Jacqueline Halton

Outcome of pediatric thromboembolic disease : A report from the Canadian Childhood thrombophilia Registry

The outcome for children with deep vein thrombosis (DVT) and pulmonary embolism (PE) is unknown. An understanding of morbidity and mortality of DVT/PE is crucial to the development of rational treatment protocols. The Canadian Childhood Thrombophilia Registry has followed 405 children aged 1 mo to 18 y with DVT/PE for a mean of 2.86 y (range, 2 wk to 6 y) to assess outcome. The all-cause mortality was 65 of 405 children (16%). Mortality directly attributable to DVT/PE occurred in nine children (2.2%), all of whom had central venous line–associated thrombosis. Morbidity was substantial, with 33 children (8.1%) having recurrent thrombosis, and 50 children (12.4%) having postphlebitic syndrome. Recurrent thrombosis and postphlebitic syndrome were more common in older children, although deaths occurred equally in all age groups. The incidence of recurrent thrombosis and postphlebitic syndrome are likely underestimated because of difficulties in diagnosis, especially in younger children. The significant mortality and morbidity found in our study supports the need for international multicenter randomized clinical trials to determine optimal prophylactic and therapeutic treatment for children with DVT/PE.

Mineral homeostasis and bone mass at diagnosis in children with acute lymphoblastic leukemia

OBJECTIVE To determine whether the osteopenia and unusual fractures observed in children with acute lymphoblastic leukemia (ALL) were related to the disease rather than to its treatment. DESIGN Prospective analysis of the bone and mineral status in 40 consecutive children with ALL seen in a pediatric tertiary-care referral center. METHODS Biochemical indicators of mineral, endocrine, and vitamin D status were measured before initiation of therapy. Bone mass was determined radiographically and by dual-photon absorptiometry of the lumbar region of the spine (L2-L4). Correlations between clinical observations, leukemia variables, bone mass, and biochemical assessment were determined. RESULTS At the time of diagnosis musculoskeletal pain was present in 36% of patients and was more common in children with CD10-positive leukemia and leukocyte counts less than 20 x 10(9) cells/L. Radiographic evidence of osteopenia and fractures was observed in 13% and 10% of children, respectively. The mean bone mineral content was normal. Bone mass measurement z scores correlated with plasma 1,25-dihydroxyvitamin D3 concentrations (r = 0.43, p < 0.05). Plasma calcium, magnesium, phosphorus, and 25-hydroxyvitamin D3 levels were normal. Low plasma osteocalcin (mean +/- SD, 1.6 +/- 1.6 nmol/L) and 1,25-dihydroxyvitamin D3 (33.4 +/- 26.4 pmol/L) values were observed. Parathyroid hormone levels were low in 14% of children. Hypercalciuria was detected in 64% of children. Urinary deoxypyridinoline was lower (p < 0.01) than in age-matched control subjects. Histomorphometric measurements of iliac bone showed abnormalities in mineralization in the biopsy specimens from three of nine children. CONCLUSION Most children with ALL have alterations in bone metabolism and bone mass when first examined. These data suggest defective mineralization as the mechanism for decreased bone mass and implicate the leukemic process as causative.

Bone and mineral abnormalities in childhood acute lymphoblastic leukemia: influence of disease, drugs and nutrition.

In children with acute lymphoblastic leukemia (ALL), abnormalities in mineral homeostasis and bone mass were first reported by our group in the late 1980s. Prospective longitudinal cohort studies in 40 consecutive patients receiving treatment according to the Dana‐Farber Cancer Institute (DFCI) protocol 87‐001 and 16 children receiving DFCI protocol 91‐001 afforded us the opportunity to explore various etiologies of the observed abnormalities in mineral and bone metabolism, specifically the leukemic disease process and chemotherapeutic drugs such as steroids and aminoglycoside antibiotics. At diagnosis of ALL, >70% of children had abnormally low plasma 1,25‐dihydroxyvitamin D, 73% had low osteocalcin and 64% had hypercalciuria, indicating an effect of the leukemic process on vitamin D metabolism and bone turnover. During remission induction, treatment with high‐dose steroid (prednisone or dexamethasone) resulted in further reduction in plasma osteocalcin and elevated parathyroid hormone levels. During 24 months of chemotherapy‐maintained remission, reduction in bone mineral content (BMC), as measured by Z‐scores, occurred in 64% of children, most severely affecting those >11 years of age. A reduction in BMC during the first 6 months had a positive predictive value of 64% for subsequent fracture. By the end of 2 years of therapy, fractures occurred in 39% of children and radiographic evidence of osteopenia was found in 83% of the entire study group. Investigations of the biochemical basis of the bone abnormalities revealed that by 6 months hypomagnesemia developed in 84% of children (of whom 52% were hypermagnesuric) and plasma 1,25‐dihydroxyvitamin D remained abnormally low in 70%. Altered magnesium status was attributed to renal wastage of magnesium following cyclical prednisone therapy and treatment with aminoglycoside antibiotics such as amikacin for fever accompanying neutropenia. Dietary intake and absorption of magnesium were normal. In 10 children treated for hypomagnesemia with supplemental magnesium for up to 16–20 weeks, plasma magnesium normalized in only 50% of subjects. Int. J. Cancer Supplement 11:35–39, 1998.

Advanced Vertebral Fracture among Newly Diagnosed Children with Acute Lymphoblastic Leukemia: Results of the Canadian STeroid-associated Osteoporosis in the Pediatric Population (STOPP) Research Program

Vertebral compression is a serious complication of childhood acute lymphoblastic leukemia (ALL). The prevalence and pattern of vertebral fractures, as well as their relationship to BMD and other clinical indices, have not been systematically studied. We evaluated spine health in 186 newly diagnosed children (median age, 5.3 yr; 108 boys) with ALL (precursor B cell: N = 167; T cell: N = 19) who were enrolled in a national bone health research program. Patients were assessed within 30 days of diagnosis by lateral thoraco‐lumbar spine radiograph, bone age (also used for metacarpal morphometry), and BMD. Vertebral morphometry was carried out by the Genant semiquantitative method. Twenty‐nine patients (16%) had a total of 75 grade 1 or higher prevalent vertebral compression fractures (53 thoracic, 71%; 22 lumbar). Grade 1 fractures as the worst grade were present in 14 children (48%), 9 patients (31%) had grade 2 fractures, and 6 children (21%) had grade 3 fractures. The distribution of spine fracture was bimodal, with most occurring in the midthoracic and thoraco‐lumbar regions. Children with grade 1 or higher vertebral compression had reduced lumbar spine (LS) areal BMD Z‐scores compared with those without (mean ± SD, −2.1 ± 1.5 versus −1.1 ± 1.2; p < 0.001). LS BMD Z‐score, second metacarpal percent cortical area Z‐score, and back pain were associated with increased odds for fracture. For every 1 SD reduction in LS BMD Z‐score, the odds for fracture increased by 80% (95% CI: 10–193%); the presence of back pain had an OR of 4.7 (95% CI: 1.5–14.5). These results show that vertebral compression is an under‐recognized complication of newly diagnosed ALL. Whether the fractures will resolve through bone growth during or after leukemia chemotherapy remains to be determined.

High Incidence of Vertebral Fractures in Children With Acute Lymphoblastic Leukemia 12 Months After the Initiation of Therapy

PURPOSE Vertebral fractures due to osteoporosis are a potential complication of childhood acute lymphoblastic leukemia (ALL). To date, the incidence of vertebral fractures during ALL treatment has not been reported. PATIENT AND METHODS We prospectively evaluated 155 children with ALL during the first 12 months of leukemia therapy. Lateral thoracolumbar spine radiographs were obtained at baseline and 12 months. Vertebral bodies were assessed for incident vertebral fractures using the Genant semiquantitative method, and relevant clinical indices such as spine bone mineral density (BMD), back pain, and the presence of vertebral fractures at baseline were analyzed for association with incident vertebral fractures. RESULTS Of the 155 children, 25 (16%; 95% CI, 11% to 23%) had a total of 61 incident vertebral fractures, of which 32 (52%) were moderate or severe. Thirteen (52%) of the 25 children with incident vertebral fractures also had fractures at baseline. Vertebral fractures at baseline increased the odds of an incident fracture at 12 months by an odds ratio of 7.3 (95% CI, 2.3 to 23.1; P = .001). In addition, for every one standard deviation reduction in spine BMD Z-score at baseline, there was 1.8-fold increased odds of incident vertebral fracture at 12 months (95% CI, 1.2 to 2.7; P = .006). CONCLUSION Children with ALL have a high incidence of vertebral fractures after 12 months of chemotherapy, and the presence of vertebral fractures and reductions in spine BMD Z-scores at baseline are highly associated clinical features.

A pilot pharmacokinetic and antiangiogenic biomarker study of celecoxib and low-dose metronomic vinblastine or cyclophosphamide in pediatric recurrent solid tumors.

Tumor vasculature is a reasonable target for cancer therapy and lower more frequent doses of traditional chemotherapeutics [low-dose metronomic (LDM) chemotherapy] has been shown to have antiangiogenic efficacy. This study evaluated the safety and pharmacokinetics of celecoxib and LDM vinblastine or cyclophosphamide in children with recurrent, refractory solid tumors. We also investigated whether a subset of circulating plasma proteins are surrogate markers of angiogenic activity. Thirty-three children were enrolled in this pilot study and received celecoxib (250 mg/m2 PO b.i.d.) and either vinblastine (1 mg/m2 IV 3×/wk) or cyclophosphamide (30 mg/m2 PO daily) continually. Celecoxib alone and with LDM chemotherapy was well tolerated and plasma concentrations were consistent with those shown to have antiangiogenic activity. Four patients (13%) had durable stable disease (28 to 78 wk) although no complete or partial responses were observed. The surrogate markers measured (vascular endothelial growth factor, basic fibroblast growth factor, soluble vascular cell adhesion molecule, soluble intercellular cell adhesion molecule, endostatin, and thrombospondin-1) were highly variable and no statistically significant relationship between them and disease progression or maintenance of stable disease was observed. We concluded that this regimen is well tolerated hence supporting the use of this form of therapy in pediatric patients. However, future studies should include more homogenous patient populations and focus on validating surrogate markers to monitor treatment activity.

Cognitive Changes in Children Treated for Acute Lymphoblastic Leukemia With Chemotherapy Only According to the Pediatric Oncology Group 9605 Protocol

The purpose of this study was to examine cognitive functioning and neuroimaging in children with leukemia treated with the Pediatric Oncology Group 9605 protocol at the Childrens Hospital of Eastern Ontario. Mean age at diagnosis was 4.88 ± 2.54 years. The mean (n = 24) Wechsler Verbal and Performance IQ fell in the low-average range (87.33 ± 15.69 and 84.83 ± 19.11, respectively). Mean (n = 20) Verbal and Visual Memory Indexes of 82.95 ± 15.46 and 88.30± 10.80, respectively, were obtained. The proportion of scores on measures of intelligence and memory falling > 1 SD below the normative mean was substantially higher than expected. Paired t-test suggested that Wechsler Verbal IQ and memory remained stable, whereas Wechsler Performance IQ declined significantly. The results of growth curve analyses replicated these findings and suggested a significant adverse effect of cumulative dosage of intrathecal methotrexate on estimated Wechsler Performance IQ. Although only two children experienced seizures, 78% of the group showed leukoencephalopathy on at least one magnetic resonance image. Reliance on seizures as a predictor of leukoencephalopathy might underestimate the incidence of neurotoxicity. (J Child Neurol 2005;20:129—133).

Growth and body composition in response to chemotherapy in children with acute lymphoblastic leukemia

Severely malnourished children afflicted by acute lymphoblastic leukemia (ALL), particularly in developing countries, have reduced tolerance to chemotherapy and a compromised prospect for survival. We investigated the prevalence and severity of alterations in growth and nutritional status in children with ALL from population‐based referral areas in Canada. All children were treated with Dana‐Farber Cancer Institute ALL Consortium protocols. First, the relative impact of cranial irradiation (CI) and chemotherapy on growth was studied in 116 children at diagnosis and at 6‐month intervals during treatment. We observed a decline in height standard deviation (SD) score in the first year in all children, and a further decline in height SD score during the second year only in the children who received CI. Weight reduction occurred in the first year, but during the second year there was a disproportionate increase in weight compared with height, suggesting that children treated with ALL have a tendency toward obesity. Both chemotherapy and CI contribute to the altered growth observed in children treated for ALL. Second, intestinal functional integrity was assessed in 16 children during post‐induction chemotherapy. Nutrient intake was adequate and there was minimal evidence of malabsorption: fat malabsorption occurred in only 1 child (after treatment‐related pancreatitis), abnormal D‐xylose absorption occurred in 2 children at 6 months of therapy (returning to normal 6 months later) and abnormal lactose absorption occurred in 4 children. Third, weight, height, whole body lean and fat mass measured by dual‐energy X‐ray absorptiometry and serum albumin were determined at diagnosis and at 6‐month intervals throughout therapy in 19 children with ALL. Height SD scores decreased significantly during treatment. Serum albumin was abnormally low in 6/19 at diagnosis and 14/18 during intensive consolidation therapy. The mean change in the ratio of lean mass to total body weight showed a 5% reduction by 6 months of therapy. Body fat increased from a mean of 22% at diagnosis to 28% at completion of therapy. The majority of children treated for ALL thus have significant changes in nutritional status manifested by reductions in growth, alterations in lean and fat body mass and abnormally low serum proteins during intensive therapy. Int. J. Cancer Supplement 11:81–84, 1998.

Prevalence of post-thrombotic syndrome following asymptomatic thrombosis in survivors of acute lymphoblastic leukemia.

Summary.  Background: Deep vein thrombosis (DVT) is a complication of treatment of acute lymphoblastic leukemia (ALL) in children but little is known about the long‐term outcomes of these DVT. Objective: To determine the incidence of post‐thrombotic syndrome (PTS) in (i) children with ALL diagnosed with asymptomatic DVT using radiographic testing and (ii) an unselected group of ALL survivors. Methods: Cross‐sectional study in two populations. Group I comprised children in the Prophylactic Antithrombin Replacement in Kids with ALL treated with L‐Asparaginase (PARKAA) study diagnosed with DVT by radiographic tests. Group II consisted of non‐selected childhood ALL survivors <21 years. PTS was assessed using a standardized scoring sheet. Results: Group I: 13 PARKAA patients (median age 12 years) were assessed, and 7 had PTS (54%; 95% CI, 25–81). All patients had collaterals, three also had increased arm circumference. Group II: 41 patients (median age 13 years) with a history of ALL were enrolled, and 10 had PTS (24%; 95% CI, 11–38). All patients had collaterals; five also had increased arm circumference. Conclusion: There is a high incidence of PTS in survivors of childhood ALL with radiographically diagnosed asymptomatic DVT. A significant proportion of ALL survivors develop PTS, indicating previously undiagnosed DVT.

Children's Oncology Group (COG) Nutrition Committee

The Childrens Oncology Group (COG) Nutrition Committee was established to further the knowledge of nutrition in children with cancer by education and the conduct of clinical trials. A survey of COG institutions revealed lack of conformity in evaluation and categorization of nutritional status, and criteria for nutritional intervention. The Committee subsequently established specific categories of malnutrition (Underweight and Overweight) based on ideal body weight or body mass index. An algorithm was developed as a guideline for nutritional intervention as well as references and resources for determining estimated needs. The Committee embarked on concepts for clinical trials of nutritional interventions. The first pilot study, evaluating the feasibility of using an immunoneutraceutical precursor for glutathione production, has been completed. This study showed weight gain and improvement in glutathione status. A pilot trial of proactive enteral feeding for patients at high risk of malnutrition has commenced. The Committee believes that nutrition is relevant to all aspects of cancer control. The paucity of nutritional investigation in children with cancer needs to be rectified. Pediatr Blood Cancer