leptin and Precursor-Cell-Lymphoblastic-Leukemia-Lymphoma

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Dysregulation of adipokine pathways is implicated in the carcinogenesis and ALL. The aim of this study is to present the most recent data available regarding the role of leptin, adiponectin and ghrelin in the pathogenesis and prognosis of ALL. The PubMed database was searched using 'Leptin', 'Adiponectin', 'Ghrelin', 'Cancer', 'Children' and 'Acute Lymphoblastic Leukemia' as keywords. The majority of the studies indicated that leptin levels are increased and adiponectin levels are decreased in ALL children at diagnosis, as well as in ALL survivors. Ghrelin levels were found to be lower at diagnosis and progressively increased during treatment. Further research is warranted, as the heterogeneity of the current studies, various treatment protocols and differences in sample sizes make it difficult to deduce solid conclusions regarding the role of adipokines in ALL.

Topics: Adiponectin; Carcinogenesis; Child; Ghrelin; Humans; Leptin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis

Acute lymphoblastic leukemia is the most common malignancy in childhood. Continuous progress in risk-adapted treatment for childhood acute lymphoblastic leukemia has secured 5-year event-free survival rates of approximately 80% and 8-year survival rates approaching 90%. Almost 75% of survivors, however, have a chronic health condition negatively impacting on cardiovascular morbidity and mortality. Obesity can be considered one of the most important health chronic conditions in the general population, with an increasing incidence in patients treated for childhood cancers and especially in acute lymphoblastic leukemia survivors who are, at the same time, more at risk of experiencing precocious cardiovascular and metabolic co-morbidities. The hypothalamic-pituitary axis damage secondary to cancer therapies (cranial irradiation and chemotherapy) or to primary tumor together with lifestyle modifications and genetic factors could affect long-term outcomes. Nevertheless, the etiology of obesity in acute lymphoblastic leukemia is not yet fully understood. The present review has the aim of summarizing the published data and examining the most accepted mechanisms and main predisposing factors related to weight gain in this particular population.

Topics: Body Mass Index; Child; Comorbidity; Energy Metabolism; Growth Hormone; Humans; Hypothalamus; Leptin; Life Style; Metabolic Syndrome; Obesity; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Radiotherapy; Risk Factors; Survivors; Weight Gain

Glucocorticoids used to treat acute lymphoblastic leukemia (ALL) are associated with cytotoxicity and obesity. The aim of the study was to investigate the effects of high-proportion medium chain triglyceride (MCT) on body fat distribution and levels of leptin and adiponectin during chemotherapy of children with ALL.New-onset ALL children treated at the Guangzhou Women and Children's Medical Center between March 2016 and March 2017 were enrolled. Children were divided into the MCT and control groups. For the MCT group, high-proportion MCT nutrition preparation was added to the diet, while no MCT was added for the control group. The MCT group was further divided into subgroups A and B based on the amount of supplement. Waist circumference, hip circumference, waist-to-hip ratio, bone marrow concentrations of leptin and adiponectin, and leptin-to-adiponectin ratio were measured before and on days 19 and 46 of chemotherapy. Body weight and body mass index (BMI) were measured on admission and discharge.Waist circumference in the control group increased by day 46 (P = .047), but did not change in the MCT group. The BMI of the children in the control group was higher than those in the MCT group on admission (P = .003), but not different at discharge. No significant differences in hip circumference, leptin levels, adiponectin levels, and body weight were observed between the 2 groups.This preliminary study suggests that short-term supplementation of high-proportion MCT nutrition preparation may help reduce the centripetal distribution of adipose induced by the application of glucocorticoids in children with ALL. This will have to be confirmed in future studies.

Topics: Adiponectin; Adiposity; Body Fat Distribution; Body Mass Index; Body Weight; Child; Child, Preschool; Dietary Supplements; Female; Glucocorticoids; Humans; Leptin; Male; Obesity; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Triglycerides; Waist Circumference

Pediatric acute lymphoblastic leukemia (ALL) survivors are at increased risk for the metabolic syndrome (MS). To establish the trajectory of development during active treatment, we followed patients longitudinally over the first year of maintenance therapy.. In a prospective cohort of 34 pediatric ALL patients, followed over the first 12 months of ALL maintenance, we evaluated changes in body mass index (BMI), blood pressure, fasting insulin and glucose, lipids, Homeostatic Metabolic Assessment (HOMA), leptin, and adiponectin.. Over the study time period, the median BMI z-score increased from 0.29 to 0.66 (P = 0.001), median fasting insulin levels increased from 2.9 to 3.1 µU/ml (P = 0.023), and the proportion of patients with insulin resistance by HOMA (>3.15) increased from 3% to 24% (P = 0.016). Median leptin increased from 2.5 to 3.5 ng/ml (P = 0.001), with levels correlated with BMI z-score. Median adiponectin level decreased from 18.0 to 14.0 µg/ml (P = 0.009), with levels inversely correlated to BMI z-score. No change in median total cholesterol and LDL levels was observed. Median triglycerides decreased (P < 0.001) and there was a trend to increase in HDL (P = 0.058). Blood pressure did not significantly change, although overall prevalence of systolic and diastolic hypertension was high (23.5% and 26.4%, respectively).. Following patients over the first year of ALL maintenance therapy demonstrated that components of the MS significantly worsen over time. Preventive interventions limiting increases in BMI and insulin resistance during maintenance therapy should be targeted during this time period to avoid long-term morbidity associated with the MS in long-term survivors.

Topics: Adolescent; Adult; Blood Glucose; Body Mass Index; Child; Child, Preschool; Fasting; Female; Follow-Up Studies; Humans; Insulin; Insulin Resistance; Leptin; Male; Obesity; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Triglycerides

Genotype/allele distributions of leptin promoter G-2548A polymorphism, serum leptin and insulin levels and body weight were not significantly different between 72 children (39 male/33 female; age range 1.08-16, median 6 years) with acute leukemia (56 acute lymphoblastic leukemia [ALL]/16 acute non-lymphoblastic leukemia [ANLL]) at diagnosis and 70 age- and sex-matched controls (p > 0.05). The - 2548GG genotype was associated with the highest leptin levels in controls and patients with acute leukemia after 7-day high-dose methylprednisolone (HDMP) therapy (p < 0.05), while no significant association of genotype with leptin levels was detected in patients at diagnosis (p > 0.05). One-week HDMP therapy in patients carrying the - 2548G allele caused a significant increase in leptin levels and body weight (p < 0.001), whereas increases in those carrying the - 2548AA genotype were insignificant (p > 0.05). Decreases in white blood cell counts of patients after therapy were insignificant in - 2548GG (p > 0.05) yet significant in - 2548GA and - 2548AA (p < 0.05) genotypes. These results revealed no association of leptin genotype with the etiology of childhood acute leukemia but a possible association with leptin levels and effects of HDMP therapy.

Topics: Acute Disease; Adolescent; Case-Control Studies; Child; Child, Preschool; Diarrhea; Dose-Response Relationship, Drug; Female; Gene Frequency; Genotype; Glucocorticoids; Humans; Hyperglycemia; Infant; Insulin; Leptin; Leukemia; Male; Methylprednisolone; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Promoter Regions, Genetic; Prospective Studies; Time Factors; Treatment Outcome

Osteopenia and excess adiposity occur following treatment of childhood acute lymphoblastic leukaemia (ALL) and the use of cranial irradiation is thought to be a significant contributory factor. Hyperleptinaemia has also been demonstrated following cessation of treatment for childhood ALL. Therefore a prospective study was undertaken to evaluate serial changes in percentage bone mineral content (BMC), adiposity and serum leptin concentrations during 2 years of treatment of children with ALL with chemotherapy but without cranial irradiation.. Only patients treated using the MRC ALL 97/ALL 97 (modified 99) protocols for childhood ALL were eligible for entry into the study. A total of 14 patients (seven male, with a median age of 7.5 years (range 3.4-16.7 years) were recruited. Serial dual energy X-ray absorptiometry (DEXA) scanning was undertaken at diagnosis and during two years of treatment. Serum leptin concentrations were determined at the same time as the scans.. Reductions in %BMC were observed at the hip and lumbar spine by 12 months (P < 0.01) and remained low after 24 months of treatment. Subanalysis of %BMC measurements at the hip demonstrated a greater reduction in %BMC at the trochanteric region compared to the femoral neck. The percentage corrected fat mass increased from 6 months whereas the body mass index (BMI) standard deviation score (SDS) was increased after 24 months of treatment (P < 0.05). Serum leptin concentrations increased following 24 months of therapy (P < 0.05).. Children treated for ALL with contemporary regimens have a predisposition to osteopenia, excess adiposity and hyperleptinaemia during treatment without cranial irradiation administration. We speculate that in addition to glucocorticoid administration, leptin resistance may account in part for these observations.

Topics: Adolescent; Bone Diseases, Metabolic; Child; Child, Preschool; Female; Humans; Leptin; Male; Obesity; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies

Disturbances in body weight regulation are often encountered during glucocorticoid treatment and are associated with increased insulin resistance and truncal fat accumulation. Children were investigated who were receiving glucocorticoid treatment for acute lymphoblastic leukaemia (ALL). They were randomized to receive either prednisolone or dexamethasone as part of induction of remission. This randomization process provided a suitable opportunity to compare the effects of these two administered steroid on surrogate markers of adipocyte activity (leptin) and hyperinsulinaemia/insulin resistance (SHBG).. Prospective study over 16 weeks of children randomized to receive prednisolone (40 mg/m2) or dexamethasone (6.5 mg/m2) as part of the MRC-ALL97/99 induction chemotherapy for ALL. Nineteen children (8 male, 11 female) with a median age 5.9 years (range 2.6-13 years) were recruited into the study. Main outcome measures were body mass index (BMI), serum leptin and sex hormone binding globulin (SHBG).. Glucocorticoid administration for 5 weeks resulted in significant (P < 0.05) increases in BMI, leptin (corrected for BMI) and the leptin : SHBG ratio and lowering of SHBG. Dose for dose, dexamethasone was significantly more potent than prednisolone in altering these parameters.. Short-term glucocorticoid treatment has significant effects on BMI, leptin and SHBG. The leptin : SHBG ratio increase indicates that this may be a novel and sensitive biochemical marker of metabolic change. Our results suggest that glucocorticoid treatment regimens should be kept as short as possible to avoid possible detrimental effects associated with increased adiposity and insulin resistance.

Topics: Adolescent; Body Mass Index; Child; Child, Preschool; Dexamethasone; Female; Glucocorticoids; Humans; Leptin; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Prospective Studies; Sex Hormone-Binding Globulin; Time Factors

Owing to advances in treatment modalities and supportive care, overall survival rates have reached up to 90% among children with acute lymphoblastic leukemia (ALL). However, due to the underlying illness and therapy, they are at a greater risk of developing lifestyle diseases. Hence, special attention is paid to early detection of the components of metabolic syndrome (MetS). This study aimed at investigating the association of plasma levels of nine diabetes markers with being overweight and components of MetS in ALL survivors. The study included 56 subjects with mean age of 12.36 ± 5.15 years. The commercially available Bio-Plex Pro Human Diabetes 10-Plex Panel kit was used to evaluate levels of diabetes biomarkers. ALL survivors presented statistically higher concentrations of GIP (p = 0.026), glucagon (p = 0.001), leptin (p = 0.022), and PAI-1 (p = 0.047), whereas the concentration of ghrelin was lower (p < 0.001) compared to the control group. Moreover, subjects within normal BMI range showed higher GIP (p = 0.005) and lower ghrelin concentration (p < 0.001) compared to healthy peers. At least one risk factor of MetS was present in 58.9% of participants, who showed significantly higher levels of C-peptide (p = 0.028), leptin (p = 0.003), and PAI-1 (p = 0.034) than survivors who did not meet any MetS criteria. In conclusion, ALL survivors are at greater risk of disturbances in carbohydrate metabolism. Understanding the pathogenesis and applicability of diabetes markers is crucial for developing strategies to prevent metabolic syndrome in ALL survivors.

Topics: Adolescent; Biomarkers; Child; Ghrelin; Glucose; Humans; Leptin; Metabolic Syndrome; Plasminogen Activator Inhibitor 1; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Survivors

Childhood cancer survivors (CCSs) who have undergone bone marrow transplantation with systemic chemotherapy and whole-body irradiation often experience impaired glucose tolerance with marked insulin resistance. Incomplete acquired diabetic lipodystrophy should be considered as a late complication of bone marrow transplantation. A 24-year-old Japanese female patient with incomplete acquired lipodystrophy, a CCS of acute lymphocytic leukemia at the age of 3 years, was treated for diabetes mellitus and dyslipidemia at our hospital. Administration of multiple daily insulin injections (70 units/day), and oral administration of 500 mg/day metformin, 15 mg/day pioglitazone, and 200 mg/day bezafibrate had proven ineffective for her metabolic disorders. Subcutaneous administration of metreleptin improved her insulin resistance and hypertriglyceridemia within a month; however, it failed to maintain adequate plasma glucose levels in the long term. When oral administration of 10 mg/day empagliflozin was added to the metreleptin supplementation, her HbA1c value (National Glycohemoglobin Standardization Program) improved from 11% to 8%, which was maintained for an additional 18 months. This is the first case report of incomplete lipodystrophy that shows efficacy of a combination therapy with metreleptin and a sodium glucose cotransporter 2 (SGLT2) inhibitor for the treatment of diabetes and dyslipidemia. An SGLT2 inhibitor attenuates hyperglycemia through urinary glucose excretion and has been suggested to enhance lipid catabolism in the extra-adipose tissues, especially in the liver and skeletal muscles. Furthermore, metreleptin supplementation could enhance the action of the SGLT2 inhibitor by promoting satiety and lipolysis through the central nervous system. Combination therapy with metreleptin and an SGLT2 inhibitor was suggested to recover the volume of adipose tissue, possibly through improvement of insulin resistance in the adipose tissue. This report highlights the pathophysiological mechanism of an SGLT2 inhibitor in the improvement of glucose metabolism in non-healthy lean CCSs with insulin resistance. Administration of SGLT2 inhibitor, along with metreleptin supplementation, could be a good alternative therapy for diabetic lipodystrophy observed in CCSs.

Topics: Benzhydryl Compounds; Bone Marrow Transplantation; Drug Therapy, Combination; Female; Glucosides; Humans; Hypoglycemic Agents; Leptin; Lipodystrophy; Pioglitazone; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome; Young Adult

Survivors of childhood acute lymphoblastic leukemia (cALL) are at higher risk of developing cardiometabolic complications. We aimed at exploring the associations between biomarkers of inflammation, oxidative stress, endothelial function, endotoxemia and cardiometabolic risk factors. We conducted a cross-sectional analysis in 246 cALL survivors (mean age, 22.1 ± 6.3 years; mean time since diagnosis, 15.5 ± 5.2 years) and evaluated the associations using a series of logistic regressions. Using structural equation models, we also tested if the relationship between endotoxemia and cardiometabolic complications was mediated by the latent (unobserved) variable inflammation inferred from the observed biomarkers CRP, TNF-α and IL-6. High leptin-adiponectin ratio was associated with obesity [adjusted OR = 15.7; 95% CI (6.2-39.7)], insulin resistance [20.6 (5.2-82.1)] and the metabolic syndrome [11.2 (2.6-48.7)]. Higher levels of plasminogen activator inhibitor-1 and tumor necrosis factor-α were associated with obesity [3.37 (1.6-7.1) and 2.34 (1.3-4.2), respectively] whereas high C-reactive protein levels were associated with insulin resistance [3.3 (1.6-6.8)], dyslipidemia [2.6 (1.4-4.9)] and MetS [6.5 (2.4-17.9)]. Our analyses provided evidence for a directional relationship between lipopolysaccharide binding protein, related to metabolic endotoxemia, inflammation and cardiometabolic outcomes. Identification of biomarkers and biological mechanisms could open new avenues for prevention strategies to minimize the long-term sequelae, improve follow-up and optimize the quality of life of this high-risk population.

Topics: Adiponectin; Adolescent; Adult; Biomarkers; Cancer Survivors; Cardiovascular Diseases; Cross-Sectional Studies; Dyslipidemias; Female; Humans; Inflammation; Leptin; Male; Metabolic Syndrome; Obesity; Oxidative Stress; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Quality of Life; Risk Factors; Young Adult

Large prospective studies on dexamethasone-induced changes in eating behavior, energy, and nutrient intake are lacking in pediatric acute lymphoblastic leukemia (ALL). We prospectively studied eating behavior, energy, nutrient intake, and the effect on leptin and adiponectin levels during dexamethasone administration in children with ALL.. Parents of patients with ALL (3-16 years) completed a dietary diary for their child during 4 days of dexamethasone (6 mg/m. Energy intake per day(kcal) (N = 44) increased significantly during dexamethasone (median day 1: 1,103 (717-1,572) versus day 4: 1,482 (1,176-1,822), P < 0.01), including an increase in total protein, fat, saturated fat, carbohydrate, and sodium intake. Intake of saturated fat (median day 4: 12 E%) and salt (median day 4: 1.9 g/day) exceeded the healthy range for age and gender. With respect to eating behavior, dexamethasone significantly decreased restrained eating (P = 0.04). Leptin levels as well as adiponectin levels increased significantly during the dexamethasone course.. Four days of dexamethasone treatment significantly increased energy intake, including excessive saturated fat and salt intake, and changed eating behavior in children with ALL. Nutritional and behavioral interventions during dexamethasone treatment are recommended to stimulate a healthy lifestyle.

Topics: Adiponectin; Adolescent; Child; Child, Preschool; Dexamethasone; Energy Intake; Feeding Behavior; Female; Humans; Leptin; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies

Metabolic complications are prevalent in individuals treated with cranial radiotherapy (CRT) for childhood acute lymphoblastic leukemia (ALL). The hypothalamus is a master regulator of endocrine and metabolic control. The aim of this study was to investigate whether the hypothalamic volume would be associated to metabolic parameters in ALL survivors. Thirty-eight (21 women) survivors participated in this study 34 years after diagnosis and with a median age of 38 (27-46) years. All were treated with a median CRT dose of 24 Gy and 11 years (3-13) of complete hormone supplementation. Comparisons were made to 31 matched controls. We performed analyses of fat mass, fat free mass, plasma (p)-glucose, p-insulin, Homa-Index (a measure of insulin resistance), serum (s)-leptin, s-ghrelin and of the hypothalamic volume in scans obtained by magnetic resonance imaging (MRI) at 3 Tesla. Serum leptin/kg fat mass (r = -0.4, P = 0.04) and fat mass (r = -0.4, P = 0.01) were negatively correlated with the HT volume among ALL survivors, but not among controls. We also detected significantly higher BMI, waist, fat mass, p-insulin, Homa-Index, leptin/kg fat mass and s-ghrelin and significantly lower fat free mass specifically among female ALL survivors (all P<0.01). Interestingly, s-ghrelin levels increased with time since diagnosis and with low age at diagnosis for childhood ALL. Our results showed that leptin/kg fat mass and fat mass were associated with a reduced HT volume 34 years after ALL diagnosis and that women treated with CRT after ALL are at high risk of metabolic abnormalities. Taken together our data suggest that the hypothalamus is involved in the metabolic consequences after CRT in ALL survivors.

Topics: Adult; Blood Glucose; Body Composition; Body Mass Index; Case-Control Studies; Cranial Irradiation; Female; Ghrelin; Growth Hormone; Hormone Replacement Therapy; Humans; Hypothalamus; Insulin; Insulin Resistance; Leptin; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Risk; Survivors

The aim of this study was to evaluate the relationship between body composition, metabolic profile, adipokines, and carotid intima-media thickness (cIMT) in young survivors of childhood acute lymphocytic leukemia (ALL).. This cross-sectional study compared 55 ALL survivors, of chronological age between 15 years and 24 years, assigned into two groups according to the exposure to cranial radiation therapy (CRT; 25 irradiated and 30 nonirradiated) with 24 leukemia-free controls, and assessed body fat mass (dual-energy X-ray absorptiometry), computed tomography scan-derived abdominal adipose tissue, lipid profile, blood pressure (BP), adipokines, and cIMT by a multiple regression analysis.. Treatment with CRT had an effect on all of the variables derived from the computed tomography scan: visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) (P<0.050). In a multiple linear regression model, cIMT positively correlated with exposure to CRT (P=0.029), diastolic BP (P=0.016), and leptin-to-adiponectin ratio (P=0.048), while negatively related to SAT (P=0.007).. In young survivors of childhood ALL, CRT modified the distribution of fat and played a critical role in determining cIMT. Leptin-to-adiponectin ratio, a biomarker of abdominal obesity and metabolic syndrome, and diastolic BP also influenced cIMT, a marker of subclinical atherosclerosis. Nonetheless, adiposity-associated vascular disease might be attenuated by SAT. Changes in body fat must be evaluated in this group of patients in the early course of survivorship in order to avoid premature cardiovascular disease associated with atherosclerosis. Yet, further research as regards the possible protective effect of SAT on vascular disease is warranted.

Topics: Absorptiometry, Photon; Adiponectin; Adiposity; Adolescent; Biomarkers; Carotid Artery Diseases; Carotid Intima-Media Thickness; Case-Control Studies; Cranial Irradiation; Cross-Sectional Studies; Female; Humans; Intra-Abdominal Fat; Leptin; Linear Models; Male; Multivariate Analysis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Predictive Value of Tests; Risk Factors; Subcutaneous Fat; Survivors; Tomography, X-Ray Computed; Treatment Outcome; Young Adult

Mesenchymal stromal cells (MSCs) are a major component of the leukemia bone marrow (BM) microenvironment. Connective tissue growth factor (CTGF) is highly expressed in MSCs, but its role in the BM stroma is unknown. Therefore, we knocked down (KD) CTGF expression in human BM-derived MSCs by CTGF short hairpin RNA. CTGF KD MSCs exhibited fivefold lower proliferation compared with control MSCs and had markedly fewer S-phase cells. CTGF KD MSCs differentiated into adipocytes at a sixfold higher rate than controls in vitro and in vivo. To study the effect of CTGF on engraftment of leukemia cells into BM, an in vivo model of humanized extramedullary BM (EXM-BM) was developed in NOD/SCID/IL-2rg(null) mice. Transplanted Nalm-6 or Molm-13 human leukemia cells engrafted at a threefold higher rate in adipocyte-rich CTGF KD MSC-derived EXM-BM than in control EXM-BM. Leptin was found to be highly expressed in CTGF KD EXM-BM and in BM samples of patients with acute myeloid and acute lymphoblastic leukemia, whereas it was not expressed in normal controls. Given the established role of the leptin receptor in leukemia cells, the data suggest an important role of CTGF in MSC differentiation into adipocytes and of leptin in homing and progression of leukemia.

Topics: Adipocytes; Animals; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; Cell Cycle; Cell Differentiation; Cell Proliferation; Cell Separation; Chemokine CXCL12; Connective Tissue Growth Factor; Down-Regulation; Gene Knockdown Techniques; Humans; Leptin; Leukemia; Leukemia, Myeloid, Acute; Mesenchymal Stem Cells; Mice; Precursor Cell Lymphoblastic Leukemia-Lymphoma

After SCT in childhood, survivors may develop disorders of glucose metabolism. The role of obesity is controversial. We measured insulin sensitivity using the homeostasis model assessment (HOMA) and the frequently sampled i.v. glucose tolerance test (FSIVGTT), as well as body composition using dual-energy X-ray absorptiometry in 18 young adults median 18.2 years after SCT and compared them with matched controls. We also measured growth hormone (GH) secretion, and levels of leptin and adiponectin. HOMA showed insulin resistance in eight patients (44%), as opposed to none of the controls (P=0.008) and FSIVGTT showed a decreased sensitivity index in the patients (2.98 vs 4.54 mU/L/min, P=0.042). Dual energy X-ray absorptiometry showed a higher percentage fat mass in the patients (34.9 vs 24.3%, P=0.011), which correlated inversely with the sensitivity index (r=-0.52, P=0.032). The patients had a lower peak value of GH (GH(max) 9 vs 20.7 mU/L, P=0.002). Time post SCT correlated with percentage fat mass and inversely with GH(max). The patients had higher levels of leptin and lower levels of adiponectin, even after adjustment for fat mass. We propose that the decreased insulin sensitivity may primarily be explained by the adverse body composition, which may owe to long-standing GH deficiency.

Topics: Absorptiometry, Photon; Adiponectin; Adolescent; Adult; Blood Glucose; Body Composition; Case-Control Studies; Child; Child, Preschool; Cross-Sectional Studies; Female; Humans; Insulin; Leptin; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Stem Cell Transplantation; Transplantation Conditioning; Whole-Body Irradiation; Young Adult

Excess adiposity is a complication of childhood acute lymphoblastic leukaemia (ALL) and is commonly attributed to cranial radiation (CRT) administration. Hyperleptinaemia also occurs during ALL treatment, but there are no data on long-term alterations to adipocytokines following treatment without CRT.. Fifty-four survivors (50% female) and 51 controls (59% female) were recruited. Body composition assessment was by BMI, air displacement plethysmography (BODPOD), bioelectrical impedance analysis (BIA) and skinfold thickness (SFT). Fasting blood samples were analysed for adipocytokines (leptin, adiponectin, resistin, tumour necrosis factor-α, interleukin-6).. The BMI standard deviation score (0.71 vs. 0.04, p < 0.05) and fat percentage measured by BIA (29.8% vs. 24.6%, p = 0.01) and SFT (31.7% vs. 28.2%, p = 0.007) were greater in female survivors compared with controls. Adiposity was similar in male survivors and controls. Absolute leptin (17.8 vs. 7.8 ng/ml, p = 0.01) and fat-adjusted leptin concentrations (p < 0.05) were higher in female survivors compared to controls. Female survivors were less insulin sensitive than controls (p = 0.02). These findings were not observed in males. There were no differences in the other adipocytokines between survivors and controls.. Long-term unfavourable alterations to body composition and adipocyte function are observed in female, but not male, survivors of ALL treatment without CRT.

Topics: Adipocytes, White; Adiposity; Adolescent; Case-Control Studies; Child; Diet; Exercise; Female; Humans; Leptin; Lipid Metabolism; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Approximately 20% of children and adolescents in Europe are overweight. Survivors of pediatric acute lymphoblastic leukemia (ALL) are at increased risk of overweight and obesity. The purpose of this study was to assess leptin and leptin soluble receptor levels, as well as polymorphisms of selected genes in survivors of pediatric ALL, and the influence of chemo- and radiotherapy on development of overweight in the context of leptin regulation.. Eighty two patients (55% males), of median age 13.2 years (m: 4.8 years; M: 26.2 years) were included in the study. The ALL therapy was conducted according to modified Berlin-Frankfurt-Munster (BFM; n = 69) regimen or New York (n = 13) regimen. In 38% of patients cranial radiotherapy (CRT) was used in median dose of 18.2Gy (m: 14Gy; M: 24Gy). Median age at diagnosis was 4.5 (m: 1 year; M: 16.9 years) and median time from completion of ALL treatment was 3.2 years (m: 0.5 year; M: 4.3 years). Patients with BMI ≥85 percentile were classified as overweight. Correlation of plasma levels of leptin and leptin soluble receptor, and polymorphisms of leptin gene -18G > A, leptin receptor genes K109R and Q223R, and the overweight status were analyzed in relation to gender, intensity of chemotherapy (high intensity vs. standard intensity regimens) and to the use of CRT.. Significant differences of leptin levels in patients treated with and without CRT, both in the entire study group (22.2+/- 3.13 ng/ml vs. 14.9+/-1.6 ng/ml; p < 0.03) and in female patients (29.9+/-4.86 ng/ml vs. 16.9+/-2.44 ng/ml; p = 0.014), were found. Significant increase of leptin levels was also found in overweight patients compared to the non-overweight patients in the entire study group (29.2+/-2.86 ng/ml vs. 12.6+/-1.51 ng/ml; p < 0.0001), female patients (35.4+/-6.48 ng/ml vs. 18.4+/-2.5 ng/ml; p = 0.005), and male patients (25.7+/-2.37 ng/ml vs. 6.9+/-0.95 ng/ml; p < 0.0001). Negative correlation was observed for plasma levels of soluble leptin receptor and overweight status, with significant differences in overweight and non-overweight patients, both in the entire study group (18.2+/-0.75 ng/ml vs. 20.98+/-0.67 ng/ml; p = 0.017) and in male patients (18.2+/-1.03 ng/ml vs. 21.8+/- 1.11 ng/ml; p = 0.038). Significant (p < 0.05) negative correlation was found between leptin and leptin receptor levels in the entire group (correlation coefficient: 0.393) and in both gender subgroups (correlation coefficient in female patients: -0.427; in male patients: -0.396).. The prevalence of overweight in our cohort was higher than in general European population (31% vs 20%) and increased regardless of the use of CRT. Leptin and leptin receptor levels may be used as useful markers of high risk of becoming overweight in ALL survivors, particularly in females treated with CRT. Polymorphisms of leptin gene -18G > A and leptin receptor genes K109R and Q223R were not associated with overweight status in ALL survivors.

Topics: Adolescent; Anthropometry; Child; Child, Preschool; Female; Genotype; Humans; Infant; Leptin; Male; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Receptors, Leptin; Survivors

Along with the growing epidemic of overweight the risk of atherosclerosis, cardiovascular disease morbidity and mortality are increasing markedly. Metabolic syndrome (MS) is a condition clustering together several risk factors of those complications such as visceral obesity, glucose intolerance, arterial hypertension and dislipidemia. The risk of obesity in acute lymphoblastic leukemia (ALL) survivors is higher than in general population. We aimed to assess (1) the relationships between chosen adipokines and neuropeptides, chemotherapy, CRT, and body fatness and (2) evaluate adipokines and neuropeptides concentrations as a new markers of MS in children. We conducted cross-sectional evaluation of 82 ALL survivors (median age: 13.2 years; range: 4,8-26,2; median time from treatment: 3.2 years), including fasting laboratory testing: peptides (leptin, GLP-1, orexin, PYY, apelin), total cholesterol and its fractions, triglycerides; anthropometric measurements (weight, height), systolic and diastolic blood pressure. We estimated percentiles of body mass index and percentiles of blood pressure. Between 82 survivors overweight and diastolic hypertension was diagnosed in 31% of patients (35% in CRT group) and 15% respectively. At least one abnormality in lipids concentrations was found in 43%. Girls were more affected than boys. Statistically significant increased in leptin and apelin concentrations and decreased in soluble leptin receptor concentrations in the overweight group were observed compared to the non overweight subjects. Significant increase in orexin levels in females who had received CRT compared to those who had not received CRT was found. CRT is the main risk factor of elevated of body mass among survivors of childhood leukemia. Dyslipidemia and hypertension, along with increased adiposity indicate higher risk of MS development. Girls are more affected than boys. Leptin, orexin and apelin seem to be good markers of increased adiposity especially after CRT. Higher leptin levels may be related to central resistance to those peptides. Survivors of childhood acute lymphoblastic leukemia should be screened for markers of the metabolic syndrome.

Topics: Adipokines; Adolescent; Adult; Age Distribution; Biomarkers; Child; Child, Preschool; Cross-Sectional Studies; Female; Humans; Hypertension; Intracellular Signaling Peptides and Proteins; Leptin; Male; Metabolic Syndrome; Neuropeptides; Obesity; Orexins; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Risk Factors; Young Adult

To investigate adipocytokine secretion, at diagnosis and during chemotherapy in children with the acute lymphoblastic leukemia (ALL).. Serial measurements (6/patient) of the anti-inflammatory cytokine adiponectin and the proinflammatory adipocytokines leptin and resistin were performed at diagnosis and in nearly the entire period of therapy (up to 21 months), in 9 patients with ALL aged 2 to 7 years (median 4.3 y). Body mass index and leukemic burden were estimated at the same time points and correlated with adipocytokine levels. Nine healthy children matched for age, sex, and body mass index were used as controls.. At diagnosis, mean adiponectin levels were low (P<0.001) and mean leptin and resistin levels were high, compared with controls (P<0.001). During maintenance phase, adiponectin increased significantly (P=0.024), whereas leptin and resistin decreased (P=0.018 and P=0.020, respectively), compared with baseline values. However, adiponectin, despite its progressive increase, remained at lower levels toward the end of the maintenance phase, compared with controls, (P<0.001). Delta (final-baseline) mean adiponectin was negatively correlated with leukemic burden (P=0.019), whereas delta mean leptin and resistin were positively correlated with it (P=0.011 and P=0.031, respectively).. Low-plasma adiponectin and high leptin and resistin level are present at the ALL diagnosis. Adipocytokines alterations are progressively restored during therapy.

Topics: Adipokines; Adiponectin; Biomarkers, Tumor; Case-Control Studies; Child; Child, Preschool; Humans; Leptin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Resistin; Time Factors; Tumor Burden

Survivors of childhood acute lymphoblastic leukemia (ALL) may face an increased risk of metabolic and cardiovascular late effects. To determine the prevalence of and risk factors for adverse cardiometabolic traits in a contemporary cohort of pediatric ALL survivors, we recruited 48 off-therapy patients in remission treated with conventional chemotherapy and 26 treated with total body irradiation (TBI)-based hematopoietic cell transplantation (HCT) in this cross-sectional pilot study. At a median age of 15 years (range, 8-21 years), HCT survivors were significantly more likely than non-HCT survivors to manifest multiple cardiometabolic traits, including central adiposity, hypertension, insulin resistance, and dyslipidemia. Overall, 23.1% of HCT survivors met the criteria for metabolic syndrome (≥ 3 traits), compared with 4.2% of non-HCT survivors (P = .02). HCT survivors also had increased C-reactive protein and leptin levels and decreased adiponectin, suggestive of underlying inflammation and increased visceral fat. In multivariate analyses, history of HCT remained associated with ≥ 2 traits (odds ratio [OR]. 5.13; 95% confidence interval [CI], 1.54-17.15) as well as with ≥ 3 traits (OR, 16.72; 95% CI, 1.66-168.80). Other risk factors included any cranial radiation exposure and family history of cardiometabolic disease. In summary, pediatric ALL survivors exposed to TBI-based HCT as well as to any cranial radiation may manifest cardiometabolic traits at an early age and should be screened accordingly.

Topics: Adolescent; Adult; C-Reactive Protein; Cardiovascular Diseases; Child; Cohort Studies; Cross-Sectional Studies; Hematopoietic Stem Cell Transplantation; Humans; Insulin Resistance; Leptin; Metabolic Syndrome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Risk Factors; Survivors; Whole-Body Irradiation; Young Adult

Obesity is associated with an increased incidence of many cancers, including leukemia, although it is unknown whether leukemia incidence is increased directly by obesity or rather by associated genetic, lifestyle, health, or socioeconomic factors. We developed animal models of obesity and leukemia to test whether obesity could directly accelerate acute lymphoblastic leukemia (ALL) using BCR/ABL transgenic and AKR/J mice weaned onto a high-fat diet. Mice were observed until development of progressive ALL. Although obese and control BCR/ABL mice had similar median survival, older obese mice had accelerated ALL onset, implying a time-dependent effect of obesity on ALL. Obese AKR mice developed ALL significantly earlier than controls. The effect of obesity was not explained by WBC count, thymus/spleen weight, or ALL phenotype. However, obese AKR mice had higher leptin, insulin, and interleukin-6 levels than controls, and these obesity-related hormones all have potential roles in leukemia pathogenesis. In conclusion, obesity directly accelerates presentation of ALL, likely by increasing the risk of an early event in leukemogenesis. This is the first study to show that obesity can directly accelerate the progression of ALL. Thus, the observed associations between obesity and leukemia incidence are likely to be directly related to biological effects of obesity.

Topics: Adiponectin; Age of Onset; Animals; Diet; Disease Models, Animal; Disease Progression; Genes, abl; Humans; Insulin; Interleukin-6; Leptin; Mice; Mice, Inbred AKR; Mice, Transgenic; Obesity; Precursor Cell Lymphoblastic Leukemia-Lymphoma

It is well known that survivors of acute lymphoblastic leukemia (ALL) show a tendency to become overweight. Cranial irradiation (CRT), is considered to be the primary risk factor for development of obesity.. The aim of our study was to evaluate body mass index (BMI) and serum leptin levels in survivors of childhood ALL.. Subjects (Group I) consisted of 93 survivors of childhood ALL (53 males > or = 9 years old, 40 females > or = 8 years old) diagnosed between January 1975 and December 2002 in the Hematology-Oncology Division in Cerrahpasa Medical Faculty, Istanbul University after a follow up 10.21 +/- 4.90 (mean +/- SD) years. Fifty healthy individuals of similar chronological age were taken as controls (29 males, 21 females). Seventy-four subjects had received radiotherapy (Group IA) and 19 had not (Group I B).. In Group I, BMI was significantly higher than in Group II (21.65 +/- 4.02 vs 20.31 +/- 3.49, p = 0.04). However, BMI was significantly higher only in Group I A (21.83 +/- 4.27) than in Group II (p = 0.032). Leptin levels were significantly higher in Group I A females than in Group II females. There was a significant correlation between BMI-SDS and serum leptin levels in group IA females.. Leukemia treatment leads to obesity. Higher leptin levels in girls may suggest that sex may be a differentiating factor for this late effect.

Topics: Adolescent; Adult; Body Mass Index; Child; Cranial Irradiation; Female; Humans; Leptin; Male; Obesity; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Sex Factors; Survivors

It has been reported that children treated for acute lymphoblastic leukemia (ALL) in developed countries show an increased risk of overweight and obesity in adolescence and adulthood. However, the majority of patients who came to our observation in Brazil have low or normal body weight and only one of them was obese. Therefore, we have decided to assess some biochemical parameters possibly related to the intermediate metabolism and body composition in these patients.. Two groups of subjects were studied: 27 survivors of childhood ALL (14.0 +/- 4.2 years old; post-treatment interval 8.6 +/- 3.9 years) (ALL group) and 17 healthy subjects (12.8 +/- 4 years old) (control group) selected on the basis of their kinship with the patients.. 14/27 patients of the ALL group and 4/17 of the control group had leptin levels higher than the normal range for age and sex (p < 0.05). The leptin level was significantly higher in the ALL group (15.5 +/- 1.8 ng/ml) than in the control group (10.7 +/- 2 ng/ml) (p < 0.05). When adjusted by sex, BMI z-score, and age, the level of leptin in patients of the ALL group was 8.5 higher than in subjects of the control group (p = 0.006). Leptin/insulin correlation in the ALL group was 0.08 and in the control group it was +0.585 (p < 0.05).. The data indicate the presence of alterations in the homeostatic regulatory mechanisms controlling body weight in Brazilian patients treated for ALL in childhood, still, it did not lead to obesity in the absence of favorable environmental conditions.

Topics: Adolescent; Body Mass Index; Brazil; Child; Female; Follow-Up Studies; Humans; Incidence; Insulin; Insulin-Like Growth Factor I; Leptin; Male; Obesity; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Waist-Hip Ratio

Survivors of childhood acute lymphoblastic leukemia (ALL) become obese, and are at increased risk for morbidity and mortality post therapy.. We determined the association of cranial radiotherapy (CRT) and/or sex with levels of total, regional, and ectopic fat storage, metabolic risk, IGF-I, and leptin in adult ALL survivors.. A cross-sectional analysis of 52 male (15 CRT treated) and 62 female (24 CRT treated) young adult ALL survivors was conducted.. We assessed levels of visceral fat, sc abdominal and thigh fat, and liver and muscle fat using computed tomography, total fat and lean body mass using dual-energy x-ray absorptiometry, and IGF-I and leptin levels by radioimmunoassay.. Controlled for age and race, ALL survivors treated with CRT had higher levels of abdominal and visceral fat, body fat percentage, metabolic risk (insulin resistance and dyslipidemia), and leptin but lower lean mass and IGF-I levels than non-CRT survivors (P 0.1).. Among young adult ALL survivors, CRT is a risk factor for elevated total, abdominal, and visceral adiposity, a reduced fat-free mass, elevated metabolic risk, and altered IGF-I and leptin levels.

Topics: Abdominal Fat; Adult; Age of Onset; Body Composition; Body Fat Distribution; Child; Cross-Sectional Studies; Female; Humans; Insulin-Like Growth Factor I; Intra-Abdominal Fat; Leptin; Liver; Male; Morbidity; Muscle, Skeletal; Obesity; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Risk Factors; Sex Distribution; Survivors

Leptin has been hypothesized to play a role in the development of obesity in leukemia survivors, particularly those who have received cranial radiotherapy. This cross-sectional study evaluated the relationship between leptin levels and body mass index (BMI) in a sample of 26 acute lymphocytic leukemia survivors of both sexes, treated with and without cranial irradiation, aged 7.6 to 17 years, at a mean 3.4+/-2.0 years off treatment. There were significantly more males among the irradiated group (P<0.001), even though no differences were encountered in pubertal stage (P=1.000), BMI standard deviation score (mean+/-SD) (0.68+/-1.00 vs. 1.19+/-0.78; P=0.164), or leptin concentrations (17.01+/-17.04 vs. 23.3+/-13.4; P=0.309). Nonetheless, there was a positive correlation between the natural logarithm of leptin and BMI standard deviation score [t(22)=2.348, P=0.028], however, no differences were recorded among irradiated and nonirradiated patients [F(2,22)=0.384, P=0.685]. When this relationship was compared between sexes, a significant difference was encountered [F(2,22)=4.907, P=0.017], with males having the strongest association (R(2)males=65.5%, R(2)females=34.7%). Leptin is a reliable adiposity index as it strongly correlates with BMI. Overall, the current data suggest that cranial irradiation did not play a role upon this relationship; however, sex differences influenced positively this correlation.

Topics: Adolescent; Body Mass Index; Child; Child, Preschool; Cranial Irradiation; Female; Humans; Leptin; Male; Obesity; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Survivors of childhood-onset (CO) acute lymphoblastic leukemia (ALL) treated with prophylactic cranial radiotherapy often exhibit GH deficiency (GHD), which is associated with increased prevalence of cardiovascular risk factors and cardiac dysfunction.. The objective of the study was to evaluate the effect of GH replacement on cardiovascular risk factors and cardiac function in former CO ALL patients.. Eighteen former CO ALL patients (aged 19-32 yr) treated with cranial radiotherapy (18-24 Gy) and chemotherapy and with confirmed GHD were studied at baseline and after 12 (n = 18) and 24 months (n = 13) of GH treatment (median 0.5 mg/d). A group of 18 age- and sex-matched subjects served as controls.. After 12 months of GH treatment, a significant decrease in serum leptin (P = 0.002), leptin per kilogram fat mass (FM) (P = 0.01), plasma glucose (P = 0.004), FM (P = 0.002), and hip (P = 0.04) and waist (P = 0.02) circumference and increased muscle mass (P = 0.004) were recorded in the patients. Before GH treatment six patients had a metabolic syndrome, but after 12 months only one had it and after 24 months none. After 24 months of GH treatment, an increase in left ventricular mass index (P = 0.06) and significant improvements in cardiac systolic function, measured as fractional shortening (P = 0.03) and ejection fraction (P = 0.03), were recorded.. Improvement in cardiac systolic function and reduced prevalence of metabolic syndrome were recorded after 2 yr of GH replacement in former CO ALL patients with GHD. Long-term follow-up is highly warranted.

Topics: Absorptiometry, Photon; Adult; Body Composition; Body Mass Index; Body Weight; Child; Echocardiography, Doppler; Exercise; Female; Growth Hormone; Heart; Heart Function Tests; Heart Rate; Human Growth Hormone; Humans; Leptin; Lipoproteins; Male; Metabolic Syndrome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Risk Factors; Survivors; Waist-Hip Ratio

We analyzed the relationship between serum leptin levels and body mass index in children treated for acute lymphoblastic leukemia during and after the maintenance therapy.. We studied 99 survivors (62 boys) in mean age 12.65 years +/- who have been treated for ALL according to the Polish Paediatric Leukemia and Lymphoma Study Group. During the maintenance therapy there were n=34 patients (23 boys) and after treatment n=75 (39 boys). 16 patients received cranial irradiation (12 Gy). We calculated body mass index (BMI) using the formula weight/(height)2 (kg/m2). Leptin levels were measured with the RIA method. The results were expressed as SDS.. 1. No difference was found in leptin SDS and BMI SDS from zero -- in the whole study group, similar in boys and girls. The leptin/BMI ratio was significantly higher in girls than in boys. 2. No differences were observed in the group during and after therapy in values of BMI SDS and leptin SDS. We found higher leptin SDS in boys during (4.86+/-1.01) and after puberty (1.53+/-0.75). We found higher leptin SDS in boys than in girls during (1.6+/-1.1 vs. 0.6+/-0.6) and after therapy. 3. In boys and girls diagnosed before puberty leptin SDS were higher in boys (1.7+/-1.3 vs. 0.2+/-1.7). The leptin/BMI ratio was significantly higher in girls than in boys diagnosed before puberty. 4. We found correlations between leptin levels and BMI in the whole group as well as in boys and girls analysed according to puberty and time of treatment. 5. No differences were observed between patients with and without cranial irradiation.. Anti-neoplastic treatment for acute lymphoblastic leukemia and age of disease did not influence body mass index and leptin level in the examined population.

Topics: Adipose Tissue; Adolescent; Adult; Antineoplastic Agents; Body Composition; Body Mass Index; Child; Child, Preschool; Cranial Irradiation; Female; Follow-Up Studies; Humans; Leptin; Male; Poland; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Puberty; Reference Values; Sex Factors

Leptin is an adipocyte-derived hormone regulating energy homeostasis and body weight. Leptin also plays a role in hematopoiesis, cell cycle regulation, and in oncogenesis. The leptin receptor is a single transmembrane protein belonging to the superfamily of cytokine receptors, structurally related to the hemopoietin receptor family. The aim of the study was to evaluate bone marrow and peripheral blood leptin level and frequency of distribution of leptin receptor gene polymorphism Gln223Arg in children with acute leukemia. The examined group included 92 children with acute leukemia (83 ALL and 9 AML) and 39 non-leukemic control children. Leptin level was measured by ELISA method at the day of leukemia diagnosis. Genomic DNA was isolated with the use of a column method and the genotyping of DNA sequence variation was carried out by the restriction enzyme analysis of PCR - amplified DNA. The samples were then electrophoresed on 2.5% agarose gel. Leptin level in leukemic children was lower than in healthy children. Bone marrow leptin level was significantly lower than that in the blood in leukemic children with ALL-T and AML. An analysis of frequency distribution of the Gln233Arg polymorphism in the leptin receptor gene in leukemic children showed lack of differences between the patients and controls. There was no difference in the genotype frequencies between the leukemic AML and ALL groups either. The results indicate a possible relation between the leptin level and leukemia development in children. The effectory effect of the hormone seems not related to Gln223Arg polymorphism of its receptor.

Topics: Adolescent; Bone Marrow; Child; Child, Preschool; Humans; Infant; Leptin; Leukemia; Leukemia, Myeloid, Acute; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Receptors, Leptin

Obesity is frequently reported in patients treated for childhood leukaemia. Obesity, particularly abdominal obesity, is one of the main characteristics of the metabolic syndrome and a risk factor for cardiovascular disease and non-insulin-dependent diabetes mellitus (NIDDM).. All patients treated for acute lymphoblastic leukaemia (ALL) before the onset of puberty in the region of western Sweden, between 1973 and 1985, and in first remission, were included. 35 out of 47 patients aged 20-32 years participated. 19 patients had received cranial radiotherapy, and the median follow-up time was 20 years. The focus of this report was to study body composition and signs of the metabolic syndrome and correlate the findings to spontaneous growth hormone (GH) secretion.. Body composition was assessed using dual-energy X-ray absorbtiometry (DEXA). We analyzed serum concentrations of insulin, glucose, leptin and lipids.. No patient was obese according to World Health Organization criteria (body mass index, BMI > or = 30 kg/m2) but one-third were overweight (BMI 25-29.9 kg/m2). The maximal GH peak during 24 h (GHmax) was correlated to percentage of total body fat (r = -0.42; P = 0.017), trunk fat (r = -0.5; P = 0.005) and fat-free mass (r = 0.42; P = 0.017). GHmax was also correlated to s-triglycerides (r = -0.54; P = 0.001), low-density lipoprotein-cholesterol (r = -0.382; P = 0.024) and high-density lipoprotein-cholesterol (r = 0.45; P = 0.007).. We found little effect on BMI but an increased percentage of total body fat, especially trunk fat, and a tendency for an unfavourable lipid profile in adult survivors of childhood leukaemia. These findings were related to low endogenous GH secretion due to cranial irradiation.

Topics: Adipose Tissue; Adult; Body Composition; Body Mass Index; Child, Preschool; Female; Follow-Up Studies; Humans; Infant; Insulin Resistance; Leptin; Lipids; Male; Metabolic Syndrome; Obesity; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Risk Factors; Survivors; Waist-Hip Ratio

The aim of the study was to estimate the anthropometric parameters and their relationship to serum levels of IGF-I, IGF-II, IGFBP-3, IGFBP-2 and leptin before and during intensive antineoplastic treatment for acute lymphoblastic leukaemia in children.. In 46 children in median age 6.6 years (range from 1.6 to 16) we evaluated at the time of diagnosis, after protocol I and after intensive treatment, height, body mass index (BMI) and IGF-I, IGF-II, IGFBP-3, IGFBP-2 and leptin.. Height SDS lowered in successive points of analysis whereas BMI SDS rose after protocol II. IGF-I SDS was low and similar at each point, IGF-II SDS and IGFBP-3 SDS values augmented progressively and IGFBP-2 SDS was significantly elevated before treatment and lowered (but not normalized) during the therapy. Leptin SDS was elevated, especially after protocol I.. Leukaemia and its treatment affect directly growth factors, its binding proteins and leptin production leading to growth retardation and overweight.

Topics: Adolescent; Antineoplastic Agents; Body Constitution; Body Height; Child; Child, Preschool; Female; Growth Disorders; Humans; Infant; Insulin-Like Growth Factor Binding Protein 2; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Leptin; Male; Overweight; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, and until recently prophylactic cranial radiotherapy (CRT) was important for achieving long-term survival. Hypothalamic-pituitary hormone insufficiency is a well-recognized consequence of CRT for childhood cancer. Another problem is increased cardiovascular risk, which has been shown in long-term survivors of other childhood cancers. In the only previously reported study on cardiovascular risk after childhood ALL, obesity and dyslipidemia were recorded in a small subgroup treated with CRT, compared with patients treated with chemotherapy. The mechanisms behind the increase in cardiovascular risk in survivors of childhood cancer are not clarified. The aim of the present study was to elucidate mechanisms of increased cardiovascular risk in former childhood ALL patients. A group of 44 ALL survivors (23 males, median age 25 yr, range 19-32 yr at the time of study) treated with CRT (median 24 Gy, 18-30 Gy) at a median age of 5 yr (1-18 yr) and chemotherapy were investigated for prevalence of GH deficiency and cardiovascular risk factors. Comparison was made with controls randomly selected from the general population and individually matched for sex, age, smoking habits, and residence. All patients and controls underwent a GHRH-arginine test, and patients with a peak GH 3.9 microg/liter or greater were further investigated with an additional insulin tolerance test. Significantly higher plasma levels of insulin (P = 0.002), blood glucose (P = 0.01), and serum levels of low-density lipoprotein cholesterol, apolipoprotein (Apo) B, triglycerides, fibrinogen, and leptin (all P

Topics: Adolescent; Apolipoproteins B; Arginine; Blood Glucose; Body Height; Cardiovascular Diseases; Carotid Arteries; Child; Child, Preschool; Cholesterol, LDL; Echocardiography, Doppler; Exercise; Female; Fibrinogen; Growth Hormone-Releasing Hormone; Human Growth Hormone; Humans; Infant; Insulin; Leptin; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Predictive Value of Tests; Risk Factors; Triglycerides

Adult survivors of childhood acute lymphoblastic leukaemia (ALL) often exhibit GH deficiency (GHD), due to prophylactic cranial radiotherapy (CRT). It is not known whether the observed risk for adiposity in these patients is associated with impaired insulin sensitivity and whether the insulin sensitivity is affected by GH replacement therapy.. Eleven patients with GHD (median age 29 years), previously given prophylactic CRT for ALL, and 11 sex-, age- and body mass index (BMI)-matched controls were investigated with bioimpedance analysis (BIA) and analysis of serum leptin, serum free fatty acids (FFA) and serum insulin. Insulin sensitivity was measured by a euglycaemic-hyperinsulinaemic clamp technique (IS-clamp). Moreover, the effects of 12 months of individually titrated GH treatment (median dose 0.5 mg/day) on these parameters were investigated.. At baseline, the patients had lower fat free mass (FFM) (P = 0.003), higher percentage fat mass (FM) (P = 0.05), serum insulin (P = 0.02) and serum leptin/kg FM (P = 0.01) than controls. The patients had a tendency towards impaired IS-clamp (P = 0.06), which disappeared after correction for body composition (IS-clamp/kg FFM; P > 0.5). In the patients, time since CRT was positively correlated with percentage FM (r = 0.70, P = 0.02), and there was an independent negative association between serum FFA and IS-clamp (P = 0.05). Twelve months of GH treatment increased serum IGF-I (P = 0.003) and FFM (P = 0.02) and decreased percentage FM (P = 0.03), but no significant changes were seen in serum leptin/kg FM, serum FFA, FFA-clamp, serum insulin or IS-clamp (all, P > or = 0.2).. Young adult survivors of childhood ALL with GHD had increased fat mass, hyperleptinaemia and impaired insulin sensitivity, which could be a consequence of radiation-induced impairment of GH secretion or mediated by other hypothalamic dysfunctions, such as leptin resistance or other unknown factors, affected by CRT. Twelve months of individualized GH replacement therapy led to positive effects on body composition, but the hyperleptinaemia, hyperinsulinaemia and the impaired insulin sensitivity remained unchanged.

Topics: Adult; Blood Glucose; Body Composition; Body Mass Index; Case-Control Studies; Fatty Acids, Nonesterified; Female; Glucose; Growth Hormone; Humans; Insulin; Insulin-Like Growth Factor I; Leptin; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Survivors

Leptin alone and in combination with other cytokines has a stimulatory effect on proliferation of leukaemic cells. This effect may be due to prevention of apoptosis of progenitor cells or upregulation of specific receptors on leukaemic precursors that make them more responsive to stimuli. This work investigates the relationship between serum leptin level, serum interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) in acute leukaemic patients. The relationship to blood cell counts, haemoglobin and response to chemotherapy was also investigated. The study included 25 acute leukaemic male patients [15 acute myeloid leukaemia (AML) and 10 acute lymphoblastic leukaemia (ALL)] and 15 age and sex matched healthy controls. All were subjected to thorough history taking, clinical examination, complete blood picture, hepatic and renal function tests and determination of serum leptin, IL-6 and VEGF levels. In addition, patients were subjected to bone marrow aspiration, cytochemistry and immunophenotyping study and serum leptin assay after chemotherapy. Serum leptin level showed statistically significant elevation only in AML group (p<0.01). This elevation was unrelated to the presence of extramedullary infiltration or response to chemotherapy and correlated only with body mass index (p<0.05). In ALL, the mean serum leptin level was insignificantly different from the controls. In both AML and ALL, there was no significant difference in serum leptin level before and after treatment. Statistically significant elevation of IL-6 and VEGF, uncorrelated with serum leptin level was detected in AML patients when compared with the controls. No correlation was found between serum leptin level and any of the studied haematological parameters. It is concluded that the release of leptin, IL-6 and VEGF may be regulated by different mechanisms leading to diversity in clinical features of the disease.

Topics: Adolescent; Adult; Aged; Case-Control Studies; Humans; Interleukin-6; Leptin; Leukemia, Myeloid, Acute; Male; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Vascular Endothelial Growth Factor A

Recently, leptin has been shown to play a regulatory role for differentiation within the myeloid and erythroid cell lineage, whereas results of its regulatory effects on lymphocytes and related tumor cells have been contradictory. To investigate whether leptin plays a role in acute lymphoblastic leukemia (ALL), we investigated the levels of leptin in plasma with enzyme-linked immunosorbent assays and the expression of the leptin receptor on malignant lymphoblasts with reverse transcriptase polymerase chain reaction (RT-PCR). At diagnosis, the leptin levels of bone marrow-derived plasma in children with ALL were found to be significantly lower than the levels of healthy control subjects (0.92 +/- 0.79 ng/mL versus 3.01 +/- 2.27 ng/mL, respectively). Notably, at complete hematologic remission (at day 33 of chemotherapy), leptin levels had normalized to 2.6 +/- 2.4 ng/mL. To elucidate the underlying mechanism of this phenomenon, we analyzed the expression of the leptin receptor on the mononuclear cell populations of the patients. RT-PCR analysis revealed gene expression rates of 33% at diagnosis versus 71% at remission, compared with 100% for healthy control subjects. Results of immunohistochemical staining supported these findings by showing that the tumor clones themselves do not express the leptin receptor. Finally, some hypotheses that might explain the decrease of leptin levels in the presence of the tumor clone are discussed.

Topics: Adolescent; Adult; Bone Marrow; Case-Control Studies; Child; Child, Preschool; Humans; Infant; Leptin; Leukocytes, Mononuclear; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Receptors, Cell Surface; Receptors, Leptin

The aim of this study was to follow auxological parameters and their relationship to serum growth hormone-binding protein (GHBP) and leptin levels in children with acute lymphoblastic leukemia (ALL).. In total, 26 prepubertal children with ALL were studied. We report these data at the time of the clinical diagnosis (n=26) and at 6 (n=21), 12 (n=21), 18 (n=21), 24 (n=20), 30 (n=16) and 36 months (n=16) after beginning treatment.. Serum GHBP levels decreased during the first 18 months and returned to normal when therapy was withdrawn. Height SDS increased at 24 months after diagnosis. Weight and the upper arm circumference had increased 6 months after chemotherapy withdrawal, whereas tricipital and subscapular skinfolds had increased both at 6 months after diagnosis and 6 months after therapy had stopped. Therefore, the tendency to become overweight is both an early and a late side-effect of anti-leukemia therapy. A significant positive correlation was found between serum leptin levels and every nutritional anthropometric parameter, with body mass index having the best relationship. However, serum GHBP levels were only correlated with BMI at the end of the study. No correlation was found between leptin and GHBP.. In children with ALL, linear growth is compromised during the acute phase of their illness and therapy; this is probably secondary to a state of partial and transient GH insensitivity. These patients tend to become obese after therapy withdrawal, with leptin being an excellent nutritional marker.

Topics: Anthropometry; Antineoplastic Combined Chemotherapy Protocols; Body Mass Index; Body Weight; Carrier Proteins; Child; Child, Preschool; Female; Humans; Infant; Leptin; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Regression Analysis; Skinfold Thickness

To investigate the prevalence and potential risk factors of obesity after therapy for childhood acute lymphoblastic leukemia (ALL).. 39 ALL patients (age 10.7-20.5 years) who were in first remission for 3.4-14.6 years after standardized treatment with chemotherapy plus cranial irradiation (n = 25) or with chemotherapy alone (n = 14) were examined. After fasting overnight, the following parameters were investigated: body mass index (BMI) of patients and their parents; patients' BMI before ALL therapy; serum free thyroxin, growth hormone-dependent factors, estradiol, testosterone, cortisol, leptin and c-peptide; fat-free mass (bioelectrical impedance); resting metabolic rate (RMR, indirect calorimetry); caloric intake (24-hour recall); and physical activity (questionnaire). RMR data were applied to the fat-free mass and compared with 83 controls.. The prevalence of obesity (criterion: BMI > 2 SDS) was significantly (p < 0.05) higher after ALL therapy (38%; irradiated patients 48%, non-irradiated patients 21%) than before therapy (3%). Compared to non-irradiated patients, irradiated patients had significantly lower RMRs (-1.07 +/- 0.24 vs. -0.32 +/- 0.21 SDS; p < 0.05), reduced physical activity levels (1.41 +/- 0.03 vs. 1.52 +/- 0.03; p < 0.05), and lower concentrations of insulin-like growth factor-binding protein-3 (-0.65 +/- 0.17 vs. 0.25 +/- 0.33 SDS; p < 0.05) and of free thyroxin (1.17 +/- 0.06 vs. 1.38 +/- 0.08 ng/dl; p < 0.05). Caloric intake was adequate.. After ALL during childhood, patients face a higher risk of obesity. In the cranially irradiated patients, the likely causes are low physical activity, RMRs and hormonal insufficiency.

Topics: Adolescent; Adult; Basal Metabolism; Body Composition; Body Mass Index; C-Peptide; Child; Energy Intake; Energy Metabolism; Estradiol; Female; Humans; Hydrocortisone; Leptin; Male; Obesity; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Testosterone; Thyroxine

In order to explore the mechanism of obesity in long-term survivors of childhood leukaemia, fat mass, lean body mass and serum leptin were assessed in a cohort of 32 (17 males) adults who had received cranial irradiation (XRT) in childhood as part of their treatment for acute lymphobiastic leukaemia (ALL), and compared with 35 age and body mass index (BMI) matched young adults (18 male).. Thirty-one patients and 18 controls had fat mass and lean body mass assessed by dual x-ray absorptiometry (DEXA), using a lunar DPX-L scanner. Serum leptin concentrations were also measured in 27 patients and all controls. Growth hormone status had previously been determined using an insulin tolerance test and arginine stimulation test. Nine patients were classified as severe growth hormone (GH) deficient (group 1), 12 patients as GH insufficient (group 2) and 11 patients as normal (group 3).. BMI and absolute fat mass were not significantly different between the patients and controls regardless of their gender (P = 0.1 and P = 0.14 respectively). In contrast, absolute lean mass was significantly reduced (P < 0.01) and leptin concentrations were significantly increased (P < 0.001) in patients compared with controls. BMI, fat mass and leptin concentrations but not lean mass were significantly different between the three GH status groups (P < 0.01, P < 0.01, P = 0.004, and P = 0.67 respectively). When leptin concentrations were expressed per unit of fat mass, they were increased in the patients compared with the controls (P = 0.03) with significant differences between the GH status groups (P = 0.004), being significantly higher in the severe GH deficient group.. Young adults who receive cranial irradiation in childhood are prone to GH deficiency and hyperleptinaemia. The pathophysiological significance of the hyperleptinaemia remains to be established but it has occurred either as a consequence of radiation induced hypothalamic damage or GH deficiency.

Topics: Adolescent; Adult; Analysis of Variance; Body Composition; Case-Control Studies; Child; Female; Follow-Up Studies; Growth Hormone; Humans; Hypothalamus; Leptin; Linear Models; Male; Obesity; Pituitary Irradiation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Proteins; Statistics, Nonparametric