Metastatic neuroblastoma in infants: are survival rates excellent only within the stringent framework of clinical trials?

INTRODUCTION: SIOPEN INES protocol yielded excellent 5-year survival rates for MYCN-non-amplified metastatic neuroblastoma. Patients deemed ineligible due to lack or delay of MYCN status or late registration were treated, but not included in the study. Our goal was to analyse survival at 10 years among the whole population. MATERIALS AND METHODS: Italian and Spanish metastatic INES patients' data are reported. SPSS 20.0 was used for statistical analysis. RESULTS: Among 98 infants, 27 had events and 19 died, while 79 were disease free. Five- and 10-year event-free survival (EFS) were 73 and 70 %, and overall survival (OS) was 81 and 74 %, respectively. MYCN status was significant for EFS, but not for OS in multivariate analysis. CONCLUSIONS: The survival rates of patients who complied with all the inclusion criteria for INES trials are higher compared to those that included also not registered patients. Five-year EFS and OS for INES 99.2 were 87.8 and 95.7 %, while our stage 4s population obtained 78 and 87 %. Concerning 99.3, 5-year EFS and OS were 86.7 and 95.6 %, while for stage 4 we registered 61 and 68 %. MYCN amplification had a strong impact on prognosis and therefore we consider it unacceptable that many patients were not studied for MYCN and probably inadequately treated. Ten-year survival rates were shown to decrease: EFS from 73 to 70 % and OS from 81 to 74 %, indicating a risk of late events, particularly in stage 4s. Population-based registries like European ENCCA WP 11-task 11 will possibly clarify these data.

Guidelines for the use of long-term central venous catheter in children with hemato-oncological disorders. On behalf of supportive therapy working group of Italian Association of Pediatric Hematology and Oncology (AIEOP).

In the last 30 years, the use of long-term central venous catheters (CVC) is increased especially for children with hemato-oncological disorders. However, the use of CVC is associated to complications, as mechanical accidents, thrombosis, and infections that can determine a prolongation of hospital stay, an increase of costs, and sometimes life-threatening conditions that require urgent systemic treatment or CVC removal. CVC removal may be troublesome especially in neonates, infants, or any other "highly needed CVC patients"; in these selected cases, the prevention and treatment of CVC-related complications play a pivotal role and specific surveillance programs are crucial. While extensive literature is focused on CVC management in adults, no guidelines are available for children. To this aim, the first recommendations for the management of CVC infectious complication in pediatric age have been written after pediatric and adult literature review and collegial discussion among members of Supportive Therapy working group of Italian Association of Pediatric Hematology and Oncology. Compared to the adult age, the necessity of peripheral vein cultures for the diagnosis of CVC-related infection remains controversial in children because of the poorer venous asset and a conservative, pharmacologically focused management through CVC remains mandatory, with CVC removal to be performed only in selected cases.

Two-stage phase II study of imatinib mesylate in subjects with refractory or relapsing neuroblastoma.

BACKGROUND: Cure rate for subjects with refractory or relapsing metastatic neuroblastoma is <5%. In the search for a novel therapy, continuous daily oral administration of imatinib mesylate was evaluated. PATIENTS AND METHODS: Twenty-four subjects were enrolled in a two-stage study. Imatinib was administered for the first 4 weeks (cycle) at 170 mg/sqm b.i.d. If no major toxicity occurred, the dose was escalated to 300 mg/sqm b.i.d. for a maximum of 12 cycles. Clinical response and toxicity were evaluated according to international criteria. Pharmacokinetics (PK) profiles and tyrosine hydroxylase (TH) mRNA expression were also determined in a subset of subjects. RESULTS: Five (21%) complete responses, with one subject still alive at 68 months, and 2 (8%) partial responses lasting up to 29 months were obtained. No grade 4 toxicity was observed. At steady-state, PK exposure (69.7 µg h/ml) was similar to that of adults receiving 1000 mg/die. Responses appear to correlate with the absence or presence of metastasis in the bone marrow (BM) alone, with low TH expression levels at study entry and low imatinib exposure. CONCLUSIONS: Imatinib mesylate was well-tolerated and effective in the subset of subjects with low BM infiltration as only site of metastasis. Study identifier EudraCT: 2005-005778-63.

Bloodstream infections in children with cancer: a multicentre surveillance study of the Italian Association of Paediatric Haematology and Oncology. Supportive Therapy Group-Infectious Diseases Section.

A one-year prospective, multicentre surveillance study on aetiology, main clinical features and outcome of bloodstream infections in children with cancer was conducted in 18 paediatric haematology centres belonging to the Italian Association for Paediatric Haematology and Oncology. A total of 191 bloodstream infections were reported during the study period. Of them, 123 (64%) occurred in neutropenic and 68 (36%) in non-neutropenic patients. Gram-positive cocci caused 45% (85/191) of the episodes, gram-negative rods 41% (78/191), and fungi 9% (18/191). The remaining 5% (10/191) of the episodes were poly-microbial infections. A total of 204 pathogens were isolated (46% gram-positive cocci; 44% gram-negative rods; and 10% fungi). The aetiologic distribution was similar among neutropenic and non-neutropenic patients. A correlation between the infection and the presence of an indwelling central venous catheter was found in 20% (23/114) of the episodes among neutropenic patients and in 55% (23/62) among non-neutropenic patients. Gram-negative micro-organisms were isolated in an unusually high proportion of catheter-related infections (48%). The overall mortality rate from any cause within 30 days from the first positive blood culture was 11%, and was higher among patients who were neutropenic at the onset of the infection than among those who were not neutropenic (15 versus 4%, P = 0.03). In addition, the mortality was significantly higher in recipients of bone marrow transplantation than in patients with acute leukaemia or solid tumour (21, 11 and 6%, respectively) and was also higher in fungaemias and poly-microbial infections (22 and 30%) than in single gram-positive and gram-negative bacteraemias (11 and 6%).

Italian guidelines for the management of infectious complications in pediatric oncology: empirical antimicrobial therapy of febrile neutropenia.

The Italian Association for Paediatric Haematology and Oncology prepared a guideline document aimed at unifying and rationalising as much as possible the management of febrile neutropenia in children with cancer, because of the potential impact of these procedures on hospital costs and on the development of antibiotic resistance. Before starting anti-infective therapy, at least 2 blood cultures, a throat swab, urine-culture, and cultures from any suspected infected site, should be performed. Routine chest X-rays at onset of febrile neutropenia are probably not necessary, in absence of respiratory signs. At the present time, the safer option probably remains the combination of a beta-lactam and an aminoglycoside, and treating febrile neutropenia outside of hospital should be considered an investigational approach. The choice of the most appropriated regimen for each institution should be based also on the local bacteriological statistics and patterns of bacterial resistance. Antibiotic toxicity and cost should be other important factors. Every subsequent addition or substitution of antibiotics should be based on objective signs of clinical deterioration. The only accepted empirical modification is empirical antifungal therapy, while the empirical addition of a glycopeptide antibiotic cannot be recommended.

[Malignant tumors in children living in the province of Trieste, 1972-1993: descriptive epidemiology and the quality of diagnostic-therapeutic services]. / I tumori maligni nei bambini residenti nella provincia di Trieste, 1972-1993: epidemiologia descrittiva e qualità dei servizi diagnostico-terapeutici.

The study objectives were: 1) to analyse the incidence and death rates from cancer among children aged 0-14 years resident in the north-eastern Italian province of Trieste between 1972-1993, using data from the population-based Trieste Cancer Registry; 2) to evaluate the local diagnostic facilities by analysing the accuracy of histological diagnoses, the causes of delay in the diagnosis, and the interval between onset of symptoms and diagnosis of cancer; 3) to calculate the proportion of patients treated following the most effective therapy protocols known at the time of the tumour detection, and to compute the actuarial five-year survival rates since diagnosis. We recorded 123 new cases of cancer (93% microscopically verified) corresponding to a rate, age-standardized to the world population, of 161.9 (standard error [SE] = 15.1) per million child-years. The most common diagnostic group was that of primary brain tumours: 40 cases, rate = 51.0 (SE = 8.4). In 102 cases the diagnosis was made at hospitals in the province of Trieste, with a median time of seven days (25th-75th percentile = 1-16) between admission and diagnosis. In 37 cases the length of the interval between the advancing of the diagnostic hypothesis of cancer and the microscopic diagnosis ranged from eight to 57 days: 20% of the interval was spent in the identification of the lesion, 50% elapsed between the identification and the biopsy, and 30% was spent in performing the microscopic diagnosis. Out of 123 cases, 30 were partly treated or completely treated at centres not located in our province, i.e., at seven different Italian hospitals (14 cases), nine European hospitals (15 cases), and at one North-American centre (one case). The 40 children with brain tumours were spread among 12 institutions. The five-year survival rate increased from 52.4% (SE = 6.3) for the 63 children with cancers diagnosed in 1972-1981 to 62.5% (SE = 7.0) for the 48 with malignancies detected in 1982-1990.

Human granulocyte colony-stimulating factor (rHuG-CSF) for treatment of neutropenia in Shwachman syndrome.

We report a boy affected by Shwachman syndrome (SS) who presented severe neutropenia and frequent suppurative infections, which we treated successfully with granulocyte colony-stimulating factor (rHuG-CSF). Daily injections of 7.5 micrograms/kg/day significantly increased the absolute neutrophil count and he was free from infections. In order to avoid the risk of side effects and to improve the child's quality of life, we intermittently administered lower doses of rHuG-CSF. A weekly dose of 2 micrograms/kg/day was able to maintain the absolute neutrophil count high enough (0.58-1.2 x 10(9)/L) to prevent suppurative infections. During the follow-up period (2.5 years) we tried suspending rHuG-CSF twice, but the absolute neutrophil count (0.18-0.31 x 10(9)/L) fell significantly and suppurative infections reoccurred (otitis, perianal abscess). rHuG-CSF may be a useful therapeutic agent in patients with symptomatic neutropenia in SS.

Avascular necrosis of bone in children undergoing allogeneic bone marrow transplantation.

Avascular necrosis of bone (AVNB) is reported in two children after allogeneic bone marrow transplantation. Preparation therapy for transplantation included cyclophosphamide and total body irradiation. Corticosteroids, cyclosporine A, and methotrexate were used for graft-versus-host-disease prophylaxis. The possible role of combination therapy in development of AVNB is discussed, but a direct relationship with single agents was not found. However, an early diagnosis is important to institute conservative treatment and prevent irreversible damage to affected joints. Magnetic resonance imaging was found to be more sensitive than plain radiography in early detection of AVNB.

[Computerized tomography of the skull in children with lymphoblastic leukemia treated with prophylactic cranial radiation]. / Tomografia computerizzata del cranio in bambini con leucemia acuta linfoblastica sottoposti ad irradiazione cranica profilattica.

Thirty asymptomatic patients with acute lymphoblastic leukemia who had received prophylactic cranial irradiation (16 pts had 2400 cGy, 14 pts 1800 cGy) and intrathecal methotrexate were studied by computed tomography of the brain 60 to 148 months after initiation of prophylaxis. Three of 30 (10%) patients presented abnormal findings: widening of frontal subarachnoid space (1 patient), little area of decreased attenuation coefficient (1 patient), and intracerebral calcifications (1 patient Tomography abnormalities could be detected either in patients treated with 2400 cGy and in those treated with 1800 cGy. None of our patients showed central nervous system dysfunctions on physical examination. The results of our study suggest that tomography findings have a poor clinical significance.

Leukemia in a child with Wilms' tumor.

A case is described which illustrates an acute non-lymphocytic leukemia following multimodal control and apparent cure of Wilms' tumor. Literature cases are reviewed, and therapeutic inadequacies according to present protocols and their importance for the subsequent development of secondary leukemia are discussed.

[Bilateral adrenal neuroblastoma of multicentric origin]. / Neuroblastoma surrenale bilaterale di origine polifocale.

Bilateral neuroblastoma is extremely rare. In the literature few cases are reported which are mostly considered to represent metastases rather than multicentric tumoral occurrence. A case of bilateral adrenal neuroblastoma is reported; given its various aspects, and especially the prognosis features, this tumor is, in our opinion, of a multicentric origin.