In-depth Clinical and Biological Exploration of DNA Damage Immune Response as a Biomarker for Oxaliplatin Use in Colorectal Cancer.

PURPOSE: The DNA damage immune response (DDIR) assay was developed in breast cancer based on biology associated with deficiencies in homologous recombination and Fanconi anemia pathways. A positive DDIR call identifies patients likely to respond to platinum-based chemotherapies in breast and esophageal cancers. In colorectal cancer, there is currently no biomarker to predict response to oxaliplatin. We tested the ability of the DDIR assay to predict response to oxaliplatin-based chemotherapy in colorectal cancer and characterized the biology in DDIR-positive colorectal cancer. EXPERIMENTAL DESIGN: Samples and clinical data were assessed according to DDIR status from patients who received either 5-fluorouracil (5-FU) or 5FUFA (bolus and infusion 5-FU with folinic acid) plus oxaliplatin (FOLFOX) within the FOCUS trial (n = 361, stage IV), or neoadjuvant FOLFOX in the FOxTROT trial (n = 97, stage II/III). Whole transcriptome, mutation, and IHC data of these samples were used to interrogate the biology of DDIR in colorectal cancer. RESULTS: Contrary to our hypothesis, DDIR-negative patients displayed a trend toward improved outcome for oxaliplatin-based chemotherapy compared with DDIR-positive patients. DDIR positivity was associated with microsatellite instability (MSI) and colorectal molecular subtype 1. Refinement of the DDIR signature, based on overlapping IFN-related chemokine signaling associated with DDIR positivity across colorectal cancer and breast cancer cohorts, further confirmed that the DDIR assay did not have predictive value for oxaliplatin-based chemotherapy in colorectal cancer. CONCLUSIONS: DDIR positivity does not predict improved response following oxaliplatin treatment in colorectal cancer. However, data presented here suggest the potential of the DDIR assay in identifying immune-rich tumors that may benefit from immune checkpoint blockade, beyond current use of MSI status.

Multiple micronutrient supplementation during pregnancy in low-income countries: review of methods and characteristics of studies included in the meta-analyses.

This paper reports on the methods and characteristics of 12 studies from developing countries included in a meta-analysis of the impact of antenatal supplements of multiple micronutrients compared with iron-folic acid on micronutrient status, maternal nutritional status, birth outcomes, and neonatal survival.

Multiple micronutrient supplementation during pregnancy in low-income countries: a meta-analysis of effects on birth size and length of gestation.

BACKGROUND: Multiple micronutrient deficiencies are common among women in low-income countries and may adversely affect pregnancy outcomes. OBJECTIVE: This meta-analysis reports the effects on newborn size and duration of gestation of multiple micronutrient supplementation mainly compared with iron plus folic acid during pregnancy in recent randomized, controlled trials. METHODS: Original data from 12 randomized, controlled trials in Bangladesh, Burkina Faso, China, Guinea-Bissau, Indonesia, Mexico, Nepal, Niger, Pakistan, and Zimbabwe, all providing approximately 1 recommended dietary allowance (RDA) of multiple micronutrients to presumed HIV-negative women, were included. Outcomes included birthweight, other birth measurements, gestation, and incidence of low birthweight (LBW) (< 2500 g), small-for-gestational age birth (SGA, birthweight below the within-each-population 10th percentile), large-for-gestational age birth (LGA, birthweight above the within-each-population 90th percentile), and preterm delivery (< 37 weeks). RESULTS: Compared with control supplementation (mainly with iron-folic acid), multiple micronutrient supplementation was associated with an increase in mean birthweight (pooled estimate: +22.4 g [95% CI, 8.3 to 36.4 g]; p = .002), a reduction in the prevalence of LBW (pooled OR = 0.89 [95% CI, 0.81 to 0.97]; p = .01) and SGA birth (pooled OR = 0.90 [95% CI, 0.82 to 0.99]; p = .03), and an increase in the prevalence of LGA birth (pooled OR = 1.13 [95% CI, 1.00 to 1.28]; p = .04). In most studies, the effects on birthweight were greater in mothers with higher body mass index (BMI). In the pooled analysis, the positive effect of multiple micronutrients on birthweight increased by 7.6 g (95% CI, 1.9 to 13.3 g) per unit increase in maternal BMI (p for interaction = .009). The intervention effect relative to the control group was + 39.0 g (95% CI, +22.0 to +56.1 g) in mothers with BMI of 20 kg/m2 or higher compared with -6.0 g (95% CI, -8.8 to +16.8 g) in mothers with BMI under 20 kg/m2. There were no significant effects of multiple micronutrient supplementation on birth length or head circumference nor on the duration of gestation (pooled effect: +0.17 day [95% CI, -0.35 to +0.70 day]; p = .51) or the incidence of preterm birth (pooled OR = 1.00 [95% CI, 0.93 to 1.09]; p = .92). CONCLUSIONS: Compared with iron-folic acid supplementation alone, maternal supplementation with multiple micronutrients during pregnancy in low-income countries resulted in a small increase in birthweight and a reduction in the prevalence of LBW of about 10%. The effect was greater among women with higher BMI.

Multiple micronutrient supplementation during pregnancy in low-income countries: a meta-analysis of effects on stillbirths and on early and late neonatal mortality.

BACKGROUND: Multiple micronutrient deficiencies are common among women in low-income countries and may adversely affect pregnancy outcomes. OBJECTIVE: To conduct a meta-analysis of the effects on stillbirths and on early and late neonatal mortality of supplementation during pregnancy with multiple micronutrients compared with iron-folic acid in recent randomized, controlled trials. METHODS: Twelve randomized, controlled trials were included in the analysis (Bangladesh; Burkina Faso; China; Guinea-Bissau; Indramayu and Lombok, Indonesia; Mexico; Sarlahi and Janakur, Nepal; Niger; Pakistan; and Zimbabwe), all providing approximately 1 recommended dietary allowance (RDA) of multiple micronutrients or iron-folic acid to presumed HIV-negative women. RESULTS: Supplementation providing approximately I RDA of multiple micronutrients did not decrease the risk of stillbirth (OR = 1.01; 95% CI, 0.88 to 1.16), early neonatal mortality (OR = 1.23; 95% CI, 0.95 to 1.59), late neonatal mortality (OR = 0.94; 95% CI, 0.73 to 1.23), or perinatal mortality (OR = 1.11; 95% CI, 0.93 to 1.33). CONCLUSIONS: Our meta-analysis provides consistent evidence that supplementation providing approximately 1 RDA of multiple micronutrients during pregnancy does not result in any reduction in stillbirths or in early or late neonatal deaths compared with iron-folic acid alone.