Max J. Coppes

Choroid plexus tumours

Choroid plexus tumours are rare epithelial brain tumours and limited information is available regarding their biology and the best treatment. A meta-analysis was done to determine prognostic factors and the influence of various treatment modalities. A thorough review of the medical literature (1966–1998) revealed 566 well-documented choroid plexus tumours. These were entered into a database, which was analysed to determine prognostic factors and treatment modalities. Most patients with a supratentorial tumour were children, while the most common sites in adults were the fourth ventricle and the cerebellar pontine angle. Cerebellar pontine angle tumours were more frequently benign. Histology was the most important prognostic factor, as one, five, and 10-year projected survival rates were 90, 81, and 77% in choroid plexus-papilloma (n=353) compared to only 71, 41, and 35% in choroid plexus-carcinoma respectively (P<0.0005). Surgery was prognostically relevant for both choroid plexus-papilloma (P=0.0005) and choroid plexus-carcinoma (P=0.0001). Radiotherapy was associated with significantly better survival in choroid plexus-carcinomas. Eight of 22 documented choroid plexus-carcinomas responded to chemotherapy. Relapse after primary treatment was a poor prognostic factor in choroid plexus-carcinoma patients but not in choroid plexus-papilloma patients. Treatment of choroid plexus tumours should start with radical surgical resection. This should be followed by adjuvant treatment in case of choroid plexus-carcinoma, and a ‘wait and see’ approach in choroid plexus-papilloma.

The role of WT1 in Wilms tumorigenesis

Genetic alterations in tumor suppressor genes are believed to play an important role in the initiation of childhood and adult malignancies. Tumor‐specific loss of heterozygosity for particular chromosomal regions has provided the starting point for the cloning of different tumor suppressor genes, including the Wilms tumor predisposing gene, WT1, at chromosome 11p13. This article reviews the pathology and genetics of Wilms tumor, the cloning of WT1, and the WT1 mutations reported thus far in 15 hereditary and nonhereditary Wilms tumors. The presence of constitutional WT1 mutations in 35 patients with the Denys‐Drash syndrome (a syndrome consisting of nephropathy, intersex disorders, and Wilms tumor) is also described. To date, mutations in the WT1 gene have been found in less than 10% of Wilms tumors specimens examined and in greater than 95% of Denys‐Drash patients. The possible significance of this observation with regard to both the cellular function of the WT1 protein and the involvement of alternative loci in the development of Wilms tumor is discussed.—Coppes, M. J., Campbell, C. E., Williams, B. R. G. The role of WT1 in Wilms tumorigenesis. FASEB J. 7: 886‐895; 1993.

Factors affecting the risk of contralateral Wilms tumor development

Approximately 1% of children with unilateral Wilms tumor develop contralateral disease. The authors assessed the demographic and histologic features associated with metachronous bilateral Wilms tumor (BWT).

Alternative Therapies for the Treatment of Childhood Cancer

To the Editor: Recently, we have been deeply disturbed by the decision of several families to use alternative therapies exclusively as front-line treatment for their childrens cancer, or to use al...

Clinical Presentation and Treatment

In the past two decades, there has been a considerable improvement in the understanding and management of Wilms tumor and other primary renal childhood malignancies. Wilms tumor is usually diagnosed in children under the age of six, although occasionally older children are affected. Current treatment for Wilms tumor includes surgery and chemotherapy for all patients and radiation therapy for those with advanced disease or specific adverse prognostic features. This has led to cure rates exceeding 80%,1 permitting most affected children to reach adulthood.

Decreased expression of the INK4 family of cyclin-dependent kinase inhibitors in Wilms tumor

Cyclin‐dependent kinase (CDK) inhibitors represented by the INK4 family (including p16INK4a, CDKN2A, p15INK4b, CDKN2B, p18INK4c, CDKN2C, and p19INK4d, CDKN2D) are regulators of the cell cycle shown to be aberrant in many types of human cancer. We tested the hypothesis that these CDK inhibitors are a target for altered gene expression in Wilms tumor. Using RT‐PCR, gene expression of the INK4 family was found to be decreased in 9 of 38 Wilms tumor samples obtained from the National Wilms Tumor Study Group (NWTSG) tissue bank. All the affected tumor samples were of favorable histology. Methylation‐specific PCR revealed that methylation in the p16 promoter region may be responsible for altered expression. The incidence of loss of p16 expression may increase with increasing tumor stage, i.e., 1/10 (10%) with stage I/II FH Wilms tumor, 2/10 (20%) with stage III FH Wilms tumor, and 4/10 (40%) with stage IV FH Wilms tumor. Thus, determining the expression status of the INK4 family may have potential prognostic value in the management of Wilms tumor. Genes Chromosomes Cancer 29:63–69, 2000.

Congenital extrarenal non-central nervous system malignant rhabdoid tumor

Malignant rhabdoid tumor (MRT) is a rare tumor occurring mostly in kidneys and central nervous system (CNS). Its prognosis is not good. Occasionally, MRTs are diagnosed at or immediately after birth. A female neonate presented with MRT in the chest wall, axilla, right elbow, and bone marrow. Chest wall lesion was resected completely. Although the masses in axilla and bone marrow responded rapidly to chemotherapy, the elbow lesion increased in size. Despite intense treatment, the tumor relapsed in lungs and the patient died 12 months after diagnosis. Review of the literature showed twenty additional congenital MRTs arising from sites outside of the kidney and central nervous system were published in the literature. Eighteen patients had disseminated disease at diagnosis. The median overall survival time for all (n = 21) patients was 2.0 months (0–24 months). The only patient who survived had a localized tumor at initial diagnosis. Congenital, extrarenal, non-CNS MRTs are aggressive tumors with poor outcome.

Hematopoietic stem cell transplantation (HSCT) with a conditioning regimen of busulfan, cyclophosphamide, and etoposide for children with acute myelogenous leukemia (AML): a phase I study of the Pediatric Blood and Marrow Transplant Consortium.

BACKGROUND Hematopoietic stem cell transplantation (HSCT) is an important treatment modality for children with AML. The optimal conditioning regimen is unknown. The aim of this study was to determine the appropriate dosing of etoposide in combination with busulfan and cyclophosphamide in this setting. PROCEDURE Twenty patients with a diagnosis of AML in first or second remission, or myelodysplasia scheduled for bone marrow transplantation, were included in this study. Patients received busulfan 640 mg/m(2) in 16 doses, cyclophosphamide 120 to 150 mg/kg in two doses, and etoposide from 40-60 mg/kg as a single dose. Extensive toxicity data was collected. RESULTS Nineteen patients were evaluable for toxicity. Mucositis was seen in all patients. Four patients developed bacteremia and one patient died from overwhelming sepsis on day +3. Four patients developed moderate to severe skin toxicity. The major dose-limiting +3 toxicity was hepatic toxicity, which occurred in 14 of 19 patients. Eight patients developed clinical veno-occlusive disease, including three patients at dose level 4, two of whom had life-threatening disease. This hepatic toxicity defined the MTD of 640 mg/m(2) busulfan, 120 mg/kg of cyclophosphamide, and 60 mg/kg of etoposide. Overall, 9 of 20 patients enrolled in the study survive in remission, 8/14 allogeneic (median follow-up 44 months), and one of six autologous patients (follow-up, 54 months). CONCLUSIONS We conclude that the combination of busulfan, cyclophosphamide, and etoposide at the doses defined above has activity in the treatment of children with high-risk AML/MDS undergoing allogeneic HSCT. Whether it offers an advantage over other conditioning regimens will require a randomized trial with a larger cohort of patients.

Open‐label comparison of the antiemetic efficacy of single intravenous doses of dolasetron mesylate in pediatric cancer patients receiving moderately to highly emetogenic chemotherapy

BACKGROUND Nausea and vomiting are among the most unpleasant adverse side effects of cancer therapy. PROCEDURE An open-label dose-escalation study was conducted to assess the appropriate intravenous dose of dolasetron for pediatric patients undergoing chemotherapy. Patients received dolasetron in single intravenous doses of 0.6 (n = 10), 1.2 (n = 12), 1.8 (n = 12), or 2.4 (n = 12) mg/kg 30 min before receiving emetogenic chemotherapy. Pharmacokinetic parameters were evaluated at each dose level and efficacy was evaluated over the first 24 hr following the administration of dolasetron. RESULTS A complete response was achieved in 10% of patients given 0.6 mg/kg, 25% of patients given 1. 2 mg/kg, 67% of patients given 1.8 mg/kg, and 33% of patients given 2.4 mg/kg. Peak plasma concentrations (Cmax) were observed between 0. 33 and 0.75 hr following dolasetron infusion. Cmax and area under plasma concentration-time (AUC) increased with larger doses of dolasetron, while terminal disposition half-life (t1/2) and apparent clearance (Clapp) were not significantly changed with respect to dose. For 1.8-mg/kg dolasetron, the t1/2 was 4.98 hr and the maximum plasma concentration (tmax) 0.47 hr. Adverse events were mild to moderate. No serious events occurred. Conclusions. This study suggests that a single intravenous dose of 1.8 mg/kg is the optimum single intravenous dose for controlling chemotherapy-induced emesis in pediatric patients.

Safety, tolerability, antiemetic efficacy, and pharmacokinetics of oral dolasetron mesylate in pediatric cancer patients receiving moderately to highly emetogenic chemotherapy.

PURPOSE The safety, antiemetic efficacy, and pharmacokinetics of single oral doses of dolasetron, a new highly selective 5-HT3 receptor antagonist, were evaluated in children with cancer undergoing treatment with moderately to highly emetogenic chemotherapy. PATIENTS AND METHODS A total of 32 children, ages 3 to 18 years, were enrolled in a nonrandomized, multicenter, open-label, dose-escalation study. Three oral dose levels (0.6, 1.2, or 1.8 mg/kg) were studied. Safety, efficacy, and pharmacokinetic parameters were assessed over 24 hours at each dosage level. RESULTS The most effective dose was 1.8 mg/kg; 60% of the patients achieved a complete or major response (< or =2 emetic episodes in 24 hours). A complete response was achieved in 3 of 9 patients (33%) who received 0.6 mg/kg, 4 of 13 (31%) patients who received 1.2 mg/kg, and 5 of 10 (50%) patients who received 1.8 mg/kg of dolasetron. Overall, dolasetron was well tolerated. Adverse events were mild and similar to those reported in adults. Peak plasma concentrations (Cmax) of dolasetrons active reduced metabolite, MDL 74,156, were dose proportional and occurred, on the average, within 1 hour of oral administration. The half-life (t1/2) in plasma was approximately 6 hours for all dose levels, and the mean clearance (CLapp) was unrelated to dose. CONCLUSIONS Oral dolasetron is safe and effective in reducing chemotherapy-induced nausea and vomiting, particularly at the 1.8-mg/kg dose level. These results support further evaluation of oral dolasetron in larger randomized clinical trials in the pediatric cancer population.