Pediatric thrombotic events: a single-center study.

Recent literature has reported an apparent increase in the incidence of pediatric venous thromboembolism over the last 10 years. In our study, data were collected from all children (ages 0 to 18 y) with a thrombotic event between January 2000 and May 2012, to determine whether an increased incidence of thromboembolism (TE) was evident and to investigate mitigating factors in the development of the TE. A total of 134 patients were entered into the study, 42% under the age of 1 year. There was no conclusive evidence of an increased incidence in our population over the period of the study. Within our population the peripheral venous system was the most common location for TE followed by cerebral vascular accidents. A thrombophilic risk factor was found in 84% of the patients. In our study 4.5% of the children had a second event.

Cancer in Australian Aboriginal children: room for improvement.

AIM: The study aims to analyse clinical data and outcome in Aboriginal and non-Aboriginal children with cancer. METHODS: This is a retrospective case-note review of biological features, treatment outcome and survival in Aboriginal and non-Aboriginal children with a malignancy who were treated at the Women's and Children's Hospital, a tertiary referral hospital, from January 1997 through March 2011. Two separate analyses were performed: firstly, for each Aboriginal patient comparisons were made with two age, sex and diagnosis-matched control patients; then secondly, results for the Aboriginal group of patients were compared with the whole non-Aboriginal group of patients. RESULTS: In the first analysis, Aboriginal children had a significantly higher 'remoteness index' (6.14 vs. 0.95; P < 0.001) and were less likely to be enrolled on clinical trials. Survival analysis of the Aboriginal patients and their matched controls showed a trend towards inferior overall survival for the Indigenous children (P = 0.066). In the second analysis, Aboriginal children tended to have a higher proportion of leukaemias and lymphomas and had an overrepresentation of acute myeloid leukaemia (AML) (P = 0.009). The mean age among Aboriginal children with AML and lymphoma was lower (AML: 3.5 vs. 8 years, P = 0.065; lymphoma: 7.5 vs. 11.9 years, P = 0.01). A higher proportion of Aboriginal children died (P = 0.004). CONCLUSIONS: Aboriginal children present with a somewhat different pattern of cancer, are less likely to be enrolled on studies and seem to have increased mortality. There is a need for improvement in study enrolment, treatment delivery, care coordination and suitably supported residential facilities.

Improved outcome with hematopoietic stem cell transplantation in a poor prognostic subgroup of infants with mixed-lineage-leukemia (MLL)-rearranged acute lymphoblastic leukemia: results from the Interfant-99 Study.

To define a role for hematopoietic stem cell transplantation (HSCT) in infants with acute lymphoblastic leukemia and rearrangements of the mixed-lineage-leukemia gene (MLL(+)), we compared the outcome of MLL(+) patients from trial Interfant-99 who either received chemotherapy only or HSCT. Of 376 patients with a known MLL status in the trial, 297 (79%) were MLL(+). Among the 277 of 297 MLL(+) patients (93%) in first remission (CR), there appeared to be a significant difference in disease-free survival (adjusted by waiting time to HSCT) between the 37 (13%) who received HSCT and the 240 (87%) who received chemotherapy only (P = .03). However, the advantage was restricted to a subgroup with 2 additional unfavorable prognostic features: age less than 6 months and either poor response to steroids at day 8 or leukocytes more than or equal to 300 g/L. Ninety-seven of 297 MLL(+) patients (33%) had such high-risk criteria, with 87 achieving CR. In this group, HSCT was associated with a 64% reduction in the risk of failure resulting from relapse or death in CR (hazard ratio = 0.36, 95% confidence interval, 0.15-0.86). In the remaining patients, there was no advantage for HSCT over chemotherapy only. In summary, HSCT seems to be a valuable option for a subgroup of infant MLL(+) acute lymphoblastic leukemia carrying further poor prognostic factors. The trial was registered at www.clinicaltrials.gov as #NCT00015873 and at www.controlled-trials.com as #ISRCTN24251487.

A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial.

BACKGROUND: Acute lymphoblastic leukaemia in infants younger than 1 year is rare, and infants with the disease have worse outcomes than do older children. We initiated an international study to investigate the effects of a new hybrid treatment protocol with elements designed to treat both acute lymphoblastic leukaemia and acute myeloid leukaemia, and to identify any prognostic factors for outcome in infants. We also did a randomised trial to establish the value of a late intensification course. METHODS: Patients aged 0-12 months were enrolled by 17 study groups in 22 countries between 1999 and 2005. Eligible patients were stratified for risk according to their peripheral blood response to a 7-day prednisone prophase, and then given a hybrid regimen based on the standard protocol for acute lymphoblastic leukaemia, with some elements designed for treatment of acute myeloid leukaemia. Before the maintenance phase, a subset of patients in complete remission were randomly assigned to receive either standard treatment or a more intensive chemotherapy course with high-dose cytarabine and methotrexate. The primary outcomes were event-free survival (EFS) for the initial cohort of patients and disease-free survival (DFS) for the patients randomly assigned to a treatment group. Data were analysed on an intention-to-treat basis. This trial was registered with ClinicalTrials.gov, number NCT 00015873, and at controlled-trials.com, number ISRCTN24251487. FINDINGS: In the 482 enrolled patients who underwent hybrid treatment, 260 (58%) were in complete remission at a median follow-up of 38 (range 1-78) months, and EFS at 4 years was 47.0% (SE 2.6, 95% CI 41.9-52.1). Of 445 patients in complete remission after 5 weeks of induction treatment, 191 were randomised: 95 patients to receive a late intensification course, and 96 to a control group. At a median follow-up of 42 (range 1-73) months, 60 patients in the treatment group and 57 controls were disease-free. DFS at 4 years did not differ between the two groups (60.9% [SE 5.2] for treatment group vs 57.0% [5.5] for controls; p=0.81). During the intensification phase, of 71 patients randomly assigned to the treatment group, and for whom toxicity data were available, 35 (49%) had infections, 21 (30%) patients had mucositis, 22 (31%) patients had toxic effects on the liver, and 2 (3%) had neurotoxicity. All types of rearrangements in the (mixed lineage leukaemia) MLL gene, very high white blood cell count, age of younger than 6 months, and a poor response to the prednisone prophase were independently associated with inferior outcomes. INTERPRETATION: Patients treated with our hybrid protocol, and especially those who responded poorly to prednisone, had higher EFS than most reported outcomes for treatment of infant ALL. Delayed intensification of chemotherapy did not benefit patients.

The impact of a cerebellar tumour on language function in childhood.

BACKGROUND/AIMS: Childhood-acquired cerebellar studies to date have appeared to present a concordant pattern of specific neuropsychological profiles depending on lesion site. The aim was to determine the impact of a cerebellar tumour specifically on language function in children by reporting both the general and high-level language abilities of 4 cases with differing sites of hemispheric and vermal involvement. METHODS: The language abilities of 4 children (aged from 7 years 9 months to 13 years), treated with surgery and/or radiotherapy for cerebellar tumour 6 months to 3 years previously, were examined. A standardized battery of general and high-level language assessments was administered. RESULTS: Analysis revealed intact abilities across all 4 cases on measures of general language, including receptive language, expressive language, receptive vocabulary and naming. While 2 of the 4 cases also demonstrated intact high-level language skills across all measures, the remaining 2 demonstrated specific deficits in linguistic problem solving at 6 months after treatment. Follow-up assessment of 1 case also demonstrated further decline in this area 12 months later. CONCLUSION: Findings of high-level language deficits in problem solving in 2 of the 4 cases examined supported previous reports of specific impairments in high-level language and in thinking flexibility and problem solving following cerebellar hemispheric damage in childhood.

Sertoli-Leydig cell tumor of the ovary, a rare cause of precocious puberty in a 12-month-old infant.

We report a 12-month-old infant who presented with a 4-month history of isosexual precocious puberty secondary to an estrogenizing Sertoli-Leydig cell tumor of the ovary. Total serum immunoreactive inhibin and subunits A and B were markedly elevated before surgical resection and subsequently decreased 7 wk later into the normal prepubertal range. Twenty weeks following surgical removal, the patient presented again with central precocious puberty; inhibin B levels were raised on this occasion, a luteinizing releasing hormone stimulation test confirmed central precocious puberty. This is the youngest reported occurrence of this rare sex cord stromal neoplasm. The prognosis of this extremely rare tumor presenting at this early juvenile stage is uncertain. This report illustrates the usefulness of serum inhibin as a tumor marker during therapeutic suppression with leuprorelin acetate for central precocious puberty. Analysis of genomic and tumor DNA revealed a normal nucleotide sequence for the LH receptor and the Galpha(s) gene. To understand the molecular pathogenesis of this tumor we analyzed mRNA levels for the inhibin A and B subunits, FSH receptor, LH receptor aromatase, steroidogenic factor-1 and the ER beta genes. Molecular characterization reveals the presence of genes specific for granulosa and Leydig cells; the relative expression of these genes, in addition to its histologic characteristics, suggests that this tumor may result from a dysdifferentiation of a primordial follicle.

Successful treatment of disseminated mucormycosis in a neutropenic patient with T-cell acute lymphoblastic leukaemia.

Mucormycosis is a rare angioinvasive fungal infection, more commonly seen in immunosuppressed patients, with reported mortality rates of 95% in disseminated disease. We present a case report of a patient with T-cell acute lymphoblastic leukaemia who developed disseminated infection with mucormycosis (involving the pancreas, left occipital lobe, right lower lobe of lung, appendix and right kidney) after having completed induction and consolidation chemotherapy. Growth of Lichtheimia corymbifera was initially isolated following a right pleural tap with fungal elements identified repeatedly on subsequent pathology specimens. Following radical surgical debridement and concurrent treatment with combination antifungal therapy, the patient survived. This case demonstrates that aggressive multisite surgical de-bulking of disseminated fungal foci, in conjunction with combination antifungal therapy and reversal of immunosuppression, can result in survival despite the grave prognosis associated with disseminated mucormycosis.

A pedigree with autosomal dominant thrombocytopenia, red cell macrocytosis, and an occurrence of t(12:21) positive pre-B acute lymphoblastic leukemia.

Sampling and analyzing new families with inherited blood disorders are major steps contributing to the identification of gene(s) responsible for normal and pathologic hematopoiesis. Familial occurrences of hematological disorders alone, or as part of a syndromic disease, have been reported, and for some the underlying genetic mutation has been identified. Here we describe a new autosomal dominant inherited phenotype of thrombocytopenia and red cell macrocytosis in a four-generation pedigree. Interestingly, in the youngest generation, a 2-year-old boy presenting with these familial features has developed acute lymphoblastic leukemia characterized by a t(12;21) translocation. Tri-lineage involvement of platelets, red cells and white cells may suggest a genetic defect in an early multiliear progenitor or a stem cell. Functional assays in EBV-transformed cell lines revealed a defect in cell proliferation and tubulin dynamics. Two candidate genes, RUNX1 and FOG1, were sequenced but no pathogenic mutation was found. Identification of the underlying genetic defect(s) in this family may help in understanding the complex process of hematopoiesis.

Re-entering life: paediatric acute myeloid leukaemia at one year post treatment.

To date, there is scant psychosocial research on the experience of childhood AML. This article presents findings from the perspective of the child patients, their parents and siblings at one year post-treatment. The findings highlight challenges associated with re-entering life post-treatment with an emphasis on the ongoing sense of uncertainty, the changed sense of normalcy, and the difficulty of returning to the hospital for check-ups. A number of recommendations are made including the desirability of providing hospital space for check-ups away from the treatment area and the need for ongoing reassurance and support.