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Despite remarkable advances in the clinical outcome of most children with acute lymphoblastic leukemia, a substantial number of patients ultimately relapse or suffer from side effects of treatment. In the present study, we investigated components of the IGF system for their predictive value to identify patients with an increased risk of relapse. Serum levels of IGF-I, IGF-II, IGF binding protein (IGFBP)-1, IGFBP-2, and IGFBP-3 were measured in 162 children with acute lymphoblastic leukemia treated by the Berlin Frankfurt Munster Study Group. At diagnosis we found elevated IGFBP-2, low IGFBP-3, low IGF-I, and low normal IGF-II, but normal IGFBP-1 levels. Highly elevated IGFBP-2 and low IGFBP-3 at the time of diagnosis correlated with a higher risk of an event such as lack of remission or a relapse. Serum IGFBP-2 was identified as an independent factor that adds additional information for the prediction of events (relapse or treatment failure) to the conventional prognostic factors such as white blood cell count and platelet count at diagnosis.

Background: Alterations in the insulin-like growth factor (IGF) system have been reported for different tumours. They are of particular interest in the search for new prognostic and therapeutic approaches in cancer. In childhood acute lymphoblastic leukaemia (ALL) the amount of "tumour mass" at diagnosis can exceed 1 kg. To understand the endocrine, paracrine, and autocrine potential of the malignant transformed progenitor cells, the ability of these cells to express components of the IGF system needs to be investigated., Aim: To characterise the expression pattern of genes of the IGF system in malignant lymphoblasts of children suffering from ALL., Methods: Reverse transcription polymerase chain reaction of Ficoll separated mononuclear cells from 142 children with ALL, 127 cord blood samples, and 55 blood samples of age matched controls were studied., Results: The expression of IGF-I, IGF-II, IGF binding protein 5 (IGFBP-5), and CTGF (IGFBP-rP2) was seen in a higher proportion of mononuclear cells of patients with ALL than in controls. Patients with ALL who were in continuous remission had a lower percentage of IGFBP-2 and IGFBP-3 expressing mononuclear cells at diagnosis than did those who developed a relapse. Only malignant lymphoblasts of B cell origin showed expression of CTGF (IGFBP-rP2). Malignant lymphoblasts of T cell origin more often expressed IGFBP-2 and IGFBP-5, whereas IGF-II and IGFBP-3 expression was seen more often in lymphoblasts of B cell origin., Conclusions: Malignant lymphoblasts of patients with ALL express components of the IGF system and therefore promote their own growth in an autocrine, paracrine, or endocrine manner. Whether these components will be useful as prognostic factors in the stratification of ALL treatment in children needs to be evaluated.

Insulin-like growth factor-binding proteins (IGFBPs) are important modulators of IGF action. In 50 children suffering from acute lymphoblastic leukaemia (ALL), we studied the serum levels of IGFBP-1,-2 and-3. The mean standard deviation score (SDS) values were estimated to be 0.7, 3.1 and -1.7 for the IGFBP-1,-2 and-3, respectively, compared with the normal range defined by a SDS from -2 to +2. IGFBP-1 and-3 were normal, but for IGFBP-2 we found a significantly elevated serum level compared with control groups (P < 0.05). However, during chemotherapy this increased serum IGFBP-2 normalized. In addition, we found a correlation between higher serum levels and the detection rate of the IGFBP-2 transcript in corresponding cells. In patients with ALL, the detection rates of IGFBP-2 mRNA were estimated to be 72% and 35% at the time of diagnosis and at day 33 of chemotherapy respectively; in the control groups (healthy children and children at their initial presentation of diabetes mellitus), the values were 28% and 33% respectively. Based on the correlation between IGFBP-2 serum levels and the corresponding gene expression as well as the normalization of IGFBP-2 levels during chemotherapy, we concluded that the increased serum level mainly originated from the tumour clone itself. Furthermore, possible functional consequences of elevated IGFBP-2 were outlined.

Unlabelled: Endocrine dysfunction and damage of the epiphysial growth plates have been reported as late effects of antileukaemic treatment during childhood. It is a common opinion that cranial irradiation (CI) is the most important factor for blunted growth. Accordingly, recent therapeutic strategies in acute lymphoblastic leukaemia (ALL) avoid cranial irradiation. Here we analysed longitudinal data on growth and puberty of 54 children in first complete remission, who were treated with 18 Gy CI or not submitted to radiotherapy. Two chemotherapeutic protocols were compared which were similar during the induction period but differed in the intensity of maintenance therapy. In cranial irradiated patients both in males and females the pubertal growth spurt started at a mean age of 1.2 years (SD: 0.93 years) earlier than controls. Age at diagnosis and age at pubertal growth spurt were significantly correlated (r = 0.35, P = 0.017). Similarly, menarche occurred at a mean age (n = 22) of 12.1 years and was correlated with the age at start of therapy in girls who were treated with 18 Gy CI (r = 0.61, P = 0.01). Adult height was reached spontaneously in 30 patients treated during prepubertal age and in 10 treated shortly before or during puberty. In all prepubertal patients treated for 2-3 years with intensive maintenance therapy blunted growth resulted in a significant loss of -1.85 H-SDS (median, P = 0.0051) compared to height at diagnosis. However, if continuation treatment used only methotrexate and 6-mercaptopurine (i.e. BFM protocol) final height equalled projected adult height, despite 18 Gy CI., Conclusions: (1) multiagent chemotherapy is of major impact for growth and puberty; (2) 18 Gy cranial irradiation is below the critical dosage responsible for blunted growth; (3) loss in potential growth might be prevented by current CT strategies; (4) onset of puberty depends on age when antileukaemic therapy is applied.

Unlabelled: The insulin-like growth factor (IGF) signaling pathway may be of importance for the proliferation of different tumours (e.g. breast cancer and Wilms tumour). The bioavailability of both IGF-I and IGF-II is regulated by specific IGF-binding proteins (IGFBPs). IGFBP-2 is the predominant binding protein during fetal life, where it is expressed in most tissues. In contrast, postnatally it is mainly released by specific cell types (hepatocytes, astroglia, kidney cells, prostate cells) and a range of tumour cell lines. Furthermore, phytohaemagglutinin stimulated normal lymphoblasts and malignant lymphoblasts express IGFBP-2. In order to investigate the IGF regulatory pathway in leukaemia serum levels of IGF-I, IGF-II, IGFBP-2 and IGFBP-3 were determined in 28 leukaemic children. Whereas serum levels of IGF-I (mean/range: -2.7/-0.1 to -6.7 SDS), IGF-II (-3.6 SDS/-1.3 to -8.7) and IGFBP-3 (-2.0/+2.2 to -7.1 SDS) were significantly decreased comparable to levels in growth hormone deficiency, IGFBP-2 levels (+4.0/-0.45 to +7.4 SDS) were found to be markedly elevated and inversely correlated to IGF-I (r = -0.51, P = 0.013). After haematological remission upon chemotherapy all four parameters had normalized in the 16 re-investigated children. Similar findings have been observed in one boy with a relapse including CNS leukaemia., Conclusion: This study demonstrates that the proliferation of malignant lymphoblasts (at diagnosis vs treatment) occurs in the presence of decreased serum levels of IGF-I, IGF-II and IGFBP-3 and that diminished production of these peptides may contribute to impaired growth. It further indicates that serum levels of IGFBP-2 may be directly related to the proliferation of lymphoblasts.

A total of 74 children suffering from acute lymphoblastic leukaemia (ALL) or non-Hodgkin lymphoma (NHL) were involved in a retrospective analysis of their physical growth during and after the therapy. Out of this total number, 54 children were subjected to radiochemotherapy in compliance with the VII/(81) scheme, and another 20 children in compliance with the LSA2L2 scheme. At the beginning of the therapy the average height-standard deviation score (H-SDS) for both groups of patients corresponded with the population average. The patients subjected to the VII/(81) scheme showed, throughout the observation period of five years from the beginning of the therapy, a height normal for their age group. Contrary to this observation, the patients subjected to the LSA2L2 scheme experienced a significantly different growth in the period under observation and continually lost height in comparison to the normal population. The same results were experienced with a smaller group of patients whose growth was followed up for eight years from the beginning of therapy. 16 patients (VII/81 n = 4/LSA2L2 n = 12) reached their final height. For the patients of the VII/(81) scheme the final height showed an average H-SDS of 0.27 and for the patients of the LSA2L2 scheme of -1.22 (p = 0.068). Considering that the same cranial radiotherapy (max. 18 Gy for both schemes) and a comparable intensive induction therapy were applied, it must be concluded that the intensity and duration of the maintenance treatment are the critical factors initiating a different growth behaviour of the two groups subjected to radiochemotherapeutical schemes.

The IGF regulatory system has been shown to mediate mitogenic effects during normal growth and tumor proliferation. The bioavailability of both IGF-I and IGF-II is regulated by at least six specific IGF binding proteins (IGFBPs). Whereas IGFBP-3 is the main IGFBP postnatally, IGFBP-2 is the predominant IGFBP during fetal life. In addition, IGFBP-2 is expressed in a range of tumor cell lines. In order to investigate the IGF regulatory pathway in malignancies we analyzed by RIA serum samples of 49 children with leukemia, Non-Hodgkins' Lymphoma (NHL) or solid tumors at the time of diagnosis. Serum concentrations of IGF-I (mean/range: -2.4/0.3 to -9.9 SDS), IGF-II (-2.5/0.2 to -5.6 SDS) and IGFBP-3 (-1.3/2.2 to -6.8 SDS) were significantly decreased, but IGFBP-2 (3.2/-0.9 to 8.6 SDS) was elevated. Both absolute as well as SDS values of IGF-I, -II and the sum of IGF-I and IGF-II (r = -0.49, p < 0.01) were inversely correlated with IGFBP-2. Serum levels of the growth factors IGF-I and IGF-II were significantly decreased in different types of malignancies to concentrations usually seen only in patients with growth hormone deficiency or during starvation. However, the elevated levels of IGFBP-2 in 70% of our patients exceeded by far those in growth hormone deficiency. Furthermore, in this study we could demonstrate that serum levels of IGF-I and IGF-II were inversely correlated to IGFBP-2 independent on the type of malignancy, indicating a common regulatory mechanism of the IGF signaling pathway in these diseases.

Adult height in 20 patients, successfully treated for childhood leukemia, led to reduced height less than 2 standard deviations (S.D.). The loss in projected final height of 0.8 S.D. was mainly due to intensity of maintenance therapy of protocol LSA2L2 (14). In contrast, less intensive maintenance therapy (6-MP and MTX) of protocol BFM 81 (13) showed a transient growth spurt. Final height equals projected target height. Neither 18-Gy nor gold-198 intrathecally compromised final height.