Stefano Mastrangelo

Treatment of advanced neuroblastoma: feasibility and therapeutic potential of a novel approach combining 131-I-MIBG and multiple drug chemotherapy

Biological and clinical observations suggest that initial marked reduction of resistant clones may be critical in any attempt to improve long-term results in advanced neuroblastoma (NB). The aim of this pilot study is to determine short-term toxicity and efficacy of a new therapeutic model based on the simultaneous use of multiple drug chemotherapy and specific irradiation using 131-I-MIBG. The study population consisted of 21 patients, from 1 to 8 years of age with good 131-I-MIBG uptake. 16 extensively pre-treated patients with refractory or relapsed disease were divided into 2 groups. In Group 1 (9 patients) the basic chemotherapy regimen consisted in cisplatin at the dose of 20 mg/m2i.v. per day infused over 2 h, for 4 consecutive days; on day 4 Cy 2 g/m2i.v. was administered over 2 h followed by Mesna. Group 2 (7 patients) was treated with basic chemotherapeutic regimen plus VP16 and Vincristine. VP16 at the dose of 50 mg/m2i.v. per day was administered as a 24 h infusion on days 1–3; Vincristine 1.5 mg/m2i.v. was administered on days 1 and 6. On day 10 a single dose of 131-I-MIBG (200 mCi) with a high specific activity (>1.1 GBq/mg) was administered to both Groups by i.v. infusion over 4–6 hours. A further 5 patients were treated at diagnosis: 2 with the same regimen as Group 1 and 3 with the same as Group 2. The severity of toxicity was graded according to World Health Organization (WHO) criteria. Assessment of tumour response was monitored 4–6 weeks after the beginning of combined therapy (CO-TH). Response was defined according to INSS (International Neuroblastoma Staging System) criteria. No extra-medullary toxicity was observed in any patient. Haematological toxicity was the only toxicity observed and seemed mainly related to chemotherapy. Myelosuppression was mild in the 5 patients treated at diagnosis. No serious infections or significant bleeding problems were observed. In the 16 resistant patients, 12 PR, 1 mixed response and 3 SD were obtained. In the 5 patients treated at diagnosis 2 PR, 1 CR and 2 VGPR were observed. No alteration in 131-I-MIBG uptake was observed after the chemotherapy preceding radio-metabolic treatment. The therapeutic results of this pilot regimen of CO-TH resulted in a high percentage of major response after only a single course in both resistant patients and patients treated at diagnosis. Because of the minimal toxicity observed in patients studied at diagnosis so far, there is room for gradual intensification of the treatment. It is to be hoped that this suggested novel approach may represent an important route of investigation to improve final outcome in patients with advanced NB.

Constitutional trisomy 8 and myelodysplasia: Report of a case and review of the literature

A diagnosis of myelodysplastic syndrome was made in an 18-year-old patient with Warkany syndrome due to constitutional trisomy 8 mosaicism. The possible causal role of this particular chromosome constitution with respect to myelodysplasia and embryonal childhood tumors is discussed.

Optimal use of the 131-I-metaiodobenzylguanidine and cisplatin combination in advanced neuroblastoma

Neuroblastoma (NB), a childhood radiosensitive tumor, is very aggressive and malignant; in its disseminated form, despite very intensive chemotherapy, prognosis continues to be dismal. Owing to its capacity to concentrate in NB lesions, large doses of 131-I-MIBG, have given very encouraging therapeutic results in patients resistant to conventional therapy as well as at diagnosis.We recently reported the first attempt in combination therapy (CO-TH) using 131-I-MIBG and cisplatin. This new form of CO-TH appears very effective in obtaining a rapid and excellent response in relapsed patients.In this report, we describe the results of further experience with CO-TH in disseminated NB. We have attempted to verify to what extent interaction between the effects of the two agents may produce therapeutic benefit, and we have sought the optimization of CO-TH use.Three stage IV NB patients were treated with CO-TH. The following treatment schedule, was planned: day 1, cisplatin 50 mg/m2 i.v. over 6 h; day 2, 131-I-MIBG 100—130 mCi at high specific activity (- 1.1 Gbq/mg) i.v. over 6 h followed, a week later, by the same treatment combination.The therapeutic results were encouraging. However, hematological toxicity continued to represent a major limiting factor. In view of the overall effectiveness of CO-TH, at the price of lasting hematological toxicity, it may be indicated as a consolidationregimen some time before conditioning chemotherapy for autologous bone marrow transplantation.

Successful treatment with oral valganciclovir in immunocompetent infant with gastrointestinal manifestations of cytomegalovirus infection

A 3-month-old male infant was admitted to hospital with anemia. Follow-up controls revealed the presence of specific cytomegalovirus (CMV) antibodies. Virus was isolated from urine, blood, and saliva. At 7 months of age, he presented with melena. Polymerase chain reaction (PCR) of biopsy samples from the duodenum was positive for CMV. Anemia resolved after starting antiviral therapy with oral valganciclovir.

Interactions between antiepileptic and chemotherapeutic drugs in children with brain tumors: Is it time to change treatment?

Epileptic seizures are a common clinical problem in children with brain tumors. The conventional antiepileptic drugs (AEDs) permit a good seizure control in most of these children. An emerging problem is the possible interactions between AEDs and chemotherapeutic drugs, because many of these drugs are metabolized by the cytochrome P450. The aim of this article is to propose a novel therapeutic approach for new‐onset epilepsy in children with brain tumors. Among the new AEDs not metabolized by the P450 system, levetiracetam seems to be a promising AED owing to its pharmacokinetic features, efficacy, and safety. Pediatr Blood Cancer 2010;54:193–198.

Treatment of advanced neuroblastoma in children over 1 year of age: The critical role of 131I‐metaiodobenzylguanidine combined with chemotherapy in a rapid induction regimen

The prognosis of patients with advanced neuroblastoma (NB) remains poor. Major and early responses have an important bearing on treatment outcome. Iodine‐131‐metaiodobenzylguanidine (131I‐MIBG) has the potential to deliver large doses of radiation specifically to NB cells. We evaluated the toxicity of, and response to, a novel induction regimen that included 131I‐MIBG combined with cisplatin, cyclophosphamide, etoposide, vincristine, and doxorubicin.

Phase I study of temozolomide combined with oral etoposide in children with recurrent or progressive medulloblastoma

BACKGROUND The prognosis of recurrent or progressive medulloblastoma (MB) is still poor. This study was designed to investigate the potential therapeutic benefit of combination therapy with temozolomide (TMZ) and oral etoposide (VP-16) in children with progressive or relapsed MB. Given the oral administration of both drugs the regimen was administered outpatient. METHODS A phase I trial was conducted to establish the maximum tolerated dose (MTD) of TMZ and oral VP-16. This orally administered combination was investigated by classical 3+3 design. Cohorts of patients were enrolled at four different levels: (1) TMZ 120 mg/m(2) on days 1-5 and VP-16 50 mg/m(2) on days 1-8; (2) TMZ 150 mg/m(2) on days 1-5 and VP-16 50 mg/m(2) on days 1-8; (3) TMZ 150 mg/m(2) on days 1-5 and VP-16 50 mg/m(2) on days 1-10; (4) TMZ 150 mg/m(2) on days 1-5 and VP-16 50 mg/m(2) on days 1-12. Therapy was administered in 28-d courses. A total of 66 courses were administered to 14 patients with a median age of 5.7 years. RESULTS None of the 3 patients at dose levels 1 and 2 had dose-limiting toxicity (DLT). Of the 6 patients at dose level 3, 1 patient had DLT. At dose level 4, grade 4 thrombocytopaenia and neutropaenia were observed in the first 2 patients enrolled. Therefore, the MTD was established at dose level 3. CONCLUSION The recommended phase II dose in children is TMZ 150 mg/m(2) on days 1-5 and VP-16 50 mg/m(2) on days 1-10 every 28 d. The combination was well tolerated and demonstrated antitumour activity.

Central pontine and extrapontine myelinolysis in a pediatric patient following rapid correction of hypernatremia.

Central pontine and extrapontine myelinolysis are uncommon disorders characterized by distinctive clinical features and typical findings on neuroimaging. Only a few cases are reported in the pediatric age group. We describe the case of a leukemic, malnourished 14-year-old boy with a high serum sodium concentration that gradually increased to 170 mmol/L. During a septic shock episode, hydration with a low sodium concentration at the rate of 104 mL/h for 24 h was administered. A rapid correction of the high serum sodium occurred, exceeding 0.5 mmol/L/h. The following day the patient developed rapid and progressive neurological impairment with clinical features characteristic of central pontine and extrapontine myelinolysis. Magnetic resonance imaging confirmed the diagnosis 11 days later. The patient was treated with steroids and intravenous immunoglobulins. He achieved an almost full neurological recovery and radiological improvement. The reported case demonstrates that central pontine and extrapontine myelinolysis can occur after excessively rapid correction of hypernatremia.

Severe Hyperleukocytosis and multifocal intracranial haemorrhage: not always a fatal outcome.

Severe hyperleukocytosis caused by acute lymphoblastic leukaemia (ALL) is associated with an increased risk of early death due to the intracranial haemorrhage. We report on a boy who presented with ALL with an extremely high leukocyte count, who developed neurological deterioration due to multiple intracerebral haemorrhages. Adequate measures for managing this medical emergency include appropriate supportive measures and initiation of therapy to prevent symptoms of leukostasis. Aggressive measures as a decompressive craniectomy should be considered to improve the poor outcome observed in this subset of patients.

Anthracycline-related cardiotoxicity: risk factors and therapeutic options in childhood cancers

Anthracyclines play an important role in chemotherapeutic regimens for a wide spectrum of childhood tumors, but they can cause cytotoxic damage to cardiac cells, especially in combination with radiotherapy. Furthermore, cardiotoxicity increases with the cumulative dose and may lead to congestive heart failure and cardiomyopathy. Other factors, including age, pre-existing cardiac disease, length of follow-up, gender, route of administration, concomitant exposure to some chemotherapeutic drugs, trisomy 21 and black race, play a role in increasing the risk of cardiac dysfunction. The prevention of anthracycline-induced cardiotoxicity is mandatory as children are expected to survive for decades after being cured of their cancer. The purpose of this work is to point out the major risk factors of cardiotoxicity in children and to summarize some strategies to limit or prevent this complication and to treat the development of acute heart failure.