Reinhard Hartmann

Prognostic value of minimal residual disease in relapsed childhood acute lymphoblastic leukaemia

Molecular monitoring by quantitative PCR techniques of residual leukaemia cells during the first phases of treatment can predict outcome in children with acute lymphoblastic leukaemia. We did a retrospective study of 30 children who had been treated according to the ALL-REZ BFM trials to assess whether amount of minimal residual disease during the first stages of treatment for relapsed acute lymphoblastic leukaemia could predict outcome. In children with minimal residual disease of less than 10(-3) at day 36, probability of event-free survival was 0.86 (95% CI 0.77-0.95), compared with 0 in children with minimal residual disease of 10(-3) or greater (p<0.001). Our results suggest that information about molecular response to treatment can be used to predict long-term outcome in relapsed childhood acute lymphoblastic leukaemia.

Risk factors for the development of retinopathy in children and adolescents with Type 1 (insulin-dependent) diabetes mellitus

SummaryIn our preceding paper, the prevalence and development of retinopathy in 231 Type 1 diabetic children and adolescents were reported to be associated with the duration of diabetes and its age at onset. This paper analyses the relationships between the development of retinopathy and the following factors: age, sex, puberty, blood pressure, insulin dosage, HLA antigens, long-term glycaemic control, and serum cholesterol and triglycerides. All these variables were longitudinally evaluated in a cohort of 322 insulin-dependent patients aged 16.2 ± 4.9 years with diabetes for 7.4 ± 5.2 years, including those 231 subjects whose eyes were examined once or repeatedly by ophthalmoscopy and fluorescein angiography. Long-term glycaemic control from the onset of diabetes to the retinal examination was assessed by both an arbitrary score comprising different parameters and by mean values of glycosylated haemoglobin, and was categorised as good, fair, and poor. With life-table analysis, the overall median individual risk for developing early retinal changes (9.1 years) was found to be significantly influenced by glycaemic control. Minimal lesions developed earlier (8.0 years) with poor control, but later with fair (10.5 years) and good glycaemic control (12.5 years) (p < 0.01). Mean HbA1 values below 10% delayed the onset of both incipient (10.8 years) and background retinopathy (16.6 years), while values above 10% advanced it (8.0 and 11.8 years respectively) (p < 0.05 and < 0.008). By multivariate regression and stepwise discrimination analyses, only 4 out of 14 variables were found to exert significant independent influences on the development of retinopathy: diabetes duration, long-term glycaemic control, serum triglycerides and age. The correlation coefficients with retinopathy cumulatively increased fromr=0.78 for duration of diabetes only tor=0.81 for the sum of these four factors. None of the other variables was found to increase this value any further.

Long-term glycemic control has a nonlinear association to the frequency of background retinopathy in adolescents with diabetes : follow-up of the Berlin retinopathy study

OBJECTIVE To assess the influence of long-term glycemic control on the development of background retinopathy in adolescents followed longitudinally from the onset of insulin-dependent diabetes mellitus (IDDM). RESEARCH DESIGN AND METHODS Repeated retinal fluorescein angiographies, in intervals of 1–2 years, were evaluated prospectively in 346 patients (190 males, 156 females; 19.8 [8.8–35.4] years of age; diabetes duration of 10.4 [1.1–27.4] years at their latest eye examination, median [range]). The influences of long-term HbA1c (mean of 18 [1–95] determinations per person) and microalbuminuria (≥2 of ≥3 measurements ≥ 15 μg/min × 1.73 m2) were studied by multiple linear regression, life-table analysis, and trend analyses. RESULTS The rate of background retinopathy per 100 patient-years increased with poorer glycemic control from 0.7 (long-term HbA1c < 7% to 7.3 (HbA1c > 11%) following an exponential function. Life-table analysis after subdivision in HbA1c quartiles of equal sizes (HbA1c < 8, 8–9, 9–10, and > 10%) revealed an individual median expectation of background retinopathy after more than 25, 16.2, 12.7, or 12.0 years of diabetes, respectively. However, significant differences were found only between 8–9% and 9–10%, calculated either as prevalence, life-table analysis, or relative incidence, thus suggesting that a threshold model may also fit the data. After 12 years of diabetes, < 25% of those patients exhibiting microalbuminuria (n = 18) were expected to be free from retinopathy compared with 81% of those with normoalbuminuria (n = 86). CONCLUSIONS Two statistical models are appropriate to explain the relationship between glycemic control and risk for background retinopathy: 1) a continuous exponential relationship as described by the DCCT or 2) the presence of a threshold HbA1c level at 9%. Thus, diabetes treatment in children should aim at long-term HbA1c levels < 9.0%, but every progress closer to normal may further reduce the risk.

Assessment of glycemic control by continuous glucose monitoring system in 50 children with type 1 diabetes starting on insulin pump therapy.

Abstract:u2002 Objective:u2002 To report experience with a continuous glucose monitoring system (CGMS) and to identify factors influencing glycemic control in a large cohort of children and adolescents with type 1 diabetes and change to insulin pump therapy via continuous subcutaneous insulin infusion (CSII).

Predictive Value of Tubular Markers for the Development of Microalbuminuria in Adolescents with Diabetes

The predictive value of tubular proteinuria and/or enzyme excretion for the development of microalbuminuria in patients with diabetes mellitus was investigated over a period of 7.5 years in 64 children and adolescents without microalbuminuria at baseline. An abnormal urinary excretion of N-acetyl-β-D-glucosaminidase (NAG) preceded the increase of albumin excretion in all 8 patients (12.5%) developing microalbuminuria during this period (positive/negative predictive value 0.2 and 1.0, respectively). Also both, the actual as well as the long-term glycemic control (HbA1c) up to the onset of abnormal NAG excretion were predictive for the development of microalbuminuria. Fifty percent of those patients with both an elevated NAG excretion and an HbA1c ≧9% developed micro-albuminuria within the next 5 years. Therefore, periodic monitoring of urinary NAG excretion should be incorporated into the follow-up of patients with type 1 diabetes mellitus.

Treatment with insulin glargine reduces asymptomatic hypoglycemia detected by continuous subcutaneous glucose monitoring in children and adolescents with type 1 diabetes

Objective:u2002 Unsatisfactory basal insulin substitution may lead to asymptomatic hypoglycemia in children and adolescents with type 1 diabetes (T1D). To investigate the effects of multiple daily injections before and after changing to insulin glargine (IG), continuous glucose monitoring system (CGMS) data were used to analyze glycemic control and hypoglycemic episodes during the two different therapy regimens.

Early treatment with l‐thyroxine in children and adolescents with type 1 diabetes, positive thyroid antibodies, and thyroid gland enlargement

Aim:u2002 To investigate whether early treatment with l‐thyroxine may prevent deterioration of thyromegaly and progression to subclinical or clinical hypothyroidism in pediatric patients with type 1 diabetes, positive thyroid antibodies, and ultrasound abnormalities of the thyroid gland.

Prevalence of 20S proteasome, anti-nuclear and thyroid antibodies in young patients at onset of type 1 diabetes mellitus and the risk of autoimmune thyroiditis.

Patients with type 1 diabetes mellitus (DM1) are at high risk to develop further autoimmune disorders, which are mostly characterized by the presence of organ-specific antibodies in serum and a subclinical disease course. Diabetes-related (glutamic acid decarboxylase, tyrosine phosphatase, IA-2) and thyroid-specific (thyroperoxidase, thyroglobulin) as well as antibodies to 20S proteasome, and anti-nuclear antibodies, were measured at DM1 onset in 147 children and adolescents. Patients were followed prospectively for the development of autoimmune thyroiditis (TSH elevation and/or sonographic thyroid gland enlargement in the presence of thyroid antibodies) up to 12 years, median observation time 4.4 years. Eight of 147 (5.4%) patients developed autoimmune thyroiditis. The cumulative incidence (+/-SE) at 5 years was 0.08+/-0.03. The prevalence of thyroid antibodies was 16.7%, of DM-related 88.4%, 20S proteasome 21.9%, and anti-nuclear antibodies 20.0%. There was a positive correlation between thyroid and anti-nuclear antibodies (p <0.001). Clinical course of DM1 and remission duration were not influenced by the presence of autoantibodies. However, in contrast to patients without antibodies, those with positive antibodies had significantly (p <0.001) elevated cumulative incidence of autoimmune thyroiditis at 5 years: thyroperoxidase 0.40+/-0.13, thyroglobulin 0.38+/-0.15, and anti-nuclear antibodies 0.29+/-0.12, respectively. These data underline that autoimmunity in patients with DM1 is not only restricted to beta-cell antigens at the onset of disease. In particular, patients with positive thyroid and anti-nuclear antibodies are at high risk to develop autoimmune thyroiditis during the first 5 years of DM1.

Age-specific levels of diabetes-related GAD and IA-2 antibodies in healthy children and adults

Glutamic acid decarboxylase (GAD) and tyrosine phosphatase IA-2 antibody levels were measured in 375 healthy children and adults and in 187 children with newly diagnosed type 1 diabetes mellitus (DM). GAD antibody levels were determined by radioimmunoassay, and IA-2 antibody levels by immunoprecipitation. Healthy children had higher GAD antibody levels than adults (p < 0.001). The 98th percentile was 1.60 U/ml in children and 1.16 U/ml in adults. IA-2 antibody levels did not differ between these two cohorts. Children with DM had higher GAD and IA-2 antibody levels than healthy children (p <0.001). Based on receiver operating characteristics (ROC) analysis, elevated levels of these antibodies showed high specificity rates (+/- SE) of 0.968 +/- 0.14 to 1.00 +/- 0.00. The sensitivity ranged between 0.439 +/- 0.037 (both antibodies elevated) and 0.850 +/- 0.027 (at least one antibody elevated). These data emphasize the importance of establishing age-specific reference values for DM-related antibodies in the background population before applying them for screening and intervention studies.

Acute toxicity and effectiveness of idarubicin in childhood acute lymphoblastic leukemia.

Abstract:u2002 Anthracyclines have become important components of multi‐agent remission induction and continuation therapy of acute lymphoblastic leukemia (ALL). New anthracycline derivatives are being investigated in an attempt to shift the balance of side effects and antileukemic potency. To evaluate the toxicity and efficacy of idarubicin (IDA) in childhood ALL, a prospective multicenter phase‐II study was performed. A total of 51 children with prognostically poor recurrences of ALL were enrolled, all of whom had been exposed to anthracyclines during front‐line treatment. A single 48‐h continuous infusion of IDA at 24 mg/m2 was started on the first day of salvage treatment without concomitant systemic cytostatic agents. The response was assessed by reduction of leukemic blasts in the bone marrow and other compartments 2 wk later. IDA monotherapy caused complete and partial remissions in 5 and 20 patients, respectively (49%). Delays of treatment with subsequent polychemotherapy courses were frequent and mainly caused by prolonged intervals of myelosuppression and high rates of systemic infection. Non‐hematological toxicities including acute cardiac reactions were transient and moderate. Our findings suggest that IDA is an effective drug for remission induction in children with ALL, with acute hematological toxicity being dose‐limiting.