Busulfan-melphalan in high-risk neuroblastoma: the 30-year experience of a single institution.

High-dose chemotherapy (HDC) was investigated in high-risk neuroblastoma (HR-NBL) to reduce the risk of relapse. We report the results of the 30-year experience of a cohort of patients with HR-NBL treated with high-dose (HD) busulfan (Bu)-containing regimens. From 1980 to 2009, 215 patients aged >1 year with stage 4 NBL were treated with HD Bu-containing regimens at Gustave Roussy. These data were prospectively recorded in the Pediatric Transplantation Database. The median age at diagnosis was 40 months (12-218 months). All patients had a stage 4 neuroblastoma. NMYC amplification was displayed in 24% of the tumors. The hematopoietic support consisted of bone marrow or PBSCs in 46% and 49% of patients, respectively. The 5-year event-free survival and overall survival rates of the whole cohort were 35.1% and 40%, respectively. Age at diagnosis, bone marrow involvement and tumor response after induction chemotherapy were significant prognostic factors. Toxicity was manageable and decreased over time, owing to both PBSC administration and better supportive care. Based on this experience, HD Bu-melphalan (Mel) has been implemented in Europe and compared with Carboplatin-Etoposide-Mel in the European SIOP Neuroblastoma (SIOPEN)/HR-NBL randomized protocol. It has now become the standard HDC in the SIOPEN HR strategy.

Magnetism of the chromium thio-spinels Fe1-xCuxCr2S4 studied using muon spin rotation and relaxation.

Powder samples of Fe1-xCuxCr2S4 with x = 0,0.2,0.5,0.8 were studied, between 5 and 300 K. The results reveal that for x < 1, the magnetic order in the series is more varied than the simple collinear ferrimagnetic structure traditionally assumed to exist everywhere from the Curie point to T â†’ 0. In FeCr2S4 several ordered magnetic phases are present, with the ground state likely to have an incommensurate cone-like helical structure. Fe0.8Cu0.2Cr2S4 is the compound for which simple collinear ferrimagnetism is best developed. In Fe0.5Cu0.5Cr2S4 the ferrimagnetic spin structure is not stable, causing spin reorientation around 90 K. In Fe0.2Cu0.8Cr2S4 the ferrimagnetic structure is at low temperatures considerably distorted locally, but with rising temperature this disorder shows a rapid reduction, coupled to increased spin fluctuation rates. In summary, the present data show that the changes induced by the replacement of Fe by Cu have more profound influences on the magnetic properties of the Fe1-xCuxCr2S4 compounds than merely a shift of Curie temperature, saturation magnetization and internal field magnitude.

Experimental demonstration of a synthetic aperture compression scheme for multi-Petawatt high-energy lasers.

We present the experimental demonstration of a subaperture compression scheme achieved in the PETAL (PETawatt Aquitaine Laser) facility. We evidence that by dividing the beam into small subapertures fitting the available grating size, the sub-beam can be individually compressed below 1 ps, synchronized below 50 fs and then coherently added thanks to a segmented mirror.

Procalcitonin guidance and reduction of antibiotic use in acute respiratory tract infection.

Increasing worldwide development of antimicrobial resistance and the association of resistance development and antibiotic overuse make it necessary to seek strategies for safely reducing antibiotic use and selection pressure. In a first step, in a non-interventional study, the antibiotic prescription rates, initial procalcitonin (PCT) levels and outcome of 702 patients presenting with acute respiratory infection at 45 primary care physicians were observed. The second part was a randomised controlled non-inferiority trial comparing standard care with PCT-guided antimicrobial treatment in 550 patients in the same setting. Antibiotics were recommended at a PCT threshold of 0.25 ng·mL(-1). Clinical overruling was permitted. The primary end-point for non-inferiority was number of days with significant health impairment after 14 days. Antibiotics were prescribed in 30.3% of enrolled patients in the non-interventional study. In the interventional study, 36.7% of patients in the control group received antibiotics as compared to 21.5% in the PCT-guided group (41.6% reduction). In the modified intention-to-treat analysis, the numbers of days with significant health impairment were similar (mean 9.04 versus 9.00 for PCT-guided and control group, respectively; difference 0.04; 95% confidence interval -0.73-0.81). This was also true after adjusting for the most important confounders. In the PCT group, advice was overruled in 36 cases. There was no significant difference in primary end-point when comparing the PCT group treated as advised, the overruled PCT group and the control group (9.008 versus 9.250 versus 9.000 days; p = 0.9605). A simple one-point PCT measurement for guiding decisions on antibiotic treatment is non-inferior to standard treatment in terms of safety, and effectively reduced the antibiotic treatment rate by 41.6%.

Low temperature incommensurately modulated and noncollinear spin structure in FeCr2S4.

FeCr(2)S(4) orders magnetically at T(N)≈ 170 K. According to neutron diffraction, the ordered state down to 4.2 K is a simple collinear ferrimagnet maintaining the cubic spinel structure. Later studies, however, claimed trigonal distortions below ∼ 60 K coupled to the formation of a spin glass type ground state. To obtain further insight, muon spin rotation/relaxation (µSR) spectroscopy was carried out between 5 and 200 K together with new (57)Fe Mössbauer measurements. Below ∼ 50 K, our data point to the formation of an incommensurately modulated noncollinear spin arrangement like a helical spin structure. Above 50 K, the spectra are compatible with collinear ferrimagnetism, albeit with a substantial spin disorder on the scale of a few lattice constants. These spin lattice distortions become very large at 150 K and the magnetic state is now better characterized as consisting of rapidly fluctuating short-range ordered spins. The Néel transition is of second order, but ill defined, extending over a range of ∼ 10 K. The Mössbauer data around 10 K confirm the onset of orbital freezing and are also compatible with the noncollinear order of iron. The absence of a major change in the quadrupole interaction around 50 K renders the distortion of crystal symmetry to be small.

Measurement of the in-medium K0 inclusive cross section in pi(-) -induced reactions at 1.15 GeV/c.

The K0 meson production by pi(-) mesons of 1.15 GeV/c momentum on C, Al, Cu, Sn, and Pb nuclear targets was measured with the FOPI spectrometer at the Schwer-Ionen-Synchrotron accelerator of GSI. Inclusive production cross sections and the momentum distributions of K0 mesons are compared to scaled elementary production cross sections and to predictions of theoretical models describing the in-medium production of kaons. The data represent a new reference for those models, which are widely used for interpretation of the strangeness production in heavy-ion collisions. The presented results demonstrate the sensitivity of the kaon production to the reaction amplitudes inside nuclei and point to the existence of a repulsive KN potential of 20+/-5 MeV at normal nuclear matter density.

Risk factors for hepatic veno-occlusive disease: a retrospective unicentric study in 116 children autografted after a high-dose BU-thiotepa regimen.

At our Institute, during the last decade, the incidence of hepatic veno-occlusive disease (HVOD) appears to be on the increase among pediatric patients treated with BU-thiotepa (BU-TTP)-conditioning regimen. We thus performed a retrospective analysis to identify the risk factors for HVOD, which could explain such a change. In total, 116 patients treated at Institut Gustave Roussy, between May 1998 and December 2005 were eligible for this study having received BU-TTP as their first high-dose chemotherapy regimen, followed by autologous hematopoietic SCT (AHSCT). According to McDonald's clinical criteria, HVOD was diagnosed in 31% of these children. Demographic, clinical, biological and therapeutic parameters were evaluated in uni- and multivariate analyses that showed a significant correlation between previous carboplatin therapy and risk of developing post transplant HVOD (P=0.028). Comparable results were found for etoposide (P=0.048). In addition, a correlation between HVOD and risk of post transplant death was linked to its association with other types of organ failure (P=0.029). This study demonstrates that previous VPCARBO administration in conventional chemotherapy significantly increases the risk of HVOD among brain tumor patients later consolidated with BU-TTP followed by AHSCT.

A writing workshop for children with cancer.

We present and comment on several short texts written in a writing workshop by children and adolescents treated for cancer. In addition to the obvious themes, the patients communicate the intense elements of the experience they are going through, including fear of injections, fear of not being cured, revolt, hope and a feeling of unreality, and raise the question "Why?". They are proud to express their feelings, thoughts and creativity, and relieved to be able show that they remain themselves. This can help them maintain or regain confidence in themselves and in the ability of their parents and medical staff to understand them. We consider their pleasure, their parents' and caregivers' reactions and the quality of their work as it relates to their age, academic level, cultural environment and cognitive capacities. These examples may help to inform physicians and nurses about how they perceive patients (children or adults) and their needs and abilities, and thereby improve the quality of the relationship.

[A multidisciplinary consultation for children with brain tumors]. / Une consultation multidisciplinaire pour les enfants traités pour une tumeur cérébrale.

UNLABELLED: School achievement of children with brain tumors is hampered by progressive neurologic and cognitive sequelae. To help the children and their family, we have created in 1997 a multidisciplinary consultation together with Necker's hospital. MATERIAL AND METHODS: The study describes the organization of the consultation and analyses the files of 69 children seen between September 2001 and June 2002. RESULTS AND CONCLUSION: The authors conclude that this consultation is an irreplaceable mean to coordinate the complex rehabilitation process of a child treated for a brain tumor.

Elevated plasma ferritin and busulfan pharmacodynamics during high-dose chemotherapy regimens in children with malignant solid tumors.

Hepatic veno-occlusive disease (HVOD) is a frequent complication during hematopoietic stem-cell transplantation (HSCT). A strong relationship has been demonstrated between busulfan exposure and HVOD for busulfan-cyclophosphamide and allogeneic HSCT in adults. Busulfan disposition after the first intake was studied in 77 children treated for solid malignancies with high-dose busulfan-containing regimens and autologous HSCT. Busulfan was combined with cyclophosphamide and melphalan (n=30), melphalan (n=27), and thiotepa (n=20). No relationship was observed between busulfan exposure and HVOD. In contrast, plasma ferritin at baseline was higher in patients with HVOD (750 ng/ml (20-3,110)) compared with those without HVOD (189 ng/ml (8-3,967), P=0.012). Multivariate analysis showed that a ferritin level exceeding 300 ng/ml was the only risk factor for HVOD with an odds ratio of 4.0 (confidence interval 95% (1.5-11.2), P=0.0071). A high ferritin level at baseline was explained by the diagnosis of neuroblastoma, related treatments and transfusions.

Haematopoietic stem cell transplantation trends in children over the last three decades: a survey by the paediatric diseases working party of the European Group for Blood and Marrow Transplantation.

This paper describes the trends in haematopoietic stem cell transplantation (HSCT) activity for children in Europe over the last three decades. We analysed 31,713 consecutive paediatric HSCTs reported by the European Group for Blood and Marrow Transplantation (EBMT) centres between 1970 and 2002. Data were taken from the EBMT registry and were compared according to period and centre category (paediatric or combined). Since 1996, there has been a significant increase in the number of HSCTs performed exclusively by paediatric centres, as well as in the number of alternative donor HSCTs, and in the use of peripheral blood stem cells (P<0.0001). The number of allogeneic HSCTs (allo-HSCTs) for acute lymphoblastic leukaemia, acute myeloblastic leukaemia and chronic myeloid leukaemia remained stable, whereas it increased for myelodysplastic syndromes and lymphomas, and decreased significantly for non-malignant diseases (P<0.0001). Multivariate analysis showed that younger age, human leukocyte antigen genoidentical donors, HSCT performed after 1996 and transplant centres performing more than 10 allo-HSCT/year were all associated with decreased transplant-related mortality (TRM) (P<0.0001). The number of autologus HSCTs (auto-HSCTs) for acute leukaemia decreased significantly, whereas it increased for solid tumours (P<0.0001). Multivariate analysis showed that both auto-HSCT performed before 1996 and paediatric solid tumours (P<0.0001) had higher TRM. Indications for paediatric HSCT have changed considerably during the last seven years. These changes provide tools for decision making in health-care planning and counselling.

[Malignant solid tumors in neonates: a study of 71 cases]. / Tumeurs solides malignes néonatales: à propos de 71 cas.

UNLABELLED: Malignant neonatal tumors are rare and comprise 2% of childhood malignancies. Clinical features, histologic types, prognosis were very different from those seen in older children, facing oncologists with diagnostic, therapeutic and ethical problems. PATIENTS AND METHODS: In a retrospective study from January 1987 to January 2004, we reviewed the management of neonates treated at the Institute Gustave Roussy for a malignant solid tumor for whom symptoms started in the first month of life. RESULTS: Seventy-one neonates were treated, comprising 1,2% of the overall patients treated during the same period of time. Of these 71 patients, 42 (59%) presented with neuroblastomas, 12 (17%) with mesenchymal tumors, 6(8%) with cerebral tumors and 11 with various other types of tumors. Fifty-nine patients underwent surgical resection. Thirty-eight neonates received chemotherapy, administered at a 30 to 50% reduced dose. Hematologic toxicities and infections were the main therapeutic complications. Very small doses of radiotherapy were used in only 5 children. There has been no therapy-related mortality. Twenty-two of the 57 survivors have sequelae, especially patients with intraspinal neuroblastoma. The 5 year overall survival was 79%. CONCLUSIONS: Neonatal malignant solid tumors, except for cerebral tumors, have a good prognosis. The young age of patients resulted in problems of treatment tolerance. The therapeutic regimen should take into account the risk of acute iatrogenic toxicity and long term sequelae. Surgery remains the treatment of choice but chemotherapy, with dose reduction, managed by expert teams, is essential and safer in a lot of case.

siRNA-mediated AML1/MTG8 depletion affects differentiation and proliferation-associated gene expression in t(8;21)-positive cell lines and primary AML blasts.

The chromosomal translocation t(8;21) is associated with 10-15% of all cases of acute myeloid leukaemia (AML). The resultant fusion protein AML1/MTG8 interferes with haematopoietic gene expression and is an important regulator of leukaemogenesis. We studied the effects of small interfering RNA (siRNA)-mediated AML1/MTG8 depletion on global gene expression in t(8;21)-positive leukaemic cell lines and in primary AML blasts using cDNA arrays, oligonucleotide arrays and real-time reverse transcription-polymerase chain reaction (RT-PCR). Suppression of AML1/MTG8 results in the increased expression of genes associated with myeloid differentiation, such as AZU1, BPI, CTSG, LYZ and RNASE2 as well as of antiproliferative genes such as IGFBP7, MS4A3 and SLA both in blasts and in cell lines. Furthermore, expression levels of several genes affiliated with drug resistance or indicative of poor prognosis AML (BAALC, CD34, PRG2, TSPAN7) are affected by AML1/MTG8 depletion. In conclusion, siRNA-mediated suppression of AML1/MTG8 cause very similar changes in gene expression pattern in t(8;21)-positive cell lines and in primary AML blasts. Furthermore, the results suggest that the specific targeting of AML1/MTG8 function may be a promising approach for complementing existing treatment strategies.

Inhibition of retinoic acid receptor signaling by Ski in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a heterogeneous disease with multiple different cytogenetic and molecular aberrations contributing to leukemic transformation. We compared gene expression profiles of 4608 genes using cDNA-arrays from 20 AML patients (nine with -7/del7q and 11 with normal karyotype) with 23 CD34+ preparations from healthy bone marrow donors. SKI, a nuclear oncogene, was highly up regulated. In a second set of 183 AML patients analyzed with real-time PCR, the highest expression level of SKI in AML with -7/del7q could be confirmed. As previously described, Ski associates with the retinoic acid receptor (RAR) complex and can repress transcription. We wanted to investigate the interference of Ski with RARalpha signaling in AML. Ski was co-immunoprecipitated and colocalized with RARalpha. We also found that overexpression of wild-type Ski inhibited the prodifferentiating effects of retinoic acid in U937 leukemia cells. Mutant Ski, lacking the N-CoR binding, was no more capable of repressing RARalpha signaling. The inhibition by wild-type Ski could partially be reverted by the histone deacetylase blocking agent valproic acid. In conclusion, Ski seems to be involved in the blocking of differentiation in AML via inhibition of RARalpha signaling.

[Targeted therapies in pediatric oncology: a new therapeutic approach?]. / Thérapies ciblées en oncologie pédiatrique: nouvelle approche thérapeutique.

A multidisciplinary therapeutic approach has led to significant increase in survival of children with cancer, however often with a high rate of severe sequela. Better understanding in tumor cell biology and transformation process allowed to describe active tyrosine kinases (mainly growth factor receptors) as a new target for cancer treatment. This review presents 2 approaches to target receptor tyrosine kinase activity: on one hand, antibodies that target the extracellular domain, the natural ligand binding site, and on the other hand, small inhibiting molecules, such as imatinib, targeted against the activated intracellular receptor tyrosine kinase. We focus on their clinical development and current application in the treatment of childhood cancer. Targeted therapies are in full rise and new perspectives are explored, such as their association to other treatment modalities and the targeting of microenvironment. This new therapeutic approach necessitates well designed clinical trials that include relevant biomarkers to evaluate its real therapeutic potential.

[Ifosfamide induced encephalopathy: 15 observations]. / Encéphalopathie induite par l'ifosfamide: 15 observations.

INTRODUCTION: Ifosfamide is an alkylating agent used in the treatment of germ-cell tumors, sarcomas and lymphomas. One of its main side effects is the encephalopathy of which the incidence may reach 30% in the literature, in adults and children just as well. OBJECTIVES: Based on both our experience and a review of the literature, we propose some recommendations for the management of this complication. PATIENTS AND METHODS: We report 15 encephalopathy cases in non-brain tumor patients, which occurred between January 1987 and March 2002 in children from 2 to 17 years old, treated for solid tumors at the Institut Gustave Roussy. Ifosfamide was administered at a posology between 5.4 and 15 g/m(2)/course, associated with other antimitotics such as actinomycin D, etoposide or vincristine. RESULTS: Six patients experienced a grade III neurological toxicity according to the NCI classification, which developed as excess drowsiness lasting up to 36 hours. Six other patients developed grade IV neurotoxicity, including two comas resolving within 4 days and four short generalized convulsions. Three other children experienced grade II drowsiness. Brain MRIs were normal and EEG showed an aspecific encephalopathy tracing. This early central neurotoxicity appeared right from the first administration, and occurred immediately after the first injection or during the second or third day of treatment. It was most often reversible, usually 3 to 5 days after the last ifosfamide administration. Five patients were administered a treatment with Methylene Blue with a demonstrable efficacy in only one case. No death or neurological sequelae have been noted. Ifosfamide has been renewed after the neurological accident in 7 of those patients. Only 1 of those 7 patients developed grade IV neurotoxicity during the next course of treatment. In 2 of those 7 children, Methylene Blue was used in a prophylactic way. No neurological disorders have been noted during the next courses of treatment. DISCUSSION: In the literature, the following are described as risk factors for ifosfamide encephalopathy: advanced pelvic disease, previous cisplatyl treatment and renal failure. We have not found any of these predisposing factors in our series, but three of the fifteen patients had severe neurotoxicity associated with Vincristin during previous treatments. CONCLUSION: Facing a clinical diagnosis of ifosfamide encephalopathy, it is recommended to discontinue administration of ifosfamide and inject by intravenous route 50 mg Methylene Blue every 4 hours until the symptomatology recedes. The re-challenge of Ifosfamide is not contra-indicated and should be performed under prophylactic treatment with Methylene Blue by intravenous route at the dose of 50 mg every 6 hours.

Expression profiling of Wilms tumors reveals new candidate genes for different clinical parameters.

Wilms tumor is the most frequent renal neoplasm in children, but our understanding of its genetic basis is still limited. We performed cDNA microarray experiments using 63 primary Wilms tumors with the aim of detecting new candidate genes associated with malignancy grade and tumor progression. All tumors had received preoperative chemotherapy as mandated by the SIOP protocol, which sets this study apart from related approaches in the Unites States that are based on untreated samples. The stratification of expression data according to clinical criteria allowed a rather clear distinction between different subsets of Wilms tumors. Clear-cut differences in expression patterns were discovered between relapse-free as opposed to relapsed tumors and tumors with intermediate risk as opposed to high risk histology. Several differentially expressed genes, e.g.TRIM22, CENPF, MYCN, CTGF, RARRES3 and EZH2, were associated with Wilms tumor progression. For a subset of differentially expressed genes, microarray data were confirmed by real-time RT-PCR on the original set of tumors. Interestingly, we found the retinoic acid pathway to be deregulated at different levels in advanced tumors suggesting that treatment of these tumors with retinoic acid may represent a promising novel therapeutic approach.

Ethical issues in pediatric oncology phase I-II trials based on a mother's point of view.

Phase I-II trials are developing in Pediatrics and raise many complex relational, psychological and ethical issues. We present and discuss these based on an interview in a pediatric oncology setting, with a mother who accepted that her daughter be included in such trials and who expressed why she accepted with great sensitivity and profoundness. She explained that after many years of inefficient treatments she had lost all her landmarks and was ready to accept any proposition, even those she would have considered unacceptable earlier. She did not know whether there is a limit to what is acceptable. Her only objective was to gain any time possible in order to continue living with her daughter. She found it important that the research doctor be different from the doctor involved in patient care, and that the latter remains the major decision-maker and correspondent: thus the child's best interests take precedence over that of research. Interviews with the psycho-oncologist can help the parents and the doctors gain a better insight into the various aspects, rational and irrational, conscious and unconscious, involved in the proposition to participate in a clinical trial and in the parents' or the child's acceptance or refusal.

High-dose busulfan and thiotepa followed by autologous stem cell transplantation (ASCT) in previously irradiated medulloblastoma patients: high toxicity and lack of efficacy.

We previously demonstrated that Busulfan-Thiotepa (Bu-Thio) and ASCT effectively treated patients with locally relapsed medulloblastoma after surgery and conventional chemotherapy. We thus evaluated the administration of Bu-Thio in patients relapsing after conventional CNS irradiation. Patients were scheduled to receive Busulfan (600 mg/m(2)) and Thiotepa (900 mg/m(2)) and ASCT. Resection of residual tumour and additional irradiation were performed if necessary and feasible after Bu-Thio. Toxicity was compared to that observed in 35 patients treated without previous CNS irradiation. From 5/88 to 3/02, 15 patients were treated according to this strategy. Toxicity was significantly higher than that observed in unirradiated patients: thrombocytopenia <50,000/mm(3) lasting 56 days (13-732) (P=0.02) and 30 days (4-124), respectively, HVOD (10/15 and 12/35 patients, respectively) (P=0.06), neurological toxicity (8/15 vs 3/35 patients) (P=0.01). Tumour response was assessable in seven patients and consisted in two CR, three PR and two NR. Currently, two of 15 patients are alive with no evidence of disease. In conclusion, the toxicity of Bu-Thio was significantly more severe in previously irradiated patients. In spite of a high response rate, this strategy failed to improve the prognosis of previously irradiated patients with a relapse from a medulloblastoma.