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Randomized phase 2 study of gemcitabine and cisplatin with or without vitamin supplementation in patients with advanced esophagogastric cancer.
van Zweeden, AA, van Groeningen, CJ, Honeywell, RJ, Giovannetti, E, Ruijter, R, Smorenburg, CH, Giaccone, G, Verheul, HMW, Peters, GJ, van der Vliet, HJ
Cancer chemotherapy and pharmacology. 2018;(1):39-48
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Abstract
PURPOSE Preclinical research and prior clinical observations demonstrated reduced toxicity and suggested enhanced efficacy of cisplatin due to folic acid and vitamin B12 suppletion. In this randomized phase 2 trial, we evaluated the addition of folic acid and vitamin B12 to first-line palliative cisplatin and gemcitabine in patients with advanced esophagogastric cancer (AEGC). METHODS Patients with AEGC were randomized to gemcitabine 1250 mg/m2 (i.v. days 1, 8) and cisplatin 80 mg/m2 (i.v. day 1) q 3 weeks with or without folic acid (450 µg/day p.o.) and vitamin B12 (1000 µg i.m. q 9 weeks). The primary endpoint was response rate (RR). Secondary endpoints included overall survival (OS), time to progression (TTP), toxicity, and exploratory biomarker analyses. Cisplatin sensitivity and intracellular platinum levels were determined in adenocarcinoma cell lines cultured under high and low folate conditions in vitro. RESULTS Adenocarcinoma cells cultured in medium with high folate levels were more sensitive to cisplatin and this was associated with increased intracellular platinum levels. In the randomized phase 2 clinical trial, which ran from October 2004 to September 2013, treatment was initiated in 78 of 82 randomized pts, 39 in each study arm. The RR was similar; 42.1% for supplemented patients vs. 32.4% for unsupplemented patients; p = 0.4. Median OS and TTP were 10.0 and 5.9 months for supplemented vs. 7.7 and 5.4 months for unsupplemented patients (OS, p = 0.9; TTP, p = 0.9). Plasma homocysteine was lower in the supplemented group [n = 20, 6.9 ± 1.6 (mean ± standard error of mean, SEM) µM; vs. 12.5 ± 4.0 µM; p < 0.001]. There was no significant difference in the Cmax of gemcitabine and cisplatin in the two treatment groups. CONCLUSION Folic acid and vitamin B12 supplementation do not improve the RR, PFS, or OS of cisplatin and gemcitabine in patients with AEGC.
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ALDH1L1 and ALDH1L2 Folate Regulatory Enzymes in Cancer.
Krupenko, SA, Krupenko, NI
Advances in experimental medicine and biology. 2018;:127-143
Abstract
Epidemiological studies implicate excess ethanol ingestion as a risk factor for several cancers and support the concept of a synergistic effect of chronic alcohol consumption and folate deficiency on carcinogenesis. Alcohol consumption affects folate-related genes and enzymes including two major folate-metabolizing enzymes, ALDH1L1 and ALDH1L2. ALDH1L1 (cytosolic 10-formyltetrahydrofolate dehydrogenase) is a regulatory enzyme in folate metabolism that controls the overall flux of one-carbon groups in folate-dependent biosynthetic pathways. It is strongly and ubiquitously down-regulated in malignant tumors via promoter methylation, and recent studies underscored this enzyme as a candidate tumor suppressor and potential marker of aggressive cancers. A related enzyme, ALDH1L2, is the mitochondrial homolog of ALDH1L1 encoded by a separate gene. In contrast to its cytosolic counterpart, ALDH1L2 is expressed in malignant tumors and cancer cell lines and was implicated in metastasis regulation. This review discusses the link between folate and cancer, modifying effects of alcohol consumption on folate-associated carcinogenesis, and putative roles of ALDH1L1 and ALDH1L2 in this process.
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Efficacy of Folic Acid and Vitamin B12 Replacement Therapies in the Reduction of Adverse Effects of Isotretinoin: A Randomized Controlled Trial.
Ghiasi, M, Mortazavi, H, Jafari, M
Skinmed. 2018;(4):239-245
Abstract
Previous studies have reported elevated homocysteine levels and folic acid and/or vitamin B12 deficiencies after isotretinoin therapy, which increase the risk of cardiovascular and neuropsychiatric disorders. Homocysteine is metabolized in the liver, a process requiring folate and vitamin B12. We conducted a randomized controlled trial to investigate whether folate and vitamin B12 replacement therapy with isotretinoin would be useful for preventing hyperhomocysteinemia. A total of 66 patients with acne were randomized into two groups: group A took isotretinoin, folic acid, and vitamin B12, whereas group B took isotretinoin alone. Treatment was continued for 2 months. Blood homocysteine, folic acid, and vitamin B12 levels were measured before and after treatment. In group A, a significant decrease in homocysteine level was observed after treatment (P=.0004), although it was still within the normal range. Folic acid and vitamin B12 levels significantly increased (P=.0026 and P=.0002, respectively). In group B, no significant changes were observed in the levels of homocysteine and vitamin B12, but folic acid levels decreased significantly (P=.02). We concluded that folic acid and vitamin B12 supplementation during isotretinoin therapy could be useful for preventing folate deficiency and improving blood homocysteine levels; this might as a result reduce the risks for cardiovascular and neuropsychiatric disorders in patients taking isotretinoin.
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Neural tube defects: Sex ratio changes after fortification with folic acid.
Poletta, FA, Rittler, M, Saleme, C, Campaña, H, Gili, JA, Pawluk, MS, Gimenez, LG, Cosentino, VR, Castilla, EE, López-Camelo, JS
PloS one. 2018;(3):e0193127
Abstract
BACKGROUND Historically, neural tube defects (NTDs) have predominated in female infants but the reasons remain unclear. In South America, the pre- folic acid fortification (FAF) rates of NTDs were around 18/10,000 births for females and 12/10,000 births for males, with an estimated sex ratio (male/female) of 0.67. During the post- FAF period, unpublished routine reports have indicated changes in the sex ratio for these defects while some descriptive reports are controversial. To date and to our knowledge, however, no studies specifically focusing on these changes to test this hypothesis directly have been undertaken. The aim of this study was to analyze changes in the sex ratio of infants with NTDs after FAF in South American countries. MATERIALS AND METHODS With a descriptive cross-sectional study design, 2,597 infants with isolated NTDs born between 1990 and 2013 in 3 countries participating in the Latin American Collaborative Study of Congenital Malformations (ECLAMC) network were included: (Chile N = 521 and Argentina N = 1,619 [with FAF policies]; Venezuela N = 457 [without FAF policies; used as control]; total births = 2,229,561). The differences-in-differences method and Poisson regressions were used to evaluate the sex ratio shift from female to male before vs. after FAF, and to assess whether these differences were related to the fortification. RESULTS AND CONCLUSIONS In Chile and Argentina the prevalence of NTDs, particularly anencephaly and cervico-thoracic spina bifida, showed a greater reduction rate in females than in males after FAF, resulting in a change of the sex ratio of infants with NTDs. Some mechanisms possibly involved in this differential reduction are proposed which might be useful to identify the pathogenesis of NTDs as a whole and specifically of those susceptible to the protective effect of folic acid.
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Maintained Folic Acid Supplementation Reduces the Risk of Mortality in Continuous Ambulatory Peritoneal Dialysis Patients.
Rong, R, Zhou, Q, Lin, J, Huang, N, Li, W, Qiu, Y, Yu, X, Mao, H
Blood purification. 2018;(1-3):28-35
Abstract
BACKGROUND The association between folic acid (FA) supplementation and mortality in continuous ambulatory peritoneal dialysis (CAPD) patients is unclear. METHODS FA exposure was calculated as a percentage of cumulative duration of drug usage to total follow-up duration (FA%). A total of 1,358 patients were classified by a cutoff value of FA%. The association of FA with mortality was evaluated using Cox proportional hazards models. RESULTS The cutoff value of FA% for predicting mortality was <34% at a median follow-up of 40.7 months. FA ≥34% was associated with decreased risk for all-cause (adjusted hazard ratios [HRs] 95% CI 0.64 [0.48-0.85] and cardiovascular mortality 0.67 (95% CI 0.47-0.97). Moreover, the adjusted HRs per 10% higher FA for all-cause and cardiovascular mortality were 0.925 (95% CI 0.879-0.973) and 0.926 (95% CI 0.869-0.988), respectively. CONCLUSIONS Longer period of FA supplementation led to a reduction in risk of both all-cause and cardiovascular mortality in CAPD patients.
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Supplementation of folic acid in pregnancy and the risk of preeclampsia and gestational hypertension: a meta-analysis.
Liu, C, Liu, C, Wang, Q, Zhang, Z
Archives of gynecology and obstetrics. 2018;(4):697-704
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Abstract
OBJECTIVES We aimed to systematically assess the relationship between folic acid supplementation in pregnancy and risk of preeclampsia and gestational hypertension. METHODS The relevant studies were included by retrieving the Embase, PubMed and Cochrane library databases. Data extraction was conducted by two investigators independently. The risk ratio (RR) and 95% confidence interval (CI) were used as effect indexes to evaluate the relationship between folic acid supplementation and risk of gestational hypertension or preeclampsia. A subgroup analysis was performed according to the supplementation patterns of folic acid. The homogeneity of the effect size was tested across the studies, and publication biases were examined. RESULTS In total, 13 cohort studies and 1 randomized controlled trial study was included, containing 160,562 and 149,320 women with and without folic acid supplementation during pregnancy. Pooled results showed that risk of gestational hypertension was not associated with the supplementation of folic acid. However, folic acid supplementation during pregnancy could significantly reduce the risk of preeclampsia. Moreover, the results of subgroup analysis showed that the decreased preeclampsia risk was associated with supplementation of multivitamins containing folic acid rather than folic acid alone. CONCLUSIONS Our findings indicate that the supplementation of multivitamins containing folic acid during pregnancy could significantly lower preeclampsia risk.
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Folic acid/methylfolate for the treatment of psychopathology in schizophrenia: a systematic review and meta-analysis.
Sakuma, K, Matsunaga, S, Nomura, I, Okuya, M, Kishi, T, Iwata, N
Psychopharmacology. 2018;(8):2303-2314
Abstract
RATIONALE This study aims to examine whether folate/folic acid/methylfolate/folinic acid supplemented to antipsychotics (FA + AP) is beneficial in schizophrenia treatment. OBJECTIVE We conducted a comprehensive systematic review and meta-analysis of double-blind, placebo-controlled, randomized clinical trials (RCTs) of FA + AP for schizophrenia. METHODS The primary outcome was an improvement in total symptoms. Other outcomes were psychopathology subscales (positive, negative, general, and depressive symptoms), discontinuation due to all-cause and adverse events, and individual adverse events. The meta-analysis evaluated the effect size based on a random-effects model. RESULTS Although we included ten RCTs with 925 patients in total (seven folic acid RCTs (n = 789), two methylfolate RCTs (n = 96), and one folinic acid RCT (n = 40)) in the systematic review, only seven RCTs were included in the meta-analysis. Pooled FA + AP treatments were not superior to placebo + AP in the improvement of total (N = 7, n = 340; standardized mean difference (SMD) = - 0.20, 95% confidence interval (CI) = - 0.41, 0.02, p = 0.08, I2 = 0%), positive, general, or depressive symptoms. Pooled FA + AP treatments were more effective than placebo + AP for negative symptoms (N = 5, n = 281; SMD = -0.25, 95% CI = -0.49, -0.01, p = 0.04, I2 = 0%). Although pooled FA + AP treatments were associated with a lower incidence of serious adverse events than placebo treatments (N = 4, n = 241; risk ratio = 0.32, 95% CI = 0.12-0.82, p = 0.02, I2 = 0%; number needed to harm = not significant), there were no significant differences in other safety outcomes between both treatments. CONCLUSIONS Our findings suggest that pooled FA + AP treatment improves negative symptoms in schizophrenia patients. Moreover, this treatment was well tolerated. However, because our results might exhibit a small-study effect, future studies with a larger sample should be conducted to obtain more robust results.
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The effects of folate supplementation on lipid profiles among patients with metabolic diseases: A systematic review and meta-analysis of randomized controlled trials.
Tabrizi, R, Lankarani, KB, Akbari, M, Naghibzadeh-Tahami, A, Alizadeh, H, Honarvar, B, Sharifi, N, Mazoochi, M, Ostadmohammadi, V, Fatholahpour, A, et al
Diabetes & metabolic syndrome. 2018;(3):423-430
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Abstract
BACKGROUND AND OBJECTIVE Although several studies have assessed the effect of folate supplementation on lipid profiles among patients with metabolic diseases, findings are inconsistent. This review of randomized controlled trials (RCTs) was conducted to summarize the evidence on the effects of folate supplementation on lipid profiles among patients with metabolic diseases. METHODS Randomized-controlled trials (RCTs) published in PubMed, EMBASE, Web of Science and Cochrane Library databases up to until 20 August 2017 were searched. Two review authors independently assessed study eligibility, extracted data, and evaluated risk of bias of included studies. Heterogeneity was measured with a Q-test and with I2 statistics. Data were pooled by using the fix or random-effect model based on the heterogeneity test results and expressed as standardized mean difference (SMD) with 95% confidence interval (CI). RESULTS A total of thirteen randomized controlled trials were included. Folate supplementation did not affect systolic blood pressure (SMD -0.87; 95% CI, -1.83, 0.09) and diastolic blood pressure (SMD -0.59; 95% CI, -1.55, 0.37), and lipid profiles including triglycerides (SMD 0.10; 95% CI, -0.42, 0.63), total- (SMD 0.06; 95% CI, -0.31, 0.43), HDL- (SMD 0.04; 95% CI, -0.36, 0.44), VLDL- (SMD 0.08; 95% CI, -0.24, 0.41), and LDL-cholesterol (SMD -0.14; 95% CI, -0.55, 0.28). CONCLUSIONS Folate supplementation did not affect blood pressures and lipid profiles among patients with metabolic diseases. Additional prospective studies regarding the impact of folate supplementation on blood pressures and lipid profiles in patients with metabolic diseases are necessary.
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A systematic review of the vitamin B12, folate and homocysteine triad across body mass index.
Wiebe, N, Field, CJ, Tonelli, M
Obesity reviews : an official journal of the International Association for the Study of Obesity. 2018;(11):1608-1618
Abstract
OBJECTIVE Multiple studies have explored the association between serum or plasma vitamin B12 status and obesity, in part because of the relationship between elevated homocysteine concentrations and atherosclerosis. This review will address the inconsistent finding of these studies with the objective of determining whether vitamin B12 concentrations are lower in people with higher body mass indices. DESIGN MEDLINE and EMBASE were searched to February 2017. Observational studies in general and clinical populations comparing serum/plasma B12 concentrations across groups of different body mass indices were selected. We did network and pairwise meta-analyses of serum/plasma B12, folate and homocysteine using frequentist techniques. Evidence-based items potentially indicating risk of bias were assessed. RESULTS Of 844 citations, we identified 19 eligible observational studies with 7,055 participants. The overall network, while showing no significant inconsistency between indirect and direct comparisons (P = 0.34), was qualitatively inconsistent. Based on the results of the meta-regression, in an exploratory sub-network meta-analysis where obesity groups were combined, we excluded disease-specific populations and studies with inadequate description of populations. The direction of the indirect and direct evidence was consistent. The pairwise results from this sub-network showed lower levels of B12 in people with higher body mass indices: obesity versus control difference in means (MD) -56 pmol L-1 (95% CI -90, -23), obesity versus overweight MD -21 pmol L-1 (95% CI -37, -5) and overweight versus control MD -51 pmol L-1 (95% CI -51, -24). Heterogeneity remained very large for most comparisons, and all the studies carried a high risk for bias. CONCLUSIONS This review did not establish an inverse association (or J-curve) between serum or plasma B12 concentrations and body mass index, but the direct pairwise evidence is consistent with an inverse association and supports further investigation.
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The effect of universal maternal antenatal iron supplementation on neurodevelopment in offspring: a systematic review and meta-analysis.
Jayasinghe, C, Polson, R, van Woerden, HC, Wilson, P
BMC pediatrics. 2018;(1):150
Abstract
BACKGROUND Although antenatal iron supplementation is beneficial to mothers, its impact on the neurodevelopment of offspring is controversial. A systematic review and meta-analysis was undertaken to assess whether routine maternal antenatal iron supplementation confers later neurodevelopmental benefit to offspring. METHODS Electronic databases were searched using MESH terms or key words and identified papers were reviewed by two independent reviewers. The study quality was assessed using the Cochrane risk of bias assessment tool. The review was registered in the PROSPERO CRD data base. RESULTS Seven publications were identified, based on four randomised trials published between 2006 and 2016. Three of the trials were in the Asian sub-continent. A range of tools were used to evaluate neurodevelopment. Meta-analysis of outcomes from the three RCTs meeting our inclusion criteria showed minimal effect of antenatal iron supplementation on the neurodevelopment of offspring, which was not statistically significant: weighted mean difference of 0.54 (95% CI: -0.67 to 1.75); test for overall effect Z = 0.87; p = 0.38; and heterogeneity 48%. Meta-analysis of outcomes of these RCTs at later stages of development produced similar results. CONCLUSIONS The benefit of routine antenatal iron supplementation on neurodevelopment in offspring was not statistically significant in this relatively limited set of trials, and some benefit cannot be excluded in areas with a high prevalence of maternal anaemia. A large randomized controlled trial showing significant benefit would be required to modify our conclusions.