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Background: One fourth of infants with disseminated neuroblastoma experience unfavorable outcome. Treatment strategies vary and are based on clinical characteristics at diagnosis which lead to the definition of stage 4 or 4s. To identify the distribution and effect of different prognostic factors, a series of such infants diagnosed in Italy between 1991-1999 was reviewed., Material/methods: Data were retrospectively retrieved from the Italian Neuroblastoma Registry. One hundred infants, 32 stage 4 and 68 stage 4s, were eligible. Clinical and biological characteristics evaluated at diagnosis for their impact on survival were demographics, primary site, urinary excretion of vanillylmandelic and homovanillic acids, serum neuron specific enolase, LDH, and ferritin together with analysis for MYCN gene, DNA index, and 1p36 chromosome., Results: Stage 4 prevailed in the second six months of life and stage 4s in the first six months. Events were distributed over two years in stage 4, but occurred very early in stage 4s patients. Survival was respectively 72% and 77.9%. Unfavorable factors were MYCN amplification for both stages, elevated NSE and LDH and normal VMA for stage 4, and di-tetraploid DNA for stage 4s., Conclusions: The frequency of stage 4s was greater than stage 4. MYCN amplification was the most unfavorable prognostic factor. Survival was similar to previous series, confirming that a part of such infants cannot be cured by current therapies.

Background: Neurotoxicity has been reported in about 5% of children treated with ifosfamide for tumors not involving the central nervous system. The entity of ifosfamide neurotoxicity can be of different degree, from very light and transient to fatal., Case Reports: All cases of ifosfamide neurotoxicity recorded at the Pediatric Hematology and Oncology Unit in the 15-year period between 1989 and 2003 are reported. Five cases of neurotoxicity occurring during or immediately after ifosfamide infusion were recorded in children with both solid tumors or leukemia. The drug was administered in different chemotherapeutic associations and dosages. Concomitant clinical conditions possibly playing a role as risk factors were the administration of other neurotoxic drugs, the presence of cerebral metastasis, a subclinical lysis syndrome, and altered respiratory function. Symptoms were transient in all cases and consisted in all but one of partial or generalized seizures. In four cases the treatment was continued, substituting ifosfamide with cyclophosphamide., Conclusions: Particularly in patients presenting risk factors, we advise paying attention to the risk of ifosfamide neurotoxicity and rapidly suspending the drug administration to avoid irreparable damage to the central nervous system. Thereafter the treatment can be reassessed. If ifosfamide is considered the best option for the given case, it could be safely readministered in association with methylene blue or thiamine. If encephalopathy reappears, substitution of ifosfamide with cyclophosphamide could offer the same opportunities of cure to the patient.

Background: Neuroblastoma (NB) occurs rarely during adolescence, and information is scarce on its characteristics and clinical course in this age group., Methods: Patients with NB who were included in the Italian Neuroblastoma Registry were considered for the current study. The clinical characteristics and survival of adolescents (age at diagnosis between 10 yrs and 18 yrs) were compared with those of children (ages 1-9 yrs). Infants (age < 1 yr) were excluded because of their well known favorable clinical course., Results: Between 1116 children and 53 adolescents who were evaluated, no differences were documented with regard to the primary tumor site and the prevalence of advanced stage at diagnosis. If only patients with Stage IV NB were considered, then adolescents were less likely to be diagnosed with bone/bone marrow metastases (77%) compared with children (94%; P = 0.038), but adolescents were more likely to have metastases at unusual sites, such as the lung parenchyma or the central nervous system (23% vs. 7%, respectively; P = 0.005). With regard to biologic characteristics, adolescents did not differ significantly from children, although they always had a lower prevalence of unfavorable markers. In particular, MYCN amplification was documented in 21% of children and in 11% of adolescents (P = 0.173). At age 10 years, adolescents had a 20% overall survival rate and a 22% event-free survival rate. Adolescents who had resectable disease had a 73% overall survival rate, which was worse compared with the rate among children with the same disease stage (89%), although the difference did not reach statistical significance (P = 0.159). No differences in survival were observed among patients with Stage IV NB, and adolescents had a probability of survival almost identical to that among children (6% vs. 16%, respectively; P = 0.481). However, when the analysis was restricted to events that occurred after patients developed a recurrence, even if the final outcome was poor for both groups, the difference was statistically significant (P = 0.022) mostly because of the more indolent disease course observed among the adolescents. This effect was even more evident for patients with Stage IV NB. When the 6-year cut-off point was used to separate children from adolescents, a significantly worse overall survival rate (P = 0.036) was documented for adolescents who had resectable disease (81% vs. 93% in children)., Conclusions: NB in adolescents had clinical and biologic characteristics similar to those observed among children. The clinical course of NB probably is correlated significantly with age at diagnosis, but information is scarce on the role of the biologic risk factors in this age group. The authors were able to identify a group of patients with a cut-off age between 6 years and 10 years that had a more indolent course but a worse prognosis., ((c) 2006 American Cancer Society.)

IFN-gamma inhibits the growth and differentiation of erythroid precursor cells and mediates hemopoietic suppression through mechanisms that are not completely understood. We found that treatment of human erythroid precursor cells with IFN-gamma up-regulates the expression of multiple members of the TNF family, including TRAIL and the recently characterized protein TWEAK. TWEAK and its receptor fibroblast growth factor-inducible 14 (Fn14) were expressed by purified erythroblasts at all the stages of maturation. Exposure to recombinant TWEAK or agonist anti-Fn14 Abs was able to inhibit erythroid cell growth and differentiation through caspase activation. Because other members of the TNF family such as TRAIL and CD95 ligand (CD95L) are known to interfere with erythroblast growth and differentiation, we investigated the role of different TNF/TNFR family proteins as potential effectors of IFN-gamma in the immature hemopoietic compartment. Treatment of erythroid precursor cells with agents that blocked either TRAIL, CD95L, or TWEAK activity was partially able to revert the effect of IFN-gamma on erythroid proliferation and differentiation. However, the simultaneous inhibition of TRAIL, TWEAK, and CD95L resulted in a complete abrogation of IFN-gamma inhibitory effects, indicating the requirement of different receptor-mediated signals in IFN-gamma-mediated hemopoietic suppression. These results establish a new role for TWEAK and its receptor in normal and IFN-gamma-mediated regulation of hematopoiesis and show that the effects of IFN-gamma on immature erythroid cells depend on multiple interactions between TNF family members and their receptors.

Background and Aims: About 20% of patients with germ cell tumor (GCT) are still resistant to therapy. To investigate which features are present in resistant patients, a multicenter study on GCT in children was undertaken to correlate clinical and laboratory parameters with the outcome., Methods: Patients aged less than 16 years, with histologically proven extracranial GCT were included., Results: Ninety-five patients (median age 33 months, 45 males) were eligible. The site of the primary tumor was gonadal in 59, extragonadal in 36. The stage was I in 39; II in 5; IIIa (microscopic residue) in 7; IIIb (macroscopic residue) in 16; IIIc (unresectable) in 13; IV in 15. The treatment was surgery alone in 31; surgery plus radiotherapy in 1; chemotherapy +/- surgery in 63. Post-chemotherapy resection in 19 (10 complete, 9 partial). The chemotherapy regimen was carboplatin 400 mg/m2/day on days 1, 2; etoposide 150 mg/m2/day on days 1, 2; ifosfamide 1,500 mg/m2/day on days 21, 22; dactinomycin 1.5 mg/m2/day on day 21; vincristine 1.5 mg/m2/day on day 21. Three patients died because of toxicity and two non-responders (to primary chemotherapy), died of progression; among the remaining 90 patients 20 relapsed, 9 are in second remission, 2 are alive with disease, and 9 died of disease progression (one from progression and intracranial hemorrhage). Overall survival was 82.7% and event-free survival: 71.5%. Survival according to: (a) site: testis: 100%; ovary: 88%; sacrococcyx: 69.6%; other sites: 33.3% (P < 0.001); (b) stage: I and II: 100%; IIIa: 83.3%; IIIb: 84.6%; IIIc: 60.6%; IV: 53.2% (P < 0.001); (c) AFP levels: normal: 85.5%; 42-9,470 ng/ml: 84.6%; >/=10,000 ng/ml: 58.7% (P = 0.02). All the pts who had complete resection of the primary tumor at diagnosis or at delayed surgery, remained in remission., Conclusions: Multivariate analysis showed that the primary site of tumor was the only independent prognostic factor for survival and EFS., (Copyright 2003 Wiley-Liss, Inc.)

Purpose: To compare the outcomes associated with modifications in three consecutive protocols employed by the Italian Co-Operative Group for Neuroblastoma (ICGNB) in disseminated neuroblastoma., Patients and Methods: Between January 1985 and November 1997, a total of 359 children aged 1 to 15 years with newly diagnosed stage 4 neuroblastoma were enrolled in three consecutive protocols. Compared with ICGNB-85, the ICGNB-89 protocol contained two more chemotherapy cycles, and some drugs were given at greater doses, whereas in the ICGNB-92 protocol, the induction phase included a chelating agent, and individual cycles contained four drugs instead of two., Results: A total of 330 of 359 evaluable children were included in this analysis; 106 children were treated with ICGNB-85, 65 children were treated with ICGNB-89, and 159 children were treated with ICGNB-92 protocols. Radical resection of primary tumor was carried out in 59.4%, 50.8%, and 57.9% of the patients, respectively. Major tumor response after induction therapy was achieved in 66.7%, 69.2%, and 68.6% of the patients, respectively. A total of 218 of 232 patients received consolidation therapy consisting of conventional chemotherapy in 65 patients and of high-dose chemotherapy in 153 patients. Disease recurrence or progression occurred in 82.1%, 69.2%, and 74.8% of the patients, respectively. Therapy-related deaths occurred in 1.9%, 12.3%, and 6.9% of the patients, respectively. Five-year overall survival (OS) for the three studies was 26%, 23%, and 28%, and event-free survival (EFS) was 19%, 17%, and 17%, respectively., Conclusion: The therapeutic modifications adopted in the ICGNB-89 and ICGNB-92 protocols were not associated with a significant improvement in response rate or in the 5-year OS and EFS as compared with the ICGNB-85 protocol. Attempts at intensifying chemotherapy were associated with greater toxicity.

Background: (131)I-metaiodobenzylguanidine ((131)I-MIBG) is selectively taken up by cells of neural crest origin, allowing targeted radiotherapy of tumors such as neuroblastoma (NB) and pheochromocytoma. Radiotherapy may provide additional benefits in the treatment of NB, with moderate side effects such as hematologic and thyroid toxicity. However, with longer follow-up, other complications might occur. We describe our experience with second cancers occurring in children treated with (131)I-MIBG and chemotherapy., Methods: The clinical records of 119 consecutive NB cases treated with (131)I-MIBG at a single institution between 1984 and 2001 were reviewed for the occurrence of a second malignant neoplasm (SMN)., Results: Overall, five cases of SMN occurred in the study patients. In particular, two cases of myeloid leukemia, one of angiomatous fibrous histiocytoma, one of malignant schwannoma, and one case of rhabdomyosarcoma were detected. The schwannoma and the rhabdomyosarcoma developed within the residual neuroblastic mass after first-line therapy., Conclusions: Should (131)I-MIBG treatment become more broadly employed in the therapeutic strategy for neuroblastoma, the risk of second cancer will have to be taken into consideration. The organization of an international registry of subjects treated with (131)I-MIBG might better define the frequency and features of second malignancies following this radiometabolic approach., (Copyright 2003 American Cancer Society.)