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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

Infection is a significant cause of death in patients with aplastic anaemia (AA). However, few studies have examined the characteristics of infections in patients with AA, especially in children. The aim of this retrospective study was to evaluate the incidence and types of infections in a large cohort of paediatric patients with AA referred to eight AIEOP (Italian Association of Paediatric Oncology and Haematology) centres in Italy. The study included 78 patients, 45 boys and 33 girls, median age 9.29 yrs (1st–3rd quartile 3.59– 13.09) diagnosed with AA. During the study period, 111 infectious episodes were observed in 42 (54%) patients. Fifty-one (46%) episodes were fever of unknown origin and 60 (54%) were documented infections (DI). In this group, microbiologically documented infection (MDI) with bacteremia accounted for 23 (38%) episodes, MDI without bacteremia for 7 (12%), clinically documented infection for 25 (42%) and invasive fungal diseases for 5 (8%). The rate (episodes ⁄ 1000 d at risk) was similar in severe aplastic anemia and very severe aplastic anemia both before and after day 120. During the first 120 d from diagnosis, the cumulative risk of a DI was 21% (95% CI 12–29) with the last episode at day 117, but the 50% of episodes were observed in the first 24 d. After day 120, the cumulative risk of DI was again 21% (95% CI 12–29), with the last episode at day 445 of follow-up, with 50% of episodes observed in the first 120 d of observation (240 d from the diagnosis of AA). We found a statistically significant association between the grade of aplasia at diagnosis and the incidence of IEs (P = 0.0002). No association was found between gender, age at diagnosis, response at day +120 and at day +180, use of G-CSF and occurrence of IEs. The actuarial overall survival at 5 yrs was 90% ± 3.6. The mortality rate attributable to infection complication was 9%. This is a large paediatric cohort study reporting the epidemiology of infectious complications in children with AA and that allow us to compare the epidemiological data in this diseases with that of the most recent studies in neutropenic children with cancer. Our findings confirm that infections represent the main cause of death in patients with AA and they are important for the design of management strategies of febrile neutropenia in these patients.

Background Data on the epidemiology of bacteremias and invasive fungal diseases (IFD) in children with acute myeloid leukemia (AML) are scarce. Design and Methods In a multi-center, retrospective study, we analyzed proportion, rate per 1,000 person-days at risk, and cumulative risk of bacteremias and IFD in children with AML. Results Between January 1998 and December 2005, 240 children were treated for AML at 8 Italian Centers, for a total of 521 treatment courses and 63,232 person-days at risk. Bacteremia was observed in 32% of treatment courses and IFD was seen in 10% (P

To describe the course of hepatitis C in a cohort of 105 survivors after childhood cancer.Data on chemo/radiotherapy, clinical status, serial alanine aminotransferase (ALT) evaluation, and virological parameters after the end of treatment were collected for each patient. Liver biopsies, when performed, were centrally evaluated by a pathologist.All patients were alive at the end of follow-up and did not show hepatic insufficiency. ALT evaluation along the entire follow-up showed a moderate (87%) or a remarkable (13%) cytolytic pattern. Young age at diagnosis, hematopoietic stem cell transplantation, and duration of infection significantly correlate with a worse hepatic activity. Type of tumor and chemo and/or radiotherapy regimens did not influence the pattern of hepatic cytolysis. Liver biopsy, centrally reviewed in 30% of the cohort, showed one case of cirrhosis and mild fibrosis in 71% of the group. Higher degrees of fibrosis did not seem to be related to any exposition to chemo/radiotherapy but correlated significantly with the more remarkable cytolytic course.The outcome of hepatitis C in our patients is comparable to the one described in European cohorts of adult cancer survivors and perinatally infected subjects. Nevertheless, progression to high degrees of hepatic damage has to be monitored by a careful follow-up.

The aims of this study were to assess the incidence and risk factors of major central venous catheter (CVC)-related complications in a large cohort of children affected by oncological, hematological, or immunological diseases in a 7-year prospective observational study at a single center. Nine hundred fifteen CVCs were inserted in 748 children for a total period of 307,846 CVC-days. Overall, 298 complications were documented with a complication rate of 0.97/1,000 CVC-days: 105 mechanical complications (dislocations 0.30/1,000 CVC-days, ruptures 0.04/1,000 CVC-days), 174 infections (bloodstream infections 0.46/1,000 CVC-days, tunnel infections 0.10/1,000 CVC-days), and 19 thrombosis (0.06/1,000 CVC-days). Significant risk factors were: diagnosis of acute lymphoblastic leukemia (ALL) and ageor=3 years for dislocations; nonmalignant disease for ruptures; ALL for thrombosis; double-lumen and partially implanted CVCs for bloodstream infections; ageor=3 years for tunnel infections. In conclusion, the rate of CVC-related complications in children was lower than that usually reported.

Risk factors of central venous lines-related thrombosis in children with acute lymphoblastic leukemia during induction therapy: a prospective study

Background Invasive aspergillosis (IA) is a serious problem in patients suffering from hematological malignancies. Surgical resection has been reported to improve disease control and patient survival. There are few reports describing the role of surgery in children with pulmonary IA. Procedure From October 1998 to September 2005, 21 patients fulfilled the inclusion criteria. Demographic and clinical data, as well as type and duration of antifungal therapy; surgery and related complications; time elapsing from surgery to resumption of chemotherapy were collected retrospectively through a specially designed form filled in by each investigator. Results Eleven males and 10 females, aged between 2 and 17 years underwent one or more surgical lung resections for diagnostic and therapeutic purposes. Surgical complications were reported in three patients. Two patients, who underwent a wedge resection and a lobectomy, respectively, had no fungal lesions detected at surgery. Seventeen of 20 patients with malignancy resumed chemotherapy after a median of 19 days from surgery, range 7–81, and 11 of them underwent hematopoietic stem cell transplantation after a median time of 60 days from surgery, range 19–110. After a median follow-up of 1.7 years, 12 patients are alive while 9 patients have died from progression of their underlying disease. Conclusions This study suggests that the combination of medical antifungal therapy and early surgical excision is a feasible and an effective strategy in pediatric patients with IA. In order to avoid unnecessary surgical procedures, we advise checking the response to antifungal therapy by chest-computed tomography immediately before the date of surgery. Pediatr Blood Cancer 2007;49:909–913. © 2006 Wiley-Liss, Inc.

The aim of this retrospective study was to test the residual humoral immunity to compulsory vaccines after the end of chemotherapy for acute lymphoblastic leukaemia in a cohort of 70 Italian children. All the patients, who had been immunised according to the Italian schedule prior to the disease, were tested for antibody levels against tetanus and hepatitis B at a median of 10 months after the end of therapy. Median age at diagnosis of leukaemia was 48 months, and median age at vaccine titration was 84 months. The protective level of antibodies for tetanus and hepatitis B was shown in 83% and 81% of patients, respectively; the remaining 17% and 19% were not protected against the two pathogens. Double negativity was observed in only four of 62 (6%) patients in the cohort. These data were comparable with published data regarding healthy children of the same age and from the same geographical areas. Therefore, given the direct and indirect costs of performing laboratory tests, as well as the cost of revaccination, our proposal is to continue the vaccination schedule according to the child's age without any titration screening 6 months after the end of therapy. Larger studies are needed to confirm these observations.

Purpose To compare two types of central venous catheters (Broviac and valved clampless) for the incidence and severity of catheter-related complications in children. Patients and methods The authors report data on the mechanical and infectious complications collected in a prospective analysis of 92 catheters inserted in 82 children from January 2000 to March 2001. Results Two different devices were inserted: 51 Broviac and 41 clampless valved catheters. During the follow-up of 17,803 catheter-days 52 complications were observed: 40 mechanical episodes and 12 infectious events. In the Broviac group the median follow-up was 179 days and the total number of catheter-days was 10,911. A total of 29 complications were observed, occurring in 22 catheters (43%), with an overall incidence of 0.27/100 catheter-days. In the clampless group the median follow-up was 134 days and the total number of catheter days was 6893. A total of 23 complications were observed, occurring in 19 devices (46%), with an incidence of 0.32/100 catheter days. Conclusions There were no major differences in the incidence of mechanical or infectious complications between the two devices. Malfunction was more frequent in Broviac catheters, whereas catheter displacement occurred more frequently in clampless valved catheters. These results show the importance of central venous catheter-related mechanical complications in the management of children with hematologic or oncologic malignancies.

Objective.Vaccinations are the most important tool to prevent infectious diseases. Chemotherapy-induced immune depression may impact the efficacy of vaccinations in children.Patients and Methods. A panel of experts of the supportive care working group of the Italian Association Paediatric Haematology Oncology (AIEOP) addressed this issue by guidelines on vaccinations in paediatric cancer patients. The literature published between 1980 and 2013 was reviewed.Results and Conclusion. During intensive chemotherapy, vaccination turned out to be effective for hepatitis A and B, whilst vaccinations with toxoid, protein subunits, or bacterial antigens should be postponed to the less intensive phases, to achieve an adequate immune response. Apart from varicella, the administration of live-attenuated-virus vaccines is not recommended during this phase. Family members should remain on recommended vaccination schedules, including toxoid, inactivated vaccine (also poliomyelitis), and live-attenuated vaccines (varicella, measles, mumps, and rubella). By the time of completion of chemotherapy, insufficient serum antibody levels for vaccine-preventable diseases have been reported, while immunological memory appears to be preserved. Once immunological recovery is completed, usually after 6 months, response to booster or vaccination is generally good and allows patients to be protected and also to contribute to herd immunity.

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%).

We report three cases of invasive Geotrichum capitatum infection in patients with acute leukemia for which an enzyme-linked immunosorbent assay (ELISA) for Aspergillus galactomannan was positive, with no evidence of aspergillosis. Supernatants obtained from suspensions of 17 G. capitatum strains gave positive reactions with the Aspergillus galactomannan ELISA. These clinical and laboratory data seem to suggest that G. capitatum produces a soluble antigen that is cross-reactive with Aspergillus galactomannan.

Tunnel infection is an uncommon but serious complication observed in patients with partially implanted central venous catheters. International guidelines suggest that should include antibiotics and catheter removal. A success rate of only 5-20% was reported without catheter removal. We treated 13 episodes of tunnel Gram-positive bacterial infection occurring in pediatric patients with cancer or serious blood disorders with 24-hr intra-catheter antibiotic continuous infusion. This approach led to a 69% success rate. Continuous infusion might be an attractive option to treat tunnel Gram-positive bacterial infections when catheter removal might not be feasible or advisable.

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.

The most intensive chemotherapy regimens were used in the past for leukemia patients who were the main focus of trials on infections; today there are increasing numbers of children with solid cancer and considerable risk of infection who do receive intensive stand ard-dose chemotherapy. Despite a continuous will to protect the immune-compromised child from infections, evidence-based indications for intervention by non-pharmacological tools is still lacking in the pediatric hematology-oncology literature. Guidelines on standard precautions as well as precautions to avoid transmission of specific infectious agents are available. As a result of a consensus discussion, the Italian Association for Pediatric Hematology-Oncology (AIEOP) Cooperative Group centers agree that for children treated with chemotherapy both of these approaches should be implemented and vigorously enforced, while additional policies, including strict environmental isolation, should be restricted to patients with selected clinical conditions or complications. We present here a study by the working group on infectious diseases of AIEOP.

Influenza A (H1N1) pandemic reached its peak in Europe in autumn 2009. H1N1 infection can be a serious complication in patients with comorbidity or immunodepression. Here, we report of a boy with newly diagnosed acute promyelocytic leukemia with a very severe respiratory distress caused by influenza A (H1N1) infection in pulmonary aspergillosis, successfully treated with antifungal therapy, oseltamivir, and extracorporeal membrane oxygenation.

Background Fungal infections are diagnosed increasingly often in patients affected by hematological diseases and their mortality has remained high. The recent development of new antifungal drugs gives the clinician the possibility to assess the combination of antifungal drugs with in-vitro or in animal-model synergistic effect. Methods We analyzed retrospectively the safety and efficacy of caspofungin-based combination therapy in 40 children and adolescents, most of them were being treated for a malignant disease, who developed invasive aspergillosis (IA) between November 2002 and November 2005. Results Thirteen (32.5%) patients developed IA after hematopoietic stem cell transplantation (HSCT), 13 after primary diagnosis, usually during remission-induction chemotherapy, and 14 after relapse of disease. Severe neutropenia was present in 31 (78%) out of the 40 patients. IA was classified as probable in 20 (50%) and documented in 20 (50%) patients, respectively. A favorable response to antifungal therapy was obtained in 21 patients (53%) and the probability of 100-day survival was 70%. Different, though not significant, 100-day survival was observed according to the timing of diagnosis of IA: 51.9% after HSCT; 71.4% after relapse; and 84.6% after diagnosis of underlying disease, p 0.2. After a median follow-up of 0.7 years, 20 patients are alive (50%). Overall, the combination therapy was well tolerated. In multivariate analysis, the factors that were significantly associated to a better overall survival were favorable response to antifungal therapy, p 0.003, and the timing of IA in the patient course of underlying disease, p 0.04. Conclusion This study showed that caspofungin-based combination antifungal therapy is an effective therapeutic option also for pediatric patients with IA. These data need to be confirmed by prospective, controlled studies.

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.

Invasive aspergillosis is an uncommon but often lethal complication in immunocompromised patients. Despite the progress obtained with new antifungal drugs, intracranial aspergillosis often requires a combined medical and surgical approach. Most cases previously reported in immunocompromised children were fatal. We describe 4 immunosuppressed children with intracranial aspergillosis successfully treated with surgery and antifungal long-term therapy.

Aim To evaluate the incidence of surgical site infections and bacteremias occurring within 30 days from insertion of partially implanted central venous catheters. Patients and Methods Four hundred eighteen devices positioned in children with cancer or undergoing bone marrow transplant were followed prospectively. Results During a follow-up of 12,394 catheter-days, a total of 13 infectious episodes were documented, with an overall incidence of 3.1% and 1.05 episodes/1,000 catheter-days. Coagulase-negative staphylococci represented the causative pathogens of all episodes. Overall, surgical wound infections occurred in 1.4% of all catheters, with a rate of 0.48/1,000 catheter-days, while isolated bacteremias were observed in 1.7% of all inserted devices, with a rate of 0.57/1,000 catheter-days. Conclusions Infections are rare events within 30 days from insertion of partially implanted central venous catheters and coagulase-negative staphylococci represent the most frequently isolated cause of these complications. Pediatr Blood Cancer 2007;48:35–38. © 2005 Wiley-Liss, Inc.

To evaluate the possible link between malfunctioning events and catheter related infections in indwelling central venous devices in children with cancer.Prospective observation of 418 devices inserted in 2 Italian tertiary care pediatric cancer centers. The presence of a relationship was identified if a malfunctioning event was followed by a catheter related infection within 10 days, or vice versa.The 418 catheters were followed for a period of 107,012 days. Among the malfunctioning events 2 out of 141 (1%) were followed by a catheter related infection while among infectious episodes 3 out of 93 (3%) were followed by a malfunctioning event.Malfunctioning events followed by catheter related infections and catheter related infections followed by malfunctioning are both rare events in children with cancer.

s / Digestive and Liver Disease 46 (2014) e85–e127 e101 TREATING ANDMONITORING VIRAL HEPATITIS B INFECTION IN PAEDIATRIC PATIENTS RECEIVING IMMUNOSUPPRESSIVE THERAPIES OR WITH THE PROSPECTIVE OF HAEMATOPOIETIC STEM CELL TRANSPLANTATION Sara Tardito1,∗, Michele Pinon1, Sebastian Dorin Asaftei2, Francesca Carraro2, Mareva Giacchino2, Franca Fagioli 2, Alfredo Marzano3, Pier Luigi Calvo1 1 Department of Pediatric Gastroenterology and Hepatology, Regina Margherita Children’s Hospital, Azienda Ospedaliera Citta della Salute e della Scienza, University of Turin, Turin, Italy 2 Paediatric Onco-Haematology, Stem Cell Transplantation and Cellular Therapy Division, Regina Margherita Children’s Hospital, Azienda Ospedaliera Citta della Salute e della Scienza, University of Turin, Turin, Italy 3 Gastro-Hepatology Unit, Azienda Ospedaliera Citta della Salute e della Scienza, University of Turin

The purpose of the present study was to analyze the characteristics of infectious complications occurring during the first 100 days after bone marrow transplantation (BMT) in a cohort of 123 pediatric patients with hematological malignancies (n = 73), solid tumors (n = 32) and nonmalignant disorders (n = 18). Fifty-eight patients received allogeneic grafts, and 65 patients an autologous transplant. Fever developed in 107 (87%) children; 82% of infectious complications occurred during the neutropenic period. Documented infection developed in 33 (31%) patients, while 74 (69%) patients had possible infection (i.e. fever of unknown origin). The incidence of bacteremia was 21%, and gram-positive cocci were the predominant pathogens; non-bacteremic microbiologically documented infection developed in 6% of patients; clinically evident infection developed in 4% of subjects. The incidence of primary febrile episodes was not significantly different between autologous and allogeneic BMT (86% vs 88%); nor did the median number of days to the onset of fever (5 days in both groups) or the median duration of fever (5 days in both groups) differ. In contrast, the frequency of secondary febrile episodes was significantly higher (P = 0.0001) in allogeneic BMT recipients (40%) than in autologous recipients (15%). The mortality rate due to infections was 2/36 (5%) for matched sibling donor BMT, and 1/13 (8%) for matched unrelated donor BMT. No deaths occurred in the 65 patients who were autografted. Invasive fungal infections accounted for 2 of the 3 infectious deaths. In conclusion, the majority of children undergoing BMT experienced at least one infectious episode; allogeneic BMT recipients were at high risk of developing secondary febrile episodes, but the overall mortality rate due to infection in the first 100 days after transplantation was low.

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.

In patients undergoing bone marrow transplantation cryptococcosis is rarely encountered. We report a fatal case of Cryptococcus meningitis in a 12-year-old girl with acute lymphoblastic leukemia (ALL) in second remission who had a transplant from a human leukocyte antigen (HLA)-identical unrelated bone marrow donor. The conditioning regimen was thiotepa, cyclophosphamide, and total body irradiation (TBI); graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporin A, methotrexate, and antilymphocyte globulin (ALG). The patient experienced stage III GVHD responsive to high-dose corticosteroids. On day +54 a thrombotic microangiopathy occurred. On day +64 neurological status worsened; a brain computed tomographic (CT) scan showed hyperdense lesions suggesting fungal infection. Detection of cryptococcal antigen by latex agglutination was positive but India ink stain and culture were negative. Despite treatment with amphotericin B, 5-flucytosine, and granulocyte-macrophage colony-stimulating factor, the patient died 13 days after the diagnosis.

Amphotericin B, despite its intrinsic servere toxicity, is the most commonly used empirical antifungal therapy in cancer patients with unexplained fever not responding to empirical antibacterial therapy. The aim of this study was to show whether fluconazole was as effective as, and less toxic than, amphotericin, with no effort made to compare the antifungal activity of the two drugs. A group of 112 persistently febrile (> 38 degrees C) and granulocytopenic (< 1000 cells/mm3) cancer patients, not receiving any absorbable antifungal antibiotic for prophylaxis, with a mean age of 27 years (range 1-73 years), undergoing chemotherapy for a variety of malignancies and with a diagnosis of unexplained fever after at least 96 h of empirical antibacterial therapy, were randomised to receive either fluconazole (6 mg/kg/day up to 400 mg/day) or amphotericin B (0.8 mg/kg/day) as empirical antifungal treatment. Patients were required to have normal chest X-rays at randomisation, no previous history of aspergillosis and negative surveillance cultures for Aspergillus. The intention-to-treat analysis showed defervescence and survival without treatment modification in 42 of 56 patients (75%) in the fluconazole group and in 37 of 56 (66%) in the amphotericin B group (P = 0.4). Duration of therapy was 6 days (95% CI = 4-8 days) in both groups. Death occurred in 3 patients (5%) in the fluconazole and in 2 (4%) in the amphotericin B group. No fungal death was documented in either group. Adverse events developed in 18 of 56 patients (32%) in the fluconazole group and in 46 of 56 (82%) in the amphotericin B group (P < 0.001). In the amphotericin B group, 5 patients had treatment discontinued because of toxicity, versus none in the fluconazole group, a difference which approached statistical significance (P = 0.06). This study shows that fluconazole is by far less toxic than amphotericin B and suggests that it might be as effective as amphotericin B, in pragmatical terms and for this specific indication. However, numbers are too small to allow definitive conclusions about efficacy, and the use of fluconazole for this indication remains experimental. Future studies should try to identify patients more at risk of fungal infections, with the aim of individualising antifungal approaches.

1. Serum lipids and lipoprotein profiles were determined in children affected by different types of malignancies (leukaemias or lymphomas and solid tumours) both before any treatment and after remission of the disease following chemical or surgical therapy. 2. At the time of diagnosis, children bearing tumours showed hypertriglyceridaemia and reduced concentrations of plasma high-density lipoprotein cholesterol levels, the decrease being particularly prominent in patients with haematological tumours. Children bearing solid tumours displayed an increase of total cholesterol, while those with haematological cancer showed decreased phospholipid levels; low-density lipoprotein cholesterol in neoplastic patients was not significantly different from control values. High triacylglycerol and low high-density lipoprotein cholesterol levels were also evident in cancer patients divided according to age into three groups (0–5, 6–10 and 11–15 years) when compared with age-matched control subjects. Similarly, high triacylglycerol and low high-density lipoprotein cholesterol levels were also observed in both male and female children when patients were divided according to sex and compared with corresponding controls. 3. Clinical remission after therapy was accompanied by an increase of high-density lipoprotein cholesterol levels compared with values observed at diagnosis. In contrast, post-treatment levels of triacylglycerol were higher than those observed before therapy. These results support the hypothesis that alterations of high-density lipoprotein cholesterol levels may be related, at least in part, to the rate of tumour growth, while modifications of triacylglycerol levels may be mediated by different mechanisms.