Peter Vorwerk

Serum levels of insulin-like growth factor-I,-II and insulin-like growth factor binding proteins-2 and-3 in children with acute lymphoblastic leukaemia

AbstractThe 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.ConclusionThis 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.

Expression of components of the IGF signalling system in childhood acute lymphoblastic leukaemia.

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.

Multimodal treatment, including interferon beta, of nasopharyngeal carcinoma in children and young adults: preliminary results from the prospective, multicenter study NPC-2003-GPOH/DCOG.

The authors report preliminary results from a prospective multicenter study (Nasopharyngeal Carcinoma [NPC] 2003 German Society of Pediatric Oncology and Hematology/German Childrens Oncology Group [NPC‐2003‐GPOH/DCOG]).

Elevated serum levels of IGFBP-2 found in children suffering from acute leukaemia is accompanied by the occurrence of IGFBP-2 mRNA in the tumour clone.

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.

CTGF (IGFBP-rP2) is specifically expressed in malignant lymphoblasts of patients with acute lymphoblastic leukaemia (ALL)

Connective tissue growth factor (CTGF) is a major chemotactic and mitogenic factor for connective tissue cells. The amino acid sequence shares an overall 28–38% identity to IGFBPs and contains critical conserved sequences in the amino terminus. It has been demonstrated that human CTGF specifically binds IGFs with low affinity and is considered to be a member of the IGFBP superfamily (IGFBP-rP2). In the present study, the expression of CTGF (IGFBP-rP2) in human leukaemic lymphoblasts from children with acute lymphoblastic leukaemia (ALL) was investigated. RNA samples from tumour clones enriched by ficoll separation of bone marrow or peripheral blood mononuclear cells (MNC) from 107 patients with childhood ALL at diagnosis and 57 adult patients with chronic myeloid leukaemia (CML) were studied by RT-PCR. In addition MNC samples from children with IDDM and cord blood samples from healthy newborns were investigated as control groups. Sixty-one percent of the patients with ALL (65 of 107) were positive for CTGF (IGFBP-rP2) expression. In the control groups, no expression of CTGF (IGFBP-rP2) in peripheral MNC was detected, and in the group of adult CML patients only 3.5% (2 of 57) were positive for this gene. The role of CTGF (IGFBP-rP2) in lymphoblastic leukaemogenesis requires further evaluation, as does its potential utility as a tumour marker.

Loss of imprinting of IGF-II gene in children with acute lymphoblastic leukemia

Insulin-like growth factor-II (IGF-II) is known to be involved in the regulation of growth, differentiation and cell death in normal human tissues. In a variety of human tumors, the IGF-II gene is overexpressed and considered to be a stimulator for tumor growth through autocrine and paracrine mechanisms. The IGF-II gene is normally parental imprinted, only the paternal allele being expressed in most tissues. Several reports about biallelic expression (loss of imprinting (LOI)) of the IGF-II gene in different tumors suggest a role of dysregulation of IGF-II imprinting in tumorigenesis. However, biallelic expression of IGF-II gene has also been reported in different tissues of a significant number of normal controls, indicating either a normal phenomenon or an elevated cancer risk in this group of persons. Although LOI of IGF-II presumably promotes tumorigenesis by increasing IGF-II expression, elevated IGF-II levels in those patients have not been reported. We studied IGF-II gene expression in malignant lymphoblasts of 124 children suffering from acute lymphoblastic leukemia, 196 cord blood samples from healthy newborns and mononuclear cells (MNC) from 50 healthy age matched children. The ApaI polymorphism in exon 9 of the IGF-II gene and allele-specific exon-connection RT-PCR was used for determination of the imprinting status. From 44 informative ALL-patients, 24 (54%) showed LOI of the IGF-II gene. Twenty percent of the informative cord blood samples (N=56) and 14% of the informative MNC samples from healthy controls (N=22) showed biallelic expression of IGF-II. In the ALL-patients, no statistical significant correlation between LOI patients and relapse rate, surviving rate and risk groups could be detected. We conclude that LOI of IGF-II occurs in malignant lymphoblasts of children suffering from acute lymphoblastic leukemia in more than 50% of the patients. In MNC from cord blood and peripheral MNC from healthy controls, biallelic expression could be detected in up to 20% of all cases. The importance of LOI in ALL-patients needs to be further evaluated to determine its impact in leukemogenesis.

Neuroendocrine tumors of the appendix in children and adolescents

Neuroendocrine tumors (NET) of the appendix in children and adolescents are rare and mostly detected postoperatively by a histopathological examination. Since the malignant potential of these tumors remains unclear, therapeutic recommendations are not evidence based. The Society of Pediatric Oncology and Hematology (GPOH) has prospectively registered and followed children with appendical NET since 1997 (GPOH‐MET trial). The objective of this study was to critically evaluate the therapeutic recommendations for appendical NET in children.

Final height and puberty in 40 patients after antileukaemic treatment during childhood

AbstractEndocrine 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.

Childhood cancer predisposition syndromes—A concise review and recommendations by the Cancer Predisposition Working Group of the Society for Pediatric Oncology and Hematology

Heritable predisposition is an important cause of cancer in children and adolescents. Although a large number of cancer predisposition genes and their associated syndromes and malignancies have already been described, it appears likely that there are more pediatric cancer patients in whom heritable cancer predisposition syndromes have yet to be recognized. In a consensus meeting in the beginning of 2016, we convened experts in Human Genetics and Pediatric Hematology/Oncology to review the available data, to categorize the large amount of information, and to develop recommendations regarding when a cancer predisposition syndrome should be suspected in a young oncology patient. This review summarizes the current knowledge of cancer predisposition syndromes in pediatric oncology and provides essential information on clinical situations in which a childhood cancer predisposition syndrome should be suspected.

Exocrine Pancreatic Tumors in Childhood in Germany

Pancreatic tumors (PT) in childhood are rare. Standard therapeutic approaches are lacking. Our aim was to analyze treatment modalities and outcome in children with PT.