Indications and results of diagnostic biopsy in pediatric renal tumors: A retrospective analysis of 317 patients with critical review of SIOP guidelines.

OBJECTIVES: According to the Renal Tumor Study Group (RTSG) of the International Society of Paediatric Oncology (SIOP), diagnostic biopsy of renal tumors prior to neoadjuvant chemotherapy is not mandatory unless the presentation is atypical for a Wilms tumor (WT). This study addresses the relevance of this strategy as well as the accuracy and safety of image-guided needle biopsy. METHODS: Clinical, radiological, and pathological data from 317 children (141 males/176 females, mean age: 4 years, range, 0-17.6) consecutively treated in one SIOP-affiliated institution were retrospectively analyzed. RESULTS: Presumptive chemotherapy for WT was decided for 182 patients (57% of the cohort), 24 (8%) were operated upfront, and 111 (35%) were biopsied at diagnosis. A non-WT was confirmed after surgery in 5/182 (3%), 11/24 (46%), and 28/111 (25%), respectively. Age at diagnosis was the most commonly (46%) used criterion to go for biopsy but a nine-year threshold should be retrospectively considered more relevant. Tumor volumes of clear cell sarcoma of the kidney and WT were significantly higher than those of other tumors (P = 0.002). The agreement between core-needle biopsy (CNB) and final histology was 99%. No significant morbidity was associated with CNB. CONCLUSION: The use of SIOP criteria to identify patients eligible for presumptive WT neoadjuvant chemotherapy or upfront surgery avoided biopsy in 65% of children and led to a 97% rate of appropriate preoperative chemotherapy. Image-guided CNB is a safe and accurate diagnostic procedure. The relevance of SIOP biopsy criteria might be improved by using an older age threshold (9 years instead of 6 years) and by adding initial tumor volume.

Pseudomonas aeruginosa septic trapezo-metacarpal arthritis after prostate laser vaporization.

Prostatic laser vaporization resection is a new and fast growing technique. Most publications compare this technique to the standard diathermic snare prostate resection without considering its particular complications. Septic arthritis of the trapezio-metacarpal joint is particularly rare if it has a haematogenous origin. We present here the case of a 65-year-old man with an isolated trapezio-metacarpal Pseudomonas aeruginosa arthritis with a haematogenous origin following a laser vaporization prostate resection.

Microbiological diagnosis of vertebral osteomyelitis: relevance of second percutaneous biopsy following initial negative biopsy and limited yield of post-biopsy blood cultures.

The purpose of this investigation was to evaluate the microbiological diagnosis yield of post-biopsy blood cultures (PBBCs) and second percutaneous needle biopsy (PNB) following an initial negative biopsy in vertebral osteomyelitis (VO) without bacteremia. A retrospective multicenter study was performed. Patients with VO, pre-biopsy negative blood culture(s), ≥1 PNB, and ≥1 PBBC (0-4 h) were included. One hundred and sixty-nine PNBs (136 first and 33 following initial negative biopsy) were performed for 136 patients (median age = 58 years, sex ratio M/F = 1.9). First and second PNBs had a similar yield: 43.4 % (59/136) versus 39.4 % (13/33), respectively. Only two PBBCs (1.1 %) led to a microbiological diagnosis. The strategy with positive first PNB and second PNB following an initial negative result led to microbiological diagnosis in 79.6 % (74/93) of cases versus 44.1 % (60/136) for the strategy with only one biopsy. In the multivariate analysis, young age (odds ratio, OR [95 % confidence interval (CI)] = 0.98 [0.97; 0.99] per 1 year increase, p = 0.02) and >1 sample (OR = 2.4 ([1.3; 4.4], p = 0.007)) were independently associated with positive PNB. To optimize microbiological diagnosis in vertebral osteomyelitis, performing a second PNB (after an initial negative biopsy) could lead to a microbiological diagnosis in nearly 80 % of patients. PBBC appears to be limited in microbiological diagnosis.

Malformations, genetic abnormalities, and Wilms tumor.

BACKGROUND: Wilms Tumor (WT) can occur in association with tumor predisposition syndromes and/or with clinical malformations. These associations have not been fully characterized at a clinical and molecular genetic level. This study aims to describe clinical malformations, genetic abnormalities, and tumor predisposition syndromes in patients with WT and to propose guidelines regarding indications for clinical and molecular genetic explorations. PROCEDURE: This retrospective study analyzed clinical abnormalities and predisposition syndromes among 295 patients treated for WT between 1986 and 2009 in a single pediatric oncological center. RESULTS: Clinically identified malformations and predisposition syndromes were observed in 52/295 patients (17.6%). Genetically proven tumor predisposition syndromes (n = 14) frequently observed were syndromes associated with alterations of the chromosome WT1 region such as WAGR (n = 6) and Denys-Drash syndromes (n = 3), syndromes associated with alterations of the WT2 region (Beckwith-Wiedeman syndrome, n = 3), and Fanconi anemia (n = 2). Hemihypertrophy and genito-urinary malformations (n = 12 and n = 16, respectively) were the most frequently identified malformations. Other different syndromes or malformations (n = 10) were less frequent. Median age of WT diagnosis was significantly earlier for children with malformations than those without (27 months vs. 37 months, P = 0.0009). There was no significant difference in terms of 5-year EFS and OS between WT patients without or with malformations. CONCLUSIONS: The frequency of malformations observed in patients with WT underline the need of genetic counseling and molecular genetic explorations for a better follow-up of these patients, with a frequently good outcome. A decisional tree, based on clinical observations of patients with WT, is proposed to guide clinicians for further molecular genetic explorations.

Clinical benefit of infectious diseases consultation: a monocentric prospective cohort study.

PURPOSE: To determine the association of clinical outcomes with the adherence to Infectious Diseases Consultation (IDC) recommendations. METHODS: From March to August 2009, all patients hospitalized in our hospital, for whom an IDC was requested, were prospectively enrolled. The adherence to recommendations was ascertained after 72 h from the IDC. The primary objective of the study was to evaluate the clinical cure rate 1 month after the IDC, according to the adherence to IDC recommendations. RESULTS: An IDC was requested for 258 inpatients. The infectious disease (ID) was most often non-severe (66%), community-acquired (62%), and already under treatment (47%). IDC proposals were most often formulated via a formal consultation (57%). Physicians' adherence to IDC recommendations was 87% for diagnostic tests and 90% for antibiotherapy. In the multivariate analysis, severe infections and direct consultation were independently associated with increased odds of adherence to recommendations for performing diagnostic tests (odds ratios 5.4 and 4.0, respectively). The overall clinical cure rate was 84% and this did not differ according to the adherence to IDC recommendations for diagnostic tests (84.3 vs. 71.4%, p = 0.15) and antimicrobial treatment (84.8 vs. 77.8%, p = 0.34). CONCLUSIONS: Some limitations of the study may explain the lack of evidence of a clinical benefit, such as the very high level of adherence to IDC recommendations and the low proportion of severe infections. However, clinical improvement was always better when recommendations were followed. Therefore, further larger randomized multicentric studies including more patients suffering from more severe IDs may be needed in order to demonstrate a clinical impact.

Use of antibiotics in pyogenic flexor tenosynovitis.

Pyogenic flexor tenosynovitis is a frequent and serious condition. However, there is no consensus on the use of antibiotics. The objective of our study was to describe the treatment of this condition and to identify the surgical and medical management parameters to propose an effective and consensual postoperative antibiotic therapy protocol. We retrospectively reviewed pyogenic flexor tenosynovitis of the thumb or fingers treated between 01/01/2013 and 01/01/2018 at a teaching hospital. Inclusion criteria were confirmation of the clinical diagnosis intraoperatively and a minimum post-antibiotic follow-up of 6 months. Comorbidities, type of surgery, antibiotic therapy parameters, and treatment outcome were assessed. One hundred and thirteen patients were included. Fifty-four percent had comorbidities. The most frequent germ was staphylococcus, all patients received postoperative antibiotic therapy. Intravenous or intravenous followed by oral administration did not provide any benefit compared to an exclusively oral treatment (p = 0.46). The duration of postoperative antibiotic therapy (less than 7 days, between 7 and 14 days or more than 14 days) did not lead to any difference in healing rate (p = 0.67). However, treating for less than 7 days versus 7-14 days seemed to be associated with a higher risk of failure, although not statistically significant. Oral postoperative antibiotic therapy with amoxicillin + clavulanic acid for 7-14 days appears to be effective, allowing for outpatient management.

Segmental chromosomal alterations lead to a higher risk of relapse in infants with MYCN-non-amplified localised unresectable/disseminated neuroblastoma (a SIOPEN collaborative study).

BACKGROUND: In neuroblastoma (NB), the presence of segmental chromosome alterations (SCAs) is associated with a higher risk of relapse. METHODS: In order to analyse the role of SCAs in infants with localised unresectable/disseminated NB without MYCN amplification, we have performed an array CGH analysis of tumours from infants enrolled in the prospective European INES trials. RESULTS: Tumour samples from 218 out of 300 enroled patients could be analysed. Segmental chromosome alterations were observed in 11%, 20% and 59% of infants enroled in trials INES99.1 (localised unresectable NB), INES99.2 (stage 4s) and INES99.3 (stage 4) (P<0.0001). Progression-free survival was poorer in patients whose tumours harboured SCA, in the whole population and in trials INES99.1 and INES99.2, in the absence of clinical symptoms (log-rank test, P=0.0001, P=0.04 and P=0.0003, respectively). In multivariate analysis, a SCA genomic profile was the strongest predictor of poorer progression-free survival. CONCLUSION: In infants with stage 4s MYCN-non-amplified NB, a SCA genomic profile identifies patients who will require upfront treatment even in the absence of other clinical indication for therapy, whereas in infants with localised unresectable NB, a genomic profile characterised by the absence of SCA identifies patients in whom treatment reduction might be possible. These findings will be implemented in a future international trial.

Criteria for evaluation of disease extent by (123)I-metaiodobenzylguanidine scans in neuroblastoma: a report for the International Neuroblastoma Risk Group (INRG) Task Force.

BACKGROUND: Neuroblastoma is an embryonic tumour of the sympathetic nervous system, metastatic in half of the patients at diagnosis, with a high preponderance of osteomedullary disease, making accurate evaluation of metastatic sites and response to therapy challenging. Metaiodobenzylguanidine (mIBG), taken into cells via the norepinephrine transporter, provides a sensitive and specific method of assessing tumour in both soft tissue and bone sites. The goal of this report was to develop consensus guidelines for the use of mIBG scans in staging, response assessment and surveillance in neuroblastoma. METHODS: The International Neuroblastoma Risk Group (INRG) Task Force, including a multidisciplinary group in paediatric oncology of North and South America, Europe, Oceania and Asia, formed a subcommittee on metastatic disease evaluation, including expert nuclear medicine physicians and oncologists, who developed these guidelines based on their experience and the medical literature, with approval by the larger INRG Task Force. RESULTS: Guidelines for patient preparation, radiotracer administration, techniques of scanning including timing, energy, specific views, and use of single photon emission computed tomography are included. Optimal timing of scans in relation to therapy and for surveillance is reviewed. Validated semi-quantitative scoring methods in current use are reviewed, with recommendations for use in prognosis and response evaluation. CONCLUSIONS: Metaiodobenzylguanidine scans are the most sensitive and specific method of staging and response evaluation in neuroblastoma, particularly when used with a semi-quantitative scoring method. Use of the optimal techniques for mIBG in staging and response, including a semi-quantitative score, is essential for evaluation of the efficacy of new therapy.

High dose chemotherapy and autologous hematopoietic cell transplantation for Wilms tumor: a study of the European Society for Blood and Marrow Transplantation.

Survival for subgroups of patients with Wilms tumor (WT), such as those who suffer from relapse, is disappointing. Some patients' treatment plans include high-dose chemotherapy (HDT) with autologous hematopoietic cell transplantation (aHCT), although proof for its benefit is lacking. To increase the level of evidence regarding children with WT receiving aHCT as consolidation of first or second remission (after first relapse), we extracted relevant data from the European Blood and Marrow Transplantation Registry concerning 69 patients. Different HDT regimens were administered, mostly either melphalan-containing (n = 34) or thiotepa-containing (n = 14). For the whole population, 5-year overall survival (OS) and event-free survival (EFS) probabilities were 0.67 (±0.06) and 0.63 (±0.06), respectively (median observation time 7.8 years); for children transplanted in first remission, OS and EFS were 0.69 (±0.09) and 0.72 (±0.08). In univariate analysis, male gender and relapse in multiple sites were associated with lower OS probabilities. The use of a given pretransplant regimen (i.e. melphalan alone versus regimens with multiple drugs) did not seem to influence EFS/OS probability after aHCT, but significantly influenced platelet engraftment (more delayed with thiotepa). We here provide further data to improve the basis for future evidence-based clinical decision-making when using HDT and aHCT in relapsed/refractory WT.

Treatment of localised resectable neuroblastoma. Results of the LNESG1 study by the SIOP Europe Neuroblastoma Group.

Main objective of this study was to confirm that surgery alone is an effective and safe treatment for localised resectable neuroblastoma except stage 2 with amplified MYCN gene (MYCNA). Of 427 eligible stages 1-2 patients, 411 had normal MYCN and 16 had MYCNA. Of the 288 stage 1 patients with normal MYCN, 1 died of complications and 16 relapsed, 2 of whom died; 5-year relapse-free survival (RFS) and overall survival (OS) rates were 94.3% (95% confidence interval (CI): 91.6-97) and 98.9% (95% CI: 97.7-100), respectively. Of the 123 stage 2 patients with normal MYCN, 1 died of sepsis and 22 relapsed, 8 of whom died (RFS 82.8%, 95% CI: 76.2-89.5; OS 93.2%, 95% CI: 88.7-97.8). In stage 2, OS and RFS were worse for patients with elevated LDH and unfavourable histopathology. Of 16 children with MYCNA, 7 were stage 1 (5 relapses and 4 deaths) and 9 were stage 2 (3 relapses and 2 deaths) patients. In conclusion, surgery alone yielded excellent OS for both stage 1 and 2 neuroblastoma without MYCNA, although stage 2 patients with unfavourable histopathology and elevated LDH suffered a high number of relapses. Both stage 1 and 2 patients with MYCNA were at greater risk of relapse.

Enhancement of natural killer function through activation of the T11 E rosette receptor.

Natural killer (NK) cells, which represent a small fraction of normal peripheral blood mononuclear cells, were purified by immunofluorescent cell sorting of NKH1+ cells. cytotoxicity of NKH1+ cells could be enhanced through activation by monoclonal antibodies (anti-T11(2) and anti-T11(3)) specific for epitopes of the sheep erythrocyte receptor or by recombinant interleukin-2 (rIL-2). After 18 h, incubation with both anti-T11(2/3) and rIL-2 resulted in similar levels of enhanced cytotoxicity against NK-resistant as well as NK-sensitive targets. Before and after induction, cytotoxicity was found predominantly within the NKH1+ population. These results suggest that several distinct mechanisms may be capable of enhancing NK activity and that the cells responsible for lymphokine-activated killing are likely to be the same population capable of spontaneous or natural killing before activation in vitro.

Final height and gonad function after total body irradiation during childhood.

Short stature and gonad failure can be a side effect of total body irradiation (TBI). The purpose of the study was to evaluate the factors influencing final height and gonad function after TBI. Fifty young adults given TBI during childhood were included. Twenty-seven had been treated with growth hormone (GH). Those given single 10 Grays (Gy) or fractionated 12 Gy TBI had similar characteristics, GH peaks, final heights and gonad function. After the end of GH treatment, 11/20 patients evaluated had GH peak >10 microg/l. Final height was <-2s.d. in 29 (58%). The height loss between TBI and final height (2.4+/-1.1 s.d.) was greater in those who were younger when irradiated (P<0.0001). When the GH-treated and -untreated patients were analyzed separately, this loss was correlated with the age at TBI at 4-8 years for the GH-treated and at 6-8 years for the untreated. Boys showed negative correlations between testicular volume and plasma follicle-stimulating hormone (FSH, P=0.0008) and between plasma FSH and inhibin B (P=0.005) concentrations. We concluded that the indications for GH treatment should be mainly based on the age at irradiation, taking into account the GH peak. The plasma FSH and inhibin B concentrations may predict sperm function.

Characterization of functional surface structures on human natural killer cells.

Recent studies on human NK cells have identified a number of surface antigens that can be utilized to define this population of cells and to identify functionally distinct subsets within this heterogeneous population. In addition, it has been possible to associate specific functional activities with several antigens expressed on NK cells as well as other hematopoietic cells. This information, which is summarized in Table III can be utilized to develop a framework for the classification of cytolytic effector cells. Of primary importance, this classification identifies subsets of cytolytic cells with distinct functional repertoires and distinct cytolytic mechanisms. The majority of NK cells in unstimulated peripheral blood and the majority of NK clones express NKH1 and CD2 antigens but do not express CD3 antigen. These cells morphologically appear as large granular lymphocytes and have broad cytolytic activity against a variety of allogeneic targets without primary sensitization. Consistent with the finding that these cells are CD3 negative, they have not been found to have rearrangement of genes encoding for TCR, or functional mRNA transcripts of either TCR alpha, TCR beta, or TCR gamma genes. In addition, these cells do not express heterodimeric surface proteins similar to those that have now been demonstrated to be MHC-restricted T cell receptors for antigen. Taken together, these findings provide strong evidence that NKH1+CD3- NK clones do not interact with target cells through a T cell receptor-like structure. Nevertheless, these NK cells do share several properties with conventional CTL. These functional T cell characteristics include (1) expression of CD2-T11/E rosette receptor antigen, and (2) utilization of LFA-1 surface antigen to enhance effector cell adhesion to target cells. As previously demonstrated for T cells, NK cells can be activated through the CD2 molecule and this has recently been shown to result in the enhancement of cytolytic function by these effectors. Since CD2 can also function as a cell surface ligand for LFA-3, an antigen expressed on NK targets, the CD2 molecule may be considered as a potential NK receptor structure. The fact that a very small subset of NK cells (approximately equal to 10%) as well as some NK clones (JT11) does not express CD2 argues against a potential role for CD2 as the NK cell receptor. Certainly, further studies will be necessary to clarify the role of CD2 on NK cells and to identify the mechanisms whereby NKH1+CD3- NK cells interact with targets in a non-MHC-restricted fashion.(ABSTRACT TRUNCATED AT 400 WORDS)

Cost-minimization analysis of prophylactic granulocyte colony-stimulating factor after induction chemotherapy in children with non-Hodgkin's lymphoma.

BACKGROUND: Colony-stimulating factors promote the proliferation of certain bone marrow cell populations. The primary objective of treating patients with these factors prophylactically following chemotherapy is to reduce the risk of infection, thereby minimizing the need for hospitalization and parenteral antibiotics. The use of colony-stimulating factors in children is widespread, despite the absence of conclusive supportive data and the high cost of these drugs. Consequently, the cost-benefit ratio of using prophylactic colony-stimulating factors is an important issue in cancer therapy. METHODS: During the period from January 1994 through June 1996, 149 afebrile children with newly diagnosed non-Hodgkin's lymphoma were randomly assigned either to receive granulocyte colony-stimulating factor (G-CSF) (lenograstim; 5 microg/kg body weight per day subcutaneously) or not to receive it (the control) at the end of the first two courses of induction chemotherapy with cyclophosphamide, vincristine, prednisone, doxorubicin, and methotrexate. A cost-minimization analysis was performed to assess the cost of chemotherapy in each group and to quantify how much could be economized by prescribing G-CSF. RESULTS: The total cost for induction chemotherapy was $29,765 in the G-CSF-treated group and $30,774 in the control group, indicating that the treatment strategy with G-CSF was slightly less expensive than the strategy without G-CSF (mean difference = $1009; 95% confidence interval = -$1474 to $3492). CONCLUSION: Treatment with G-CSF following chemotherapy in children with non-Hodgkin's lymphoma--previously shown to be of limited clinical benefit--also does not appear to reduce the costs of chemotherapy.

A new member of the ETS family fused to EWS in Ewing tumors.

As a result of chromosome translocations, the EWS gene is fused to a variety of transcription factors in human solid neoplasia. In Ewing tumors EWS can be fused to four different members of the ETS family, namely FLI-1, ERG, ETV1 and E1AF. We have identified a new member of the ETS family, called FEV, which is fused to EWS in a subset of Ewing tumors. FEV encodes a 238 amino acid protein which contains an ETS DNA binding domain closely related to that of FLI-1 and ERG. However, the N-terminal portion of FEV is only 42 amino acids long which suggests that FEV is lacking important transcription regulatory domains contained in FLI-1 and ERG N-terminal parts. The C-terminal end of FEV is rich in alanine residues which may indicate that FEV is a transcription repressor. The FEV gene is encoded by three exons and is located on chromosome 2. FEV expression was only detected in adult prostate and small intestine but not in other adult nor in fetal tissues, thus indicating that FEV has a restricted expression pattern. Following a scheme similar to previously described translocations in Ewing tumors, a t(2;22) chromosome translocation fuses the N-terminal domain of EWS to the ETS DNA binding domain of FEV.

Presence of tumor cells in bone marrow but not in blood is associated with adverse prognosis in patients with Ewing's tumor. Société Française d'Oncologie Pédiatrique.

PURPOSE: Gene fusions that result from the chromosome translocations observed in Ewing's tumor (ET) provide tumor-specific markers that can be used to detect the presence of tumor cells in peripheral blood (PB), bone marrow (BM), and stem cell collection (SCC). These markers were used to evaluate, at diagnosis, a series of 67 ET patients. PATIENTS AND METHODS: RNA was extracted from nucleated cells from PB and BM and a nested reverse-transcriptase polymerase chain reaction (RT-PCR) was performed to search for EWS-FLI-1 or EWS-ERG fusion transcripts that resulted from the t(11;22) or t(21;22) translocations, respectively. RESULTS: At diagnosis, 16 of 62 (26%) patients had circulating tumor cells. This was not correlated with any clinical parameter. In contrast, Ewing's cells were detected by RT-PCR in BM in 14 of 43 (33%) patients and were associated with the presence of clinically detectable metastases and a statistically significant unfavorable outcome in univariate analysis. There was no correlation between the RT-PCR results in PB and in BM. CONCLUSION: These results suggested that the monitoring of BM but not of PB by RT-PCR might constitute an important criterion for the staging, at diagnosis, of patients with ET. Further studies should appreciate the relationship or independence of this marker toward other classical prognostic factors in ET, particularly to the presence of clinically detectable metastases.

Interleukin-2 and lymphokine-activated killer cells in 15 children with advanced metastatic neuroblastoma.

A phase II trial using interleukin-2 (IL2) and lymphokine-activated killer (LAK) cells was carried out in an attempt to treat children with end-stage neuroblastoma. Fifteen patients (median age, 7 years) were enrolled in the study. Twelve were in relapse after massive chemotherapy and autologous bone marrow transplantation (ABMT), and three had a primary refractory disease after conventional chemotherapy. IL2 was administered as an 18 x 10(6) IU/m2/d continuous infusion. One course consisted of a double 5-day treatment period separated by a 6-day break. Cytapheresis to harvest LAK progenitor cells was performed during the rest period. After a 4-day in vitro culture, LAK cells were reinjected during the second cycle of therapy. A phenotypic and functional analysis of immunologic parameters was conducted along with the therapeutic protocol. Toxicity was significant with two toxic deaths (cardiotoxicity and respiratory distress). The reinfusion of large amounts of LAK cells was clearly involved in one case, but this particularly severe toxicity has to be related to the patient's status (ie, heavy pretreatment). No significant clinical response was seen. The immunologic monitoring showed phenotypic and functional modifications in these patients before initiation of treatment and an unexpected absence of evolution of these parameters during IL2 therapy. Although the origin of these immune dysfunctions is not clear, they could be involved in the failure of IL2 therapy. Future studies of IL2 therapy in neuroblastoma should be undertaken earlier in the course of the disease.

Combined continuous infusion etoposide with high-dose cyclophosphamide for refractory neuroblastoma: a phase II study from the Société Française d'Oncologie Pédiatrique.

PURPOSE: Patients older than 1 year with stage IV neuroblastoma who fail to achieve complete remission (CRem) have a particularly poor long-term prognosis. In an attempt to improve the outcome of these refractory patients, we tested a new drug combination. PATIENTS AND METHODS: Twenty-nine children with advanced neuroblastoma (27 stage IV and two stage III) were entered onto this phase II study. All were refractory to conventional chemotherapy and had measurable disease at the time of the trial. The regimen was a combination of high-dose cyclophosphamide (2 g/m2/d) on days 2, 3, and 4, and etoposide (VP16; 50 mg/m2/d) by continuous intravenous (IV) infusion on days 1 to 5. A pharmacokinetic study of VP16 was conducted in eight patients to determine whether the goal of persistent plasma levels between 1 and 5 micrograms/mL was achieved. RESULTS: Patients received a median of two courses, for a total of 58 courses. The median interval between each course was 32 days. In the 28 assessable patients, the overall response rate was 43%, with one CRem and 11 partial remissions (PRems). No life-threatening complication was observed in these heavily pretreated patients. The median duration of neutropenia (< 5 x 10(9)/L) was 14 days, and that of thrombocytopenia (< 50 x 10(9)/L) was 11 days. The overall incidence of sepsis was 27%. Gastrointestinal toxicity was frequent, but mild. Electrolyte disturbance with antidiuretic hormone (ADH)-like syndrome occurred in eight courses, but resolved rapidly. Grade > or = 2 hemorrhagic cystitis was observed in three courses. No cardiac toxicity was observed. There were no treatment-related deaths. Pharmacokinetic analysis showed that mean steady-state plasma levels (Css) of VP16 were greater than 1 microgram/mL during all the courses. CONCLUSION: This new drug combination appears to be effective in advanced neuroblastoma. Its toxicity remains manageable, with no life-threatening complications. Further evaluation in patients with less-advanced disease is warranted.

Etoposide and carboplatin in neuroblastoma: a French Society of Pediatric Oncology phase II study.

PURPOSE: A phase II study of etoposide (VP 16) and carboplatin (CBDCA) was performed in patients with metastatic neuroblastoma (NB). The aim of the study was to find an alternative treatment for induction with different toxicities than the VP 16/cisplatin (CDDP) combination. PATIENTS AND METHODS: Forty-seven patients who were from 6 months to 16 years of age, with either relapsed (29) or primary resistant (18) NB, were included in a cooperative multicenter phase II study of the French Society of Pediatric Oncology (SFOP). The schedule consisted of 5 consecutive days of VP 16 100 mg/m2/d and CBDCA 160 mg/m2/d. RESULTS: The response rate for the 39 assessable patients was 43%; there were four complete remissions and 13 partial remissions. Neither the status of the patients nor the total dose of CDDP that was received previously influenced response. Hematologic toxicity was marked and caused considerable delay between courses (median interval, 39 days). In these heavily pretreated patients, 16% had a more than 50% decrease in creatinine clearance and a 22% World Health Organization (WHO) grade 2 ototoxicity. CONCLUSION: This VP 16/CBDCA combination deserves further evaluation for efficacy and toxicity in newly diagnosed patients, and the combination of both drugs should be considered for high-dose therapy with bone marrow transplantation.

Granulocyte colony-stimulating factor in induction treatment of children with non-Hodgkin's lymphoma: a randomized study of the French Society of Pediatric Oncology.

PURPOSE: To determine whether granulocyte colony-stimulating factor (G-CSF; lenograstim) decreases the incidence of febrile neutropenia after induction courses in treatment of childhood non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Patients were randomized to receive (G-CSF+) or not receive (G-CSF-) prophylactic G-CSF, 5 microg/kg/d, from day 7 until an absolute neutrophil count > or = 500/microL was sustained over 48 hours, after two consecutive induction courses of cyclophosphamide 1.5 or 3 g/m(2), vincristine 2 mg/m(2), prednisone 60 mg/m(2)/d x 5, doxorubicin 60 mg/m(2), high-dose methotrexate 3 or 8 g/m(2), and intrathecal injections (COPAD[M]) on protocols LMB89, LMT89, and HM91 of the French Society of Pediatric Oncology. RESULTS: One hundred forty-eight patients were assessable, 75 G-CSF+ and 73 G-CSF-. Although duration of neutropenia less than 500/microL was 3 days shorter in G-CSF+ patients (P = 10(-4)), incidence of febrile neutropenia (89% v. 93% in the first course, 88% v. 88% in the second course), durations of hospitalization and antimicrobial therapy, percentages of infections, mucositis, and transfusions were not significantly different. Although the percentage of G-CSF+ patients commencing the following course on day 21 was significantly higher (84% v 68% after the first and 57% v. 38% after the second course; P <.05), the median delay between the two courses was only 1 day less in G-CSF+ patients (median delay after first COPAD(M), 19 v. 20 days, P =.01; after second, 21 v. 22 days, P = not significant). Remission and survival rates were similar in both arms. CONCLUSION: This study demonstrates that G-CSF did not decrease treatment-related morbidity, nor increase the dose-intensity in children undergoing COPAD(M) induction chemotherapy for NHL.