Clinical implications of acute myeloid leukemia presenting as myeloid sarcoma.

In this retrospective study, we aim to analyze the characteristics, treatments, and overall survival of all patients presenting with isolated myeloid sarcoma (MS) or MS with concomitant acute myeloid leukemia (AML) compared with all patients with AML, treated during the same period. We identified patients with AML with or without MS at diagnosis, presenting to our medical center between the years 1990 and 2005. There was no statistically significant difference between the groups regarding gender, age, cytogenetic risk groups, rate of complete remission, number of cycles of chemotherapy needed to achieve complete remission, and rate of first relapse. The time to death in the MS group was not significantly different (p = 0.60) from the AML group, and radiotherapy did not affect the median time to death. Transplantation prolonged survival in both groups (p = 0.018 and p < 0.0001, respectively). Patients with MS at diagnosis might benefit from upfront aggressive treatment with hematopoietic stem cell transplantation.

11ß-Hydroxysteroid dehydrogenase type 1 activity in short small-for-GA children and in response to GH therapy.

Small for GA (SGA) children are at risk for developing the metabolic syndrome. Those who do not catch up, and remain short (SSGA), may benefit from GH therapy. 11ß Hydroxysteroid dehydrogenase type 1 (11ß-HSD-1) is expressed in visceral fat and is implicated in metabolic morbidity. We hypothesized that SSGA children will have increased basal and glucocorticoid (GC)-stimulated 11ß-HSD-1 activity. Twenty SSGA children, aged 7.1 ± 1 y (mean ± SD), were studied before and while on GH therapy and compared with 12 normal age-matched controls. 11ß-HSD-1 activity was evaluated by gas chromatography mass spectrometry (GCMS) of urinary steroid product/substrate ratios. GC-stimulated 11ß-HSD-1 activity was assessed after overnight dexamethazone (DEX), by oral cortisone conversion to cortisol. In SSGA children, 11ß-HSD-1 activity was lower (p < 0.05) and GC-stimulated activity enhanced. SSGA children had maximal cortisol generation of 883 ± 108 compared with 690 ± 63 nmol/L in controls (p < 0.04). GH treatment suppressed 11ß-HSD-1 activity. GC-stimulated enzyme activity correlated negatively with GA (r = -0.53, p < 0.01) and birth weight (r = -0.55, p < 0.01). SSGA is associated with enhanced GC-stimulated 11ß-HSD-1 activity. This may be programmed in utero, as it is not a function of body composition or secondary metabolic derangement. GH therapy normalizes GC-stimulated 11ß-HSD-1 activity.

Parturition itself is the basis for fetal adrenal involution.

CONTEXT: Newborn infants show a postnatal decline in androgen levels as the fetal adrenal glands involute. HYPOTHESIS: Placental factors up-regulate dehydroepiandrosterone sulfate (DHEA-S) generation. Hence, regardless of age, parturition will result in fetal adrenal involution and decline in DHEA-S levels. SUBJECTS AND METHODS: Premature neonates (n = 30) with gestational age 26-35 wk were studied. Adrenal volume by ultrasonography and serum DHEA-S, cortisol, and androstendione levels were followed weekly between d 1 and 28 of life. RESULTS: Serum DHEA-S was high on d 1 of life, declining rapidly regardless of gestational age during the first week of life (P < 0.001), and serum androstenedione and cortisol levels followed a similar pattern. Androstenedione levels showed a rise as of d 21 of life in boys but not in girls. The adrenals decreased in ultrasonographic volume from d 1 to 14 of life (P < 0.001), regardless of gestational age. CONCLUSIONS: Involution of the adrenal is faster than previously reported and, regardless of gestational age, occurs within the first week of life in terms of hormone secretion and within 2 wk in adrenal size. Involution involves a decline in DHEA-S but also in androstenedione and cortisol secretion, with a change in enzymatic activity. Males and females differ in their androstenedione levels and enzymatic activity. Parturition itself is the basis for fetal adrenal involution, supporting a key role for placental factors in maintaining the fetal adrenal and generating adrenal androgens.

Polymorphisms in the human organic cation transporter and the multidrug resistance gene: correlation with imatinib levels and clinical course in patients with chronic myeloid leukemia.

The optimal tyrosine kinase inhibitor for any individual patient with chronic myeloid leukemia (CML) is not predictable. Pharmacogenetic parameters and trough levels of imatinib (IM) have each been independently correlated with response. We therefore studied the human organic cation transporter (hOCT1) and multidrug resistance (MDR1) single nucleotide polymorphisms (SNPs) and correlated these with IM levels and major molecular response (MMR) (3-log reduction) in 84 patients with CML, the first such study performed in Caucasians. We studied MDR1 G2677T and C3435T, and for hOCT1, C480G and A1222G. IM levels varied significantly with dose (< or > 400 mg/day) (p = 0.038) and were significantly lower in 20 patients who lost MMR (p = 0.042). Adjusting for dose, trough IM levels were not significantly correlated with SNPs. Patients with MDR1 3435 TT had significantly longer times to MMR compared to CC/CT genotypes (p = 0.047). Genotypes did not predict treatment failure when controlling for IM levels. We conclude that IM levels, but not the SNPs studied here, determine IM failure.

Androgen replacement therapy in Turner syndrome: a pilot study.

CONTEXT: Women with Turner syndrome (TS) have reduced levels of androgens due to ovarian failure. HYPOTHESES: Morbidity associated with TS, such as bone fragility, metabolic changes, obesity, neurocognitive profile, and sexual problems may partly relate to androgen insufficiency and improve on androgen replacement therapy (ART). OBJECTIVES: The objective of the study was to determine the effect of androgens on morbidity in TS. DESIGN: Fourteen TS women (aged 17-27 yr) participated in a randomized, double-blind, placebo-controlled crossover pilot. The study was conducted in a hospital outpatient clinic between December 2001 and July 2004. INTERVENTION: TS patients were on estrogen/progestin replacement therapy. Subjects received oral 1.5 mg methyl testosterone (ART) or placebo for 1 yr and the alternative for another year. MAIN OUTCOME MEASURES: The study compared body composition as a primary outcome, and physiology, biochemistry, visceral fat, cognition, and quality of life (QOL) as secondary outcomes. RESULTS: ART as compared with placebo reduced total cholesterol, triglycerides, and high-density lipoprotein cholesterol. It improved bone mineral density, increased lean body mass, and decreased fat mass. ART improved attention, reaction time, and verbal memory and had no effect on executive functions and spatial cognition. Patients reported improved QOL, including general health, coping with stress, and sexual desire. CONCLUSIONS: Androgen insufficiency plays a role in TS-impaired body composition, neurocognition, and QOL, and these aspects improve with ART, which was safe and effective when given for 1 yr.

Physiological and catecholamine response to sympathetic stimulation in turner syndrome.

OBJECTIVE: Women with Turner syndrome have increased heart rate and high blood pressure (BP), and have been described as having high tolerance for emotional stress. We hypothesized that women with Turner syndrome have reduced catecholaminergic and physiological response to sympathetic stimulation, and that changes in BP and heart rate are related to their catecholamine response to sympathetic stimulation. DESIGN AND PATIENTS: Ten young women with Turner syndrome, age 17-34 years were the subjects of this study. Their response to sympathetic stimulation was compared to a group of 10 age-matched healthy women. MEASUREMENTS: After a period of 30 min resting, subjects and controls were subjected to an escalating series of sympathetic stimulation: orthostatic, cold pressor and exercise, and their plasma catecholamines and haemodynamic response were monitored and compared to resting levels. RESULTS: Resting heart rate was higher in Turner syndrome patients at 83 +/- 9 beats per min (bpm, mean +/- SD), as compared to controls (74 +/- 10 bpm, P < 0.05). Their supine BP was also higher at 122 +/- 9/84 +/- 6 vs. 106 +/- 11/70 +/- 9 mmHg (P < 0.02/< 0.02). The corresponding resting norepinephrine, but not epinephrine, was higher in Turner syndrome patients (2.54 +/- 1.09 nmol/l) as compared to controls (1.69 +/- 0.55 nmol/l, P < 0.02). In response to orthostatic stimulation and cold pressor test the systolic, but not the diastolic BP or heart rate, increased in Turner syndrome patients but not in the control group (P < 0.01). The change in blood catecholamine levels was comparable in both groups. Their physiological response to exercise was normal. Yet, the exercise-induced surge of norepinephrine and epinephrine in Turner syndrome patients was lower (P < 0.02). CONCLUSIONS: Turner syndrome is associated with dysregulation of the sympathetic nervous system (SNS), leading to tachycardia and high BP, increased resting norepinephrine levels, and a greater tolerance of the cathecholamine response to exercise.