH-CH=CH-CH=O add water and then they are cleaved by retroaldol reactions. 2,4-Decadienal is degraded in the absence of iron ions to 2-butenal, hexanal and 5-oxodecanal. Small amounts of buten-1,4-dial were also detected. Addition of m-chloroperbenzoic acid transforms 2,4-decadienal to 4-hydroxy-2-nonenal. 4,5-Epoxy-2-decenal, synthetically available by treatment of 2,4-decadienal with dimethyldioxirane, is hydrolyzed to 4,5-dihydroxy-2-decenal.
Air↗
Observation of exotic meson production in the reaction pi- p --> eta'pi- p at 18 GeV/c.
An amplitude analysis of an exclusive sample of 5765 events from the reaction pi- p-->eta'pi- p at 18 GeV/c is described. The eta'pi- production is dominated by natural parity exchange and by three partial waves: those with J(PC) = 1(-+), 2(++), and 4(++). A mass-dependent analysis of the partial-wave amplitudes indicates the production of the a2(1320) meson as well as the a4(2040) meson, observed for the first time decaying to eta'pi-. The dominant, exotic (non- qq) 1(-+) partial wave is shown to be resonant with a mass of 1.597+/-0.010(+0.045)(-0.010) GeV/c2 and a width of 0.340+/-0.040+/-0.050 GeV/c2. This exotic state, the pi1(1600), is produced with a t dependence which is different from that of the a2(1320) meson, indicating differences between the production mechanisms for the two states.
Journal Article↗
Pharmacokinetics of cisplatin and relation to nephrotoxicity in paediatric patients.
BACKGROUND: Cisplatin is a highly effective and frequently used drug in the chemotherapy of solid tumours in children, but only limited data are available on the pharmacokinetics of cisplatin and its associated nephrotoxicity in paediatric patients. METHODS: We investigated the pharmacokinetics of free platinum (Pt) in 12 children (25 courses) receiving cisplatin (75-120 mg/m2) either as a continuous 72-h infusion, prolonged single 6-h infusion or repetitive 1-h infusions. Plasma and urinary Pt concentrations were analysed using atomic absorption spectroscopy. Cisplatin-induced nephrotoxicity was determined using creatinine clearance and several glomerular and tubular marker proteins. RESULTS: Using a two-compartment model the pharmacokinetic parameters for free Pt were: initial half-life 21.6 +/- 9.6 min, terminal half-life 25.9 +/- 16.2 h, area under the plasma concentration-time curve (AUC) 13.5 +/- 4.97 (microg/ml) x h/(100 mg/m2) and cumulative renal elimination(infinity) 41.7 +/- 6.6% of dose. Higher cisplatin delivery rates led to higher peak concentrations of free Pt in plasma and urine and to lower cumulative renal Pt elimination (P < 0.01). During all courses, increases of urinary albumin and alpha1-microglobulin excretion were documented. The creatinine clearance decreased significantly to 70% of baseline values. Correlations were found between both peak free Pt concentrations in plasma and in urine and the maximum of urinary excretions of albumin and of N-acetyl-beta-D-glucosaminidase and the nadir of the glomerular filtration rate (P < 0.05). CONCLUSIONS: With respect to nephrotoxicity, long-term infusions of cisplatin seem to be preferable over intermittent bolus administration in paediatric patients. The best predictive pharmacokinetic parameters for cisplatin-associated nephrotoxicity in children are peak free Pt concentrations in plasma and urine.
Adolescent↗
Efficacy of fludarabine, intermittent sequential high-dose cytosine arabinoside, and mitoxantrone (FIS-HAM) salvage therapy in highly resistant acute leukemias.
Patients with refractory acute leukemias after intensive induction and salvage attempts have a particularly poor prognosis and therapeutic options are limited. In the current study, the pharmacologically based FIS-HAM regimen was applied, which included fludarabine 15 mg/m2 q 12 h (days 1, 2, 8, and 9), cytosine arabinoside as a 45-min infusion every 3 h at 750 mg/m2 per single application (days 1, 2, 8, and 9), and mitoxantrone 10 mg/m2 (days 3, 4, 10, 11). Twenty-six intensively pretreated patients [median age: 38 years; range: 22-65; 16 cases of acute myeloid leukemia (AML) and 10 of acute lymphoblastic leukemia (ALL)] were included. Of 16 patients with AML, 5 achieved a complete remission (CR, 31%), 1 a partial remission (PR, 6%), 2 were nonresponders (13%), and 8 succumbed to early death (ED, 50%). Of 10 patients with ALL, 5 achieved a CR, 1 a PR, 1 was a nonresponder, and 3 died early. Overall, the CR rate was 38%. The median disease-free survival time was 50 days and median survival 90 days. Two patients underwent allogeneic bone marrow transplantation and are alive after 27 and 28 months. Neutropenia amounted to a median of 46 days. Toxicity WHO III/IV included infection (61%), diarrhea (48%), nausea/vomiting (43%), impairment of heart function (30%), and mucositis (26%). The current data indicate a significant activity of FIS-HAM chemotherapy in advanced acute leukemias. However, due to its pronounced toxicity, this regimen should be restricted to third-line therapy for patients expecting a suitable donor for allogeneic transplantation, and supportive treatment should be optimized.
Acute Disease↗
Carboplatin pharmacokinetics in patients receiving carboplatin and paclitaxel/docetaxel for advanced lung cancers: impact of age and renal function on area under the curve.
PURPOSE: To further define the most appropriate way of choosing the dose of carboplatin. PATIENTS AND METHODS: The pharmacokinetics of carboplatin were analyzed in 30 patients with advanced lung cancer receiving a total of 48 cycles of carboplatin plus paclitaxel/ docetaxel combination chemotherapy. Platin concentrations of ultrafiltrated plasma and urine samples were determined by flameless atomic absorption spectrometry. A multiple regression analysis was performed for interactions between pharmacokinetic parameters and pretreatment characteristics. RESULTS: Using a twocompartment-model, the following parameters were obtained (mean, coefficient of variation): initial half-life, 0.903 h (48%); terminal half-life, 13.6 h (116%); maximum plasma concentration (Cmax), 38.5 microM (86%); AUC, 111.9 microM/h (86%); volume of distribution, 411 l (130%); total clearance (Ct), 579 ml/min (75%); renal clearance (Cr), 453 ml/min (80%); renal elimination, 76% of dose (17%). In the univariate analysis, age was significantly related to Cmax (P = 0.0303), AUC (P = 0.0050), Ct (P = 0.0020), Cr (P = 0.0092). Plasma creatinine (Crp) was related to Cmax (P = 0.0228), and 1/[Crp] was related to Cmax (P = 0.0015) and AUC (P = 0.0054), while body weight was related to Cmax (P = 0.0365). No interaction with the schedule of application of the two drugs was observed. In the multivariate analysis, factors significantly related to AUC were 1/[Crp] (P < 0.01) and age (P < 0.01). Crp (P < 0.05) and 1/[Crp] (P < 0.01) were significantly associated with Cmax. CONCLUSIONS: These data stress the importance of dosing carboplatin according to renal function and age and warrant further analyses to validate this concept prospectively.
Adult↗
Cisplatin nephrotoxicity in children after continuous 72-h and 3x1-h infusions.
Little is known about the association between the rate of cisplatin administration and the severity of cisplatin-induced renal damage in children. The purpose of this study was to compare severity and reversibility of renal damage in children after continuous and repetitive bolus administration of cisplatin and to correlate these data with pharmacokinetic parameters. Study subjects included six children (ten courses) receiving cisplatin as 1-h bolus infusions on three consecutive days (3x40 mg/m2) and four children (eight courses) receiving 72-h continuous infusions (120 mg/m2). In all courses, signs of glomerular and tubular damage were seen, as evidenced by elevated urinary excretion of alpha1-microglobulin, albumin and N-acetyl-beta-D-glucosaminidase and decreased glomerular filtration rate (GFR). Comparing the two infusion regimens, the 1-h bolus administration of cisplatin was followed by significantly higher peak free platinum concentrations in plasma and urine (P<0.001), resulting in lower nadirs of the GFR (P<0.005). Correlations were found between both peak free platinum concentrations in plasma and urine and maxima of urinary albumin and N-acetyl-beta-D-glucosaminidase excretion. Within 12 months after completion of cisplatin therapy, children in the 1-h bolus group had recovered only partially from subclinical nephrotoxicity, with five out of six showing pathological proteinuria. The results provide clear evidence that long-term ciplatin infusions are less nephrotoxic than repetitive bolus infusions.
Adolescent↗
Gain of an isochromosome 5p: a new recurrent chromosome abnormality in acute monoblastic leukemia.
In acute myeloid leukemia (AML) close associations are known between cytomorphology and cytogenetics such as in AML M3/M3v showing a t(15;17) and in AML M4eo associated with inv(16)/t(16;16). In AML M5 a heterogenous cytogenetic pattern is observed. We describe the gain of an isochromosome of the short arm of chromosome 5 together with the gain of chromosome 8 as the sole abnormalities in two cases of acute monoblastic leukemia. In a third case of acute monoblastic leukemia we also observed the gain of an isochromosome 5p together with trisomy 8. This patient showed in addition an unbalanced translocation between the long arm of chromosome 1 and the short arm of chromosome 14 leading to a trisomy 1q. So far only two cases of AML with i(5)(p10) have been published. In no other hematological malignancy has an isochromosome 5p been reported up to now. As an isochromosome 5p can be misinterpreted as a deletion 5q, which occurs frequently in AML, fluorescence in situ hybridization with loci specific probes is a helpful method to detect this rare abnormality.
Adult↗
Phase I and pharmacokinetic study of hepatic arterial infusion with oxaliplatin in combination with folinic acid and 5-fluorouracil in patients with hepatic metastases from colorectal cancer.
BACKGROUND: To determine dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of oxaliplatin administered as hepatic arterial infusion. PATIENTS AND METHODS: Patients with isolated hepatic metastases from colorectal cancer were treated every three weeks with increasing doses of oxaliplatin (4 hours; starting dose 25 mg/m2, escalation in steps of 25 mg/m2) in combination with folinic acid (1 hour, 200 mg/m2) and 5-fluorouracil (2 hour, 600 mg/m2). RESULTS: Twenty-one patients (median age, 61 years) have been entered all of whom are fully evaluable. The DLT has been observed at dose level 6, i.e., at 150 mg/m2/cycle and consisted of leucopenia, obliteration of the hepatic artery, and acute pancreatitis. Overall, toxicity mainly consisted of nausea/vomiting (16 of 21 patients), anemia (16 of 21), upper abdominal pain (15 of 21), sensory neuropathy (10 of 21), diarrhea (9 of 21), and thrombocytopenia (9 of 21). The mean PK parameters were: terminal half-life of ultrafiltrable platin, 17.75 +/- 9.29 hours; renal elimination, 48.7% +/- 14.1% of the applied dose; renal clearance 135.55 +/- 45.32 ml/min. The mean area under the plasma-concentration curve (AUC) increased linearly from 3.22 +/- 0.61 microg x h/ml to 18.45 +/- 8.90 microg x h/ml through the first five dose levels (P = 0.0004). Ten of eighteen evaluable patients achieved a complete or partial response (59%). CONCLUSIONS: The recommended dose for phase II studies is 125 mg/m2 oxaliplatin.
Adult↗
Hyperinsulinemia causes activation of the hypothalamus-pituitary-adrenal axis in humans.
OBJECTIVE: Hyperactivity of the hypothalamus-pituitary-adrenal (HPA) axis is frequently found in hyperinsulinemic subjects, such as patients with diabetes or abdominal obesity. Here, the question has been posed as to whether hyperinsulinemia increases HPA secretory activity. METHODS: We performed paired-euglycemic and stepwise hypoglycemic (76-66-56-46 mg/dl)-clamp experiments in two groups (each of 15 healthy men) at different insulin infusions rates, ie, 1.5 mU/min/kg (low-insulin condition) and 15.0 mU/min/kg (high-insulin condition). RESULTS: During the euglycemic clamp, the high rate insulin infusion increased plasma ACTH levels, whereas plasma ACTH levels remained essentially unchanged during the low-insulin condition (condition by time interaction, P=0.008). Likewise, serum cortisol levels were higher during the high- vs low-insulin condition (condition by time interaction, P=0.004). During the hypoglycemic clamp, plasma ACTH levels did not differ between the low- vs high-insulin condition, while serum cortisol levels were higher during the high- vs low-insulin condition at the beginning of the clamp (plasma glucose approximately 76 mg/dl; P=0.032). CONCLUSION: Data indicate that hyperinsulinemia acutely increases HPA secretory activity in healthy men. This finding appears to be relevant to the pathogenesis of many clinical abnormalities associated which diabetes and abdominal adiposity, often referred to as the metabolic syndrome.
Adrenocorticotropic Hormone↗
Proliferative activity of leukaemic blasts and cytosine arabinoside pharmacodynamics are associated with cytogenetically defined prognostic subgroups in acute myeloid leukaemia.
The biological mechanisms responsible for the association of specific karyotypes with prognosis in acute myeloid leukaemia (AML) remain largely unclear. A prospective study was performed to evaluate how far cytogenetically defined prognostic subgroups of AML differ in their proliferative activity as a potential mechanism for differential sensitivities to S-phase-specific induction chemotherapy comprising cytosine arabinoside (AraC). One hundred and eighty-seven patients with de novo AML were included in the study; 25 patients with a favourable [inv(16), t(8;21), t(15;17)] karyotype, 99 with a normal karyotype, 29 with an unfavourable karyotype (-5, 5q-, -7, 7q-, complex aberrations) and 34 with cytogenetic aberrations of unknown prognostic significance (all others). The favourable group demonstrated the highest ex vivo proliferative activity (PA) (3.41 pmol/105 cells), significantly (P = 0.02) exceeding the unfavourable group with the lowest PA (0.72) and the group with a normal karyotype (1.06) or with karyotype of unknown significance (1.05) that both demonstrated an intermediate PA. Samples with a high PA (> median of the whole group) were more likely to produce interleukin 3, granulocyte macrophage colony-stimulating factor (GM-CSF), granulocyte CSF (G-CSF) (56%, 43% and 50%) than cells with a low PA (33%, 36% and 36%; n.s.). The effect of priming by exogenous GM-CSF or G-CSF was significantly more pronounced in samples with a low PA than in rapidly proliferating samples (P < 0.01). For the whole group, a high PA was closely associated with an increased incorporation of AraC triphosphate (AraCTP) into the DNA (P < 0.0001). Clinically, a high PA was associated with a better complete remission (CR) rate in the normal (95% versus 62%) and the unfavourable group (75% versus 33%). The significant differences in proliferative activity between cytogenetic subgroups of AML are associated with increased cytosine arabinoside pharmacodynamics and constitute one potential mechanism for the different response of cytogenetic subgroups to AraC-based induction therapy.
Adult↗
Fatigue and hyponatremia in a 75-year-old woman: unusual presentation of hypophysitis.
A 75-year-old woman presented with general fatigue progressing to somnolence. Laboratory tests showed marked hyponatremia. TSH in the normal range, but low levels of free T3 and free T4. Evaluation of pituitary hormones and magnetic resonance imaging of the pituitary unmasked findings characteristic for hypophysitis with secondary adrenal insufficiency and secondary hypothyroidism. Hormonal substitution with hydrocortisone and levothyroxine resulted in rapid improvement of all symptoms and signs. Without additional treatment shrinkage of the pituitary gland could be documented. Our report extends the known clinical and pathological spectrum of hypophysitis and illustrates the need to include this uncommon entity in the differential diagnosis of hyponatremia even in elderly patients.
Adrenal Insufficiency↗
Improving influence of insulin on cognitive functions in humans.
Insulin receptors have been identified in limbic brain structures, but their functional relevance is still unclear. In order to characterize some of their effects, we evaluated auditory evoked brain potentials (AEP) in a vigilance task, behavioral measures of memory (recall of words) and selective attention (Stroop test) during infusion of insulin. The hormone was infused at two different rates (1.5 mU/kg x min, "low insulin", and 15 mU/kg x min, "high insulin"), inducing respectively serum levels of 543 +/- 34 and 24,029 +/- 1,595 pmol/l. This experimental design allowed to compare cognitive parameters under two conditions presenting markedly different insulin levels, but with minimal incidence on blood glucose concentrations since these were kept constant by glucose infusion. A "no insulin treatment" group was not included in order to avoid leaving patients infused with glucose without insulin treatment. Measures were taken during a baseline phase preceding insulin infusion and every 90 min during the 360 min of insulin infusion. Compared with "low insulin", "high insulin" induced a slow negative potential shift in the AEP over the frontal cortex (average amplitude, high insulin: 0.27 +/- 0.48 microV; low insulin: 1.87 +/- 0.48 microV, p < 0.005), which was paralleled by enhanced memory performance (words recalled, high insulin: 22.04 +/- 0.93; low insulin: 19.29 +/- 0.92, p < 0.05). Also, during "high insulin" subjects displayed enhanced performance on the Stroop test (p < 0.05) and expressed less difficulty in thinking than during "low insulin" (p < 0.03). Results indicate an improving effect of insulin on cognitive function, and may provide a frame for further investigations of neurobehavioral effects of insulin in patients with lowered or enhanced brain insulin, i.e., patients with Alzheimer's disease or diabetes mellitus.
Adult↗