International journal of cancer. Supplement = Journal international du cancer. Supplement最新文献

Over the past 18 years, our laboratory has been interested in the pathogenesis of energy imbalance caused by a variety of diseases. Our view is that a clear understanding of the various factors causing negative energy balance, which in turn results in malnutrition, is the most effective way of designing preventive and therapeutic nutritional strategies. Thus, in cancer, one of the common factors is anorexia, due either to the primary tumor or to the effects of cancer therapy. Currently there is little evidence of increased resting energy expenditure in children with cancer, except in cases with very high tumor burden. Conversely, there are suggestions of a failure to down-regulate resting energy expenditure in the presence of reduced food intake in patients with cancer. Damage to the gastrointestinal tract, due to the effects either of the tumor or of tumor therapy, may result in maldigestion and/or malabsorption. Thus, as a result of a combination of reduced intake, reduced absorption and increased needs, the child with cancer may become malnourished. Prevention and treatment are dependent on the type of cancer and the pathogenesis of the negative energy balance. In broad terms, we try as far as possible to use external routes. With the advent of percutaneously placed gastrostomies and gastrojejunal tubes, we use these methods increasingly to provide nutritional support. Only in patients whose gastrointestinal tract cannot be used do we turn to i.v. feeding. In these patients, the placement of a central venous line is required, but great care must be taken to avoid infection. Whatever form of nutritional support is used, whether enteral or parenteral, we measure the body composition and energy expenditure in the patient, so that the nutritional therapy can be tailored to the child's specific needs. Using these approaches, we are having significant success in preventing and reversing malnutrition in children with cancer and those undergoing bone-marrow transplantation.

Leukemia in the first year of life is extremely rare world-wide. However, unlike leukemias in older children, nearly 75% of infant leukemias demonstrate a specific abnormality involving a gene, MLL, on chromosome band 11q23. Molecular studies suggest strongly that these leukemias occur in utero. Treatment-related acute myeloid leukemias (AML), associated with specific chemotherapeutic agents that inhibit DNA topoisomerase II (topo 2), also manifest identical abnormalities involving the MLL gene. This led us to speculate that maternal exposure during pregnancy to environmental agents that inhibit DNA topo 2 may be associated with the development of leukemia in infants. DNA topo 2 inhibitors have been found in specific fruits and vegetables, and in soy, coffee, wine, tea and cocoa, as well as in certain pesticides, solvents and medications. In a preliminary study, we reinterviewed mothers of infant cases and their matched controls who had participated previously in 1 of 3 epidemiologic studies of childhood leukemia conducted by the Children's Cancer Group over a 10-year period. We evaluated potential DNA topo 2 inhibitor exposure through maternal diet and medications. Of the 84 original matched sets who were reinterviewed, there was no positive association with increasing maternal consumption of DNA topo 2 inhibitor-containing foods either for the overall group or for infants in the acute lymphoblastic leukemia stratum. However, there was an approximately 10-fold higher risk of infant AML with increasing maternal consumption of DNA topo 2 inhibitor-containing foods. The assay to screen environmental agents that inhibit DNA topo 2 has been established and new inhibitors are being identified routinely.

Protein-energy malnutrition and obesity are the most common nutritional disorders that complicate the clinical course of children with neoplastic diseases. Sensitive measures of nutritional status should be used to detect these problems in children with cancer. Height and weight measurements are the mainstay of the nutritional assessment of the child. These measurements can be converted to growth velocities or to height-for-age and weight-for-height Z-scores or percent of expected values to provide a measure of the degree of under- or over-nutrition in the child. Skinfold thickness and circumference measurements of the arms, legs and/or trunk may be useful to characterize the changes in peripheral fat depots and muscle mass, respectively. However, the assessments of body composition using these measurements are subject to methodological error because selected skinfold sites are excluded. Whole-body potassium, measured by 40K counting, and total body water, measured by deuterium or 18O dilution, serve as "gold standards" to determine the lean body mass and body fat status of the child, but these techniques may not be practical in all settings. The assessment of the nutritional status of the child serves as a guide to early nutritional intervention. Indicators for early nutritional intervention include: (1) height-for-age and weight-for-height or -age Z-scores more than 2 SD below the mean for age, (2) height-for-age measurements less than 95% of expected, (3) weight-for-height measurements less than 90% or greater than 120% of expected and (4) height velocities less than 5 cm/year after 2 years of age. Early nutritional intervention is essential to restore normal body composition, reverse linear growth arrest, promote tolerance to chemotherapeutic and radiation regimens and improve the quality of life in children with cancer.

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.

An international case-control study of primary pediatric brain tumors included interviews with mothers of cases diagnosed from 1976 to 1994 and mothers of population controls. Data are available on maternal vitamin use during pregnancy for 1,051 cases and for 1,919 controls from 8 geographic areas in North America, Europe and Israel. While risk estimates varied by study center, combined results suggest that maternal supplementation for 2 trimesters decreased risk of brain tumor [odds ratio (OR) = 0.7; 95% confidence interval (CI) = 0.5, 0.9], with a trend of less risk with longer duration of use (p trend = 0.0007). The greatest risk reduction was among children diagnosed under 5 years of age whose mothers used supplements during all 3 trimesters (OR = 0.5; CI = 0.3, 0.8). This effect did not vary by histology and was seen for supplementation during pregnancy rather than during the month before pregnancy or while breastfeeding. Our findings are largely driven by data from the United States, where most mothers took vitamins. The proportion of control mothers who took vitamins during pregnancy varied markedly from 3% in Israel and in France, 21% in Italy, 33% in Canada and 52% in Spain to 86-92% at the 3 U.S. centers. The composition of the various multivitamin compounds taken also varied: daily dose of vitamin C ranged from 0 to 600 mg; vitamin E from 0 to 70 mg; vitamin A from 0 to 30,000 IU; and folate from 0 to 2,000 micrograms. Mothers also took individual micronutrient supplements (e.g., vitamin C tablets), but most mothers who took these also took multivitamins, making it impossible to determine the potential independent effects of these micronutrients.

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.

Nine studies of childhood brain tumors and maternal diet during pregnancy have focused on foods related to the N-nitroso-compound(NOC) hypothesis. An association between frequent consumption of cured meat by pregnant women and increased risk is a consistent finding in most of the studies. The data on fruit and vegetable consumption are less consistent, but suggest decreased risk. Studies that assess all aspects of maternal diet during pregnancy are needed to determine whether the observed associations remain after adjustment for other aspects of diet. Such comprehensive studies also may elucidate other dietary factors that affect the risk of brain tumors in children.

Increasing attention is being paid to the role of nutrition in cancer. Dietary measures, such as decreased consumption of calories, fat, alcohol and smoked or pickled foods have been shown to reduce the incidence of specific "adult" cancers, while increased dietary fiber appears to have a protective role. However, no clear scientific evidence exists that dietary manipulation is a successful primary therapy for established cancer. A significant percentage of adult and child cancer patients take unproven therapies during their illness. Alternative nutritional therapies, of which there is a wide variety, are the commonest of these reflecting current public interest in "natural" remedies. The efficacy and potential toxicity of commonly utilized dietary therapies are here reviewed, in particular the macrobiotic philosophy, the Gerson diet, the Livingstone diet, and the use of vitamin and mineral therapy. While details may differ, most alternative approaches involve fresh whole foods, with strong emphasis on low-fat vegetarian diet. Most are nutritionally adequate, at least for adults. No anti-cancer diet has been shown to cure established cancers, even those whose incidence is decreased by dietary changes. Careful dietary manipulation may at least improve quality of life for adult cancer patients, and, together with conventional therapy, may prolong survival in selected cancer patients. Assessment by carefully controlled prospective clinical trials is essential; those in pediatric patients must be controlled very strictly, since tumors in children have not been shown to be influenced by diet, and the diets described may be inadequate for children with malignant disease.

Sensitive measures of nutritional status exist. Initial assessment must include some measure that is independent of tumour mass, particularly in children with large solid tumours. Arm anthropometry, including triceps and biceps skinfold thickness (SFT), and mid-upper-arm circumference (MUAC) are ideal in this situation, but MUAC is probably the simplest measure to use. In the clinical setting, a direct measure of fat-free body mass (FFBM) does not exist, but bio-electrical impedance (BIA) measures FFBM indirectly, and has many advantages, in particular its ease of use and immediate results. The BIA analyzer is portable and hence can be used in the field as well as by the bedside. Serum proteins and insulin-like growth factors are insufficiently sensitive as nutritional indices and have only a minor role in nutritional assessment.

Reviewed are reports on factors, identified by risk analysis, involved in the genesis of primary malnutrition in children. Data are compared with the sequence of factors in a flow diagram, based on the natural history of malnutrition, proposed 3 decades ago. Susceptibility to malnutrition is analyzed in light of observations related to inheritance, the ob gene and leptin.