Importance of nutrition in pediatric oncology.

A nutritional perspective within pediatric oncology is usually just related to the supportive care aspect during the management of the underlying malignancy. However, nutrition has a far more fundamental importance with respect to a growing, developing child who has cancer as well as viewing cancer from a nutritional cancer control perspective. Nutrition is relevant to all components of cancer control including prevention, epidemiology, biology, treatment, supportive care, rehabilitation, and survivorship. This article briefly describes this perspective of nutrition within a cancer control context and is a summary of the presentation at the "1st International SIOP-PODC Workshop on Nutrition in Children with Cancer" held in Mumbai.

An international survey of nutritional practices in low- and middle-income countries: a report from the International Society of Pediatric Oncology (SIOP) PODC Nutrition Working Group.

BACKGROUND/OBJECTIVES: Optimal nutritional status is important in children with cancer, as it can influence clinical outcomes. To improve the nutritional health of children and adolescents receiving treatment for cancer residing in low income and middle-income countries (LMIC), we investigated nutrition practices among these nations' institutions providing treatment for childhood cancer. SUBJECT/METHODS: A cross-sectional survey of nutrition practice was administered to staff members at institutions providing treatment for children with cancer between 2011 and 2012. Countries classified as low income and middle income were divided by geographical region. Final analysis was performed with 96 surveys, which included 27 institutions from Asia, 27 institutions from Latin America and Caribbean, 27 institutions from Africa and 15 institutions from Europe. RESULTS: The study found that 55% of institutions had a dietician available on their service. Access to dieticians, lack of nutrition resources and lack of nutrition education of staff were the main barriers to providing nutrition care in LMIC. Half of the institutions performed nutritional assessment at diagnosis, and the methods used varied widely. Twenty-nine percent of all institutions used complementary and alternate therapies within their clinical practice, and 35% of institutions reported that nutrition education was provided to patients and families. CONCLUSIONS: Priority areas for improving the nutritional management in LMIC include the following: (1) improved nutrition education and assessment tools for doctors and nurses; (2) increased availability of nutrition education resources for families and patients; and (3) identification of the role of complementary and alternative therapies in closing gaps in symptom management in these institutions.

Validation of variants in SLC28A3 and UGT1A6 as genetic markers predictive of anthracycline-induced cardiotoxicity in children.

BACKGROUND: The use of anthracyclines as effective antineoplastic drugs is limited by the occurrence of cardiotoxicity. Multiple genetic variants predictive of anthracycline-induced cardiotoxicity (ACT) in children were recently identified. The current study was aimed to assess replication of these findings in an independent cohort of children. PROCEDURE: . Twenty-three variants were tested for association with ACT in an independent cohort of 218 patients. Predictive models including genetic and clinical risk factors were constructed in the original cohort and assessed in the current replication cohort. RESULTS: . We confirmed the association of rs17863783 in UGT1A6 and ACT in the replication cohort (P = 0.0062, odds ratio (OR) 7.98). Additional evidence for association of rs7853758 (P = 0.058, OR 0.46) and rs885004 (P = 0.058, OR 0.42) in SLC28A3 was found (combined P = 1.6 × 10(-5) and P = 3.0 × 10(-5), respectively). A previously constructed prediction model did not significantly improve risk prediction in the replication cohort over clinical factors alone. However, an improved prediction model constructed using replicated genetic variants as well as clinical factors discriminated significantly better between cases and controls than clinical factors alone in both original (AUC 0.77 vs. 0.68, P = 0.0031) and replication cohort (AUC 0.77 vs. 0.69, P = 0.060). CONCLUSIONS: . We validated genetic variants in two genes predictive of ACT in an independent cohort. A prediction model combining replicated genetic variants as well as clinical risk factors might be able to identify high- and low-risk patients who could benefit from alternative treatment options.

Diamond-blackfan anemia and cyclosporine therapy revisited.

A girl with Diamond-Blackfan anemia diagnosed in infancy started cyclosporine A (CSA) therapy at 9 years and 8 months of age after experiencing unacceptable side effects while receiving prednisone. Since then, she has been followed-up for more than 4 years. She exhibited a dramatic response to CSA, with weaning and then cessation of steroid therapy after 5 months. She has remained transfusion-independent. Attempts to discontinue CSA therapy have been unsuccessful. Relapse of the anemia has occurred in the context of viral infections with missed CSA doses. The major clinical problem during treatment has been recurrent oral aphthous ulceration, which responds to topical therapy. She is currently maintained on CSA 100 mg twice daily with a hemoglobin of 10.2 g/dL and a reticulocyte count of 1.6%. A trial of CSA therapy should be considered in patients with Diamond-Blackfan anemia in whom steroid therapy has failed before a transfusion program is instituted or alternative donor stem cell transplantation is entertained.

Immunosuppressive therapy: a potential alternative to bone marrow transplantation as initial therapy for acquired severe aplastic anemia in childhood?

PURPOSE: Currently bone marrow transplantation (BMT) with an HLA-identical sibling donor is recommended as optimal therapy for children with acquired severe aplastic anemia (SAA). Immunosuppressive therapy (IST) has become a very successful initial therapy for SAA in children lacking a related bone marrow donor. We wished to evaluate whether current IST regimens may be as efficacious as BMT. PATIENTS AND METHODS: A retrospective review identified children treated for SAA over a 12-year period. Children with a related donor received a BMT. Children lacking a donor were treated with IST followed by a "rescue" BMT if IST was ineffective. IST consisted of anti-thymocyte globulin and steroid +/- cyclosporine A. Transfusion independence and survival rates were compared between the two groups. RESULTS: Twenty-seven children were identified. Nine received a related BMT; seven of these survive and are transfusion independent (median follow-up 54 months). Sixteen of 18 patients who received IST are transfusion-independent survivors, including three of four patients who received a rescue BMT (median follow-up 33.5 months). Actuarial survival is 75% (95% CI = 45%, 105%) and 92% (95% CI = 78%, 107%) for the BMT and IST groups, respectively (p = 0.15). Severe toxicity was not experienced by any patient as a result of IST. CONCLUSIONS: Equivalent rates of transfusion independence and survival were experienced by patients receiving BMT and IST. We propose that a prospective trial be undertaken to evaluate IST as initial therapy in all children with SAA, to be followed by BMT if there is inadequate response.

Differences in dose scheduling as a factor in the etiology of anthracycline-induced cardiotoxicity in Ewing sarcoma patients.

Clinical observation suggested a high prevalence of cardiac morbidity and mortality in children with Ewing sarcoma (ES) treated at B.C.'s Children's Hospital. We therefore compared 30 patients treated for Ewing sarcoma between 1978 and 1991 with 26 soft tissue sarcoma (STS) patients treated with similar chemotherapy over the same period of time. All patients were evaluated for cardiac function using echocardiography. Shortening fraction (SF) and left ventricular mass index (Massl) were compared before and after treatment. The role of chest irradiation, dose concentration (DC) of adriamycin (AD), total mean doses of AD, cyclophosphamide (CY) and actinomycin (AC) were analysed. SF for patients with ES and STS postchemotherapy was significantly lower (P < .001 and P = 0.0004, respectively) than pretreatment values. Postchemotherapy SF for ES was lower than STS (P = 0.0097). Massl for each group did not change significantly. Six of the ES patients had postchemotherapy SF of < 0.20, with three in congestive failure, two cardiac deaths and one heart transplant. One additional ES patient had sick sinus syndrome and needed a pacemaker. Among the STS patients only one had SF < .20 and none were symptomatic. There were no significant differences in the mean AD, CY and AC doses for ES versus STS. The difference in the DC of AD for ES (mean 744) compared to STS (mean = 362) was significant (P = < 0.001). Regression analysis indicated a trend for decreasing SF with increasing DC (P = 0.017). Chest irradiation did not appear to increase the likelihood of cardiotoxicity. ES patients had a higher prevalence of cardiac dysfunction compared to STS. Studies are required to evaluate the importance of the components of DC, i.e., size of the individual dose and frequency of administration of AD, and to look at other possible factors in the causation of cardiomyopathy in ES.

Immunocytochemical evidence for an axonal localization of GABA in the optic nerves of rabbits, rats, and cats.

We have examined, by light-microscopic immunocytochemistry, the distribution of GABA in the optic nerves of adult rabbits, rats, and cats. Within the optic nerves, immunoreactivity for GABA was restricted to a small subset of axons; some axons were strongly labelled, others weakly labelled, whilst most axons were unlabelled. Glia and other non-neuronal elements were always unlabelled. Our ability to detect GABA in optic nerve axons of adult mammals contrasts with previous reports that indicate a lack of GABA immunoreactivity in such axons. We suggest that this discrepancy may be due to the sensitivity of our immunocytochemical techniques which enable us to detect low concentrations of GABA.

Thalidomide in the management of chronic graft-versus-host disease in children following bone marrow transplantation.

Chronic graft-versus-host disease (GVHD) is the major complication in patients surviving > 100 days post-allogeneic bone marrow transplantation and occurs in 30% of pediatric patients. It is most prevalent 1-2 years post-transplant. Treatment involves corticosteroids and other immunosuppressive therapy which may affect growth and increase the likelihood of infectious complications. We report five children with severe corticosteroid-dependent chronic GVHD treated with thalidomide 12-25 mg/kg/day. Response to therapy was based on resolution of symptoms of chronic GVHD and withdrawal of other immunosuppressive therapy. All the children showed clinical response to thalidomide with cessation or diminution in other immunosuppressive medication. Side-effects were minimal and no patient developed peripheral neuropathy. All patients are alive 48-65 months post-transplantation. Thalidomide is a safe and effective drug for the treatment of chronic GVHD in children and may avoid the use of long-term corticosteroid therapy.

Obstructive lung disease in children after allogeneic bone marrow transplantation.

Obstructive lung disease (OLD) has been described as a significant complication after allogeneic bone marrow transplantation (BMT). The incidence of OLD in adults appears to be low (approximately 3%), but there is little data for children. We analyzed 89 consecutive pediatric allogeneic BMTs, > or = 1.5 years post-BMT, performed at British Columbia's Children's Hospital from 1980 to 1992 for evidence of OLD. Diagnosis of OLD was based on clinical findings (nonproductive cough, wheezing, and dyspnea with no evidence of infection), pulmonary function tests (FEV1 < 80% and FEF25-75% < 60% predicted), lung biopsy, and computed tomography scan. Sixty-seven of the 89 children evaluated survived > or = 90 days and were classified as at risk for OLD. Thirteen of 67 (19.4%), developed OLD, 3 of which were transient. The development of OLD was strongly associated with the following high-risk groups: chronic graft-versus-host disease (GVHD) (37.1% OLD), increased donor age, acute GVHD, and either mismatched related or matched unrelated donor transplants. No correlation was found with methotrexate prophylaxis for GVHD, total body irradiation, or cytomegalovirus reactivity in either donor or recipient and the development of OLD. Further analysis of only children with chronic GVHD showed that liver involvement by GVHD before the onset of OLD (57.9%) was the only other significant predictive factor. We observed an overall increased prevalence of OLD in children compared with that previously reported in adults. Further studies are required to confirm whether age is a risk factor for development of OLD after allogeneic BMT.

Allogeneic bone marrow transplantation for an adolescent with polycythemia vera.

Polycythemia vera is a rare clonal disorder of the bone marrow haematopoietic stem cell. We present the case of an adolescent female with polycythemia vera, who was treated with a curative HLA-matched allogeneic bone marrow transplant.

A multicentre randomized study of single-unit dose package of EMLA patch vs EMLA 5% cream for venepuncture in children.

Eutectic mixture of local anaesthetics (EMLA) cream with Tegaderm was compared with pre-packaged EMLA patch with regard to analgesic effect, adhesiveness and local reactions during venepuncture in 178 children from three to ten years. One EMLA patch, or half the contents of a 5 g tube of EMLA cream plus Tegaderm was applied to the dorsum of one hand or antecubital fossa for a minimum of 60 min before venepuncture. The subject and observer assessed the degree of pain on a three-point verbal rating scale. The adhesion of the patch vs Tegaderm to the skin and local reactions were recorded. There was no difference between the two groups in pain associated with venepuncture; 95% of the EMLA patch group and 94% of the EMLA cream group reported no or slight pain. There was no difference between the two treatment groups in terms of overall local reactions. The patch was less adhesive (P < 0.001), but this had no apparent influence on its effectiveness. In conclusion, EMLA patch is equivalent to 5% EMLA cream (2.5 g) in cutaneous pain relief when used for venepuncture in children.

Intensive conditioning regimen for bone marrow transplantation in children with high-risk haematological malignancies.

Between September 1987 and May 1991, 21 children aged 10 months to 15 years (median 9 years) underwent bone marrow transplantation (BMT) for advanced haematological malignancies using a conditioning regimen consisting of total body irradiation (TBI), etoposide 1.8 g/m2 by continuous infusion, and cyclophosphamide 2 g/m2 on 3 consecutive days. The patients included 14 with acute lymphoblastic leukaemia (ALL), 1 with chronic myeloid leukaemia (CML), 1 with juvenile CML, 4 with non-Hodgkin's lymphoma and 1 with acute nonlymphocytic leukaemia. Eleven had an allogeneic BMT from an HLA-matched sibling, and 1 from an unrelated donor. Nine patients received 4-hydroperoxycyclophosphamide purged autologous marrow. Median time to myeloid engraftment (ANC > 500/microliters) was 19 days in allogeneic BMT patients and 28 days in autologous BMT patients (P < .01). Mucositis was the major regimen-related toxicity (RRT). GI toxicity in the form of diarrhoea affected ten patients and five had veno-occlusive disease of the liver. Two patients had mild bladder toxicity and one died of renal toxicity. There was no CNS or cardiac toxicity. There was no significant difference in the incidence of toxicity according to the type of BMT (autologous or allogeneic), total dose, or sequence of TBI. With a median follow-up of 44 months, ten patients are alive (6/12 allogeneic BMT patients and 4/9 autologous BMT patients). Of the 11 deaths, four were related to toxicity (2 aspergillus, 1 haemorrhage following liver biopsy, and 1 from haemolytic-uraemic syndrome), and 4/12 allogeneic and 4/9 autologous BMT patients died from relapsed disease. This conditioning regimen is well tolerated in children, demonstrating mild and reversible RRT.

Malignant fibrous histiocytoma in childhood.

BACKGROUND: Malignant fibrous histiocytoma (MFH) is a neoplasm of late adult life and often is reported in the pediatric population. It is thought to behave more benignly in children than in adults. METHOD: Clinical and pathologic features, treatment, and outcome of nine pediatric patients seen at British Columbia's Children's Hospital between 1983 and 1990 were examined. The literature regarding pediatric malignant fibrous histiocytoma was reviewed. RESULTS: The tumors included one primary renal tumor and two occurring in the orbit after radiation therapy for retinoblastoma during the neonatal period. Histologic examination showed that six tumors had a storiform-pleomorphic pattern, one was myxoid, and two were angiomatoid in type. Six children are alive with a disease-free survival of 20 months to 8 years after surgical resection. Two of these received adjuvant chemotherapy, none had radiation therapy. Three patients have died of disease, two with pulmonary metastases that developed despite multiagent chemotherapy and radiation therapy. Poor outcome was associated with large tumors, deep and proximal location, and the storiform-pleomorphic histologic type with atypical mitoses. CONCLUSION: Malignant fibrous histiocytoma is similar in children and adults. Surgery is the mainstay of therapy, but the risk of local recurrence and pulmonary metastases indicates the need for adjuvant therapy in selected patients.

Evidence implicating heterozygous deletion of chromosome 7 in the pathogenesis of familial leukemia associated with monosomy 7.

Complete or partial monosomy 7 is a recurring cytogenetic abnormality in acute myelogenous leukemia (AML) and myeloproliferative syndromes (MPS) and is particularly common in patients with Fanconi's anemia and in secondary AML. A familial form of monosomy 7 has been recognized in which two or more siblings develop MPS or AML before age 20. We tested the hypothesis that a recessive cancer susceptibility locus on chromosome 7 was important in the pathogenesis of leukemia in familial monosomy 7 by determining the parental origins of the chromosome 7 retained in the bone marrows of three pairs of affected siblings. We found no overlapping region where all three pairs retained DNA derived from the same paternal or maternal chromosome. These data suggest that inactivation of a single allele of a putative tumor-suppressor gene may be sufficient to contribute to leukemic transformation in familial monosomy 7.

Auditory and ophthalmological findings in children with acute lymphoblastic leukemia.

The audiological and ophthalmological function in 59 children in continuous complete remission for at least 2 years since the completion of therapy for acute lymphoblastic leukemia was evaluated. Three of 42 tested had abnormal hearing assessments, but none was attributed to the leukemia or its treatment. Four of 54 patients had visual abnormalities: 3 had mild refractive errors and 1 patient had mild subcapsular cataracts consistent with steroid-induced cataracts. We conclude that as the frequency of visual and hearing impairment in these patients is low, it is not necessary to perform audiological or ophthalmological assessment during routine follow-up unless clinically indicated.

Primary hemochromatosis in children: report of three newly diagnosed cases and review of the pediatric literature.

Hereditary hemochromatosis was diagnosed in three asymptomatic siblings following the unexpected finding of elevated serum iron concentrations. This diagnosis was confirmed by hepatic biopsy. Repeated phlebotomies resulted in a significant decline of serum iron and ferritin concentrations and a decrease of hepatic iron content. This report and a review of the literature indicate that the diagnosis of hereditary hemochromatosis must be considered more frequently in childhood. Organ dysfunction from iron overload may be minimized in children by the early commencement of regular phlebotomy.