High serum folate might have a potential dual effect on risk of colorectal cancer

Abstract 5268 Folate therapy can induce or exacerbate neuro-cognitive changes in patients with clinically significant Cbl deficiency. High serum folate (sFol) values in subjects with low Cbl levels have also been associated with increases in the Cbl-dependent metabolite, methylmalonic acid (MMA) as well as with hematologic, neuro-cognitive and fetal abnormalities, raising concerns about the use of both folate supplements and folate-fortified grains. However, in a more recent study of young adults, MMA values were unaffected by high sFol values. Significantly, advanced age is also linked to increased MMA values even when Cbl values are normal. Thus, a retrospective study was performed of 91 non-diabetic subjects with normal renal function and low-normal Cbl values (201–300 pg/ml) who were evaluated for Cbl deficiency in an ambulatory care setting over a 10 year period to determine if age is a significant determinant of the metabolic interaction of sFol and Cbl when Cbl levels are within the normal reference range. In older individuals (≥60 yrs) with low-normal serum Cbl values, the geometric mean MMA value was significantly higher (401 nmol/l; n=11) when sFol values were elevated (>20 ng/ml) than when sFol values were normal (298 nmol/l; n=35)(p<0.025). In contrast, in younger subjects, mean MMA values were similar in both high and normal sFol groups (302 nmol/l; n=15 vs 270 nmol/l; n=30)(p=0.52). There was no correlation between MMA and sFol when sFol values were within the normal range in either age group (r≤0.07). Finally, when sFol levels were elevated, Cbl therapy significantly decreased MMA values in 8 of 9 younger subjects (89%) and in all 7 older individuals (100%) studied. It is concluded that: 1) MMA values are increased when sFol levels are elevated and Cbl values are low-normal but this effect is age-dependent; 2) the effect of sFol on MMA is not progressive but occurs only at sFol values above the normal range; and 3) Cbl therapy decreases MMA values in almost all subjects regardless of pretreatment sFol values. Since these findings may have clinical significance, caution in the use of folate supplements is advised. Disclosures: No relevant conflicts of interest to declare.

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Determinants of plasma homocysteine in coal miners.

Acta Biochimica Polonica ◽

10.18388/abp.2013_2005 ◽

2013 ◽

Vol 60 (3) ◽

Cited By ~ 1

Author(s):

A Görkem Mungan ◽

Murat Can ◽

Sibel Kiran ◽

Serefden Açikgöz ◽

Berrak Güven

Keyword(s):

Vitamin B12 ◽

Cystatin C ◽

Kinetic Method ◽

Serum Levels ◽

Health Problems ◽

High Serum ◽

Serum Folate ◽

Control Group ◽

Coal Miners ◽

Group Control Group

Several studies suggest that coal miners are under risk of severe health problems such as cardiovascular, pulmonary, neurological, renal, hematological and musculoskeletal disorders. However, there are limited data on biochemical changes in underground workers. In our study we aimed to evaluate the association between serum homocysteine (Hcy), vitamin B12, cystatin C and folate levels in the blood of underground coal miners. Eighty one coal miners who work as underground or surface workers were recruited into our study. The study population was divided into two groups: the surface worker group (control group, n=33) and the underground worker group (n=48). The folate, vitamin B12, Hcy, cystatin C levels and body mass indexes (BMI) of both groups were measured and compared. Serum folate, Hcy and vitamin B12 levels were measured with a competitive chemiluminescence immunassay. Serum levels of cystatin C were determined by the latex particle-enhanced turbidimetric method using a cystatin C kit. Urea values were measured with a kinetic method on an automated analyzer. There were no statistically significant differences between the underground workers and surface workers in the urea, cystatin C and vitamin B12 levels. High serum Hcy levels and low folate levels were found in underground workers compared with those in surface workers. The correlation between Hcy and folate levels was also statistically significant. Similarly, there was also a significant correlation between Hcy and vitamin B12, and between Hcy and cystatin C levels. Elevated Hcy levels may be associated with underground working but further research is necessary to understand the relation between elevated Hcy and increased prevalence of health problems in coal miners.

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High Folate and Vitamin Low B12 Status: Potential Interactions with Cognitive Function Among U.S. Older Adults, NHANES 2011–2014

Current Developments in Nutrition ◽

10.1093/cdn/nzaa057_005 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 1189-1189

Author(s):

Regan Bailey ◽

Shinyoung Jun ◽

Lisa Murphy ◽

Ralph Green ◽

Josh Miller

Keyword(s):

Older Adults ◽

Folic Acid ◽

Cognitive Function ◽

Vitamin B12 ◽

Cognitive Performance ◽

High Serum ◽

Serum Folate ◽

Cognitive Test ◽

Digit Symbol Substitution Test ◽

Cut Points

Abstract Objectives Potential safety concerns may exist with high folate/folic acid exposures combined with low vitamin B12 (B12) status relative to cognitive function; therefore, we investigated this relationship, leveraging cognitive test performance with folate and B12 biomarker data among a nationally-representative survey of U.S. older adults. Methods We analyzed data from 2420 older adults (≥60 y) from the 2011–2014 NHANES. High folate status was defined as unmetabolized serum folic acid (UMFA) > 1 nmol/L or serum folate > 74.1 nmol/L. Low B12 status was defined using age-specific cut-points for serum B12 [≤429 pmol/L (in 60–69 y) and ≤370 pmol/L (in ≥70 y)] or using a combination of traditional cut-points [elevated methylmalonic acid (>271 nmol/L) and deficient serum B12 (< 150 pmol/L)]. Multivariable logistic regression models estimated odds ratios (OR) of scoring low on one of four cognitive tests: Digit Symbol Substitution Test (DSST), Consortium to Establish a Registry for Alzheimer's Disease [CERAD; Word Learning (WL) and Delayed Recall (DR)], and Animal Fluency Test (AF). Results Among older adults with low B12 status, high UMFA was associated with a higher OR of having a low score on the DSST (<34, OR 2.16; 95% CI 1.05–4.47) and high serum folate was associated with a higher OR of having a low score on the AF (<14, OR 1.93; 95% CI 1.08–3.45), only when using traditional cut-points for B12. Among those with normal B12 status, having a high UMFA was protective on the CERAD-DR, regardless of B12 status being defined using age-specific or traditional cut-points. Compared to those with normal B12 (using traditional cut-points) and high UMFA, those with low B12 and high UMFA had a higher risk of scoring low on the DSST (<40, OR 2.22; 95% CI 1.31–3.75) and AF (<14, OR 1.97; 95% CI 1.30–2.97), those with low B12 and lower UMFA had a higher risk of scoring low on the DSST (<40, OR 1.69; 95% CI 1.16–2.47), and those with normal B12 and lower UMFA had a higher risk of scoring low on the CERAD-DR (<17, OR 1.38; 95% CI 1.02–1.85); similar patterns were found with serum folate. Conclusions In older adults, high folate was associated with better cognitive performance when vitamin B12 status is normal, whereas high folate was associated with poorer cognitive performance when vitamin B12 status is low. Funding Sources N/A.

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High serum TGFα, TNFα and IL6 correlate with abnormal circadian rhythms in patients with metastatic colorectal cancer (MCC)

Journal of Clinical Oncology ◽

10.1200/jco.2004.22.14_suppl.9650 ◽

2004 ◽

Vol 22 (14_suppl) ◽

pp. 9650-9650

Author(s):

P. F. Innominato ◽

T. Rich ◽

J. Boerner ◽

M. C. Mormont ◽

S. Iacobelli ◽

...

Keyword(s):

Colorectal Cancer ◽

Circadian Rhythms ◽

Metastatic Colorectal Cancer ◽

High Serum

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High serum TGFα, TNFα and IL6 correlate with abnormal circadian rhythms in patients with metastatic colorectal cancer (MCC)

Journal of Clinical Oncology ◽

10.1200/jco.2004.22.90140.9650 ◽

2004 ◽

Vol 22 (14_suppl) ◽

pp. 9650-9650

Author(s):

P. F. Innominato ◽

T. Rich ◽

J. Boerner ◽

M. C. Mormont ◽

S. Iacobelli ◽

...

Keyword(s):

Colorectal Cancer ◽

Circadian Rhythms ◽

Metastatic Colorectal Cancer ◽

High Serum

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Tumor VEGFA gene expression is associated with serum lactate dehydrogenase (LDH) levels and intratumoral mRNA expression of genes involved in glycolysis in patients with metastatic colorectal cancer (mCRC)

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.3530 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 3530-3530 ◽

Cited By ~ 1

Author(s):

M. Azuma ◽

M. M. Shi ◽

C. J. Jacques ◽

C. Barrett ◽

K. D. Danenberg ◽

...

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

Lactate Dehydrogenase ◽

Metastatic Colorectal Cancer ◽

Mrna Expression ◽

High Serum ◽

Serum Lactate Dehydrogenase ◽

Mrna Levels ◽

Glut 1 ◽

Expression Of Genes

3530 Background: It is well known that angiogenesis and glycolysis are regulated by hypoxic conditions. Recent clinical trials (CONFIRM1 and CONFIRM2) have shown that patients with mCRC with high serum LDH benefited from PTK787/ZK 222584, a VEGF receptor tyrosine kinase inhibitor. We tested the hypothesis that patients with high serum LDH have increased intratumoral expression of genes involved with hypoxia (hypoxia inducible factor (HIF1a and 2a) and lactate dehydrogenase A (LDHA) and glycolysis (glucose transporter 1 (Glut-1) and genes involved in angiogenesis such as vascular endothelial growth factor A (VEGFA) and neuropilin 1 (NRP1) in patients with mCRC. Methods: 78 formalin fixed paraffin embedded (FFPE) tumor samples from 36 patients (20 males, 16 females: Median age 59 years (range 29–84) with mCRC who underwent first line therapy (not from CONFIRM trials) were analyzed. In addition, tumor gene expression was correlated with serum LDH levels from the same group of patients. FFPE tissues were dissected using laser-captured microdissection and analyzed LDHA, VEGFA, HIF1a, HIF2a, Glut-1 and NRP1 mRNA expression using a quantitative real-time RT-PCR method. Gene expression values (relative mRNA levels) are expressed as ratios between the target gene and internal reference gene (beta-actin). Results: Spearman Rank Correlation Analysis of Associations Between serum LDH levels and Gene Expression values. Conclusions: Our results demonstrate that intratumoral gene expression of LDHA, HIF1a and HIF2a, Glut-1 and VEGFA are significantly correlated. Patients with high serum LDH have increased intratumoral gene expression of VEGFA. These results support the hypothesis that serum LDH levels may serve as a surrogate marker for activation of the HIF related genes in the tumor. These observations may explain the efficacy of PTK787 in metastatic colorectal cancer patients with high serum LDH levels. [Table: see text] [Table: see text]

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Clinical significance of serum angiopoietin-like protein 2 in colorectal cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.3_suppl.417 ◽

2014 ◽

Vol 32 (3_suppl) ◽

pp. 417-417

Author(s):

Takahito Kitajima ◽

Yuji Toiyama ◽

Tadanobu Shimura ◽

Shozo Ide ◽

Hiroki Imaoka ◽

...

Keyword(s):

Colorectal Cancer ◽

Tumor Cell ◽

Cancer Patients ◽

Clinical Significance ◽

Prognostic Significance ◽

Disease Free Survival ◽

Staining Intensity ◽

High Serum ◽

Highly Correlated ◽

Colorectal Cancer Patients

417 Background: Angiopoietin-like protein 2 (ANGPTL2) is a secreted protein belonging to the angiopoietin family. It has been reported to act as a causative mediator of chronic inflammation and metabolic abnormalities. ANGPTL2 increases inflammatory carcinogenesis in several cancers, and its expression in tumor cells is highly correlated with the frequency of tumor cell metastasis through increased tumor angiogenesis and tumor cell epithelial-to-mesenchymal transitions. However, to our own knowledge, clinical significance of serum ANGPTL2 in cancer patients remains unknown. The aim of this study was to quantify serum ANGPTL2 level using ELISA, and to evaluate its clinical and prognostic significance in patients with colorectal cancer (CRC). Methods: We quantified serum ANGPTL2 levels from 194 CRC patients and normal 48 controls (NC) by ELISA. Next, we investigated ANGPTL2 expression in matched CRC tissues (n=194) by immunohistochemistry (IHC) to identify the source of circulating ANGPTL2. The IHC score of ANGPTL2 was determined on the basis of both staining intensity and the percentage of positive cells. Results: Serum ANGPTL2 levels were significantly higher in CRC than in NC (p<0.01) and gradually increased according to TNM stage progression. Serum ANGPTL2 levels discriminated CRC from NC with high accuracy (AUC=0.837). High serum ANGPTL2 was significantly associated with larger tumor size (p=0.03), undifferentiated adenocarcinoma (p=0.03), advanced T stage (p<0.01), peritoneal metastasis (p<0.01). In addition, Kaplan–Meier curves revealed that high serum ANGPTL2 were significantly associated with poor disease free survival (p=0.01) and overall survival (p=0.03). Interestingly, ANGPTL2 levels in serum from CRC patients closely correlated with IHC scores of cytoplasmic ANGPTL2 expression in matched CRC tissues (r=0.14, p=0.03). Conclusions: Serum ANGPTL2, which might be derived from primary CRC tumor, has strong potential to serve as a noninvasive biomarker for CRC diagnosis and prognosis.

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Pre-treatment serum folate levels and toxicity in colorectal cancer patients treated with 5-fluorouracil and folinic acid.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.4_suppl.755 ◽

2016 ◽

Vol 34 (4_suppl) ◽

pp. 755-755 ◽

Cited By ~ 1

Author(s):

Michael Yan ◽

Mark David Vincent ◽

Cheryl Ho ◽

Eric Winquist ◽

Derek J. Jonker ◽

...

Keyword(s):

Colorectal Cancer ◽

Folinic Acid ◽

Cancer Patients ◽

Serum Folate ◽

Folate Level ◽

Serum Folate Level ◽

Pre Treatment ◽

Grade 3 ◽

Colorectal Cancer Patients ◽

Schedule Modification

755 Background: 5-fluorouracil (5-FU) chemotherapy is associated with severe and unpredictable toxicity in a significant proportion of patients.We hypothesized that susceptibility to 5-FU toxicity might be related to individual differences in components of reduced folate metabolism affecting intracellular 5,10-MTHF levels, detectable in blood prior to treatment. Methods: A prospective cohort of chemo-naive colorectal cancer patients planned to receive IV 5-FU and folinic acid for five consecutive days every four weeks were studied. Baseline clinical and laboratory data were collected prior to treatment. Biochemical data associated with folate metabolism was also collected and not revealed to treating physicians. The primary endpoint was occurrence of > grade 3 toxicity and/or toxicity mandating dose delay or reduction. Results: Of 78 eligible patients studied, 68% experienced > grade 3 toxicity, 69% had schedule modification, and 81% had either or both. Multivariable analyses identified only a higher pre-treatment serum folate level as an independent predictor of toxicity > grade 3 and/or mandating schedule modification (p = 0.016). An increasing toxicity trend was observed amongst folate-stratified patient cohorts, with an odds ratio of 2.87 (p = 0.09) comparing the highest and lowest quartiles. Concurrently, overall survival and relapse-free rates also increased with pretreatment folate levels in the adjuvant cohort with log rank values of 3.60 (p = 0.06) and 7.20 (p = 0.007) between the highest quartile and the lower quartiles, respectively. Conclusions: The incidence of severe toxicity with this schedule of 5-FU and folinic acid was high and positively correlated with the pretreatment serum folate level. Interestingly, a concurrent increase in overall and relapse free survival is observed with increasing serum folate levels. These results suggest that an optimal pretreatment folate level exists that balances chemotherapy treatment efficacy and toxicity.

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