Treatment of high risk medulloblastomas in children above the age of 3 years: a SFOP study.

AIM: Improvement of EFS of children older than 3 years with high risk medulloblastoma. METHODS: Between 1993 and 1999, 115 patients (3-18 years, mean 8 years) with high risk medulloblastoma were included. After surgery treatment consisted of chemotherapy ('8in1' and etoposide/carboplatin) before and after craniospinal radiotherapy. RESULTS: Patients were staged using Chang-criteria (PF residue only, M1 and M2/M3) by local investigator as well as by central review panel (82.4% concordance). Chemotherapy was well tolerated without major delays in radiotherapy. With a mean follow up of 81 months (9-119), 5-year EFS was 49.8% and OS 60.1%. In detail according to subgroups EFS was 68.8% for PF residue only, 58.8% for M1 disease and 43.1% for M2/M3. CONCLUSION: M1 patients are legitimate high risk patients. Survival rates are still very low for high risk medulloblastoma patients and future trials should therefore focus on more intensive (chemotherapy/radiotherapy) treatment.

Standard-risk medulloblastoma treated by adjuvant chemotherapy followed by reduced-dose craniospinal radiation therapy: a French Society of Pediatric Oncology Study.

OBJECTIVE: The primary objective of this study was to decrease the late effects of prophylactic radiation without reducing survival in standard-risk childhood medulloblastoma. PATIENTS AND METHODS: Inclusion criteria were as follows: children between the ages of 3 and 18 years with total or subtotal tumor resection, no metastasis, and negative postoperative lumbar puncture CSF cytology. Two courses of eight drugs in 1 day followed by two courses of etoposide plus carboplatin (500 and 800 mg/m(2) per course, respectively) were administered after surgery. Radiation therapy had to begin 90 days after surgery. Delivered doses were 55 Gy to the posterior fossa and 25 Gy to the brain and spinal canal. RESULTS: Between November 1991 and June 1998, 136 patients (median age, 8 years; median follow-up, 6.5 years) were included. The overall survival rate and 5-year recurrence-free survival rate were 73.8% +/- 7.6% and 64.8% +/- 8.1%, respectively. Radiologic review showed that 4% of patients were wrongly included. Review of radiotherapy technical files demonstrated a correlation between the presence of a major protocol deviation and treatment failure. The 5-year recurrence-free survival rate of patients included in this study with all optimal quality controls of histology, radiology, and radiotherapy was 71.8% +/- 10.5%. In terms of sequelae, 31% of patients required growth hormone replacement therapy and 25% required special schooling. CONCLUSION: Reduced-dose craniospinal radiation therapy can be proposed in standard-risk medulloblastoma provided staging and radiation therapy are performed under optimal conditions.

Hydroxyurea treatment for sickle cell disease: impact on haematopoietic stem cell transplantation's outcome.

Since 1988, 24 children have undergone haematopoietic stem cell transplantation (HSCT) for severe sickle cell disease (SCD) in our unit, 13 being grafted after having been exposed to hydroxyurea (HU) to control SCD-related complications. Different pre-transplant conditioning regimens were given over time: Bu14/Cy200 in six patients (group 1), Bu16/Cy200/antithymocyte globulin (ATG) in five (group 2) and Bu16/Cy200/ATG with HU prior to HSCT in 13 (group 3). The aim of this study is to compare the outcome after HSCT of these groups of patients, which differ according to pre-transplant drug exposure. Overall, 20 of the 24 transplanted children had stable engraftment and have remained free of SCD-related symptoms after HSCT; 19 of them are currently alive and cured of SCD. In group 1 (HU-, ATG-), we observed one unexplainable late death, one absent engraftment, one late rejection and one mixed stable chimerism. In group 2 (HU-, ATG+), we observed the absence of engraftment in two patients and one early rejection. In group 3 (HU+, ATG+), we observed no cases of either absent engraftment, mixed stable chimerism or late rejection. In our experience, pre-transplant treatment with HU seems to be associated with a lower incidence of rejection/absent engraftment in severe SCD patients. These results need to be confirmed with a larger number of patients.

Carboplatin before and during radiation therapy for the treatment of malignant brain stem tumours: a study by the Société Française d'Oncologie Pédiatrique.

Childhood malignant brain stem tumours have a very poor prognosis with a median survival of 9 months despite radiotherapy. No chemotherapy has improved survival. However, carboplatin has been reported to have activity in glial tumours as well as antitumour synergy with radiation. Our aims were to test the response rate of these tumours to carboplatin alone and to evaluate the efficacy on survival of carboplatin alone followed by concurrent carboplatin and radiotherapy. Patients younger than 16 years with typical clinical and radiological presentation of infiltrating brain stem tumour, as well as histologically-documented cases in the atypical forms, were eligible. Two courses of carboplatin (1050 mg/m2 over 3 days) were administered initially. This treatment was followed by a chemoradiotherapy phase including five weekly carboplatin courses (200 mg/m2) and conventional radiotherapy. 38 eligible patients were included. No tumour response was observed after the initial phase. This schedule of first-line carboplatin followed by concurrent carboplatin and radiotherapy did not improve survival.

Five years of experience with hydroxyurea in children and young adults with sickle cell disease.

The short-term beneficial effect of hydroxyurea (HU) in sickle cell disease (SCD) has been proven by randomized studies in children and adults. The Belgian registry of HU-treated SCD patients was created to evaluate its long-term efficacy and toxicity. The median follow-up of the 93 patients registered is 3.5 years; clinical and laboratory data have been obtained for 82 patients at 1 year, 61 at 2 years, 44 at 3 years, 33 at 4 years, and 22 after 5 years. On HU, the number of hospitalizations and days hospitalized dropped significantly. Analysis of the 22 patients with a minimum of 5 years of follow-up confirm a significant difference in the number of hospitalizations (P =.0002) and days in the hospital (P <.01), throughout the treatment when compared to prior to HU therapy. The probabilities of not experiencing any event or any vaso-occlusive crisis requiring hospitalization during the 5 years of treatment were, respectively, 47% and 55%. On HU, the rate per 100 patient-years of severe events was estimated to be 3.5% for acute chest syndrome, 1.2% for aplastic crisis, 0.4% for splenic sequestration; it was 0% for the 9 patients with a history of stroke or transient ischemic attack followed for an average of 4 years. No important adverse effect occurred. Long-term chronic treatment with HU for patients with SCD appears feasible, effective, and devoid of any major toxicity; in patients with a history of stroke, HU may be a valid alternative to chronic transfusion support. (Blood. 2001;97:3628-3632)

Characterization of functional VIP/PACAP receptors in the human erythroleukemic HEL cell line.

The presence of VIP/PACAP receptors was investigated on the human erythroleukemic cell line HEL. Specific binding of [125I]-PACAP or [125I]-VIP on HEL cells or membranes was very low and did not allow to perform competition curves. At 37 degrees C PACAP transiently increased cAMP levels in the presence of the non-specific phosphodiesterase inhibitor IBMX, suggesting rapid desensitization. Kinetic studies revealed that optimal conditions to measure the EC(50) of PACAP(1-27) were 10 min at 20 degrees C. Under those conditions, PACAP-related peptides increased cAMP levels with EC(50) in agreement with the pharmacological profile of the VPAC(1) receptor subtype: PACAP = VIP > [K(15), R(16,) L(27)]VIP(1-7)/GRF(8-27) = [R(16)]ChSn (two VPAC(1) agonists) >> helodermin = secretin. RO 25-1553, a selective activator of VPAC(2) receptor was inactive at 1 microM. Dose-response curves of VPAC(1) agonist molecules (PACAP, VIP, [K(15), R(16), L(27)]VIP(1-7)/GRF(8-27), [R(16)]ChSn) were shifted to the right by the VPAC(1) receptor antagonist [AcHis(1), D-Phe(2), Lys(15), Leu(17)]VIP(3-7)/GRF(8-27), with a K(i) of 3 +/- 1 nM (n = 3). The presence of VPAC(1) receptor mRNA was confirmed by RT-PCR. Preincubation with PACAP or PMA showed that VPAC(1) receptors underwent homologous and heterologous desensitization. This study provides the first evidence for the expression of functional VPAC(1) receptors undergoing rapid desensitization in HEL cells.

Defective functional activity and accelerated apoptosis in neutrophils from children with cancer are differentially corrected by granulocyte and granulocyte-macrophage colony stimulating factors in vitro.

We have previously shown that polymorphonuclear leucocytes (PMN) harvested from children with cancer and exposed to chemotherapy exhibit defective bactericidal activities against both Gram-positive and Gram-negative microorganisms as well as accelerated apoptosis. In this study, PMN from children with cancer were evaluated to compare in vitro the corrective effects of the two myeloid colony stimulating factors G-CSF and GM-CSF on these defective pathways. Both G-CSF and GM-CSF were able to increase the defective bactericidal activities against S. aureus and E. coli. However, GM-CSF was consistently superior to G-CSF in correcting PMN microbicidal activity; this correction was incomplete since it did not reach the level observed in normal PMN exposed to GM-CSF. The accelerated apoptosis of PMN was not affected by G-CSF. In contrast, GM-CSF significantly prolonged the survival of the PMN although it did not reach the level of survival observed with normal PMN exposed to GM-CSF. These observations were consistent with other studies indicating that in PMN, microbicidal activities and apoptosis are differentially sensitive to the myeloid growth factors G-CSF and GM-CSF.

Cross-cultural adaptation of a health status classification system in children with cancer. First results of the French adaptation of the Health Utilities Index Marks 2 and 3.

Our objective was to adapt and validate the Health Utilities Index Mark 2 (HUI 2) and HUI 3 health status classification systems self-report questionnaire in a population of children with cancer, a group of 42 children already included in a multi-centre database designed by the Group on Brain Tumors in Children of the French Society for Pediatric Oncology. Children were recruited during a routine consultation. Most of them had completed treatment. The version of the questionnaire for French adults was adapted linguistically for children. Open-ended queries by children about the comprehensiveness of the questions and very low non-response rates showed a good acceptability of the questionnaire. The main psychometric properties of the HUI 2 and HUI 3 classification systems were assessed in 3 groups of raters (child, parent, physician): construct validity was tested against the rating of the child's health state on a Likert scale and through comparison with clinical data, and internal consistency was determined through multi-trait analysis. Weighted and unweighted kappa values were used to measure the inter-rater agreement between the child's, parent's and physician's assessment of the child's health state. The convergent validity was satisfactory, with better results when the physician's assessment was used. The most affected attributes were the expected ones (i.e., cognition, pain and emotion). Disagreement was observed between the 3 raters, more often in the same direction: taking the child's assessment as the reference, the parents tended to under-estimate the health status while physicians tended to over-estimate it.

Alveolar soft-part sarcoma: further evidence by FISH for the involvement of chromosome band 17q25.

A cytogenetic study of an alveolar soft-part sarcoma, a rare tumor of probably myogenic origin, demonstrated a t(X;17)(p11;q25) as the sole chromosomal abnormality. Dual- and triple-color fluorescence in situ hybridization, performed on metaphase and interphase cells, confirmed the translocation between chromosomes X and 17 and demonstrated that this translocation resulted in loss of 17q25. Involvement of 17q25 has been described in four previously published cases of alveolar soft-part sarcoma, but without further characterization. Compared to our karyotype, it seems that the derivative chromosome 17 observed in the reported cases could also be the result of a t(X;17) with possible loss of the 17q25 band. If so, a 17q25 deletion and/or chromosome rearrangement between Xp and 17q leading either to a gene fusion or gene disruption could play an important role in the pathogenesis of alveolar soft-part sarcoma.

Prolonged but reversible neutrophil dysfunctions differentially sensitive to granulocyte colony-stimulating factor in children with acute lymphoblastic leukaemia.

Treatment of average-risk acute lymphoblastic leukaemia (ALL) in children consists of 6 months of intensive chemotherapy followed by 18 months of maintenance therapy. Polymorphonuclear leucocyte (PMN) functions from children with ALL were studied in order to evaluate and compare the toxicity of the initial intensive treatment with the toxicity of the subsequent less intensive maintenance treatment. H2O2 and O2- production, evaluated by chemiluminescence, were significantly decreased during the intensive period but returned to normal values when maintenance therapy began. In contrast, bactericidal activity against Gram-positive and Gram-negative microorganisms remained at low levels throughout the treatment but returned to normal values in patients off chemotherapy. PMN from patients on maintenance therapy exhibited an excess of morphological changes associated with apoptosis. This was confirmed by standard two-colour flow cytometry which revealed an increase in the number of hypodiploid cells, and increased expression of membrane phosphatidylserine together with a drastic reduction in the expression of the Fcgamma receptor IIIB (CD16). These defective PMN were differentially sensitive to the effects of granulocyte colony stimulating factor (G-CSF): G-CSF induced similar increase in chemiluminescence in control and patient PMN; GSF partially corrected the defective bactericidal activity; G-CSF did not affect the accelerated PMN apoptosis. These observations indicate that ALL children undergoing chemotherapy present PMN defective functions which are partially sensitive or even resistant to G-CSF.

Anemia in children with cancer is associated with decreased erythropoietic activity and not with inadequate erythropoietin production.

A defect in erythropoietin (EPO) production has been advocated as being the main cause of anemia presented at time of diagnosis or during treatment by adults with solid tumors. On the basis of this defect, anemic cancer patients, both adults and children, have been treated with recombinant human EPO (rHuEPO). To further elucidate the pathophysiology of anemia in children with cancer, we measured serum soluble transferrin receptor (sTfR), a quantitative marker of erythropoiesis, and serum EPO at time of diagnosis and during chemotherapy in children suffering from solid tumor or leukemia. We determined serum EPO in 111 children (55 leukemia, 56 solid tumors) at time of diagnosis. In the last 44 patients (23 leukemia and 21 solid tumors), sTfR levels were also measured. Serum EPO together with sTfR levels were also determined in 60 children receiving chemotherapy (29 leukemia, 31 solid tumors). These results were compared with those obtained from appropriate control groups. In all patients, we found a highly significant correlation between the logarithm of EPO (log[EPO]) and the hemoglobin (Hb) level. In all subsets of patients, sTfR levels were inappropriately low for the degree of anemia. Neither leukemic nor solid tumor groups showed a significant inverse relationship between log(sTfR) and the Hb level as would be expected in anemic patients with appropriate marrow response. Thus, in children with cancer, anemia is associated with a decreased total bone marrow erythropoietic activity which, in contrast to what has been reported in anemic cancer adults, is not related to defective EPO production.

Haematopoietic stem cell transplantation for sickle cell anaemia: the first 50 patients transplanted in Belgium.

Fifty patients affected by sickle cell anaemia underwent transplantation of HLA-identical haematopoietic stem cells (bone marrow, 48; cord blood, 2). Two groups of patients were considered for transplantation. Group 1 included 36 permanent residents of a European country who, retrospectively, met the inclusion criteria accepted at a consensus conference held in Seattle in 1990, wherein children were selected because they already had evidence of a morbid course. Group 2 included 14 patients who were transplanted earlier, had not received more than three blood transfusions and were transplanted because they had decided to return to their country of origin. Kaplan-Meier estimates of overall survival, event-free survival and disease-free survival at 11 years of the whole grafted population are 93, 82 and 85%, respectively. In group 1, overall survival, EFS and DFS were 88, 76 and 80% and in group 2, 100, 93 and 93%, respectively. Clinical manifestations of the disease, as well as disease associated haemolytic anaemia, disappeared in all successfully treated patients. Recovery of spleen function was present in seven out of 10 evaluated patients. Adverse events (death, absence of engraftment, mixed chimerism and relapse) occurred more frequently in group 1 than in group 2 (25% vs 7%, P< 0.001). Acute graft-versus-host disease (GVHD) was present in 20 patients (grade I or II, 19; grade III, 1), chronic GVHD in 10 (limited, 7; extensive, 3). One patient developed an acute myeloid leukaemia. Gonadal dysfunction was present in all patients (six boys and eight girls) transplanted close to or after puberty, although transient in one adolescent girl.

Improving survival in recurrent medulloblastoma: earlier detection, better treatment or still an impasse?

Early detection of relapse has been advocated to improve survival in children with recurrent medulloblastoma. However, the prognostic factors and the longer term outcome of these patients remains unclear. Pattern of recurrences were analysed in three consecutive protocols of the Société Française d'Oncologie Pédiatrique (1985-91). A uniform surveillance programme including repeated lumbar puncture combined with computerized tomography (CT) or magnetic resonance imaging (MRI) scan was applied for all registered patients. Forty-six out of 116 patients had progressive or recurrent disease. The median time from diagnosis to recurrence was 10.5 months and 76% relapses occurred during the first 2 years. Seventeen patients had asymptomatic relapses that were detected by the surveillance protocol. Forty-one patients were treated at time of progression. Twenty-three responded to salvage therapy and 11 achieved a second complete remission. The median survival time after progression was 5 months (<1-41 months), and only two patients remained alive at time of follow-up. Length of survival is primarily related to some specific patterns of relapse (time from diagnosis to recurrence, circumstances of relapse, extent of relapse) and to the response to salvage therapy. No evidence of long-term benefit appeared from any form of treatment.

An attempt to treat pediatric intracranial alphaFP and betaHCG secreting germ cell tumors with chemotherapy alone. SFOP experience with 18 cases. Société Française d'Oncologie Pédiatrique.

PURPOSE: Intracranial alphaFP and betaHCG secreting germ cell tumors have a very poor prognosis with local treatment alone. Because of efficacy of chemotherapy in extracranial forms, we tried in the SFOP (Société Française d'Oncologie Pédiatrique) to treat them with chemotherapeutic treatment exclusively. PATIENTS AND METHODS: Eighteen patients (10 alphaFP, 2 betaHCG, 6 alphaFP and betaHCG secretion) were enrolled from January 1988 to December 1992. After biological diagnosis patients were to receive 6 cycles of chemotherapy (vinblastine bleomycin - carboplatin or etoposide - carboplatin/ifosfamide - etoposide). After completion of chemotherapy, surgery was to be performed in case of residual tumor. Focal radiation was only to be delivered in case of viable residual tumor. RESULTS: All patients had biological remission and tumor reduction. Fifteen patients were treated according to the protocol by chemotherapy alone (13) or chemotherapy and radiation of residue (2). Twelve of the 13 non irradiated patients relapsed, 8 in local and/or regional area, 3 in cerebrospinal area and 1 in undeterminated area with mild elevation of markers except in one case. Six patients are alive in second complete remission after chemotherapy and/or surgery and then a consolidation treatment with radiation and/or high dose chemotherapy (5) or craniospinal radiation (1). Three patients received radiation after 2 or 3 cycles of chemotherapy as protocol violations and didn't relapse. Thus, 12 patients out of the 18 patients are alive with a median follow up of 68 months. All but 1 had focal radiation as part of treatment. No toxic death was observed. CONCLUSION: Although survival rate is noteworthy (66%), these tumors were not curable with this conventional chemotherapy alone and focal radiotherapy should be part of the treatment.

Comparison between vasoactive intestinal polypeptide and pituitary adenylate cyclase activating polypeptide levels in neuroblastoma tumour tissues.

Vasoactive intestinal polypeptide (VIP) is reported to exert an autocrine control on neuroblastoma cell tumours: VIP is produced by the tumour and stimulates cell differentiation. This study tested the hypothesis that the parent peptide; the pituitary adenylate cyclase activating polypeptide (PACAP) may have a similar role. It was found that PACAP mRNA and PACAP were expressed in 12/12 tumours; it was also observed that PACAP receptor mRNA and functional PACAP receptors were expressed in 12/12 and 5/9 tumours, respectively. VIP mRNA and VIP were detected in 9/12 tumours. VIP receptor mRNA was expressed in 5/12 tumours and functional VIP receptors were never demonstrated. The tumours having the highest VIP levels also had the highest PACAP contents and were associated with a watery diarrhoea syndrome due to activation of intestinal VIP receptors. As PACAP recognizes the PACAP receptors and the VIP receptors with the same high affinity it may contribute to the syndrome and is a likely candidate for an autocrine control of neuroblastoma cell growth and differentiation.

Ifosfamide and etoposide in childhood osteosarcoma. A phase II study of the French Society of Paediatric Oncology.

The aim of this phase II study was to determine the efficacy of high-dose ifosfamide with moderate dose etoposide in childhood osteosarcoma. From January 1992 to January 1995, 27 children (15 male, 12 female) with relapsed or refractory evaluable osteosarcoma were included in a phase II study of two courses of ifosfamide 3g/m2/day and etoposide 75 mg/m2/day for 4 days. Median age was 14 years (7-19 years). All but one had received high-dose methotrexate and doxorubicin as first-line treatment. 22 patients had previously received ifosfamide. This regimen was given as first-line in 1 patient, second-line in 23 and third-line in 3. Evaluable disease was lung metastases in 21 patients, local relapse in 5 and adenopathy in 1. There were six complete responses, seven partial responses, three minor responses, six stable disease and five progressive disease (including one mixed response). Response rate was 48% (95% confidence interval, 29-67%). Duration of response was not available (10 responding patients had other treatments). Response rate was equivalent in the subgroup of 22 patients who had previously received ifosfamide (4 CR, 6 PR). Among 3 patients who received the phase II regimen as third-line chemotherapy, there was 1 PR. All but 4 patients had a well tolerated grade 4 neutropenia. Transient mild confusion or seizures were each observed once. 5 patients are alive 15-31 months after the beginning of chemotherapy. This combination of drugs at this dosage has tolerable toxicity, is efficient and deserves evaluation in phase III studies.

Defective polymorphonuclear leukocyte functions in children receiving chemotherapy for cancer are partially restored by recombinant human granulocyte colony-stimulating factor in vitro.

Granulocyte colony-stimulating factor (G-CSF) has important direct and priming effects on different functions of normal mature polymorphonuclear leukocytes (PMNL). Previous study has shown an alteration in respiratory burst and bactericidal activities of PMNL harvested from children with cancer treated with chemotherapy. The present study evaluates the possibility that recombinant human (rh) G-CSF could correct these defective functions in vitro. Free radical formation in defective PMNL was enhanced by rhG-CSF to a level similar to that found in normal PMNL primed by rhG-CSF. The defective bactericidal activity against Escherichia coli and Staphylococcus aureus was also corrected. This bactericidal activity was not different from that observed in normal PMNL primed by rhG-CSF. In conclusion, correction of the altered free radical-formation pathway by rhG-CSF in these cells contributed to the restoration of normal bactericidal activity against both gram-positive and gram-negative microorganisms.

Hydroxyurea for treatment of severe sickle cell anemia: a pediatric clinical trial.

Hydroxyurea (HU) enhances the synthesis of fetal hemoglobin (HbF) and can improve the clinical course of some adult patients with sickle cell anemia (SCA). In a randomized trial, we studied the biologic effects and the clinical benefit of HU in children and young adults with severe SCA. Twenty-five patients (median age, 9 years) were randomized to receive either HU (at the initial dosage of 20 mg/kg/d) or a placebo for 6 months and were then switched to the other arm for the next 6 months. Among the 22 evaluable patients (median age, 8 years), significant increases in HbF and mean corpuscular volume occurred during the HU treatment period. The white blood cell and reticulocytes counts decreased significantly, but these changes were not clinically relevant. Sixteen of 22 patients (73%) experienced a complete disappearance of events requiring hospitalization. The number of days of hospitalization as well as the number of hospitalizations for patients on HU, as compared with those for the patients receiving placebo, were significantly reduced. We conclude that treatment with HU in children and young adults is feasible, well-tolerated, and improves the clinical course of SCA. The long-term effects of HU require further investigation.