The clinical hallmark of neuroblastoma is heterogeneity, with the likelihood of cure varying widely according to age at diagnosis, extent of disease, and tumour biology. A subset of tumours will undergo spontaneous regression while others show relentless progression. Around half of all cases are currently classified as high-risk for disease relapse, with overall survival rates less than 40% despite intensive multimodal therapy. This Seminar focuses on recent advances in our understanding of the biology of this complex paediatric solid tumour. We outline plans for the development of a uniform International Neuroblastoma Risk Group (INRG) classification system, and summarise strategies for risk-based therapies. We also update readers on new discoveries related to the underlying molecular pathogenesis of this tumour, with special emphasis on advances that are translatable to the clinic. Finally, we discuss new approaches to treatment, including recently discovered molecular targets that might provide more effective treatment strategies with the potential for less toxicity.

BACKGROUND:Viral hepatitis is a cause of hepatic dysfunction in children with ALL in remission during maintenance therapy is debated. The aims of the current study were (1) to explore the incidence of hepatic dysfunction in a group of children (Egyptian and Saudi) with ALL under maintenance therapy, (2) to study the prevalence of hepatitis B (HBV) and/or C (HCV) infection and their contributions to chronic liver disease that might be induced by maintenance therapy.PROCEDURE:The current study included 105 children with ALL (54 Egyptian and 51 Saudi). All eligible patients had been on maintenance therapy for at least 12 months and all had serial assessments of liver function. These included determination of total bilirubin, AST, ALT, and alkaline phosphatase. Markers for HBV and HCV including HBsAg, anti-HBC, and anti-HCV and for some patients HCV RNA by PCR were studied. Percutaneous liver biopsy was performed for a group of children.RESULTS:The prevalence of hepatitis infection (HBV and/or HCV) among Egyptian children was found to be high (43/54-80%). Only five Saudi children had evidence of exposure to HBV (5/51-9.8%), P<0.0001. During the period of study, 22 Egyptian patients vs. four Saudi patients (41 vs. 7.8%, P<0.0001) experienced at least one episode of elevation of liver enzymes, three times the upper limit of normal or more. Twenty-six of the 48 patients (54%) with HBV and/or HCV infection had episodes of elevated liver enzymes, while there was no occurrence among the patients negative for HBV and HCV. In patients with HBV infection, the presence of HBsAg was strongly associated (100%) with elevated liver enzymes. Histopathologic examination of liver biopsies obtained from 35 patients revealed that all five patients negative for HBV and HCV had normal liver biopsies in spite of being under maintenance therapy.CONCLUSION:In children undergoing treatment for ALL, elevations in liver enzymes may be primarily due to hepatitis viruses. However, maintenance therapy using known hepatotoxic drugs, may have additive deleterious effects. Liver enzymes are normalized in affected patients when maintenance therapy is temporarily suspended.

Due to the poor results achieved on combination chemotherapy and the unproven cost-effectiveness value of myeloablative therapy, the question has been raised; should patients with stage IV neuroblastoma be actively treated? The aim of the current study is to analyze retrospectively treatment results of 43 children with neuroblastoma with special stress on the rate and duration of remission in children with disseminated neuroblastoma.Treatment of children with neuroblastoma consisted of surgical removal of the tumor, if possible, followed by chemotherapy for unresectable residual tumor including metastases. Second look surgery was performed to resect residual masses rendered resectable on chemotherapy in the absence of distal metastases. The chemotherapy protocol used in the current study consisted of alternating combination chemotherapy regimens containing, Cyclophosphamide, Vincristine and Doxorubicin, alternating with Cis-platinum and Etoposide.The male to female ratio was 2:1 with a median age of 2.1 years. The abdomen was the primary site of involvement encountered in 32 patients (74%). According to the childrens cancer study group (CCSG) staging system, only 6 patients (14%) had localized tumors (stages I and II). Two patients (5%) were found to have stage IV. Stage III was documented in 5 patients (12%). The majority of patients (70%) had disseminated disease at presentation. The bone marrow was the most common site of metastatic deposit, encountered in 23 patients out of the 30 with stage IV disease (77%). Out of the 12 evaluable non-stage IV patients, only one patient (8%) showed treatment failure. Assessment of response by the end of the 6th month from the date of diagnosis revealed that out of the 27 evaluable patients with stage IV, 4 patients achieved complete remission, 7 patients achieved very good partial remission, 8 patients achieved partial remission and 4 patients achieved mixed response. Three patients showed progressive disease on chemotherapy. Twenty-one patients (78%) were symptom-free and were conducting normal life. Assessment of response to treatment by the end of the 12th month from diagnosis revealed that 6 patients (2 complete remissions, 1 very good partial response, 3 partial responses) were maintaining their remission. Out of the 19 patients showing complete or partial remission at early assessment, 4 patients maintained their remission for more than 18 months. Two (one was in complete remission and the other was in partial response) of them progressed in areas of previous involvement after 20 and 21 months. The other 2 patients (one was in complete remission and the other was in partial response) showed disease progression in areas not previously affected by disease at presentation after 23 and 42 months.Results of treatment by multiagent chemotherapy regimens used in the current study show that children with neuroblastoma, even those with advanced stages, should receive the benefit of intensive multimodal therapy, even those with partial response to initial therapy. These patients may experience reasonable symptom-free and sometimes, disease-free survival.

OBJECTIVE:Due to the poor results achieved on combination chemotherapy and the unproven cost-effectiveness value of myeloablative therapy, the question has been raised; should patients with stage IV neuroblastoma be actively treated? The aim of the current study is to analyze retrospectively treatment results of 43 children with neuroblastoma with special stress on the rate and duration of remission in children with disseminated neuroblastoma.METHODS:Treatment of children with neuroblastoma consisted of surgical removal of the tumor, if possible, followed by chemotherapy for unresectable residual tumor including metastases. Second look surgery was performed to resect residual masses rendered resectable on chemotherapy in the absence of distal metastases. The chemotherapy protocol used in the current study consisted of alternating combination chemotherapy regimens containing, Cyclophosphamide, Vincristine and Doxorubicin, alternating with Cis-platinum and Etoposide.RESULTS:The male to female ratio was 2:1 with a median age of 2.1 years. The abdomen was the primary site of involvement encountered in 32 patients (74%). According to the childrens cancer study group (CCSG) staging system, only 6 patients (14%) had localized tumors (stages I and II). Two patients (5%) were found to have stage IV. Stage III was documented in 5 patients (12%). The majority of patients (70%) had disseminated disease at presentation. The bone marrow was the most common site of metastatic deposit, encountered in 23 patients out of the 30 with stage IV disease (77%). Out of the 12 evaluable non-stage IV patients, only one patient (8%) showed treatment failure. Assessment of response by the end of the 6th month from the date of diagnosis revealed that out of the 27 evaluable patients with stage IV, 4 patients achieved complete remission, 7 patients achieved very good partial remission, 8 patients achieved partial remission and 4 patients achieved mixed response. Three patients showed progressive disease on chemotherapy. Twenty-one patients (78%) were symptom-free and were conducting normal life. Assessment of response to treatment by the end of the 12th month from diagnosis revealed that 6 patients (2 complete remissions, 1 very good partial response, 3 partial responses) were maintaining their remission. Out of the 19 patients showing complete or partial remission at early assessment, 4 patients maintained their remission for more than 18 months. Two (one was in complete remission and the other was in partial response) of them progressed in areas of previous involvement after 20 and 21 months. The other 2 patients (one was in complete remission and the other was in partial response) showed disease progression in areas not previously affected by disease at presentation after 23 and 42 months.CONCLUSION:Results of treatment by multiagent chemotherapy regimens used in the current study show that children with neuroblastoma, even those with advanced stages, should receive the benefit of intensive multimodal therapy, even those with partial response to initial therapy. These patients may experience reasonable symptom-free and sometimes, disease-free survival.