Yves Perel

Clinical impact and prognostic value of metaiodobenzylguanidine imaging in children with metastatic neuroblastoma.

PURPOSEnThe clinical value of metaiodobenzylguanidine (mIBG) scintigraphy in patients with disseminated neuroblastoma (NB) at the time of diagnosis and after induction chemotherapy was evaluated.nnnPATIENTS AND METHODSnThe medical records and imaging studies of 30 patients with stage 4 NB who underwent mIBG scintigraphy and 99mTc hydroxy methylene diphosphonate bone scintigraphy at the time of diagnosis were reviewed. Scores were calculated for the mIBG and bone scintigrams, and outcome according to the initial and follow-up imaging studies was determined.nnnRESULTSnDiscrepancies between bone scintigraphy and mIBG osteomedullary localization were seen in six patients. For the entire cohort, 2-year event-free survival did not significantly differ for the group of patients with initial mIBG or bone scintigraphy scores > or = 10 compared to those with scores < 10 (P = 0.23 and 0.61, respectively). However, for patients older than 1 year, a trend associating worse outcome with mIBG scores > or = 10 at diagnosis was seen (P = 0.08). A trend correlating abnormal mIBG scintigraphy after induction therapy and poor outcome was also observed (P = 0.09). Outcome did not correlate with the results of the bone scintigram studies performed after induction chemotherapy (P = 0.68).nnnCONCLUSIONnBecause a discordance between mIBG and bone scintigraphy results were seen in a subset of stage 4 NB patients, both imaging studies should be performed at the time of diagnosis. mIBG imaging studies performed at the time of diagnosis and after induction chemotherapy may be of prognostic value, particularly in stage 4 patients older than 1 year.

(P)FAPA syndrome: intérêt de la cimétidine

Resume Le (P)FAPA ( periodic fever, adenitidis, pharyngitis, aphtous stomatitis ) a ete individualise en 1987. Il sagit dun syndrome periodique de cause inconnue dont nous rapportons trois nouvelles observations. Observations Trois patientes âgees de 23 mois a huit ans ont developpe un (P)FAPA. Les autres causes de fievre periodique etaient ecartees et les differents traitements (antibiotiques, antipyretiques, anti-inflammatoires non steroidiens) etaient inefficaces. La repetition des acces periodiques entrainait des troubles depressifs, un absenteisme scolaire et un inflechissement ponderal chez la plus jeune. Deux dentre elles presentaient une atteinte sinusienne (sinusite chronique, polype) ainsi quune elevation des immunoglobulines A. Dans les trois cas, la cimetidine a la dose de 20 mg/kg/j etait bien toleree et a permis une disparition des acces periodiques. Conclusion La cimetidine en tant quagent immunomodulateur apporte un benefice dans le traitement de fond des (P)FAPA.

Oesophageal atresia, VACTERL association: Fanconi’s anaemia related spectrum of anomalies

Oesophageal atresia usually occurs without any genetic background. Three cases associated with Fanconi’s anaemia are reported. One neonate had growth retardation and numerous malformations including oesophageal atresia and four other components of the VACTERL association. In the two others, oesophageal atresia was isolated. In patients with such malformations an early diagnosis of Fanconi’s anaemia may have important genetic and therapeutic implications.

An Investigation of the Steady-State Pharmacokinetics of Oral Valacyclovir in Immunocompromised Children

Valacyclovir was administered to 28 immunocompromised children (ages 5-12 years) to obtain preliminary pharmacokinetic and safety information. Patients were randomized to valacyclovir regimens of 250 mg (9.4-13.3 mg/kg) or 500 mg (13.9-27.0 mg/kg) twice daily or 500 mg (13.2-21.7 mg/kg) 3 times a day. Acyclovir pharmacokinetics were evaluated at steady state. Valacyclovir was rapidly absorbed and converted to acyclovir. Mean (+/-SD) acyclovir peak concentrations from 250 mg and 500 mg valacyclovir were 4.11+/-1.41 and 5.19+/-1.96 microg/mL, respectively. Corresponding single dose area-under-curve values were 12.14+/-6.60 and 14.49+/-4.69h microg/mL. By using historical data for intravenous acyclovir as reference, the overall estimate of acyclovir bioavailability from valacyclovir was 48%, 2- to 4-fold greater than for oral acyclovir. In general, adverse events were not attributable to valacyclovir and were consistent with disease-related expectations and concomitant therapies. Dosage options for using valacyclovir in children are discussed.

Second thyroid neoplasms after prophylactic cranial irradiation for acute lymphoblastic leukemia

An understanding of the pathogenesis of second cancers may help in their prevention. We report on two children who were treated for acute lymphoblastic leukemia (ALL), with an exclusively cranial prophylactic irradiation (18 Gy) and who presented with a thyroid carcinoma (TC) 12 and 13 years later. From a thorough review of the literature of TC after ALL and of radiation‐induced TC, a strong case can be made that these tumors are caused by late effects of scattered radiation. The risk is at its highest in small children. After cranial irradiation, patients require clinical monitoring of the thyroid and cervical area for nodules, continued indefinitely. We suggest that, in most cases, an alternative form of neuromeningeal prophylaxis should be offered in small children with ALL. Am. J. Hematol. 59:91–94, 1998.

Myeloid leukaemia in children with Down syndrome: report of the registry-based French experience between 1990 and 2003.

To determine the epidemiology of myeloid leukaemia (ML) in children with Down syndrome (DS) and the efficacy of two approaches, low‐dose cytarabine‐based regimen (LDC) and standard‐dose intensive chemotherapy (SD).

Capillary haemangioma of the greater omentum in a 5-month-old female infant: a case report.

Abstract Capillary haemangiomas are frequent benign tumours in infancy. The authors report a case of capillary haemangioma of the greater omentum, discovered in a child of 5 months of age and studied with US, CT and MRI. The localization of such a lesion in the greater omentum is exceptional. Abdominal US revealed a heterogeneous, multinodular intraperitoneal mass. Doppler study demonstrated hypervascularity of the lesion. CT localized the mass to the greater omentum. The mass was hypodense on the unenhanced scan and enhanced massively after injection. The infant suffered a reaction to contrast medium during the CT. MRI demonstrated a mass which was hypointense on T1-weighted images and hyperintense on T2-weighted images. Laparotomy confirmed the location of the mass within the greater omentum and allowed resection of the tumour.

A dose‐intensive approach (NB96) for induction therapy utilizing sequential high‐dose chemotherapy and stem cell rescue in high‐risk neuroblastoma in children over 1 year of age

To improve outcome and overall survival (OS) in high‐risk neuroblastoma, NB96 induction therapy was intensified using sequential high‐dose chemotherapy and autologous stem cell rescue.

Curing acute lymphoblastic leukemia and avoiding osteonecrosis: Can't we have it all?

I n this issue of Pediatric Blood & Cancer, Leblicq et al. [1] describe a cohort of ALL patients treated according to DFCI regimens, and retrospectively analyze 17/242 patients with osteonecrosis (ON). Accordingly, previous studies have reported clinical manifestations of ON in 5–10% of ALL pediatric patients [2]. The detrimental role of glucocorticoid (GC) therapy is now wellestablished as well as other risk-factors: age 10 years, and possibly, female gender, high body mass index, and genetic factors [2,3]. Because ON could lead to significant morbidity, pain, and long-term debilitating arthropathy, the authors have suggested the use of pamidronate therapy after ON diagnosis and they report a rather favorable outcome. While Leblicq et al. appeared to have shown the relevance of bisphosphonate administration in ALL patients with ON, some limitations of the study should be mentioned. First, due to the retrospective analysis strategy and small sample-size, demonstration of bisphosphonate therapy efficacy was not definitively shown; accordingly, the authors acknowledge that their results are exploratory and in need of confirmation. Second, while they show that reintroduction of GC therapy was safely attempted in a subset of patients, they do not suggest any criteria that would help to define this subset of patients. A more definitive demonstration of the clinical benefit and safety of pamidronate in the treatment or prevention of ON in children with ALL could be drawn from future randomized and controlled trials; however, it is unlikely that such a large trial could be set up. Alternatively, protocols should include stringent guidelines on the management of ON (work-up and criteria of diagnosis, classification, nutritional guidance, calcium and vitamin D supplements, physical therapy, GC therapy and chemotherapy adaptations, outcome) [4]. Patients could be treated with bisphosphonates according to clinical severity; this approach should be restricted to specialized centers and a mandatory long-term survivorship program will be required for scientificdriven pharmacovigilance and evidence-based guidelines determination. It is also uncertain whether a possible beneficial effect of bisphosphonate in ON could be related to analgesic effect, modification of bone vascularization, prevention of osteoblast apoptosis, or a different mechanism not related to mineralization [1]. As suggested by Leblicq et al., ON treatment might allow clinicians to maintain or reintroduce such a fundamental treatment as GC in ALL; this might be an option, relying on palliative measures and supportive-care to maintain a dose-intensive regimen. Another historically useful option would be a stratified risk deescalation strategy of GC therapy. However, GC therapy is an essential component for cure in ALL treatment strategies and there is no way to currently omit it or to drastically cut doses. While controversial, GC area-under-the curve and EFS-rate have been reported to be higher in ALL patients with ON [3]. At a prednisone-to-dexamathasone ratio of less than seven, dexamethasone resulted in a better EFS than prednisone [4] and as highlighted by Leblicq et al., in a higher rate of ON. However, while it is not an easily accepted approach, several lines of evidence might suggest the selection of less toxic GC molecule (prednisone vs. dexamethasone), decreased GC doses and/or modified delivery schedule in patients with high-risk of ON and low-risk leukemia [4,5]; there is clearly still room for clinical research with randomized studies to determine the optimal efficacy-to-toxicity ratio for GC in ALL subtypes and for each treatment phase. In cohorts of patients, the efficacy of GC therapy in ALL is dependent on dose and duration, but the same is true about sideeffects. The third option, aimed at breaking this deadlock, will emerge from a much better understanding of the mechanisms underlying the cellular responses to GC therapy. Several studies have investigated the mechanisms of GC resistance/sensitivity and have largely focused on GC receptor (GR) in the cytoplasm and its downstream pathway (dimer formation, translocation to nucleus, activation/repression of gene expression, apoptosis) [6–9]. On the one hand, the in vivo and in vitro response of ALL cells to GC monotherapy is a strong prognostic factor of cure; GC resistance is, at least in part, an intrinsic feature of ALL cells already present at diagnosis. Reports are based on rational target-gene analyses and genome-wide strategies [6–8]; they have identified polymorphic or differential expression pointing to the SW1/SNF chromatin-remodeling complex [7] and identified an imbalance of pro and anti-apoptotic factors [8] possibly resulting from a GC-regulated network of genes downstream of the GR more than from a single critical gene [6]. On the other hand, several articles