Health status of childhood leukemia survivors who received hematopoietic cell transplantation after BU or TBI: an LEA study.

The purpose of this multicenter study was to compare the long-term impact of a preparative regimen with either BUBU or TBI on health status and quality of life (QoL) in childhood acute leukemia survivors treated with hematopoietic SCT (HSCT). Two-hundred and forty patients were included. Sixty-six had received BU, while 174 had received TBI. Median follow-up from HSCT was 10.1 years. Multivariate analyses were performed to assess the occurrence of late effects according to treatment. QoL was assessed in 130 adults using SF-36 questionnaires. Patients developed fewer late complications after BU (2.35 vs 3.01, P=0.03) while the risk to present with at least one complication was equivalent in both groups (87.9% after BU and 93.1% after TBI, P=0.66). Detailed multivariate analyses revealed a lower risk of height growth failure (OR=0.2), cataract (OR=0.1) and iron overload (OR=0.2) after BU, and an increased risk of overweight (OR=3.9) and alopecia (OR=11.2). SF-36 mental and physical composite scores were similar in both treatment groups and proved significantly lower than French norms. Late effects induced by BU might differ from those experienced after TBI. Although less frequent, they are still of considerable importance and may affect patients' QoL.

Non-invasive biological quantification of acute gastrointestinal graft-versus-host disease in children by plasma citrulline.

Clinical grading of GI involvement during acute GVHD remains a challenging issue, especially in children. Plasma citrulline, a non-protein amino acid selectively produced and released by enterocytes, is a suitable surrogate endpoint for small intestinal epithelial cell mass, irrespective of the underlying cause of cell loss. Children referred for allogeneic bone marrow transplantation who were free from chronic malabsorption or constitutional disease involving the GI tract were consecutively included in this prospective study. Plasma citrulline and albumin concentration was measured every week between day 7 and day 28 of BMT until resolution of the aGVHD or occurrence of chronic GVHD. In total, 31 children were included between 2008 and 2011. After a CR, citrulline levels fell to a minimum level on day 7 and then increased to reach the initial value on day 28. After day 28, plasma citrulline but not albumin was strongly linked to the occurrence of GI GVHD, the threshold being set at 10 µmol/L. The correlation with clinical grade of GI-aGVHD now needs to be assessed in larger populations. In pediatric patients, citrulline is valuable as a suitable non-invasive marker of GI involvement in acute GVHD.

Reduced-intensity conditioning followed by allogeneic transplantation in pediatric malignancies: a report from the Société Française des Cancers de l'Enfant and the Société Française de Greffe de Moelle et de Thérapie Cellulaire.

We report French prospective experience with reduced-intensity conditioning-allo-SCT in 46 patients (median age: 15.5 years, 4.8-20.2) presenting high-risk AL (n=11), Hodgkin's lymphoma (n=15) or solid tumors (n=20). Graft sources were BM (n=21), PBSC (n=20) and cord blood (CB; n=5) from related (n=20) or unrelated (n=26) donors. For CB grafts, only one patient out of five achieved sustained engraftment. For PBSC/BM grafts, engraftment rate was 95%, hematopoietic recovery times were not significantly different between BM, PBSC, sibling or unrelated grafts, day+100. Full donor chimerism was achieved in 94% of patients, and incidences of primary acute GVHD and chronic GVHD were 49% and 14%, respectively. Underlying disease was fatal in 39% of patients. TRM was 6.9%. Three-year OS was 49.15%. OS and EFS were not significantly different between patients transplanted with different grafts and with or without primary GVHD. Patients with solid tumor or measurable disease at transplant had poorer outcomes. Three-year EFS: 33.3% for ALL, 75.0% for AML, 51.8% for Hodgkin's lymphoma, 28.6% for neuroblastoma and 22.2% for sarcoma patients. This multicentre study concluded that Bu/fludarabine/anti-thymocyte globulin conditioning with PB or BM, related or unrelated grafts in patients with various malignancies at high-risk for transplantation toxicity results in high engraftment rates, low TRM and acceptable survival.

Molecular assessment of minimal residual disease in PBSC harvests provides prognostic information in neuroblastoma.

As almost all patients with high-risk neuroblastomas have autograft, we aimed to determine if minimal residual disease (MRD) quantified by RT-PCR for tyrosine hydroxylase in PBSC is prognostic in neuroblastomas. PBSC harvests from 38 children were analyzed. Seven had harvests positive for TH-mRNA. Patients with a positive MRD had a lower 2-year-overall-survival compared to those with negative MRD (P = 0.04) regardless of whether or not PBSC were re-infused. Patients in CR/VGPR group with positive MRD have hazard ratio of death at 7.3 [1.3-40.5]. In conclusion, molecular MRD status in PBSC of good response group may be of interest as a survival prognostic factor in high-risk neuroblastomas.

Long-term red blood cell exchange in children with sickle cell disease: manual or automatic?

Little information is available on erythrocytapheresis in children with sickle cell disease, and no comparison has ever been made with manual exchanges in a long-term blood exchange program. We matched a historical cohort of five patients who received 60 erythrocytapheresis procedures with five who received 124 manual exchanges. Long-term erythrocytapheresis was feasible and well-tolerated even in children of low weight. In a long-term approach, automated exchanges were more efficient in maintaining a low HbS level, and exchanges could be spaced out. This approach appears especially useful in the cases where the HbS level must be maintained below 30%.

[Megakaryoblastic acute leukemia: bone and joint manifestations in a 7-month-old child]. / Présentation ostéo-articulaire d'une leucémie aiguë mégacaryoblastique chez une enfant de 7 mois.

Acute megakaryoblastic leukemia accounts for approximately 3-10% of acute myeloid leukemia in children. Its diagnosis may be difficult because of associated myelofibrosis. We report the case of a 7-month-old child who presented hepatomegaly with bicytopenia. She also developed bone and joint pain with recurrent aseptic arthritis. We suggested the diagnosis of megakaryoblastic leukemia early but multiple bone marrow investigations had been processed without positive results because of sampling problems and lack of abnormal cells in the morphological, phenotypic, and cytogenetic examinations. We had a variety of indirect evidence for our assumption: the x-ray showing periosteal new bone, lytic lesions and metaphyseal bands, bone marrow aspirate smears with micromegakaryocytes, and bone marrow biopsy suggesting myelofibrosis. This was very suggestive of leukemia but we could not prove it and we finally found megakaryoblasts on bone marrow aspirate smears after more than 2 months of investigation and initiated a course of corticosteroids.

NK cytotoxicity and alloreactivity against neuroblastoma cell lines in vitro: comparison of Europium fluorometry assay and quantification by RT-PCR.

UNLABELLED: New therapies for children with high risk neuroblastoma are needed, and haploidentical stem cell transplantation with NK post-graft injections is a potential option. To develop this strategy, we compared and correlated two methods of NK cytotoxicity assay. The aim of this work is to optimize in vitro NK cytotoxicity assays, investigate the effect of interleukin stimulation on NK cells and use of antiGD2 antibodies against tumor target cells and finally establish an in vitro model for haploidentical stem cell transplantation. EXPERIMENTAL DESIGN: We evaluated NK cell cytotoxicity in vitro against NB cell lines (IMR-32 and SK-NSH) in different culture conditions using a Europium BATDA fluorescence test, and correlated the results with quantification of TH, Phox2B, and DCX transcripts evaluated by RT-PCR. RESULTS: Both IMR-32 and SK-N-SH neuroblastoma cell lines were sensitive to NK cells and particularly when NK cells were stimulated by interleukin IL-2 and IL-15 or when using anti-GD2 antibodies against tumor target cells. All these results were observed either with Europium fluorometry assay or with RT-PCR quantification. There is a clear correlation between the two methods, for the three transcripts at the ratio effector/target 50/1 (TH r=0.75, Phox2B r=0.79 and DCX r=0.8), for all the values whatever the cell line. Besides for all three transcripts, the correlations were significantly independent of the cell line and the ratio E/T (all p values non-significant) even if the best correlation was observed for the ratio 50/1. After prolonged incubation times of effector and target cells (24 h), which could be evaluated only by RT-PCR, all the transcripts clearly decreased, confirming the haploidentical effect of NK against the two neuroblastoma cell lines in our two in vitro haploidentical models but no advantage of mismatch. CONCLUSIONS: NK cytotoxicity against neuroblastoma cell lines can be evaluated by Europium assay and by RT-PCR with clear correlation for the three transcripts TH, Phox2B and DCX whatever the ratio E/T and cell line used. This new method of RT-PCR is simple and suitable for large-scale conditions like study of adherent tumor cells or prolonged incubations of target/effector cells which allowed us to observe haploidentical effect.

Growth hormone treatment impact on growth rate and final height of patients who received HSCT with TBI or/and cranial irradiation in childhood: a report from the French Leukaemia Long-Term Follow-Up Study (LEA).

The literature contains a substantial amount of information about factors that adversely influence the linear growth in up to 85% of patients undergoing haematopoietic SCT (HSCT) with TBI and/or cranial irradiation (CI) for acute leukaemia (AL). By contrast, only a few studies have evaluated the impact of growth hormone (GH) therapy on growth rate and final height (FH) in these children. We evaluated growth rates during the pre- and post-transplant periods to FH in a group of 25 children treated with HSCT (n=22), TBI (n=21) or/and CI (n=8) for AL and receiving GH therapy. At the start of GH treatment, the median height Z-score was -2.19 (-3.95 to 0.02), significantly lower than at AL diagnosis (P<0.001). Overall height gain from start of GH treatment to FH was 0.59Z (-2.72 to 2.93) with a median height Z-score at FH of -1.35 (-5.35 to 0.27). This overall height gain effect was greater in girls than in boys (P=0.04). The number of children with heights in the reference population range was greater after than before GH therapy (P=0.07). At FH the GVHD and GH treatments lasting <2 years were associated with shorter FH (P=0.02 and 0.05). We found a measurable beneficial effect of GH treatment on growth up to FH.

[Pediatric transfusion practices: A single-center retrospective study]. / Pratiques transfusionnelles en pédiatrie : étude rétrospective monocentrique.

OBJECTIVES: This study aimed to describe the professional practices in pediatric transfusion to assess the accuracy of transfusion guidelines in children. METHODS: The study retrospectively analyzed the characteristics of all the pediatric transfusions prescribed in the Clermont-Ferrand (France) university hospital center over 1 year and determined whether they conformed to the national guidelines. RESULTS: One thousand six hundred and seven blood products were delivered to 233 children (806 red cell units, 670 platelet units, and 131 plasma units), accounting for 5.3% of the center's whole blood products. Transfusions were mainly prescribed by the oncohematology unit (68.2%), the intensive care unit (15.4%), and for surgery (10.2%). Ten adverse events were reported in eight patients (0.6% of transfusions). The prescription conformed to the national guidelines in 35.9%, 41.6%, and 80.9% of the red blood cell, platelet, and plasma unit transfusions, respectively. Nonconformity was mainly due to abusive irradiation and "cytomegalovirus seronegative" specifications. CONCLUSION: Malignancies, intensive care, and surgery are the main indications for transfusion in children. Substantial discrepancy between recommendations and actual practices was observed. This illustrates the variability of risk evaluation. This should be made simpler by the use of photochemical pathogen inactivation techniques.

No improvement of survival with reduced- versus high-intensity conditioning for allogeneic stem cell transplants in Ewing tumor patients.

BACKGROUND: Outcomes of Ewing tumor (ET) patients treated with allogeneic stem cell transplantation (allo-SCT) were compared regarding the use of reduced-intensity conditioning (RIC) and high-intensity conditioning (HIC) regimens as well as human leukocyte antigen (HLA)-matched and HLA-mismatched grafts. PATIENTS AND METHODS: We retrospectively analyzed data of 87 ET patients from the European Group for Blood and Marrow Transplantation, Pediatric Registry for Stem Cell Transplantations, Asia Pacific Blood and Marrow Transplantation and MetaEICESS registries treated with allo-SCT. Fifty patients received RIC (group A) and 37 patients received HIC (group B). Twenty-four patients received HLA-mismatched grafts and 63 received HLA-matched grafts. RESULTS: Median overall survival was 7.9 months [±1.24, 95% confidence interval (CI) 5.44-10.31] for group A and 4.4 months (±1.06, 95% CI 2.29-6.43) for group B patients (P = 1.3). Death of complications (DOC) occurred in 4 of 50 (0.08) and death of disease (DOD) in 33 of 50 (0.66) group A and in 16 of 37 (0.43) and 17 of 37 (0.46) group B patients, respectively. DOC incidence was decreased (P < 0.01) and DOD/relapse increased (P < 0.01) in group A compared with group B. HLA mismatch was not generally associated with graft-versus-Ewing tumor effect (GvETE). CONCLUSIONS: There was no improvement of survival with RIC compared with HIC due to increased DOD/relapse incidence after RIC despite less DOC incidence. This implicates general absence of a clinically relevant GvETE with current protocols.

Extracorporeal photochemotherapy induces arginase 1 in patients with graft versus host disease.

The benefits of extracorporeal photochemotherapy (ECP; psoralen and UVA exposure of blood mononuclear cells) in graft-versus-host-disease (GVHD) are well-recognized, but the mechanisms of action remain elusive. As the metabolism of l-arginine in immune cells is known to play a role in immune tolerance, we investigated the effect of ECP on arginine metabolism, and the influence of extracellular l-arginine concentration on the response to ECP in cells from patients on therapy by ECP for a GVHD and healthy donors cultured before and after ECP in the presence of different concentrations of arginine (0, 50, 100, 200 and 1000 µmol/l). At baseline arginine was not metabolized through the same pathway in patients and donors. When cells were exposed to ECP, the production of ornithine but not NO° was enhanced, while mRNA of arginase 1 was up-regulated but not INOS. In GVHD patients, increasing arginine concentration resulted in down-regulation of IFNγ and TNFα mRNA expression, whereas IL10 was up-regulated especially at physiological plasma levels (between 0 and 100 µM). Overall, our study shows that ECP orients the metabolism of arginine toward the arginase pathway together with shifting the cytokine profile toward IL-10, providing new insights into the enigmatic mechanism of action of ECP.

[Benign but not harmless intracranial hypertension: a case report]. / Hypertension intracrânienne bénigne, mais pas anodine. À propos d'un cas.

Benign intracranial hypertension (BIH) is characterized as an intracranial pressure increase occurring in the absence of brain tumour, sinus thrombosis or hydrocephaly. But contrary to what its designation might suggest, it threatens the visual prognosis. We report the case of a 15-year-old girl with lymphocytic meningitis, developing secondary a BIH. Cerebrospinal fluid pressure was 70cm water, without enlargement of the cerebral ventricles. Along with the progression, bilateral 6th nerve palsy, impairment of visual acuity and bilateral papilledema appeared. No cause was found after a complete assessment. Treatment consisted in oral acetazolamide and 9 depletive spinal taps. Clinical examination, fundus examination and Goldmann visual field normalized after 8 weeks. No relapse occurred after a 1-year follow-up. This case shows that BIH, which is not a well-known disorder, is incorrectly referred to as benign: both prompt diagnosis and proper management are of major importance.

[Rationale for the use of extracorporeal photochemotherapy in children]. / Argumentaire pour une utilisation plus large de la photochimiothérapie extracorporelle chez l'enfant.

The management of immune diseases in children remains challenging, although significant advances have been made. In addition to pharmacological approaches, extracorporeal photochemotherapy (ECP) is distinctive in its ability to provide immunomodulation without immune suppression or toxicity. However, in practice, this therapy is not widely used because of logistical issues and the lack of robust clinical pediatric studies. Here, we discuss the potential clinical applications of ECP in children and emphasize the need for a rigorous and specifically pediatric clinical evaluation of ECP.

[Case report of a 2-year-old child with palpebral rhabdomyosarcoma]. / Rhabdomyosarcome palpébral chez un enfant âgé de deux ans.

Rhabdomyosarcoma is an extremely virulent rare tumor whose early diagnosis considerably improves survival and visual prognosis. We report the case of a 2-year-old child with levator palpebrae superioris muscle rhabdomyosarcoma revealed by a sudden and isolated blepharoptosis. Initially, clinical and imaging investigations did not show any abnormality but a painful tumor with some hematoma quickly developed, so the investigations were repeated. The CT-scan showed an extra-conal tumor that had developed at the superior part of the orbit. Histology confirmed the diagnosis of embryonic rhabdomyosarcoma. Because of its results, treatment consisting of chemotherapy associating ifosfamide, vincristine, actinomycin and orbital radiotherapy of 40 Gy with a local addition of 10 Gy were administrated with successful results after a 3-year-follow-up.

Evidence of a clinical response at one yr after reduced-intensity allogeneic hematopoietic stem cell transplantation in heavily pretreated adolescents with aggressive refractory Hodgkin's lymphoma.

We report results of RIC AHSCT in four adolescents with aggressive refractory HL. They all received three or four lines of therapy prior to RIC-AHSCT including autografts. At the time of RIC, they were in partial response except for one patient who had progressive chemoresistant disease. The conditioning regimen consisted of fludarabin, busulfan and ATG. They all had a matched related donor. The median follow-up was 12-16-month post-allograft. All patient transplants engrafted rapidly. The median time of hospitalization was 35 days. The median time to neutrophil recovery (>or=500/muL) was 19 days. All the patients were in complete donor chimerism at day 60. Four patients developed skin (grade

[Metabolic abnormalities in obese French children]. / Prévalence des anomalies métaboliques chez l'enfant obèse.

PURPOSE: The aim of this retrospective study was to describe the prevalence of metabolic abnormalities among obese children. PATIENTS AND METHODS: Two hundred and forty-four obese children were referred in our center between 2003 and 2007. The frequency of metabolic syndrome (MS) was assessed with the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) criteria. Insulin resistance was defined as a Homeostasis Model Assessment-Insulin Resistance (HOMA-IR) greater than the 75th percentile. RESULTS: Around 95.9% of the children had abdominal obesity, 38.1% had systolic hypertension, 19.3% diastolic hypertension, 12.3% hypertriglyceridemia, and 4.1% hypoHDLemia. Insulin resistance was present in 69.6% of children; 11.5% of children met the criteria for MS. Both the Z-score of the body mass index and the prevalence of metabolic abnormalities were higher in the group of the youngest children. CONCLUSION: The prevalence of metabolic abnormalities is high among overweight children, particularly in the youngest children. However, the management of obesity but not metabolic-specific intervention remains the priority.

Four successful pregnancies in a patient with mucopolysaccharidosis type I treated by allogeneic bone marrow transplantation.

To date, little is known about the fertility of women suffering from mucopolysaccharidosis type I (MPS I). We report on a female patient with MPS I treated by allogeneic bone marrow transplantation (BMT) at the age of 4 years (after a conditioning regimen containing busulfan 16 mg/kg and cyclophosphamide 100 mg/kg) who had four successful pregnancies without any reproductive assistance. Clinical and biological examinations of the children were normal. On the basis of this case, we discuss the fertility counselling of female MPS I patients at the time of BMT.

Hematopoietic progenitor cell mobilization and harvesting in children with malignancies: do the advantages of pegfilgrastim really translate into clinical benefit?

Our purpose was to assess success rates in children of achieving optimal hematopoietic progenitor cells (HPCs) harvest after mobilization with 300 microg/kg pegfilgrastim. Between January 2005 and January 2007, 26 children with solid malignancies who were referred for HPC collection were consecutively included. Hematopoietic progenitor cell mobilization consisted of one s.c. injection of 300 microg/kg body weight (BW) of pegfilgrastim. The success criterion was defined as at least 5 x 10(6) CD34+ cells/kg during the first standard apheresis (less than 3 blood volumes processed (BVP)). After 26 inclusions, the Bayesian analysis gave a mean estimated success rate of 60.7% (95% credibility interval: 42.0-78.0%). The first apheresis allowed the collection of 8.3 x 10(6) CD34+ cells/kg BW (range 0.6-37.8), with a median of 2.8 BVP (range 1.4-3.0). Overall, the median of CD34+ cells collected was 12.4 x 10(6)/kg (range 2.7-37.8). The cumulative dose of anthracyclin was the only variable associated with the total number of CD34+ collected cells (P<0.05). Mobilization was clinically well tolerated in 20 patients. No drug-related adverse events of grade > or =3 occurred. We conclude that a single injection of 300 microg/kg pegfilgrastim in the hematological steady state is an efficient and well-tolerated method of HPC mobilization in children with solid malignancies.

Allogeneic or haploidentical HSCT for refractory or relapsed solid tumors in children: toward a neuroblastoma model.

New concepts of allogeneic hematopoietic SCT (allo-HSCT) for neuroblastoma and other solid tumors do not rely on escalation of chemotherapy intensity and tumor load reduction but rather on a graft-vs-tumor effect. At this point, this is still an investigational and unusual application of allogeneic transplant, with 78 neuroblastoma patients reported to the European Group for Blood and Marrow Transplantation activity survey from 2002 to 2007 and less than 100 published cases. Two trends can be observed in the reviewed data: some teams have used allo-HSCT in children with refractory or progressive disease and significant tumor burden and other teams in children with CR, PR or minimal residual disease earlier in their disease process. Early studies of allo-HSCT in children with high-risk neuroblastoma suggest that this is a feasible approach that may improve outcome in this deadly disease. However, the proper timing for allo-HSCT during the disease course remains to be determined.