Giulio Andrea Zanazzo

Fungal Infections in Children With Cancer A Prospective, Multicenter Surveillance Study

Background: Data on epidemiology and survival after fungal infections in patients with cancer are primarily based on studies in adults, whereas few data are available on children. Methods: A prospective, multicenter, 2-year surveillance of fungal infections in children receiving antineoplastic treatment was performed in 15 Italian centers. For each case, defined by means of EORTC-IFIG/NIAID-MSG, information was collected on age, phase of treatment, presence of neutropenia or lymphocytopenia, administration of antifungal drugs and survival. Results: Ninety-six episodes (42 proven [19 fungemias, 23 deep tissue infections], 17 probable and 37 possible invasive mycoses) were reported. Most of them (73%) followed aggressive chemotherapy, 21% allogeneic hematopoietic stem cell transplantation and only 6% moderately aggressive treatment. Neutropenia was present in 77% of the episodes, and it had a longer duration before deep tissue mycosis as compared with fungemia (P = 0.020). Lymphocytopenia was present in 75% of the episodes observed in nonneutropenic patients. As compared with children with fungemia, patients with probable invasive mycoses had a 25.7-fold increased risk of death, whereas it was 7.7-fold greater in children with possible invasive mycoses and 5-fold higher in those with proven deep tissue infection (P = 0.004). The risk of death was also 3.8-fold higher in patients already receiving antifungals at the time of diagnosis of infection as compared with those not receiving antimycotic drugs. Conclusions: In children with cancer, aggressive antineoplastic treatment, severe and longlasting neutropenia and lymphocytopenia are associated with fungal infections. These features as the clinical pictures are similar to those reported in adults, but in children, the overall and the infection-specific (fungemia or mycosis with deep tissue infection) mortalities are lower.

Bloodstream infections in children with cancer: a multicentre surveillance study of the Italian Association of Paediatric Haematology and Oncology

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%).

Improved Survival of Children With Neuroblastoma Between 1979 and 2005: A Report of the Italian Neuroblastoma Registry

PURPOSE To describe treatment, clinical course, and survival of a cohort of Italian patients with neuroblastoma. PATIENTS AND METHODS The study includes data from 2,216 children (age 0 to 14 years) diagnosed between 1979 and 2005. Overall survival (OS) was analyzed by clinical and biologic features at presentation and periods of diagnosis: 1979 to 1984, 1985 to 1991, 1992 to 1998, and 1999 to 2005. The relative risk of second malignant neoplasm (SMN) was assessed by the standardized incidence ratio (SIR), with the Italian population selected as referent. RESULTS Yearly patient accrual increased over time from 58 to 102. Patients age 0 to 17 months represented 45.6% of the total population, and their incidence increased over time from 36.5% to 48.5%. The incidence of stage 1 patients increased over time from 5.8% to 23.2%. A total of 898 patients (40.5%) developed disease progression or relapse, 19 patients developed SMN, and two patients developed myelodysplasia. The cumulative risk of SMN at 20 years was 7.1%, for an SIR of 8.4 (95% CI, 5.1 to 13.2). A total of 858 patients (39%) died (779 of disease, 71 of toxicity, six of SMN, and two of tumor-unrelated surgical complications). Ten-year OS was 55.3% (95% CI, 53.0% to 57.6%) and increased over time from 34.9% to 65.0%; it was significantly better for females and patients age 0 to 17 months at diagnosis, with extra-abdominal primary, and stage 1 and 2 disease. OS improved significantly over time in stage 1 and 3 patients. In patients with stage 4 disease, the improvement occurred between the first and second time cohorts (6.7% v 23.5%), but not afterward. CONCLUSION The outcome of children with neuroblastoma has progressively improved. Long-term survivors bear a significant risk of SMN.

Outcome of children with neuroblastoma after progression or relapse. A retrospective study of the Italian neuroblastoma registry

The Italian Neuroblastoma Registry was investigated to describe 781 children with neuroblastoma experiencing tumour recurrence (424 progressions and 357 relapses). Ten-year overall survival (OS) was 6.8% (95% confidence interval (CI) 4.3-10.0) after progression and 14.4% (95% CI 10.5-18.9) after relapse. For both circumstances, OS was better for age at diagnosis <18 months, less advanced International Neuroblastoma Staging System (INSS) stage, normal lactate dehydrogenase (LDH) serum level, normal MYCN gene status (P<0.001) and a non-abdominal primary site (P=0.034 for progression, and P=0.004 for relapses). A local type of recurrence had a significantly better outcome only in case of relapse (P<0.001). Probability of survival increased by era of diagnosis. Survival of children with recurrent neuroblastoma is very poor. A small cohort of patients, mainly represented by children with stages 1 and 2 who underwent local recurrence or developed late relapse may still benefit from further conventional treatment. For the remaining larger proportion of patients, experimental therapies should be proposed.

Incidence of bacteremias and invasive mycoses in children with acute non-lymphoblastic leukemia: results from a multi-center Italian study.

Data on the epidemiology of bacteremias and invasive fungal diseases (IFD) in children with acute myeloid leukemia (AML) are scarce.

Morbidity of pandemic H1N1 influenza in children with cancer

To define the mortality and the current impact of the H1N1 pandemic in pediatric hematology‐oncology centers, we performed a specific survey.

A multicenter, randomized, double blind placebo-controlled trial of amoxicillin/clavulanate for the prophylaxis of fever and infection in neutropenic children with cancer.

Aim of the study. To evaluate the effectiveness of oral amoxicillin/clavulanate (25 mg/kg every 12 h) for prevention of fever and/or infection in neutropenic children with cancer. Methods. Multicenter, prospective, randomized, double blind placebo-controlled trial. Results. In the intention-to-treat analysis, amoxicillin/clavulanate had a 12% benefit increase in terms of reduction in the incidence of febrile or infectious episodes, compared with placebo [44 of 83 (53%) vs. 55 of 84 (65%); 95% confidence interval, −28% to +3%;P = 0.101]. This benefit was also associated with a 30% increase in the probability of failure-free survival at Day 15 (P = 0.138). A logistic regression analysis showed the effect of prophylaxis to be relevant, especially in patients with leukemia or lymphoma and in those not receiving hematopoietic growth factors, with 17 and 15% absolute benefit increases (logistic P = 0.014 and 0.034, respectively). Compliance with oral drugs was good, with very few and nonsevere drug-related adverse events. Conclusions. In this study amoxicillin/clavulanate was associated with a detectable clinical effect in the reduction of fever and infection in neutropenic children with cancer, especially those with acute leukemia and not receiving growth factors; the study was not powered to demonstrate a statistically significant effect in the overall patient population.

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.

Single-day trimethoprim/sulfamethoxazole prophylaxis for Pneumocystis pneumonia in children with cancer.

OBJECTIVE To determine whether a simplified, 1-day/week regimen of trimethoprim/sulfamethoxazole is sufficient to prevent Pneumocystis (jirovecii [carinii]) pneumonia (PCP). Current recommended regimens for prophylaxis against PCP range from daily administration to 3 consecutive days per week dosing. STUDY DESIGN A prospective survey of the regimens adopted for the PCP prophylaxis in all patients treated for childhood cancer at pediatric hematology-oncology centers of the Associazione Italiana Ematologia Oncologia Pediatrica. RESULTS The 20 centers participating in the study reported a total of 2466 patients, including 1093 with solid tumor and 1373 with leukemia/lymphoma (or primary immunodeficiency; n = 2). Of these patients, 1371 (55.6%) received the 3-day/week prophylaxis regimen, 406 (16.5%) received the 2-day/week regimen, and 689 (27.9%), including 439 with leukemia/lymphoma, received the 1-day/week regimen. Overall, only 2 cases of PCP (0.08%) were reported, both in the 2-day/week group. By intention to treat, the cumulative incidence of PCP at 3 years was 0.09% overall (95% CI, 0.00-0.40%) and 0.51% for the 2-day/week group (95% CI, 0.10%-2.00%). Remarkably, both patients who failed had withdrawn from prophylaxis. CONCLUSION A single-day course of prophylaxis with trimethoprim/sulfamethoxazole may be sufficient to prevent PCP in children with cancer undergoing intensive chemotherapy regimens. This simplified strategy might have implications for the emerging need for PCP prophylaxis in other patients subjected to the increased use of biological and nonbiological agents that induce higher levels of immune suppression, such as those with rheumatic diseases.

A prospective, randomized study of empirical antifungal therapy for the treatment of chemotherapy-induced febrile neutropenia in children

Given that the rationale for empirical antifungal therapy in neutropenic children is limited and based on adult patient data, we performed a prospective, randomized, controlled trial that evaluated 110 neutropenic children with persistent fever. Those at high risk for invasive fungal infections (IFI) received caspofungin (Arm C) or liposomal amphotericinB (Arm B); those with a lower risk were randomized to receive Arm B, C, or no antifungal treatment (Arm A). Complete response to empirical antifungal therapy was achieved in 90/104 patients (86·5%): 48/56 at high risk (85·7%) [88·0% in Arm B; 83·9% in Arm C (P = 0·72)], and 42/48 at low risk (87·5%) [87·5% in control Arm A, 80·0% Arm B, 94·1% Arm C; (P = 0·41)]. None of the variables tested by multiple logistic regression analysis showed a significant effect on the probability to achieve complete response. IFI was diagnosed in nine patients (8·2%, 95% confidence interval, 3·8–15·0). This randomized controlled study showed that empirical antifungal therapy was of no advantage in terms of survival without fever and IFI in patients aged <18 years and defined with low risk of IFI. Higher risk patients, including those with relapsed cancer, appear to be the target for empirical antifungal therapy during protracted febrile neutropenia.