Gudrun Fleischhack

Randomized trial comparing liposomal daunorubicin with idarubicin as induction for pediatric acute myeloid leukemia: results from Study AML-BFM 2004

Outcomes of patients with acute myeloid leukemia (AML) improve significantly by intensification of induction. To further intensify anthracycline dosage without increasing cardiotoxicity, we compared potentially less cardiotoxic liposomal daunorubicin (L-DNR) to idarubicin at a higher-than-equivalent dose (80 vs 12 mg/m(2) per day for 3 days) during induction. In the multicenter therapy-optimization trial AML-BFM 2004, 521 of 611 pediatric patients (85%) were randomly assigned to L-DNR or idarubicin induction. Five-year results in both treatment arms were similar (overall survival 76% ± 3% [L-DNR] vs 75% ± 3% [idarubicin], Plogrank = .65; event-free survival [EFS] 59% ± 3% vs 53% ± 3%, Plogrank = .25; cumulative incidence of relapse 29% ± 3% vs 31% ± 3%, P(Gray) = .75), as were EFS results for standard (72% ± 5% vs 68% ± 5%, Plogrank = .47) and high-risk (51% ± 4% vs 46% ± 4%, Plogrank = .45) patients. L-DNR resulted in significantly better probability of EFS in patients with t(8;21). Overall, treatment-related mortality was lower with L-DNR than idarubicin (2/257 vs 10/264 patients, P = .04). Grade 3/4 cardiotoxicity was rare after induction (4 L-DNR vs 5 idarubicin). Only 1 L-DNR and 3 idarubicin patients presented with subclinical or mild cardiomyopathy during follow-up. In conclusion, at the given dose, L-DNR has overall antileukemic activity comparable to idarubicin, promises to be more active in subgroups, and causes less treatment-related mortality. This trial was registered at www.clinicaltrials.gov as #NCT00111345.

Consequent and intensified relapse therapy improved survival in pediatric AML: results of relapse treatment in 379 patients of three consecutive AML-BFM trials

Relapse remains the major cause of treatment failure in pediatric acute myeloid leukemia (AML). We analyzed the clinical characteristics, treatment response to relapse treatment and overall survival (OS) of 379 children with AML relapse treated according to three consecutive frontline protocols of the AML-Berlin/Frankfurt/Muenster study group (AML-BFM-87/-93/-98). Of 313 treated patients with data on remission status, 198 children (63%) achieved a second complete remission (CR2). There were no significant differences in remission rates and OS for the intensive reinduction treatment schedules used. The 5-year OS rate was 23% for the total group and 29% for patients treated with curative intent. OS rates increased with study periods from 18 to 34% (Plog rank=0.012), whereas the proportion of patients receiving only palliative treatment decreased from 23 to 11% (PCMH=0.005). Late relapse, no allogeneic stem cell transplantation (SCT) in CR1, age <10 years and favorable cytogenetics were independent favorable prognostic factors for survival. Achievement of CR2 was the most important prognostic factor (OS 44 vs 3%; Plog rank<0.0001). Overall, one-third of children with relapsed AML can be cured today. SCT in CR2 is recommended for most patients, although its impact on CR2 is discussed.

Norovirus outbreak in a pediatric oncology unit

Objective. Norovirus (NV) is an etiologic agent of outstanding importance that can cause severe epidemic gastroenteritis in day-care centers, schools, nursing homes, and hospitals. Therefore NV requires foremost attention as a pathogen responsible for epidemics of gastroenteritis in immunocompromised inpatients. In this study, a NV outbreak in a pediatric oncology unit is described and the consequences for this high-risk population are discussed. Material and methods. Stool and vomitus samples from 11 patients were tested for NV and other relevant viruses during the outbreak by reverse transcriptase-polymerase chain reaction (RT-PCR) and/or enzyme-linked immunosorbent assay (ELISA) (whenever an appropriate ELISA was available). Norwalk virus PCR amplifications were sequenced and phylogenetic analysis was performed.Results. The index patient and the chain of infection were identified. Follow-up investigation surprisingly demonstrated viral shedding for a maximum of 140 days (median 23 days). Three patients experienced severe or life-threatening symptoms, probably related to NV infection.Conclusions. In the event of an outbreak of gastroenteritis (involving two or more symptomatic patients) in a pediatric oncology unit, the search for NV in stool or vomitus specimens should be initiated in good time. As long as the data are limited regarding whether a detectable viral antigen or RNA in stools represents an infectious virus, patients have to be isolated as long as the diagnostic assays remain positive. During the acute phase of the illness, health-care workers should wear masks in addition to practicing meticulous hand hygiene with a disinfectant of proven activity against NV. Pediatric oncology patients must be closely monitored during follow-up investigations as they may shed the virus for months. There is some evidence from the outbreak described here that those patients face a greater risk of severe NV-related complications.

Treatment of young children with localized medulloblastoma by chemotherapy alone: results of the prospective, multicenter trial HIT 2000 confirming the prognostic impact of histology.

This study was designed to confirm the previously observed favorable survival rates and prognostic factors in young children with nonmetastatic medulloblastoma (MB) treated with postoperative chemotherapy alone. Patients who received a diagnosis during the period January 2001 through December 2005 and who were aged <4 years received 3 cycles of postoperative systemic multiagent chemotherapy and intraventricular methotrexate. In cases of complete remission, treatment was terminated after 2 additional cycles of chemotherapy. Otherwise, secondary surgery, radiotherapy, and consolidation chemotherapy were recommended. At a median follow-up of 4.5 years, the 5-year event-free survival (EFS) and overall survival (OS) rates (± standard error) for 45 patients (median age, 2.5 years) were 57% ± 8% and 80% ± 6%, respectively. Nineteen patients with desmoplastic/nodular MB variants had better 5-year EFS and OS rates (90% ± 7% and 100% ± 0%, respectively) than did 23 patients with classic MB (30% ± 11% and 68% ± 10%, respectively; P < .001 for EFS; P = .008 for OS). Five-year EFS and OS rates for 3 children with anaplastic MB were 33% ± 27%. Desmoplastic/nodular histology was an independent prognostic factor for EFS. Twenty-nine of 30 patients without postoperative residual tumor remained in continuous complete remission. Our results confirm that histology of MB variants is a strong prognostic factor in this age group. Sustained tumor control can be achieved by this chemotherapy regimen in young children with desmoplastic/nodular MB variants. For children with non-desmoplastic/nonnodular MB variants, for which predominantly local relapses lead to less favorable survival rates, local radiotherapy has been introduced after chemotherapy since 2006.

Surveillance for Nosocomial and Central Line-Related Infections Among Pediatric Hematology-Oncology Patients

OBJECTIVE To determine the incidence of all nosocomial infections (NIs) in pediatric hematology-oncology patients, as well as central venous access device (CVAD)-associated infections acquired during home care. DESIGN Prospective surveillance study. SETTING The Pediatric Hematology and Oncology Department at the University Hospital Bonn. PATIENTS All patients admitted from January through October 1998 (surveillance period). METHODS Standardized surveillance system based on the Centers for Disease Control and Preventions National Nosocomial Infections Surveillance System. RESULTS A total of 143 patients were hospitalized for 3,701 days (776 admissions) during the surveillance period. Of the 40 NIs detected, 26 were CVAD-related, with 21 bloodstream infections (BSIs) and 5 local infections. Four were Clostridium difficile-associated diarrheal illnesses, 3 were pneumonias, and 7 were other infections. The incidence of NIs was 10.8 per 1,000 patient-days (5.2 NIs/100 admissions). The overall CVAD-related BSI rate was 7.4 per 1,000 utilization days, without a significant difference between implanted infusion ports and tunneled catheters. In addition, 7 CVAD-related infections occurred during home care. All 8 BSIs associated with tunneled catheters and 13 (76%) of the 17 BSIs associated with ports were acquired nosocomially. For inpatients and outpatients combined, the exit sites of tunneled catheters were more likely to become locally infected than were the needle entry sites of ports (relative risk, 8.0; P=.007). In 30 (75%) of the 40 NIs, the affected patients had severe neutropenia (<500/mm3) at the time of infection. CONCLUSIONS Most NIs in the pediatric hematology-oncology patients were associated with CVAD devices. Although many infections in this high-risk population may not be preventable through infection control measures, the careful evaluation of specific infection rates permits the identification of risk factors that may be targeted by infection control programs. Prospective surveillance for NIs on pediatric oncology units is an indispensable tool for this internal quality control.

Healthcare-associated infections in pediatric cancer patients: results of a prospective surveillance study from university hospitals in Germany and Switzerland

BackgroundPediatric cancer patients face an increased risk of healthcare-associated infection (HAI). To date, no prospective multicenter studies have been published on this topic.MethodsProspective multicenter surveillance for HAI and nosocomial fever of unknown origin (nFUO) with specific case definitions and standardized surveillance methods.Results7 pediatric oncology centers (university facilities) participated from April 01, 2001 to August 31, 2005. During 54,824 days of inpatient surveillance, 727 HAIs and nFUOs were registered in 411 patients. Of these, 263 (36%) were HAIs in 181 patients, for an incidence density (ID) (number of events per 1,000 inpatient days) of 4.8 (95% CI 4.2 to 5.4; range 2.4 to 11.7; P < 0.001), and 464 (64%) were nFUO in 230 patients. Neutropenia at diagnosis correlated significantly with clinical severity of HAI. Of the 263 HAIs, 153 (58%) were bloodstream infections (BSI). Of the 138 laboratory-confirmed BSIs, 123 (89%) were associated with use of a long-term central venous catheter (CVAD), resulting in an overall ID of 2.8 per 1,000 utilization days (95% CI 2.3 to 3.3). The ID was significantly lower in Port-type than in Hickman-type CVADs. The death of 8 children was related to HAI, including six cases of aspergillosis. The attributable mortality was 3.0% without a significant association to neutropenia at time of NI diagnosis.ConclusionOur study confirmed that pediatric cancer patients are at an increased risk for specific HAIs. The prospective surveillance of HAI and comparison with cumulative multicenter results are indispensable for targeted prevention of these adverse events of anticancer treatment.

Wound care with antibacterial honey (Medihoney) in pediatric hematology–oncology

The physiologic process of wound healing is impaired and prolonged in pediatric patients receiving chemotherapy. Due to profound immunosuppression, wound infection can easily spread and act as the source of sepsis. Referring to in vitro studies, which confirmed the antibacterial potency of special honey preparations against typical isolates of nosocomially acquired wound infections (including Methicillin-resistant Staphylococcus aureus and Vancomycin-resistant enterococci) and considering the encouraging reports from other groups, Medihoney has now been used in wound care at the Department of Pediatric Oncology, Children’s Hospital, University of Bonn for 3 years. Supplemented with clinical data from pediatric oncology patients, this article reviews the scientific background and our promising experience with Medihoney in wound care issues at our institution. To collect and analyze the available experience, we prepare an internet-based data documentation module for pediatric wound care with Medihoney.

Pharmacokinetics following intraventricular administration of chemotherapy in patients with neoplastic meningitis.

Intraventricular administration of chemotherapy is one approach to overcoming the limited distribution of anticancer drugs and their active metabolites into the CNS. This form of regional chemotherapy has led to effective treatment of occult and overt meningeal leukaemia in humans. In contrast, the efficacy of this therapy is extremely limited in the treatment of leptomeningeal dissemination of various solid tumours. Pharmacokinetic studies of the commonly intraventricularly applied anticancer agents in humans have demonstrated that, using low drug doses, very high drug concentrations can be achieved in the cerebrospinal fluid (CSF) and relatively high concentrations in the leptomeninges but not in the brain tissue and the plasma. Therefore, this approach is not an effective treatment for bulky disease of brain tissue, and results in minimal systemic toxicity. In comparison with intralumbar administration, lower interpatient variability of CSF drug concentrations and improved clinical efficacy were observed. ‘Concentration × time’ schedules, i.e. frequent small drug doses over a short period, enable long-term CSF exposure to cytotoxic drug concentrations while avoiding excessively high and potentially neurotoxic drug concentrations. The technique of ventriculolumbar cerebrospinal perfusion delivers continuously high drug concentrations throughout the CSF for several hours, but its widespread use is limited by the technical complexities of this approach.In this article, the dosages, schedules and pharmacokinetic data of routinely used intraventricular agents in humans, e.g. methotrexate, cytarabine, glucocorticoids and thiotepa, are outlined in detail. In addition, pharmacokinetic data of investigational agents for intraventricular administration (diaziquone, DTC 101, mercaptopurine, mafosfamide, etoposide, topotecan, nimustine [ACNU] and bleomycin) are presented. Better understanding of the CSF pharmacology of these drugs is an essential prerequisite for safe, effective administration of these drugs. Investigational efforts are underway to verify the feasibility and efficacy of different dosages, schedules and combination therapies of these new intra-CSF agents. Current and future clinical research should also focus on methods allowing the delivery of tumoricidal drug concentrations for extended periods into the CSF and the brain tissue while minimising neurotoxicity and systemic toxicity (e.g. liposomal drug preparations, monoclonal antibodies, immunotoxins and gene therapy).

Nimotuzumab for pediatric diffuse intrinsic pontine gliomas.

Introduction: Diffuse intrinsic pontine gliomas (DIPG) have a poor prognosis: the median survival rate is less than one year. Radiotherapy is the only effective treatment affording an overall survival of 6 – 9 months. So far, no improvement has been achieved with the addition of single/poly-chemotherapy regimens. An urgent need is to advance in this field, from both the biological and the clinical points of view. Areas covered: Among the few studies providing biological information on DIPG, Gilbertsons group demonstrated a significant increase in EGFR expression. The activity of nimotuzumab, a humanized anti-EGFR monoclonal antibody, was therefore studied within a Phase II trial in 47 relapsing pediatric patients with DIPG and high-grade gliomas, showing an interesting, persistent response, especially in the first group treated. A multicenter exploratory study combining nimotuzumab and radiotherapy showed disease control and an overall patient survival similar to previous experiences along with an improvement in the quality of patient survival and no severe side effects. Expert opinion: We recommend considering this combination in the armamentarium against DIPG. It might be improved by adding other target drugs/low-toxicity chemotherapy regimens with a synergistic effect with the anti-EGFR component.

Ovarian small cell carcinoma of the hypercalcemic type in children and adolescents: a prognostically unfavorable but curable disease.

Ovarian small cell carcinoma of the hypercalcemic type is a rare neoplasm that is associated with a poor prognosis. The objective of the current study was to investigate the clinicopathologic features of this tumor and to develop preliminary diagnostic and therapeutic guidelines.