Carlo Cappelli

Chemotherapy in low-grade astrocytoma management

Abstract The role of chemotherapy (CHT) in the management of low-grade astrocytoma (LGA) is still unclear. Nineteen children with nonresectable symptomatic LGA were treated with carboplatin (CBDCA) and etoposide (E). There were 15 newly diagnosed cases and 4 were relapses; 6 of the children were under 5 years old. In all children radiological evaluation by CT scan and/or MRI was performed after four courses of CHT. We observed complete response (CR)+ minor response (MR) in 37% of these cases and an improvement in neurological symptoms in 63%. Radiological evaluation performed in 6 patients who received CHT for longer periods (8–12 courses) showed major responses (CR+PR) in 67%. Local radiotherapy (40 Gy) was administered after CHT in 14 cases, but in 3 of these radiotherapy was delayed for 2 years. Five patients did not receive radiotherapy. The overall survival was 58% after an average follow-up of 60 months. All patients with brain stem tumors died of progressive disease even though 3 of these had shown clinical improvement after chemotherapy. In conclusion, in the treatment of nonresectable symptomatic LGA, CHT with CBDCA associated with E can be used to postpone radiotherapy in young children and even to avoid radiotherapy in some cases.

Ten-day schedule oral etoposide therapy in advanced childhood malignancies.

PURPOSE The activity of etoposide (VP-16) has been demonstrated to be schedule-dependent. Several studies have been conducted on the efficacy and safety of different schedules of VP-16 both in adults and in children, but the optimal schedule has not been determined. METHODS In the current study, the feasibility and effectiveness of prolonged oral VP-16 in children with high-risk malignancies were evaluated. Between April 1995 and February 1999, 15 pretreated patients with high-risk tumors received oral VP-16. The schedule of therapy was oral VP-16 50 mg/m2/day for 10 consecutive days and 1-week interval between cycles. Therapy was stopped after 1 year of treatment or at time of progressive disease or possible surgery. All patients had received parenteral VP-16 in their earlier chemotherapy. RESULTS Twelve patients were evaluable for tumor response. After 2 to 4 months of treatment, one patient had complete remission (CR), two had partial response (PR), two had minor response (MR), two had mixed response (MxR), three had stable disease (SD), and two had progressive disease (PD). A useful palliative effect was noted in patients with stable disease. In three patients, oral VP-16 was administered for maintenance therapy. After an average follow-up of 27.5 months (range, 7-41 months), five patients are alive without disease (in three, total surgery was performed after VP-16 therapy) and three patients are alive with disease. Six patients died of progressive disease, and one died of promyelocytic leukemia. One patient had Grade 34 thrombocytopenia; in the remaining patients, no acute toxicity was observed during treatment. CONCLUSIONS This schedule of oral VP-16 produced CRs, PRs, and MRs in medulloblastoma, neuroblastoma, teratocarcinoma, and ependymoma. Stable disease was observed in three patients, one with an Askin tumor, one with medulloblastoma, and one with hepatoblastoma. Given the possible leukemogenic risk, this schedule should be used as a palliative form of therapy or in patients with poor prognosis..

Morphological and molecular assessment of apoptotic mechanisms in peripheral neuroblastic tumours.

Multiple defects in apoptotic pathways have been described in peripheral neuroblastic tumours (NTs). Mitosis–karyorrhexis index (MKI) is a reliable morphological marker identifying favourable and unfavourable NTs. The extent to which apoptotic processes contribute to determine the clinical significance of MKI is still undefined. Apoptosis was investigated in a series of 110 peripheral NTs by comparing MKI to immunohistochemical and molecular apoptotic features. High MKI was found in 55 out of 110 NTs (50%) and was associated with advanced stage (P=0.007), neuroblastoma (NB) histological category (P=0.024), MYCN amplification (P<0.001), and poor outcome (P=0.011). Overall survival probability was 45% in patients with high MKI compared to 73% in patients with low MKI. In the same 110 NTs, the expression of Bcl-2, Bcl-XL, Bax and Mcl-1 was studied by immunohistochemistry, but no significant associations were found with clinicohistological features. Microarray analysis of apoptotic genes was performed in 40 out of 110 representative tumours. No significant association was found between the expression of apoptotic genes and MKI or clinicohistological features. Proliferative activity was assessed in 60 out of 110 representative tumours using Ki67 immunostaining, but no significant correlations with MKI or clinicobiological features were found. In NTs, the combination of apoptosis and proliferation as expressed by MKI is a significant prognostic parameter, although neither of them is per se indicative of the clinicobiological behaviour and outcome.

Tropisetron: Optimal dosage for children in prevention of chemotherapy-induced vomiting

The antiemetic efficacy and tolerability of Tropisetron (Navoban®, Novartis Pharma Switzerland AG, Bern), a selective 5‐hydroxytriptamine receptor antagonist, has been assessed in the prevention of acute vomiting in children receiving chemotherapy for solid tumors. Tropisetron iv was given 30 min before administration of chemotherapy at a dose of 5 mg in children <20 kg body weight and at a dose of 10 mg in those >20 kg. A total of 50 children were studied in 189 courses of chemotherapy. Control of emesis was defined as total in absence of acute vomiting, as major if 1 or 2 events of acute vomiting occurred, and as not controlled if >2 events of acute vomiting occurred. Response was studied, taking into account Tropisetron dosage, degree of emetogenicity of the chemotherapeutic agents in pretreated and non‐pretreated patients, and according to age groups. Tropisetron, administered in a single daily dose of 8–12 mg/m2, was found to be very effective in completely controlling acute emesis in 92% of the courses of moderately and highly emetogenic chemotherapy administered to pediatric patients with solid tumors. Moreover, Tropisetron, at this dosage, did not lead to any adverse effects. Pediatr Blood Cancer 2005; 45:48–53.

Correlation between Tyrosine Hydroxylase Immunoreactive Cells in Tumors and Urinary Catecholamine Output in Neuroblastoma Patients

The results of an immunocytochemical evaluation of tyrosine hydroxylase (TH) immunoreactivity in 30 neuroblastic tumors of infancy are reported. Although no correlations could be found between the immunoreactive pattern and the site of origin or the staging of the tumor, a positive relationship between the urinary catecholamine output and the density of TH-immunoreactive cells could be established. TH was mostly localized on the cytoplasm of the differentiating neuroblasts, whereas immature elements were rarely positive. Moreover, 2 stage IVS cases did not contain any TH immunoreactivity. The possible significance of this finding in the investigation of this form of neuroblastoma, which has a peculiar biological behavior, is considered.

A sketch of known and novel MYCN-associated miRNA networks in neuroblastoma

Neuroblastoma (NB) originates from neural crest-derived precursors and represents the most common childhood extracranial solid tumour. MicroRNAs (miRNAs), a class of small non-coding RNAs that participate in a wide variety of biological processes by regulating gene expression, appear to play an essential role within the NB context. High-throughput next generation sequencing (NGS) was applied to study the miRNA transcriptome in a cohort of NB tumours with and without MYCN-amplification (MNA and MNnA, respectively) and in dorsal root ganglia (DRG), as a control. Out of the 128 miRNAs differentially expressed in the NB vs. DRG comparison, 47 were expressed at higher levels, while 81 were expressed at lower levels in the NB tumours. We also found that 23 miRNAs were differentially expressed in NB with or without MYCN-amplification, with 17 miRNAs being upregulated and 6 being downregulated in the MNA subtypes. Functional annotation analysis of the target genes of these differentially expressed miRNAs demonstrated that many mRNAs were involved in cancer-related pathways, such as DNA-repair and apoptosis as well as FGFR and EGFR signalling. In particular, we found that miR-628-3p negatively affects MYCN gene expression. Furthermore, we identified a novel miRNA candidate with variable expression in MNA vs. MNnA tumours, whose putative target genes are implicated in the mTOR pathway. The present study provides further insight into the molecular mechanisms that correlate miRNA dysregulation to NB development and progression.

rhEPO in pediatric oncology

Recent improvement in survival of pediatric cancer patients is due to the results of combined management including surgery, chemotherapy (high-dose, adjuvant, long-term, etc.), and radiotherapy (fractionated, local therapy, plaque therapy, high dosage, etc). For many years, recombinant hematopoietic growth factors have been used to reduce the degree and duration of chemotherapy-induced myelosuppression, the main adverse effect of chemotherapy (Furman 1992; Trillet-Lenoir et al. 1993; Burdach et al. 1995; Riikonen et al. 1995; Mitchell et al. 1997; Rahiala et al. 1999).

Combination of Carboplatin and Etoposide in The Management of Intraocular Retinoblastoma

The combination of carboplatin and etoposide has been tested in intraocular retinoblastoma (IORB), in order to avoid enucleation or radiotherapy and to permit local therapy.