Utility of bronchoalveolar lavage in the diagnosis of pulmonary infection in children with haematological malignancies.

BACKGROUND: Fibre-optic bronchoscopy with bronchoalveolar lavage (BAL) is a safe procedure and is associated with low morbidity and mortality in immunocompromised children. Although many studies have highlighted the advantages of positive BAL results in the diagnosis of pulmonary infections, there have been few reports examining the impact of a negative BAL result on clinical management in immunocompromised children on empiric broad-spectrum antimicrobial therapy. AIM: The aim of this study was to evaluate BAL in the diagnosis of pulmonary infections in children with haematological malignancies who develop pneumonia unresponsive to empiric antimicrobial therapy, and also to determine whether a negative BAL result contributed to the clinical management of these patients. MATERIALS AND METHODS: A retrospective review of 44 BAL procedures performed in 33 children with haematological malignancy diagnosed and treated at Our Lady's Children Hospital, Crumlin, Dublin 12, Ireland, over a 10-year period was carried out. RESULTS: We identified a pathogen causing pneumonia in 24 of 44 BAL procedures (54.5 %). The BAL procedure resulted in modification of antimicrobial treatment after 20 of 24 procedures with positive results (83.3 %) in 16 of 20 patients (80 %). Management was changed after 8 of 20 procedures with negative results (40 %) in 8 of 18 patients (44.4 %). The procedure was well tolerated in all patients. CONCLUSIONS: Our study supports the use of bronchoscopy with BAL as a diagnostic intervention in this patient population. We consider BAL a safe procedure from which both positive and negative results contribute to the patient's clinical management.

Cytomegalovirus infection in paediatric haemopoietic stem cell transplantation.

A retrospective audit of CMV infection was undertaken to determine prevalence and outcome in the national paediatric Haemopoietic Stem Cell Transplant (HSCT) unit, with particular reference to surveillance and treatment. All patients undergoing HSCT (125 allogeneic, 50 autologous) from January 1994 to December 2004 were included. Nine underwent a second transplant for graft failure or disease recurrence. Of 134 allogeneic transplants performed, 62 were unrelated. Shell vial cultures of throat swabs and urine, and blood samples for pp65 antigenemia +/- PCR were tested weekly for a mean of 147 days post transplant. CMV negative blood products and filters were used in all. 11 rec+/donor-, 12rec-/donor+ and 10rec+/donor+ transplants were performed. All received prophylactic acyclovir, IVIG was prescribed for all but CMV -/- transplants. Initial detection of CMV was urine in 5 cases, four of whom developed antigenemia. Of ten patients who developed antigenemia, nine were treated with ganciclovir +/- foscarnet and two of these patients developed CMV pneumonitis and died. The current policy of strict surveillance, matching donor and recipient CMV status, use of CMV negative blood products and filters and pre-emptive therapy appears to be effective in controlling CMV disease/infection in the peritransplant period.

Penile malignant peripheral nerve sheath tumour (schwannoma) in a three-year-old child without evidence of neurofibromatosis.

Malignant schwannoma (malignant peripheral nerve sheath tumour, MPNST) is a rare high-grade tumour arising from peripheral nerves. We report the case of a 3-year-old male who presented with a non-tender lesion on the dorsum of his penis. The lesion was excised and a formal circumcision performed. Histology of the lesion revealed a spindle cell tumour. Immunohistochemistry showed the tumour cells to be strongly positive for S100 and Vimentin. A diagnosis of intermediate grade malignant peripheral nerve sheath tumour was made. Malignant schwannoma is rare in children and is previously unreported in the penis in the paediatric age group without evidence of neurofibromatosis.

Molecular cytogenetic analysis of recurrent unbalanced t(11;17) in neuroblastoma.

Loss of 11q material occurs in approximately 30% of advanced stage neuroblastoma and defines a distinct genetic subtype of this disease. These tumors almost always possess unbalanced gain of the 17q, along with many additional recurrent chromosomal imbalances. Loss of 11q and gain of 17q is often the consequence of an unbalanced translocation between the long arms of both chromosomes, but because of the involvement of other chromosomal mechanisms, the actual frequency of t(11;17) is unknown. In addition, chromosomal breakpoint positions for the t(11;17) are variable in different tumors, with breakpoints on neither the 11q nor 17q being well defined. We have used interphase fluorescence in situ hybridization analysis to detect a der(11)t(11;17) in a series of neuroblastomas with 11q loss/17q gain using a statistical approach which could be applicable to the detection of translocations in other solid tumors. The frequency of der(11)t(11;17) was approximately 90% in our neuroblastoma series. A balanced t(11;17) was also detected in a MYCN amplified tumor, which is a distinctly different genetic subtype from the 11q- tumors. Breakpoint positions on 11q were determined to be variable, whereas all breakpoints on 17q appeared to cluster proximal to position 43.1 Mb on the DNA sequence map. The majority of tumors had large numbers of nuclei with 2 or more copies of der(11)t(11;17), which led to unbalanced gain of 11p, and further increases in 17q imbalance. The prevalence of t(11;17) in neuroblastoma warrants additional studies to further define the range in variation in breakpoint positions on both chromosomes and to elucidate the molecular mechanisms that lead to this important and interesting recurrent genetic abnormality.

Evolution of unbalanced gain of distal chromosome 2p in neuroblastoma.

Neuroblastoma, one of the most common tumors of childhood, presents at diagnosis with a vast number of recurrent chromosomal imbalances that include hyperdiploidy for whole chromosomes, partial loss of 1p, 3p, 4p, 11q, 14q, partial gain of 1q, 7q, 17q and amplification of MYCN. These abnormalities are nonrandomly distributed in neuroblastoma as loss of 3p and 11q rarely occur in MYCN amplified neuroblastomas. Here, we report on a patient who had a non-MYCN amplified 3p-/11q- neuroblastoma at diagnosis who subsequently developed a high level of MYCN amplification in bone marrow metastases 41 months after induction of complete remission. The tumor at diagnosis had low level unbalanced gain of distal 2p. In order to assess the frequency of low level gain of distal 2p in neuroblastoma, we examined the comparative genomic hybridization results from 60 neuroblastomas. Among non-MYCN amplified neuroblastomas, 8/45 (18%) had low level gain of distal 2p. Low level gain for a segment of 2p (i.e. a region larger than the 2p23-->p24 undergoing amplification) was also detected in five of the 15 tumors that had high level MYCN amplification. The possibility that low level gain of distal 2p is a risk factor for high level MYCN amplification is discussed.

Oligonucleotide microarray analysis of gene expression in neuroblastoma displaying loss of chromosome 11q.

A number of distinct subtypes of neuroblastoma exist with different genetic abnormalities that are predicative of outcome. Whole chromosome gains are usually associated with low stage disease and favourable outcome, whereas loss of 1p, 3p and 11q, unbalanced gain of 17q and MYCN amplification (MNA) are indicative of high stage disease and unfavourable prognosis. Although MNA and loss of 11q appear to represent two distinct genetic subtypes of advanced stage neuroblastoma, a detailed understanding of how these subtypes differ in terms of global gene expression is still lacking. We have used metaphase comparative genomic hybridization (CGH) analysis in combination with oligonucleotide technology to identify patterns of gene expression that correlate with specific genomic imbalances found in primary neuroblastic tumours and cell lines. The tumours analysed in this manner included a ganglioneuroma, along with various ganglioneuroblastoma and neuroblastoma of different stages and histopathological classifications. Oligonucleotide microarray-based gene expression profile analysis was performed with Affymetrix HU133A arrays representing approximately 14 500 unique genes. The oligonucleotide microarray results were subsequently validated by quantitative real-time PCR, immunohistochemical staining, and by comparison of specific gene expression patterns with published results. Hierarchical clustering of gene expression data distinguished tumours on the basis of stage, differentiation and genetic abnormalities. A number of genes were identified whose patterns of expression were highly correlated with 11q loss; supporting the concept that loss of 11q represents a distinct genetic subtype of neuroblastoma. The implications of these results in the process of neuroblastoma development and progression are discussed.

Are gains of chromosomal regions 7q and 11p important abnormalities in neuroblastoma?

Neuroblastoma exhibiting deletion of a segment of the long arm of chromosome 11 represents a genetic subtype of tumor that is distinct from those exhibiting MYCN amplification or 1p deletion. The 11q- genetic subtype is further characterized by gain of 17q and loss of distal 3p material. Gain of 11p material has also been reported in neuroblastoma with 11q loss, but at a considerably lower frequency than gain of 17q or loss of the distal 3p region. Our results, however, indicate that gain of 11p may occur more frequently in 11q- neuroblastoma than what was previously realized. Comparative genomic hybridization analyses of neuroblastoma tissue from eleven patients indicated that six of 11 tumors (55%) with loss of 11q also possessed gain of 11p. The shortest region of 11p gain was 11p11.2-->p14. G-banding and fluorescence in situ hybridization analysis performed on tumor cells from primary and metastatic sites from one patient allowed us to infer that gain of 11p arose secondarily to the abnormality that led to the loss of 11q material. Gain of an entire chromosome 7 was detected in 17 of 43 (40%) tumors, whereas gain of 7q was detected in 5 of 43 (12%) tumors. Unlike gain of 11p, gain of an entire chromosome 7 appears to be prevalent in all tumor stages and is not limited to the 11q- tumor subtype. Gain of 7q, however, is more prevalent in higher stage tumors. G-band cytogenetic analysis indicated that an unbalanced t(3;7) was responsible for the gain of 7q and loss of 3p material in one case. We discuss the possibility that gain of 7/7q, and 11p material may contribute to either tumorigenesis or progression.

Potentiation of vincristine toxicity by itraconazole in children with lymphoid malignancies.

UNLABELLED: Eight consecutive paediatric patients with acute lymphoblastic leukaemia (ALL) (n = 7) and T-cell non-Hodgkin's lymphoma (NHL) (n = 1) presenting within a 5-wk interval were started on a standard induction protocol which included weekly treatment with vincristine for 4 wk. Itraconazole was commenced as antifungal prophylaxis, 1-21 d after the first injection of vincristine. Within 2 to 4 wk, enhanced vincristine neurotoxicity was noted in all patients, abdominal cramps and constipation occurred most frequently, and one patient developed a bowel perforation associated with paralytic ileus. Hyponatraemia associated with SIADH was observed in three patients and four patients developed seizures. An additional patient with B cell NHL developed seizures 5 d after an injection of vincristine. Recovery was complete in all patients and ranged from 2 d to 15 wk. CONCLUSION: The extent and consistency of adverse effects documented in this study support the recommendation that concurrent administration of vincristine and itraconazole should be avoided.

A comparison of oral ondansetron syrup or intravenous ondansetron loading dose regimens given in combination with dexamethasone for the prevention of nausea and emesis in pediatric and adolescent patients receiving moderately/highly emetogenic chemotherapy.

This double-blind, parallel-group, multicenter study compared the efficacy and safety of intravenous (i.v.) ondansetron with oral syrup ondansetron plus oral dexamethasone in the prevention of nausea and emesis in pediatric patients receiving moderately/highly emetogenic chemotherapy. On each day of chemotherapy, patients were administered ondansetron 5 mg/m2 i.v. and placebo syrup orally (n = 215) or ondansetron 8 mg syrup orally and placebo i.v. (n = 223) plus dexamethasone 2-4 mg p.o. Ondansetron 4 mg syrup p.o. was administered twice daily for 2 days following the cessation of chemotherapy. Complete or major control of emesis was obtained in 89% patients in the i.v. group and 88% patients in the oral syrup group during the worst day of chemotherapy treatment (90% CI: -6, 4) and in 85% and 82% patients, respectively, during the worst day of the study period (90% CI: -8, 3). Intravenous or oral syrup ondansetron plus dexamethasone was well tolerated and effective in preventing chemotherapy-induced emesis in pediatric patients.

[Oral granisetron solution as prophylaxis for chemotherapy-induced emesis in children: double-blind study of 2 doses]. / Granisétron en solution buvable dans la prévention des vomissements chimio-induits de l'enfant: comparaison en double aveugle de deux posologies.

This multicentric double-blind, dose-ranging study was to compare efficacy and safety of two oral doses of granisetron solution in the prevention of chemotherapy-induced emesis in children with malignant diseases : 294 children, aged 1 to 16, treated with a moderately or highly emetogenic chemotherapy were randomly assigned to receive oral granisetron either 20 microg/kg (n = 143) or 40 microg/kg (n = 151) before and 6 to 12 hours after the start of chemotherapy. Fifty-one percent of patients treated with 20 microg/kg bd of oral granisetron solution achieved a complete response (no vomiting, no worse than mild nausea, no rescue therapy and no withdrawal during the specified period) and 59% achieved a major response (no more than one episode of vomiting, no worse than mild nausea, no rescue therapy and no withdrawal during the specified period). There was no difference between the two oral doses of granisetron. Treatment was rated as good or very good by investigators in 70% of cases. In conclusion, oral granisetron suspension either at 20 microg/kg bd or at 40 microg/kg bd showed good efficacy and safety in the prevention of chemotherapy-induced emesis in children with malignant diseases. Oral granisetron solution can be used as prophylaxis of emesis in children receiving moderately or highly emetogenic chemotherapy.

Comparative genomic hybridization in pediatric acute lymphoblastic leukemia.

Comparative genomic hybridization (CGH) was used to clarify the chromosomal status of 15 patients diagnosed with childhood acute lymphoblastic leukemia (ALL). Bone marrow samples from 10 of the 15 patients were selected because no metaphases were obtained for cytogenetic analysis. Three patients with normal trypsin and giemsa banding (GTG) karyotypes were also studied by CGH to determine whether significant abnormalities might have been missed by banding analysis, and samples from an additional 2 patients with hyperdiploidy were also included. Seven of the 10 patients with failed GTG banding analysis were found to be chromosomally abnormal by CGH; 2 out of 3 patients with normal GTG band karyotypes were abnormal, indicating that the metaphases available for karyotyping were not malignant cells, and that CGH analysis of hyperdiploid samples provided more accurate resolution than karyotyping alone. The prognostic value of chromosomal aberrations detected by CGII and the efficiency of the technique suggest a central role for CGH in routine clinical cytogenetics.

Histological parameters as predictors of prognosis in childhood brain tumors.

Using histological parameters with high recognition reliability, we retrospectively analyzed all newly diagnosed patients under the age of 16 years (n = 100) with brain and spinal cord tumors presenting to the National Neuroscience Centres of the Richmond and Beaumont Hospitals, Dublin, Ireland, between 1985 and 1990, allowing analysis of 5-year survival in all cases. Tumor histology was reviewed by two neuropathologists blinded to previous histological diagnosis and to the site of lesion. We found that certain histological features such as very low cell density and microcyst formation had a positive effect on prognosis. Mitoses and pleomorphism had a negative effect on prognosis, whereas necrosis and meningeal involvement had no effect on prognosis. It is suggested that identification of reliably recognized histological features rather than assignation of tumors to particular diagnostic categories may be a more reliable predictor of tumor behavior in the pediatric age-group.

Conservative surgical management of bilateral Wilms tumor: results of the United Kingdom Children's Cancer Study Group.

PURPOSE: Bilateral Wilms tumor presents the clinician with a treatment dilemma. Since 1980 most centers of the United Kingdom Children's Cancer Study Group have used a conservative surgical approach with initial biopsy followed by chemotherapy and delayed surgical resection. We assess the outcome of this treatment approach in terms of survival, and preservation of renal mass and function. MATERIALS AND METHODS: We retrospectively analyzed the records of 71 children with bilateral Wilms tumor diagnosed between 1980 to 1995 at 17 United Kingdom Children's Cancer Study Group centers. In 57 patients conservative surgical treatment with initial biopsy was followed by chemotherapy and delayed tumor resection, while 13 underwent initial surgical resection followed by chemotherapy. One patient was excluded from study because the lesion in 1 kidney proved to be a benign cyst. Mean followup was 6 years (range 1 to 15). The percentage of renal tissue involved with tumor and preserved was estimated, and renal function at the last followup was recorded. RESULTS: Overall survival was 69% with similar survival in the conservatively treated and initial surgical resection groups. At the last followup renal function was normal in 80% of the patients in each group. Mean preserved renal mass was 45 and 35% in the conservatively treated and initial resection groups, respectively, with a trend toward better preservation in those treated conservatively. Bilateral Wilms tumor with an unfavorable histology was associated with a poor prognosis. CONCLUSIONS: Conservative surgical treatment of favorable histology bilateral Wilms tumor may improve the preservation of renal mass and function without impairing patient survival.

Central venous catheter infections treated with teicoplanin.

A novel way of using teicoplanin in situ to treat central venous catheters is described. Profound immunosuppression and the fact that the lines remain indwelling for long periods are two of the main reasons for these infections. In children it is also difficult to prevent these lines being played with, which increases the likelihood of infection. The different types of infection that can occur in a central venous catheter are described and the clinical definition of a catheter infection is provided. In an initial study, infective episodes in a small group of 11 children were treated successfully with in situ amikacin. Most pathogens were Gram-negative cocci. None of the catheters had to be removed, and catheter life was prolonged by a mean of 118 d. Due to the high incidence of Staphylococcus epidermidis in the initial study, in situ teicoplanin was assessed in a subsequent study. Over the course of 1 yr, 20 line infections occurred in 12 children. Empirical amikacin therapy was instituted and switched to teicoplanin once the pathogen was confirmed as Gram-positive. An antibiotic-heparin mixture was introduced into the line and left in place for 24 h, after which time it was replaced with fresh mixture until cultures were sterile. All pathogens were sensitive to teicoplanin, all infections were treated successfully and no catheters had to be removed. Overall, catheter life was prolonged by a mean of 136 d. It was concluded that in situ teicoplanin was effective and well tolerated for line infections (no side-effects were reported during the study). A minimum of 6 d therapy was recommended. The patients with less severe infections would have been suitable for treatment at home by their parents, district nurse or general practitioner (GP).

Control of a nosocomial outbreak of vancomycin resistant Enterococcus faecium in a paediatric oncology unit: risk factors for colonisation.

UNLABELLED: In order to determine the extent of vancomycin resistant enterococcus (VRE) colonisation within a paediatric oncology unit, the risk factors for the acquisition of the organism, the molecular epidemiology of the isolates and the impact of infection control measures, extensive patient and environmental surveillance was undertaken with identification, antibiotic susceptibility testing and pulsed-field gel electrophoresis (PFGE) of all VRE isolates. A matched case control study was carried out. Fourteen patients (19% of screened patients) with VRE colonisation were identified (12 with Enterococcus faecium). All isolates manifested the Van A phenotype. Extensive environmental contamination with VRE was present. PFGE of E. faecium isolates from 10 patients and from five of six environmental cultures revealed patterns suggesting genetic relatedness. Following comparison of the 14 cases with 41 controls matched for age (+/- 4 years) and cohabitation on the oncology unit, risk factors for colonisation with VRE included duration of neutropenia, (OR, 3.72; 95% CI, 1.0-13.1), and antibiotic therapy, (OR, 4.07; 95% CI, 1.08-15.3), the number of antibiotic agents received, (OR, 8.4; 95% CI, 1.34-34.3) and the duration of therapy with amikacin, (OR, 10.7; 95% CI, 1.4-81.5), ceftazidime, (OR, 11.5; 95% CI, 2.2 59.9) or teicoplanin, (OR, 12.3; 95% CI, 2.25-67.4). Implementation of stringent infection control measures reduced environmental contamination from 25% of samples in week 1 to none in week 11. Two additional colonised patients were identified during the subsequent 6 months. CONCLUSION: Risk factors for VRE colonization in paediatric oncology patients included duration of neutropenia, duration of any antibiotic therapy, exposure to ceftazidime, amikacin or teicoplanin and the number of antibiotics used. The study suggests that environmental contamination played an important role in patient-to-patient transmission of VRE and interventions including implementation of infection control measures were associated with a decreased incidence of gastro-intestinal colonisation.

SIOP Working Committee on psychosocial issues in pediatric oncology: guidelines for communication of the diagnosis.

This is the fourth official document of the SIOP Working Committee on psychosocial issues in pediatric oncology constituted in 1991. This document develops another topic discussed and approved by the SIOP Committee: "communication of the diagnosis" is addressed to the pediatric oncology community as guidelines that could be followed. The highly stressful nature of the diagnostic period must be acknowledged, and communication involving the staff and all family members should cover both medical and psychosocial issues. A well-planned and extensive initial session should be followed by continuing discussions. The goal is a knowledgeable family that can talk openly with its members and with the staff.

Langerhans' cell histiocytosis: head and neck manifestations in children.

BACKGROUND: Langerhans' cell histiocytosis (LCH) is an uncommon, poorly understood granulomatous disease, characterized by the idiopathic proliferation of Langerhan's cells or their marrow precursors. In 1985, the Philadelphia Work-shop adopted the term "Langerhans' cell histiocytosis" (LCH) to differentiate it from reactive and neoplastic causes of histiocytosis. METHODS: This study includes 73 pediatric patients diagnosed with this condition in Dublin, Ireland, and Nottingham, England, during a 34-year period (1959 to 1993). These patients are reviewed with respect to clinical presentation, difficulty with making a histological diagnosis, their management, and outcome. RESULTS: A total of 49 patients (67%) had head and neck involvement. Bony involvement was the most frequent sign, most frequently located in the skull. There were 11 deaths (15%) in this series, all associated with multisystem disease, and nine of these deaths were in children younger than 2 years of age. CONCLUSIONS: The role of otolaryngologists is important in the early and accurate evaluation, staging, and diagnosis of LCH. It may mimic more common diseases, such as otitis externa, acute mastoiditis, skin rash, gingivitis, or cervical lymphadenopathy. Patients with multisystem disease may be so ill at presentation that the head and neck lesions may be overlooked. The current management of LCH has become increasingly conservative, and in the 1990s, fewer cases are given chemotherapy or radiotherapy. The prognosis is very good for single-system disease and poor for multisystem disseminated disease with early onset.

Benign giant cell tumour of bone in a child with pulmonary metastases at presentation.

The clinical course of a 14-year-old boy who presented with a giant cell tumour of bone with pulmonary metastases is reported. There was a partial response to chemotherapy which included vincristine, adriamycin, ifosfamide, carboplatinum and etoposide. Two enlarging metastatic lung lesions were later resected because of chest pain, with symptomatic improvement. The patient is currently well almost 7 years from diagnosis despite the presence of radiological disease.

Ifosfamide nephrotoxicity in paediatric cancer patients.

Ifosfamide is an alkylating agent which has been incorporated into frontline therapy for a number of malignant paediatric tumours. Recent data appears to suggest that tubular dysfunction may result from incorporation of this drug into chemotherapy schedules and that toxicity may be dose related. A detailed investigation of renal function was performed in a group of patients, ranging in age from 8 months to 15.9 years (median 8.6 years) with rhabdomyosarcoma (n = 11) and Ewing's sarcoma (n = 9) who were currently receiving (n = 4) or had completed ifosfamide (n = 16) therapy a mean of 16 months at the time of study. All but one patient demonstrated some degree of renal dysfunction and toxicity did not necessarily appear to be dose related. Implications for incorporation of this agent into future schedules for childhood sarcomas, which can expect to cure more than 60% of such children, must be addressed. The importance of ongoing monitoring is emphasised.

Is there a danger in delaying radiotherapy in childhood medulloblastoma?

Approximately 45-50% of children with medulloblastoma are cured by conventional surgery and radiotherapy, but survivors may face severe late neuropsychological toxicity. Studies showing good partial responses to platinum-based chemotherapy in relapsed patients and the theoretical possibility of a therapeutic window immediately after surgery have prompted neoadjuvant treatment studies which are ongoing. However, the absolute benefit of chemotherapy for the treatment of medulloblastoma in childhood is, as yet, not proven. There is a danger that chemotherapy may simply delay radiotherapy, and in so doing reduce the radiological impact of this known effective treatment. We report four children with medulloblastoma presenting consecutively to this unit over a 6-month period, whose management was problematic because of either failure to respond to neoadjuvant chemotherapy or their very young age. These cases are discussed in the light of the current literature and future treatment strategies that must seek to improve the therapeutic ratio of multimodality therapy.