Reduced Relapse-Free Survival in Colorectal Cancer Patients with Elevated Soluble CD40 Ligand Levels Improved by Vitamin D Supplementation.

Although elevated serum levels of soluble CD40 ligand (sCD40L) were reported in patients with cancer, the importance of high sCD40L levels in clinical oncology remains unknown. We conducted a post hoc analysis of the AMATERASU randomized clinical trial of vitamin D3 supplementation (2000 IU/day) in patients with digestive tract cancer to assess its significance. Serum sCD40L levels were measured by ELISA in 294 residual samples, and were divided into tertiles. In patients with colorectal cancer (CRC), 5-year relapse-free survival (RFS) rates in the middle and highest tertiles were 61.6% and 61.2%, respectively, which was significantly lower than 83.8% in the lowest tertile. A Cox proportional hazard analysis showed that the lowest tertile had a significantly lower risk of relapse or death than the highest tertile even with multivariate adjustment (hazard ratio (HR), 0.30; 95% confidence interval (CI), 0.11-0.80; p = 0.016). In the subgroup of CRC patients with the highest tertile of sCD40L, the 5-year RFS rate in the vitamin D group was 77.9%, which was significantly higher than 33.2% in the placebo group (HR, 0.30; 95% CI, 0.11-0.81; p = 0.018 [Pinteraction = 0.04]). In conclusion, elevated sCD40L might be a biomarker of poor prognosis in patients with CRC, but vitamin D supplementation might improve RFS in patients with high sCD40L.

Effect of Vitamin D Supplements on Relapse or Death in a p53-Immunoreactive Subgroup With Digestive Tract Cancer: Post Hoc Analysis of the AMATERASU Randomized Clinical Trial.

Importance: Recent meta-analyses of randomized clinical trials found that daily vitamin D3 supplementation had beneficial effects on cancer mortality, although the results are still controversial. Objective: To examine whether vitamin D supplementation reduces the risk of relapse or death in a supgroup of patients with digestive tract cancer who were p53 immunoreactive. Design, Setting, and Participants: This was a post hoc subgroup analysis of the AMATERASU randomized, double-blind, placebo-controlled clinical trial. This trial included patients at a single university hospital in Japan with digestive tract cancers between January 2010 and February 2018 followed up for a median (IQR) of 3.5 (2.5-5.3) years to compare the effects of vitamin D supplementation with placebo and was reported in 2019. Patients from among 417 participants in the AMATERASU trial whose residual serum samples were available were included. Data were analyzed from October 20 to November 24, 2022. Interventions: Vitamin D3 (2000 IU/d) supplementation or placebo. Main Outcomes and Measures: The primary outcome was 5-year relapse or death. The subgroup of patients who were p53 immunoreactive was defined by positivity for anti-p53 antibodies in serum and nuclear accumulation of p53 oncosuppressor protein in more than 99% of cancer cells, which is considered a biomarker for p53 missense mutations. Anti-p53 antibody levels were measured using chemiluminescent enzyme immune assay. Immunohistochemical staining data of p53 protein in cancer tissue in pathologic specimens were obtained from a previous study and divided into 4 grades. Results: Among 392 patients with digestive tract cancer (mean [SD] age, 66 [10.7] years; 260 males [66.3%]), there were 37 patients with esophageal cancer (9.4%), 170 patients with gastric cancer (43.4%), 2 patients with small bowel cancer (0.5%), and 183 patients with colorectal cancer (46.7%). Serum anti-p53 antibody was detectable in 142 patients (36.2%), and p53-immunohistochemistry grade showed a positive association with serum anti-p53 antibody levels (coefficient = 0.19; P < .001). In the p53-immunoreactive subgroup (80 patients), relapse or death occurred in 9 of 54 patients (16.7%) in the vitamin D group and 14 of 26 patients (53.8%) in the placebo group; 5-year relapse-free survival (RFS) was significantly higher in the vitamin D group (13 patients [80.9%]) than the placebo group (1 patient [30.6%]; hazard ratio [HR], 0.27; 95% CI, 0.11-0.61; P = .002). This was significantly different from 272 patients in the non-p53 immunoreactive subgroup, in which vitamin D had no effect on 5-year RFS (vitamin D: 35 of 158 patients [22.2%] vs placebo: 24 of 114 patients [21.1%]; HR, 1.09; 95% CI, 0.65-1.84) (P for interaction = .005). Conclusions and Relevance: This study found that vitamin D supplementation reduced the risk of relapse or death in the subgroup of patients with digestive tract cancer who were p53 immunoreactive. Trial Registration: Identifier: UMIN000001977.

Efficacy of vitamin D3 supplementation on cancer mortality: Systematic review and individual patient data meta-analysis of randomised controlled trials.

To evaluate the effect of vitamin D3 supplementation on cancer mortality in the general population and on prognosis in cancer patients, a systematic review and meta-analysis of randomised, placebo-controlled trials (RCTs) and individual patient data (IPD) was conducted. Overall, 14 RCTs with a total of 104,727 participants (2015 cancer deaths) were identified and 7 RCTs, including 90 % of all study participants (n = 94,068), could be included in the IPD meta-analyses. The main meta-analysis of the 14 RCTs yielded a statistically non-significant reduction in cancer mortality by 6 % (risk ratio (RR) [95%-confidence interval (95%CI)]: 0.94 [0.86-1.02]). Subgroup analyses revealed a 12 % lower cancer mortality in the vitamin D3 group compared with the placebo group in 10 trials with a daily dosing regimen (RR [95%CI]: 0.88 [0.78-0.98]), whereas no mortality reduction was seen in 4 trials using a bolus regimen (RR [95%CI]: 1.07 [0.91-1.24]; p-value for interaction: 0.042). The IPD meta-analysis (RR [95%CI]: 0.93 [0.84; 1.02]) confirmed the finding of all trials. The IPD were used to test effect modification by age, sex, body mass index, ethnicity, baseline serum 25-hydroxyvitamin D concentration, adherence and cancer-related factors but no statistically significant findings were obtained in meta-analyses of all trials. When restricted to trials with daily dosing in a post-hoc analysis, adults aged ≥ 70 years (RR [95%CI]: 0.83 [0.77; 0.98]) and subjects with vitamin D3 therapy initiation before cancer diagnosis (RR [95%CI]: 0.87 [0.69; 0.99]) appeared to benefit most from daily vitamin D3 supplementation. Measurements of baseline 25-hydroxyvitamin D levels and inclusion of other than non-Hispanic White adults were too sparse in the trials to draw conclusions. Results for all-cause and cancer-specific survival of participants with cancer were comparable to those obtained in the general population for cancer mortality. In conclusion, vitamin D3 did not reduce cancer mortality in the main meta-analysis of all RCTs because the observed risk reduction by 6 % was not statistically significant. However, a subgroup analysis revealed that vitamin D3 administered daily, in contrast to bolus supplementation, reduced cancer mortality by 12 %.

Applying Machine Learning to Determine 25(OH)D Threshold Levels Using Data from the AMATERASU Vitamin D Supplementation Trial in Patients with Digestive Tract Cancer.

Some controversy remains on thresholds for deficiency or sufficiency of serum 25-hydroxyvitamin D (25(OH)D) levels. Moreover, 25(OH)D levels sufficient for bone health might differ from those required for cancer survival. This study aimed to explore these 25(OH)D threshold levels by applying the machine learning method of multivariable adaptive regression splines (MARS) in post hoc analyses using data from the AMATERASU trial, which randomly assigned Japanese patients with digestive tract cancer to receive vitamin D or placebo supplementation. Using MARS, threshold 25(OH)D levels were estimated as 17 ng/mL for calcium and 29 ng/mL for parathyroid hormone (PTH). Vitamin D supplementation increased calcium levels in patients with baseline 25(OH)D levels ≤17 ng/mL, suggesting deficiency for bone health, but not in those >17 ng/mL. Vitamin D supplementation improved 5-year relapse-free survival (RFS) compared with placebo in patients with intermediate 25(OH)D levels (18−28 ng/mL): vitamin D, 84% vs. placebo, 71%; hazard ratio, 0.49; 95% confidence interval, 0.25−0.96; p = 0.04. In contrast, vitamin D supplementation did not improve 5-year RFS among patients with low (≤17 ng/mL) or with high (≥29 ng/mL) 25(OH)D levels. MARS might be a reliable method with the potential to eliminate guesswork in the estimation of threshold values of biomarkers.

Effect of Vitamin D Supplements on Relapse of Digestive Tract Cancer with Tumor Stromal Immune Response: A Secondary Analysis of the AMATERASU Randomized Clinical Trial.

The aim was to examine whether vitamin D supplementation (2000 IU/day) reduces the risk of relapse in a subgroup of patients with digestive tract cancer, showing a sufficient immune response in tumor stroma by conducting secondary subgroup analyses of the AMATERASU randomized, double-blind, placebo-controlled trial (UMIN000001977). A total of 372 patients were divided into two subgroups stratified by the median density of immune cells infiltrating in tumor stroma into higher and lower halves. In the higher-half subgroup of CD56+ cells, the relapse ratio was significantly lower in the vitamin D group (7.4%) than in the placebo group (20.5%) (subdistribution hazard ratio (SHR), 0.35; 95% confidence interval (CI), 0.15-0.82), but it was equivalent (25.2% vs. 22.7%) in the lower-half subgroup of CD56+ cells (SHR, 1.21; 95% CI, 0.68-2.19) with a significant interaction (Pinteraction = 0.02). Although there were no significant differences, the risk of relapse was lower in the vitamin D group than in the placebo group in the higher half of CD45RO+ memory T cells (8.9% vs. 19.2%), and of CD8+ cytotoxic T cells (11.3% vs. 22.5%). In patients with digestive tract cancer, vitamin D supplementation was hypothesized to reduce the risk of relapse in the subgroup of patients who already have an adequate infiltration of immune cells in their tumor stroma.

Vitamin D Supplementation Regulates Postoperative Serum Levels of PD-L1 in Patients with Digestive Tract Cancer and Improves Survivals in the Highest Quintile of PD-L1: A Post Hoc Analysis of the AMATERASU Randomized Controlled Trial.

Because vitamin D responsive elements have been found to be located in the PD-L1 gene, vitamin D supplementation was hypothesized to regulate serum PD-L1 levels and thus alter survival time of cancer patients. A post hoc analysis of the AMATERASU randomized, double-blind, placebo-controlled trial of postoperative vitamin D3 supplementation (2000 IU/day) in 417 patients with stage I to stage III digestive tract cancer from the esophagus to the rectum was conducted. Postoperative serum PD-L1 levels were measured by ELISA and divided into quintiles (Q1-Q5). Serum samples were available for 396 (95.0%) of the original trial. Vitamin D supplementation significantly (p = 0.0008) up-regulated serum PD-L1 levels in the lowest quintile (Q1), whereas it significantly (p = 0.0001) down-regulated them in the highest quintile (Q5), and it did not either up- or down-regulate them in the middle quintiles (Q2-Q4). Significant effects of vitamin D supplementation, compared with placebo on death (HR, 0.34; 95% CI, 0.12-0.92) and relapse/death (HR, 0.37; 95% CI, 0.15-0.89) were observed in the highest quintile (Q5) of serum PD-L1, whereas significant effects were not observed in other quintiles (Pinteraction = 0.02 for death, Pinteraction = 0.04 for relapse/death). Vitamin D supplementation significantly reduced the risk of relapse/death to approximately one-third in the highest quintile of serum PD-L1.

Effect of Serum SPARC Levels on Survival in Patients with Digestive Tract Cancer: A Post Hoc Analysis of the AMATERASU Randomized Clinical Trial.

Observational studies suggest that physical activity may improve, whereas sarcopenia may worsen the survival of cancer patients. It has been suggested that secreted protein acidic and rich in cysteine (SPARC), one of the myokines that is secreted into the bloodstream by muscle contraction, has tumor-suppressive effects. Based on the hypothesis that serum SPARC level may be a potential prognostic biomarker, a post hoc analysis of the AMATERASU randomized, double-blind, placebo-controlled trial of postoperative oral vitamin D supplementation (2000 IU/day) in patients with stage I-III digestive tract cancer from the esophagus to the rectum (UMIN000001977) was conducted with the aim of exploring the association between serum SPARC levels after operation and survival. On multivariate analyses adjusting serum 25-hydroxyvitamin D, vitamin D supplementation, sarcopenia, body mass index, age, sex, cancer loci, stage, and adjuvant chemotherapy, patients with SPARC levels lower than the median level had a significantly higher risk for death than those with higher levels (hazard ratio, 2.25; 95% confidence interval, 1.25-4.05; p = 0.007), whereas there were no significant associations with other outcomes including recurrence. However, on the same multivariate analyses, sarcopenia was not a risk factor for death and/or relapse. These results suggest that serum SPARC levels may be a potential biomarker for death but not cancer relapse.

Vitamin D and Cancer Survival: Does Vitamin D Supplementation Improve the Survival of Patients with Cancer?

PURPOSE OF REVIEW: Clinical evidence suggesting the beneficial effects of vitamin D on survival of patients with cancer has been accumulating. Recent articles were thoroughly reviewed to determine if there is enough evidence to conclude that vitamin D supplementation improves survival of patients with cancer. RECENT FINDINGS: Meta-analyses of observational studies showed that higher blood 25-hydroxyvitamin D levels in patients with cancer at a variety of sites were associated with lower cancer-specific and overall mortalities. Moreover, meta-analyses of randomized clinical trials (RCTs) also suggested that vitamin D supplementation improved the survival of patients with cancer. However, each RCT used in these meta-analyses, as well as very recent RCTs, e.g., the SUNSHINE and the AMATERASU trial, did not show statistical significance in the primary results. For now, compelling evidence that vitamin D supplementation effectively improves survival of patients with cancer is lacking. Thus, confirmatory RCTs are still obligatory for the future.

Effect of Vitamin D Supplementation on Survival of Digestive Tract Cancer Patients with Low Bioavailable 25-Hydroxyvitamin D levels: A Post Hoc Analysis of the AMATERASU Randomized Clinical Trial.

Vitamin D has been shown to suppress the growth of cancer cells. Cancer cells are believed to take up bioavailable 25-hydroxyvitamin D (25[OH]D) (i.e., not bound to vitamin-D-binding protein (DBP)) more efficiently than DBP-bound 25(OH)D. Our aim was to use this bioavailable 25(OH)D, rather than total 25(OH)D, as a biomarker of vitamin D deficiency to investigate whether vitamin D supplementation improves the relapse-free survival (RFS) of patients with digestive tract cancer from the esophagus to the rectum by conducting a post hoc analysis of the AMATERASU trial (UMIN000001977). The bioavailable 25(OH)D levels were calculated via an equation using data of serum total 25(OH)D, albumin, and DBP levels, and DBP genotypes (rs7041 and rs4588). We estimated bioavailable 25(OH) levels in 355 patients. In a subgroup of patients with low bioavailable 25(OH)D levels (

Effect of Vitamin D on Relapse-Free Survival in a Subgroup of Patients with p53 Protein-Positive Digestive Tract Cancer: A Post Hoc Analysis of the AMATERASU Trial.

BACKGROUND: The AMATERASU randomized trial of vitamin D3 supplementation (2,000 IU/day; UMIN000001977) showed the potential benefit of vitamin D in a subgroup of patients with digestive tract cancer. By conducting post hoc analyses of this trial, we further explored whether subgroups stratified by expression levels of p53, vitamin D receptor (VDR), and Ki-67 modify the effect of vitamin D supplementation. METHODS: The primary outcome was relapse-free survival (RFS). On IHC using pathologic specimens, the degree of p53 protein expression parallel with TP53 missense mutations was classified as p53 positive (>10%) and p53 negative (≤10%). In addition, VDR and Ki-67 expression levels were divided into quartiles. RESULTS: The p53 status of 372 patients' pathologic specimens was evaluated. In a subgroup of patients with p53-positive cancer (n = 226), 5-year RFS was 79% in the vitamin D group, which was significantly higher than the 57% in the placebo group (HR, 0.52; 95% confidence interval, 0.31-0.88; P = 0.02). In the subgroup of patients with p53-negative cancer, 5-year RFS in the vitamin D group versus placebo group was 72% versus 84% (not significantly different), respectively. Effect modification by p53 positivity was significant (P interaction = 0.02). However, no significant effect modification by either VDR or Ki-67 was observed. CONCLUSIONS: These results generate a hypothesis that vitamin D supplementation may improve RFS in patients with p53-positive digestive tract cancer. IMPACT: The results are still preliminary, but potentially important, because TP53 is the most frequently mutated gene across cancers at all sites.

Effect Modification of Vitamin D Supplementation by Histopathological Characteristics on Survival of Patients with Digestive Tract Cancer: Post Hoc Analysis of the AMATERASU Randomized Clinical Trial.

Some coauthors of this study previously performed the AMATERASU randomized, double-blind, placebo-controlled trial of postoperative oral vitamin D supplementation (2,000 IU/day) in 417 patients with stage I to III digestive tract cancer from the esophagus to the rectum who underwent curative surgery (UMIN000001977). We conducted a post-hoc analysis of the AMATERASU trial to explore the effects of modification of vitamin D supplementation by histopathological characteristics on survival. Among patients with poorly differentiated adenocarcinoma, the 5-year relapse-free survival rate of patients supplemented with vitamin D was 91% compared with 63% in the placebo group (hazard ratio [HR], 0.25; 95% confidence interval [CI], 0.08 to 0.78; P = 0.017; P for interaction = 0.023). Similarly, the 5-year overall survival rate was 92% in the vitamin D group compared with 72% in the placebo group (HR, 0.25; 95%CI, 0.07 to 0.94; P = 0.040; P for interaction = 0.012). In contrast, there were no significant effects in other histopathological characteristics between vitamin D and placebo groups. These findings generated the hypothesis that oral vitamin D supplementation may improve both relapse-free survival and overall survival in a subgroup of patients with poorly differentiated adenocarcinoma.

Effect of Vitamin D Supplementation on Relapse-Free Survival Among Patients With Digestive Tract Cancers: The AMATERASU Randomized Clinical Trial.

Importance: Randomized clinical trials of vitamin D supplementation for secondary prevention in patients with cancer are needed, given positive results of observational studies. Objective: To determine whether postoperative vitamin D3 supplementation can improve survival of patients with digestive tract cancers overall and in subgroups stratified by 25-hydroxyvitamin D (25[OH]D) levels. Design, Setting, and Participants: The AMATERASU trial, a randomized, double-blind, placebo-controlled trial conducted at a single university hospital in Japan. Enrollment began in January 2010 and follow-up was completed in February 2018. Patients aged 30 to 90 years with cancers of the digestive tract from the esophagus to the rectum, stages I to III, were recruited. Of 439 eligible patients, 15 declined and 7 were excluded after operation. Interventions: Patients were randomized to receive oral supplemental capsules of vitamin D (2000 IU/d; n = 251) or placebo (n = 166) from the first postoperative outpatient visit to until the end of the trial. Main Outcomes and Measures: The primary outcome was relapse-free survival time to relapse or death. The secondary outcome was overall survival time to death due to any cause. Subgroups analyzed had baseline serum 25(OH)D levels of 0 to less than 20 ng/mL, 20 to 40 ng/mL, and greater than 40 ng/mL; because of small sample size for the highest-baseline-level group, interactions were tested only between the low- and middle-baseline-level groups. Results: All 417 randomized patients (mean age, 66 years; male, 66%; esophageal cancer, 10%; gastric cancer, 42%; colorectal cancer, 48%) were included in the analyses. There was 99.8% follow-up over a median 3.5 (interquartile range, 2.3-5.3) years, with maximal follow-up of 7.6 years. Relapse or death occurred in 50 patients (20%) randomized to vitamin D and 43 patients (26%) randomized to placebo. Death occurred in 37 (15%) in the vitamin D group and 25 (15%) in the placebo group. The 5-year relapse-free survival was 77% with vitamin D vs 69% with placebo (hazard ratio [HR] for relapse or death, 0.76; 95% CI, 0.50-1.14; P = .18). The 5-year overall survival in the vitamin D vs placebo groups was 82% vs 81% (HR for death, 0.95; 95% CI, 0.57-1.57; P = .83). In the subgroup of patients with baseline serum 25(OH)D levels between 20 and 40 ng/mL, the 5-year relapse-free survival was 85% with vitamin D vs 71% with placebo (HR for relapse or death, 0.46; 95% CI, 0.24-0.86; P = .02; P = .04 for interaction). Fractures occurred in 3 patients (1.3%) in the vitamin D group and 5 (3.4%) in the placebo group. Urinary stones occurred in 2 patients (0.9%) in the vitamin D group and 0 in the placebo group. Conclusions and Relevance: Among patients with digestive tract cancer, vitamin D supplementation, compared with placebo, did not result in significant improvement in relapse-free survival at 5 years. Trial Registration: UMIN Identifier: UMIN000001977.

Prenatal vitamin A supplementation associated with adverse child behavior at 3 years in a prospective birth cohort in Japan.

BACKGROUND: Many pregnant women take vitamin supplements during pregnancy. The aim of this paper was to clarify the effects of dietary supplementation prior to and/or during pregnancy on child behavior. METHODS: A prospective birth cohort study from pregnancy to 3 years of age involving 1271 pairs of Japanese pregnant women and their newborns, was carried out. The women completed a self-administered questionnaire during the third trimester of pregnancy. To evaluate deviations in child behavior as an endpoint, each mother completed the Japanese Child Behavior Checklist for ages 2-3 years after 3 years of birth. Participant characteristics were compared between supplement takers and non-takers. RESULTS: Among many kinds of supplements, intake of supplemental vitamin A/ß-carotene prior to and/or during pregnancy was associated with hazardous effects on child behavior at 3 years of age (total t-score, P = 0.003; internal t-score, P = 0.027; external t-score, P = 0.013). This association held true even after adjusting for age, number of deliveries, infertility treatment, consumption of fast food, smoking status, maternal and paternal education, maternal and paternal income, gestational age at birth, anthropometry at birth (weight, height, head circumference and body circumference), and the State-Trait Anxiety Inventory at 3 years of age by means of multiple imputation. CONCLUSIONS: Intake of supplemental vitamin A prior to and/or during pregnancy may worsen child behavior at 3 years of age.