Nutritional interventions in children with acute lymphoblastic leukemia undergoing antineoplastic treatment: a systematic review.

BACKGROUND: A compromised nutritional status jeopardizes a positive prognosis in acute lymphoblastic leukemia (ALL) patients. In low- and middle-income countries, ~ 50% of children with ALL are malnourished at diagnosis time, and undergoing antineoplastic treatment increases the risk of depleting their nutrient stores. Nutrition interventions are implemented in patients with cancer related malnutrition. We aimed to evaluate the effect of nutrition interventions in children diagnosed with ALL under treatment. METHODS: Using a predefined protocol, we searched for published or unpublished randomized controlled trials in: Cochrane CENTRAL, MEDLINE, EMBASE, LILACS, and SciELO, and conducted complementary searches. Studies where at least 50% of participants had an ALL diagnosis in children ≤ 18 years, active antineoplastic treatment, and a nutrition intervention were included. Study selection and data extraction were conducted independently by three reviewers, and assessment of the risk of bias by two reviewers. Results were synthesized in both tabular format and narratively. RESULTS: Twenty-five studies (out of 4097 records) satisfied the inclusion requirements. There was a high risk of bias in eighteen studies. Interventions analyzed were classified by compound/food (n = 14), micronutrient (n = 8), and nutritional support (n = 3). Within each group the interventions and components (dose and time) tested were heterogeneous. In relation to our primary outcomes, none of the studies reported fat-free mass as an outcome. Inflammatory and metabolic markers related to nutritional status and anthropometric measurements were reported in many studies but varied greatly across the studies. For our secondary outcomes, fat mass or total body water were not reported as an outcome in any of the studies. However, some different adverse events were reported in some studies. CONCLUSIONS: This review highlights the need to conduct high-quality randomized controlled trials for nutrition interventions in children with ALL, based on their limited number and heterogeneous outcomes. REGISTRATION OF THE REVIEW PROTOCOL: Guzmán-León AE, Lopez-Teros V, Avila-Prado J, Bracamontes-Picos L, Haby MM, Stein K. Protocol for a Systematic Review: Nutritional interventions in children with acute lymphoblastic leukemia undergoing an tineoplastic treatment. International prospective register of systematic reviews. 2021; PROSPERO CRD:42,021,266,761 ( https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=266761 ).

Use of Theoretical Women and Model-Based Compartmental Analysis to Evaluate the Impact of Vitamin A Intake with or without a Daily Vitamin A Supplement on Vitamin A Total Body Stores and Balance During Lactation.

BACKGROUND: Inadequate vitamin A (VA) intake is common among lactating women in many communities worldwide, but high-dose VA supplementation for postpartum women is not recommended by the World Health Organization as an effective intervention. OBJECTIVES: To simulate the impact of VA intake via diet and daily VA supplements on VA total body stores (TBS) and balance in theoretical lactating women with low/moderate TBS. METHODS: We studied 6 theoretical subjects with assigned values for TBS from 219-624 µmol. Using Simulation, Analysis, and Modeling software and a previously published compartmental model for whole-body VA metabolism, we simulated TBS over 6 mo of established lactation for each subject under 4 conditions: 1) prelactation VA intake was increased to maintain VA balance (LSS); 2) prelactation VA intake was maintained (NLSS); 3) VA intake was the same as 2) but a daily VA supplement (2.8 µmol/d) was added (NLSS+S); and 4) VA intake was as 1) and the daily VA supplement was included (LSS+S). RESULTS: To compensate for the loss of VA via milk while VA balance was maintained (LSS) over 6 mo of lactation, VA intake had to increase by 0.8-1.87 µmol/d (n = 6) compared with NLSS. Over 6 mo of NLSS treatment, VA balance was negative (geometric mean, -0.77 µmol/d) compared with LSS, whereas balance was positive under NLSS+S and LSS+S conditions (0.75 and 1.5 µmol/d, respectively). For LSS, the proportion of total VA disposal was 37% via breastmilk, 32% from VA stores, and 32% from nonstorage tissues. CONCLUSIONS: Adding a daily VA supplement (2.8 µmol/d) to the diet of lactating women with suboptimal VA intake may effectively counterbalance the negative VA balance resulting from the output of VA via breastmilk and thus benefit both mother and infant by maintaining or increasing VA stores and breastmilk VA concentration.

Direct Use of Plasma or Milk Vitamin A Specific Activity Data to Model Retinol Kinetics and Predict Vitamin A Stores in Theoretical Lactating Women.

BACKGROUND: Many applications of the Simulation, Analysis and Modeling software use data on the fraction of an orally administered tracer dose (FD) in plasma; thus, researchers must scale-up measured analyte concentration to the total plasma pool. For studies in lactating women, estimating breast milk pool size is challenging. OBJECTIVES: The objectives were to determine whether the standard vitamin A modeling approach using FD data could be modified to use vitamin A specific activity in milk (SAm) and/or plasma (SAp) for compartmental analysis of vitamin A kinetics and status in theoretical lactating women. METHODS: Using 12 previously studied theoretical subjects with a wide range of assigned values for vitamin A total body stores (TBS) and the coefficient ("FaS") needed to predict TBS using a retinol isotope dilution equation, we simulated data for SAp and SAm for 49 d after oral administration of labeled vitamin A. Then we modeled datasets for SAp and SAm, as well as only SAp or SAm, incorporating a linear scaling factor to automatically convert SA to FD and including several physiologically reasonable constraints as input data. As outcomes, we compared model-predicted TBS and FaS to assigned values. RESULTS: Scaling factors effectively adjusted SA data to adequately predict vitamin A mass in plasma and breast milk pools. Data for SAp and SAm provided model predictions of TBS that were comparable to assigned values (range: 85-107%); using only SAp, ratios ranged from 92% to 108% and for SAm from 85% to 108%. Parallel results were obtained for simulated FaS. CONCLUSIONS: Results show that SA data from plasma and/or milk can be used directly for modeling vitamin A during lactation in theoretical subjects, providing accurate estimates of TBS and FaS. Results suggest that, in free-living lactating women, researchers might measure only SAp or only SAm and adequately describe whole-body vitamin A metabolism and status.

Compartmental Modeling of Vitamin A Stable Isotope Data from Milk or Plasma Provides Comparable Predictions of Vitamin A Stores in Theoretical Lactating Women.

BACKGROUND: Previous compartmental models describing and quantifying whole-body vitamin A (VA) metabolism have been developed from plasma retinol kinetic data after human subjects ingest stable isotope-labeled VA. For humans, models based on data obtained from other sampling sites (e.g., excreta or milk) have not been proposed. OBJECTIVES: Our objective was to determine whether comparable model predictions of VA total body stores (TBS) in theoretical lactating women were obtained using tracer data from only retinol in plasma or VA in milk. METHODS: We used Simulation, Analysis and Modeling software to simulate values for TBS and the coefficients used in the retinol isotope dilution (RID) equation TBS = FaS/SAp (Fa, fraction of dose in stores; S, retinol specific activity (SA) in plasma/SA in stores; SAp, specific activity in plasma). We compared individual subject predictions of TBS and FaS based on modeling only plasma or only milk tracer data to previous results ("assigned values") for 12 theoretical lactating women when modeling was done based on tracer data for chylomicron retinyl esters, plasma retinol, and milk VA. RESULTS: For subjects with a wide range of TBS, model-predicted TBS based on only plasma data were comparable with assigned values (range: 94%-106%). Using only milk data, predictions ranged from 72% to 178%, but when VA intake was included in modeling, predictions were improved (97%-102%). Similar results were obtained for simulated FaS. CONCLUSIONS: If confirmed in free-living lactating women, results indicate that, similar to models based on serial plasma sampling, a model for whole-body VA kinetics, including predictions of TBS and FaS, can be identified based on tracer data for VA in milk when VA intake is included as a modeling constraint. Milk data have not been previously used for compartmental modeling of VA in humans.

Use of Compartmental Modeling and Datasets for Theoretical Lactating Women to Determine Conditions under Which Vitamin A-Specific Activity in Breast Milk Provides Accurate Estimates of Vitamin A Total Body Stores by Retinol Isotope Dilution.

BACKGROUND: Vitamin A concentrations in breast milk are related to maternal vitamin A intake and status. OBJECTIVES: Our objective was to identify conditions under which vitamin A specific activity in breast milk (SAm) could be used instead of retinol specific activity in plasma (SAp) to predict vitamin A total body stores (TBS) by retinol isotope dilution (RID). METHODS: We used 12 previously-studied theoretical lactating women with assigned values for TBS (219-1348 µmol) and retinol kinetic parameters; we assumed subjects ingested a dose of stable isotope-labeled vitamin A. We expanded a 9-compartment steady state tracer model to include a parallel model for tracee (unlabeled retinol) and then adapted that model so vitamin A intake entered the system in 3 meals each day. Using compartmental analysis, we first simulated SAm and SAp after an overnight fast (as in actual RID experiments) and then with vitamin A intake also restricted in sequential meals on the day before sampling for RID. RESULTS: After an overnight fast, SAm at day 21 postdosing was lower than SAp. However, if vitamin A intake was also restricted in 1, 2, or 3 meals before sampling, SAm/SAp (mean ± SD) was 0.92 ± 0.042,  0.96 ± 0.016,  or 0.99 ± 0.004,  respectively; results for days 14 and 28 were similar. When either SAp or SAm was used to predict TBS by RID on day 21 after 1-d restriction, predictions for all subjects were within 25% of assigned TBS. CONCLUSIONS: Results indicate that, for theoretical lactating women with a wide range of vitamin A status, SAm will accurately predict TBS by RID at 2-4 wk postdosing if vitamin A intake is restricted for 1 d before sampling. If confirmed in community settings, results suggest that vitamin A status in lactating women can be determined without collecting blood.

Development of a Compartmental Model for Studying Vitamin A Kinetics and Status in Theoretical Lactating Women.

BACKGROUND: Low vitamin A status and suboptimal milk vitamin A concentrations are problems in many populations worldwide. However, limited research has been done on whole-body vitamin A kinetics in women of reproductive age, especially during lactation. OBJECTIVES: Goals were to develop compartmental models describing retinol kinetics in theoretical nonlactating (NL) and lactating (L) women and to determine whether the retinol isotope dilution (RID) method accurately predicted vitamin A total body stores (TBS) in the groups and individuals. METHODS: We adapted 12 previously-used theoretical females with assigned values for retinol kinetic parameters and TBS (225-1348 µmol); subjects were NL or L (nursing one 3- to 6-mo-old infant) during 49-d kinetic studies after isotope dosing. We used an established compartmental model, adding a compartment for chylomicrons and, for L, another for mammary gland milk with inputs from holo-retinol-binding protein and chylomicron retinyl esters and output to milk. Using compartmental analysis, we simulated tracer responses in compartments of interest and calculated TBS using the RID equation TBS =   FaS/SAp [Fa, fraction of dose in stores; S, retinol specific activity in plasma/specific activity in stores; SAp, specific activity of retinol in plasma]. RESULTS: Models for both groups were well identified. Simulated plasma tracer responses were similar for NL and L, with L always below NL; milk tracer paralleled plasma from 10 d postdosing. Geometric mean FaS ratios (L/NL) were ∼0.75 during days 2-30. Using appropriate group FaS, RID provided accurate TBS predictions for >80% of NL and L subjects after day 18 when CV% for FaS was ∼10%. CONCLUSIONS: These new physiologically-based models for vitamin A kinetics may be useful for future research in women of reproductive age. Results indicate that, in groups like these, RID to assess an individual's vitamin A status should be done at 21-28 d after isotope dosing.