CNS Embryonal Tumor with PLAGL Amplification, a New Tumor Type in Children and Adolescents: Insights from a Comprehensive MRI Analysis.

BACKGROUND AND PURPOSE: CNS embryonal tumor with PLAGL1/PLAGL2 amplification (ET, PLAGL) is a newly identified, highly malignant pediatric tumor. Systematic MRI descriptions of ET, PLAGL are currently lacking. MATERIALS AND METHODS: MRI data from 19 treatment-naïve patients with confirmed ET, PLAGL were analyzed. Evaluation focused on anatomical involvement, tumor localization, MRI signal characteristics, DWI behavior, and the presence of necrosis and hemorrhage. Descriptive statistics (median, interquartile range, percentage) were assessed. RESULTS: Ten patients had PLAGL1 and nine PLAGL2 amplifications. The solid components of the tumors were often multinodular with heterogeneous enhancement (mild to intermediate in 47% and intermediate to strong in 47% of cases). Non-solid components included cysts in 47% and necrosis in 84% of the cases. The tumors showed heterogeneous T2WI hyper-and isointensity (74%), relatively little diffusion restriction (ADC values < contralateral normal-appearing WM in 36% of cases with available DWI), and tendencies towards hemorrhage/calcification (42%). No reliable distinction was found between PLAGL1-and PLAGL2-amplified tumors or compared to other embryonal CNS tumors. CONCLUSIONS: The study contributes to understanding the imaging characteristics of ET, PLAGL. It underscores the need for collaboration in studying rare pediatric tumors and advocates for the use of harmonized imaging protocols for better characterization. ABBREVIATIONS: ATRT= atypical teratoid/rhabdoid tumor; ETMR= embryonal tumor with multilayered rosettes; ET, PLAGL= CNS embryonal tumor with PLAGL amplification; EVD= external ventricular drain; IQR: interquartile range; PLAGL1= pleomorphic adenoma gene-like 1; PLAGL2= pleomorphic adenoma gene-like 2; WHO= World Health Organization.

Growth hormone treatment of children with brain tumors and risk of tumor recurrence.

GH is increasingly used for treatment of children and adults. It is mitogenic, however, and there is therefore concern about its safety, especially when used to treat cancer patients who have become GH deficient after cranial radiotherapy. We followed 180 children with brain tumors attending three large hospitals in the United Kingdom and treated with GH during 1965-1996, and 891 children with brain tumors at these hospitals who received radiotherapy but not GH. Thirty-five first recurrences occurred in the GH-treated children and 434 in the untreated children. The relative risk of first recurrence in GH-treated compared with untreated patients, adjusted for potentially confounding prognostic variables, was decreased (0. 6; 95% confidence interval, 0.4-0.9) as was the relative risk of mortality (0.5; 95% confidence interval, 0.3-0.8). There was no significant trend in relative risk of recurrence with cumulative time for which GH treatment had been given or with time elapsed since this treatment started. The relative risk of mortality increased significantly with time since first GH treatment. The results, based on much larger numbers than previous studies, suggest that GH does not increase the risk of recurrence of childhood brain tumors, although the rising trend in mortality relative risks with longer follow-up indicates the need for continued surveillance.

Increase of the bioavailability of intraperitoneal erythropoietin in children on peritoneal dialysis by administration in small dialysis bags.

OBJECTIVE: To establish the effectivity of administration of erythropoietin intraperitoneally in a small amount of fluid in children with renal anemia on continuous ambulatory peritoneal dialysis (CAPD). DESIGN: Prospective study in which children with renal anemia on CAPD were treated with erythropoietin intraperitoneally, administered in a specially designed bag containing 50 mL NaCl 0.9%. SETTING: University hospital. PATIENTS: The patient population consisted of 9 children treated with CAPD and 1 treated with nightly intermittent peritoneal dialysis. The median age was 7.8 years (range 4.1-15.2). Four of these children had not been treated with erythropoietin before (group A), and 6 had been treated with erythropoietin administered intraperitoneally in 250 mL of dialysis fluid (group B). INTERVENTIONS: Patients in group A started on a dose of approximately 300 units/kg per week (group A). Patients in group B received their previous dose. Dosage was adjusted to achieve a target hemoglobin level of 6.5-7.0 mmol/L (104-112 g/L). Serum ferritin levels and transferrin saturation were monitored and iron supplementation was prescribed in the case of iron deficiency. MAIN OUTCOME MEASURES: Weekly erythropoietin dose in relation to hemoglobin level. RESULTS: In group A, median hemoglobin level rose from 5.3 mmol/L (85 g/L) to 6.6 mmol/L (106 g/L) after 6 months of therapy, whereas the median erythropoietin dose decreased from 266 to 234 U/kg/week. In group B, hemoglobin levels remained stable and median erythropoietin dose decreased from 262 to 194 U/kg/week. One patient in this group, for unknown reasons, never responded to erythropoietin treatment. He was excluded from further analysis. In the remaining 5 patients the median cumulative erythropoietin dose was 3250 U/kg in the 3-month period prior to the start of the study and 2713 in the 3-month period starting 6 months after the beginning of the study. This difference of 17% was statistically significant using a Wilcoxon test (p < 0.05). CONCLUSION: Intraperitoneal administration of erythropoietin in a small amount of dialysis fluid leads to a decrease in the required dose.

The serum complement system in children on continuous ambulatory peritoneal dialysis.

OBJECTIVE: During continuous ambulatory peritoneal dialysis (CAPD), the loss of complement factors via the dialysate may cause complement deficiencies. This hypothesis was tested in a group of children treated with CAPD. DESIGN: Classical (CH50) and alternative (AP50) complement activity and serum levels of factors C1q, C3, C4, C3d, B, D, and P in CAPD patients were compared to normal controls and to children with preterminal renal failure. SETTING: Patients were seen in a university hospital; normal controls were seen in an outpatient clinic of a general hospital. PATIENTS: A group of 22 children on CAPD was compared to a normal control group of 44 children and to a group of 12 children with preterminal renal failure with a creatinine clearance below 25 mL/min/1.73 m2. RESULTS: CH50, AP50, C3, and B were not significantly different from the control group in both the CAPD and preterminal groups. Factors C1q (p = 0.01) and C4, C3d, D, and P (p < 0.001) were higher in the CAPD group in comparison to the normal control group. The factors D (p < 0.001) and P (p = 0.02) were also elevated in the preterminal group. For the measured factors there was no significant difference between the CAPD group and the preterminal group. CONCLUSIONS: There is no deficiency of complement in children treated with CAPD. High levels of C3d and D can be explained by the reduction of their elimination by the kidney. The increased levels of the other factors are presumably due to increased synthesis in renal failure. This does not seem to be caused by CAPD.

Adequate dialysis? Measurement of KT/V in a pediatric peritoneal dialysis population.

OBJECTIVE: To measure the urea and creatinine kinetics in a pediatric population. PATIENTS AND METHODS: In 19 children treated with peritoneal dialysis (PD) KT/V, urea and creatinine clearances (Ccr) were measured. Thirteen children were on continuous ambulatory peritoneal dialysis (CAPD) and 6 on highly intermittent peritoneal dialysis (NIPD). RESULTS: Mean KT/V per week was 2.31 +/- 0.78 and mean creatinine clearance 74 +/- 47 L/week/1.73 m2. There was no difference in dialytic KT/V between patients treated with CAPD and NIPD (1.75 +/- 0.21 vs 1.76 +/- 0.50). The correlation between KT/V urea and creatinine clearance was 0.9 (p < 0.001). There was a clear relationship of these parameters with residual renal function, but not with age or blood urea level. A weak positive correlation was found with serum albumin and protein intake. CONCLUSIONS: Mean KT/V in this patient group was higher than the values reported for most adult patient groups. Residual renal function considerably contributes to this high KT/V. It is not clearly defined which KT/V should be aimed for, since criteria for adequate dialysis are multifactorially determined and therefore difficult to interpret.

Measurement of peritoneal fluid handling in children on continuous ambulatory peritoneal dialysis using autologous hemoglobin.

OBJECTIVE: Previous measurements of peritoneal fluid handling in children treated by continuous ambulatory peritoneal dialysis (CAPD) were performed with human albumin as a fluid marker. A major disadvantage of this substance is that endogenous patient albumin enters the peritoneal cavity during the dwell period. For this reason peritoneal fluid kinetics were measured in a group of children on CAPD, using autologous hemoglobin as a volume marker. DESIGN: Autologous hemoglobin was added to dialysate containing 1.36% glucose as a volume marker. Marker clearance (MC), which is presently the best available approximation of lymphatic absorption in the clinical setting, and transcapillary ultrafiltration (TCUF) were measured during a 4-hour dwell. SETTING: University hospital. PATIENTS: Children on CAPD (N = 9), with a median age of 8.1 years (range 2.1-3.2 years). RESULTS: MC was 521 +/- 166 mL/4 hour/1.73 m2, which is high compared to the literature data on adult CAPD patients. TCUF was 519 +/- 92 mL/4 hour/1.73 m2, which is similar to data concerning adult patients. TCUF reached no maximum during the 4-hour dwell, and the deviation of the TCUF curve from linear was markedly less than usually seen in adult patients. CONCLUSIONS: MC in children treated with CAPD is higher when compared to the literature data on adults. Difficulties to achieve sufficient ultrafiltration in children could be caused by relatively small differences between MC and TCUF from the beginning to the end of the dwell.

Complement in serum and dialysate in children on continuous ambulatory peritoneal dialysis.

OBJECTIVE: During continuous ambulatory peritoneal dialysis (CAPD), activation of complement in the peritoneal cavity may theoretically occur, with inappropriately high or low levels of certain complement factors in dialysate as a consequence. In a group of children on CAPD, it was tested whether levels of a number of complement factors in dialysate were in the range that was predicted on the basis of their molecular weight. DESIGN: Serum and dialysate levels of C1q, C3, C4, C3d, B, D, and P were measured after a night dwell in children on CAPD. Simultaneously, four non-complement proteins (beta 2-microglobulin, albumin, IgG, and alpha 2-macroglobulin) were also measured in dialysate and serum. Assuming a linear relationship between the log base 10 of the dialysate/serum ratio of these non-complement proteins and the log base 10 of their molecular weight, the expected ratios of all complement factors were determined. The differences between actual and predicted ratios were tested using a modified t-test, taking into account the inaccuracy of the estimate. SETTING: University hospital. PATIENTS: A group of 14 children on CAPD, with a median age of 7.8 years (range 2.1 - 13.2). These children had been on CAPD for a median period of 42.4 months (range 0.4 - 89.1). RESULTS: The ratios of factor D (p < 0.001) and C3d (p = 0.035) were elevated, whereas those of C3 (p < 0.001), C4 (p < 0.001), and factor P (p = 0.012) were decreased. CONCLUSIONS: Relatively low dialysate/serum ratios of C4, C3, and factor P could be caused by intraperitoneal consumption of complement. High levels of C3d are compatible with this. High dialysate/serum ratios of factor D indicate intraperitoneal production of factor D. These results provide evidence for activation of complement in the peritoneal cavity in children on CAPD. A further reduction of already low levels of complement factors in dialysate as a result of this may impair host defense.

Adsorption of erythropoietin and growth hormone to peritoneal dialysis bags and tubing.

OBJECTIVE: To study the adsorption of erythropoietin and growth hormone to dialysis bags and tubing. DESIGN: In vitro study in which radiolabeled erythropoietin and recombinant human growth hormone were added to small-volume (50- and 250-mL) dialysis bags. Recovery was measured after 15-minute dwells. Experiments were performed in triplicate. SETTING: University hospital. RESULTS: Adsorption of erythropoietin and growth hormone was less than 7%. CONCLUSION: Adsorption of erythropoietin and recombinant human growth hormone to dialysis bags and tubing is minimal. This finding provides another argument in favor of intraperitoneal therapy in pediatric peritoneal dialysis.

Fractures of the intercondylar eminence in children and adolescents.

The treatment of choice of completely dislocated fractures of the intercondylar eminence is controversial. Recently, Zifko and Gaudernak [14] introduced a new classification in which they distinguish between two different types of intercondylar fractures: Type A: isolated avulsion of the anterior cruciate ligament Type B: fractures including the intercondylar eminence In order to assess whether this new classification could lead to a better selection of patients requiring open reduction, 19 children were reviewed 2-16 years after they had sustained a fracture of the intercondylar eminence. All patients with incompletely displaced fragments had an excellent or good ultimate result, independent of the kind of initial treatment received. Eleven patients sustained a complete displaced fracture. Of these, two had a poor result. Both had been treated conservatively for isolated avulsion of the anterior cruciate ligament. All conservatively treated type-B fractures had an excellent or good result. It is concluded that completely displaced type-A fractures require operative treatment by open reduction and fixation of the avulsed fragment.

Growth hormone therapy and malignancy.

The possibility that human growth hormone (GH) replacement therapy might either increase the risk of cancer recurrence in a child who has previously been treated for a brain tumour or leukaemia, or induce de novo cancer, has worried paediatricians for a number of years. Concern arises from animal experiments, the association of acromegaly with malignancy, and the Japanese experience of a cluster of de novo leukaemia cases in children treated with GH. It is reassuring that so far the results from single centre studies and from the pharmaceutical industry surveillance programmes have shown no evidence of an increased risk of malignancy, recurrent or de novo. The confidence intervals, however, are wide and the scientific nature of these studies is flawed as there has never been a prospective randomized study of GH replacement in children with radiation-induced GH deficiency. For clinical reasons, such a study is unlikely to be performed and therefore surveillance must be maintained at a very high level.

Intraperitoneal administration of recombinant human erythropoietin in children on continuous ambulatory peritoneal dialysis.

In 16 children treated by continuous ambulatory peritoneal dialysis (CAPD) recombinant human erythropoietin was administered intraperitoneally for the treatment of renal anaemia. The mean treatment period was 8.3 months. Mean haemoglobin values increased from 4.9 mmol/l at start of therapy to 6.2 after 6 months. While 11 out of 16 children needed a total of 22 transfusions during the 6 months prior to therapy, no transfusions were needed after initiation of therapy. Patients started with a dose of 300 units/kg per week. After 6 months of therapy, the mean dose was 370 and after 12 months 279 units/kg per week. No major side-effects were observed. The incidence of peritonitis was not increased. We conclude that intraperitoneal administration of erythropoietin is effective in the treatment of renal anaemia in children treated by CAPD.

Dural sinus thrombosis in children with cancer.

Dural sinus thrombosis (DST) has been reported in association with cancer in both adults and children. We describe the seven patients seen with this complication in our centre between 1981 and 1995. Diagnosis was confirmed by either cerebral CT scanning, MRI or angiography. Median age was 13 years (range 8-15). Six patients were boys. Six children were being treated for non-Hodgkin lymphoma and one for neuroblastoma. Presenting symptoms were seizures and transient neurologic deficit, often preceded by headaches. The probable cause of DST was found in two cases. Tumour localisation in the central nervous system (CNS) probably caused DST in one patient who was treated for ki 1 lymphoma. Dehydration in combination with a poor general condition seemed to be the cause of DST in the patient with neuroblastoma. In five children with stage III or IV non-Hodgkin lymphoma (three lymphoblastic lymphoma; two Burkitt's lymphoma), etiology remained unknown. In these children, DST occurred early in the course of therapy. The median interval between start of chemotherapy and onset of symptoms was 19 days (range 8-40). No child had received L-asparaginase. Prognosis was favourable, with symptoms completely disappearing without therapy within 1 to 5 days. The incidence of DST in patients with advanced stage non-Hodgkin lymphoma during induction and consolidation was calculated to be below 3%. We conclude that DST is rarely diagnosed in children with cancer. Occurrence during the initial phase of therapy for non-Hodgkin lymphoma is associated with a benign prognosis.

Pharmacokinetics of recombinant human erythropoietin in children treated with continuous ambulatory peritoneal dialysis.

UNLABELLED: In children treated by continuous ambulatory peritoneal dialysis (CAPD) renal anaemia is preferably treated by intraperitoneal administration of erythropoietin, since subcutaneous administration is painful and frightening for the child. Pharmacokinetics of erythropoietin were studied in three groups of children treated by CAPD. In group subcutaneous (SC) (n = 5) erythropoietin was administered subcutaneously, whereas in group intraperitoneal 1 (IP1) (n = 8) and intraperitoneal 2 (IP2) (n = 8) erythropoietin was given intraperitoneally during a 12-h dwell. Group IP1 received erythropoietin in 20 ml/kg of dialysis fluid, while in group IP2 the hormone was added to only 50 ml of dialysate, irrespective of body weight. The median area under the curve (AUC) was 4064 mU.h/ml (range 2647-24357) in group SC, 1698 (570-5514) in group IP1 and 3577 (1225-6555) in group IP2. In comparison to group SC the AUC was significantly lower in group IP1 (Wilcoxon: P = 0.02). The difference between group SC and group IP2 was not statistically significant. CONCLUSION: In children on CAPD the resorption of erythropoietin after intraperitoneal administration, measured as AUC, is similar to subcutaneous administration, when erythropoietin is administered in 50 ml of dialysate. The dose needed to treat renal anaemia with erythropoietin administered intraperitoneally this way will have to be established in a therapeutic study.

Transcapillary ultrafiltration and lymphatic absorption during childhood continuous ambulatory peritoneal dialysis.

Peritoneal fluid handling depends on a balance between transcapillary ultrafiltration and lymphatic absorption. Lymphatic absorption is reported to be greater in children than in adult continuous ambulatory peritoneal dialysis (CAPD) patients. The present study provides data on peritoneal fluid kinetics in a group of 17 young children (0.4-13 years of age). Net transcapillary ultrafiltration and lymphatic absorption were not dependent on age or duration of treatment. No differences were established from normal values for adult patients reported in the literature.

Peritoneal protein loss in children with nephrotic syndrome during peritoneal dialysis.

BACKGROUND: The passage of proteins across the glomerular filtration barrier is mainly determined by the size of the protein. In nephrotic syndrome (NS) the glomerular permselectivity is affected, causing proteinuria. Some authors suggest the existence of a generalized basement membrane defect. The permeability characteristics of the peritoneal basement membrane in children with NS are not known. METHODS: The transperitoneal transport of proteins with a different molecular weight (beta2-microglobulin MW 11800 D, albumin MW 69000 D, IgG MW 160000 D, and alpha2-macroglobulin MW 820000 D) was studied in a study group (group A) consisting of six stable nephrotic children (three with glomerulosclerosis and three with congenital nephrotic syndrome, one of them with mesangial sclerosis) and compared to a control group (group B) consisting of eight stable children on peritoneal dialysis. After a dwell of 6 h with Dianeal 1.36% dialysate and serum samples were collected. For each patient the dialysate to plasma (D/P) ratios of the four proteins were calculated. The D/P ratios of the nephrotic patients in group A were compared to the D/P ratios of the patients in the control group B. Data were expressed as mean +/- SD. RESULTS: The values for the D/P ratios (in percentage) of beta2-microglobulin, albumin, IgG and alpha2-macroglobulin in group A were 19.6+/-9.9, 2.7+/-1.7, 1.6+/-0.9, and 0.5+/-0.4, compared to 24.9+/-10.2, 4.0+/-2.3, 2.2 +/- 1.2, and 0.7 +/- 0.3 in the control group B. The ratios were plotted against MW on a double logarithmic scale. In all patients a linear relationship between molecular weight and D/P ratio of the proteins was obtained. The D/P ratios of the study group did not differ significantly from the control group. CONCLUSION: We conclude that the size selectivity of the capillary permeability is not affected in the peritoneal membrane in children with NS due to glomerulosclerosis and congenital nephrotic syndrome.

Intraperitoneal hypercoagulation and hypofibrinolysis is present in childhood peritonitis.

An increased rate of obstruction of peritoneal dialysis catheters is observed during peritonitis. Hypercoagulation and hypofibrinolysis may explain this increased occurrence. We studied plasminogen activator inhibitor type 1 antigen (PAI-1), tissue-type plasminogen activator antigen (t-PA), D-dimer (DD), plasmin-alpha2-antiplasmin complexes (PAP), and thrombin-antithrombin III complexes (TAT) in 7 children with peritonitis (group A) and 12 children during stable peritoneal dialysis (group B). Albumin, beta2-microglobulin, IgG, and alpha2-macroglobulin were measured for baseline transperitoneal protein transport. After a dwell of 6 h with 1.36% Dianeal, dialysate and serum samples were collected. Dialysate to plasma ratios of all proteins were calculated. During peritonitis (group A) TAT was higher: 34.7 versus 22.0 (P=0.01). PAI-1 was increased in group A: 76.5 versus 22.9 (P=0.004). PAP was decreased during peritonitis (group A): 24.9 versus 39.3 (P=0.01). In group A, DD were decreased. 10.8 versus 26.7 (P=0.002). t-PA was similar in both groups (23.7 in group A vs. 27.7 in group B; P=0.26). In both groups TAT, PAI-1, t-PA, PAP, and DD were significantly higher than in baseline transperitoneal transport, suggesting intraperitoneal production. Hypercoagulability and hypofibrinolysis were present during peritonitis compared with the control situation.

Measurement of peritoneal fluid handling in children on continuous ambulatory peritoneal dialysis using dextran 70.

Fluid kinetics were studied in children treated with continuous ambulatory peritoneal dialysis (CAPD) aged between 2 and 15 years. Dextran 70 was used as a volume marker. A 4-h dwell was studied with a dwell volume of 40 mg/kg. Transcapillary ultrafiltration was measured as well as marker clearance, which is the best available approximation of lymphatic absorption in the clinical setting. In 11 children in whom dialysate was used containing 1.36% glucose transcapillary ultrafiltration was 250 +/- 79 ml/4 h/1.73 m2 and marker clearance 236 +/- 101 ml/4 h/1.73 m2. In 13 children dialysed with 3.86% glucose, transcapillary ultrafiltration was 829 +/- 226 ml/4 h/1.73 m2 and marker clearance 307 +/- 176 ml/4 h/1.73 m2. These values are similar to those found in adult patients. There was a positive correlation between age and transcapillary ultrafiltration in the group receiving dialysate containing 3.86% glucose (r = 0.69, P = 0.009). There was no correlation between age and marker clearance. It is concluded that fluid kinetics in children and adults on CAPD are similar when corrected for body surface area. In young children transcapillary ultrafiltration is lower, probably because dwell volume is low in relation to peritoneal surface area in these children.

Effect of electric charge on the transperitoneal transport of plasma proteins during CAPD.

BACKGROUND: Controversy exists as to whether electric charges of plasma proteins influence their transport across the peritoneal membrane during CAPD. Fixed negative charges in the peritoneal membrane are diminished during peritonitis in rats. METHODS: Peritoneal clearances of 10 proteins and their isoforms were used to establish the relationship between peritoneal clearance and molecular weight. The observed protein clearances were compared with the predicted clearances based on molecular weight. Clearances of proteins with different charge but identical size were compared. Stable patients and peritonitis patients were compared. Results. Only the peritoneal clearance of lipase, LDH 4/5 and IgG3 were significantly different from the predicted values (P<=0.05). The peritoneal clearance of slightly anionic beta2 microglobulin (1072 microl/min) and cationic lysozyme (572 microl/min) showed no evidence for charge selectivity; neither did the peritoneal clearance of slightly anionic transferrin (86 microl/min) and highly anionic albumin (99 microl/min). The peritoneal clearance of IgG1, IgG2 and IgG4 were identical (32, 31 and 31 microl/min), despite their different charge. The peritoneal clearance of cationic LDH 4/5 was 137 microl/min and higher than the peritoneal clearance of neutral LDH 3 (97 microl/min, P=0.01) and LDH 1 (59 microl/min, P=0. 02). These results suggested charge selectivity; however in five additional patients during peritonitis the peritoneal clearance of LDH 4/5 increased to 10 times the peritoneal clearance of LDH 1. Local LDH isoenzyme release from the cells present in the dialysate was shown to be responsible in stable and peritonitis patients. Likewise, the higher peritoneal clearance of neutral pancreatic amylase (234 microl/min) compared to anionic salivary amylase (142 microl/min, P=0.03) could probably be attributed to local release of the former from the pancreas, as the peritoneal clearance of lipase (highly anionic) was higher than predicted and the difference remained during peritonitis. CONCLUSIONS: The peritoneal membrane constitutes a size- but probably not a charge-selective barrier for the transport of macromolecules between blood and dialysate during stable CAPD.

Differential patterns of insulin-like growth factor-I and -II mRNA expression in medulloblastoma.

Insulin-like growth factors (IGFs) play an important role in tumour growth and development. We hypothesized that this is also the case for medulloblastomas, which are highly malignant cerebellar brain tumours usually occurring in children. In these tumours the expression patterns of IGF-I and -II mRNA were studied. Tumour specimens obtained from 12 children and two adults at diagnosis were hybridized in situ with digoxigenin-labelled cRNA probes for hIGF-I and hIGF-II mRNAs. In all cases, tumour cells showed abundant expression of IGF-I mRNA. Nine of the 14 tumours showed variable but significant IGF-II expression. In these tumours, the hybridization signal almost exclusively colocalized with a subpopulation of Ki-M1P positive cells that were identified as ramified microglia (RM) cells. In the five tumours without IGF-II expression, microglia/brain macrophages with a more rounded amoeboid-like morphology predominated. RM cells in normal cerebellar tissues, residing abundantly in areas of the white and, to a less extent, in the grey matter, were IGF-II mRNA-negative. These RM cells showed a thinner and more extensively branched appearance and were more evenly distributed than those encountered in medulloblastoma. Probably, during the transformation from the resting ramified towards the amoeboid morphology (or vice versa) IGF-II mRNA expression is only temporarily induced. The physiological meaning of the induction of IGF-II mRNA expression by these cells in medulloblastoma remains unclear but any IGF-II peptide synthesized could exert unfavourable mitogenic and antiapoptotic effects on adjacent tumour cells. However, in this relatively small number of cases we could not find any indications for a relationship between clinical characteristics of the various cases and the extent of IGF-II mRNA expression.