Effects of Vitamin D Supplementation and Seasonality on Circulating Cytokines in Adolescents: Analysis of Data From a Feasibility Trial in Mongolia

Vitamin D deficiency is prevalent in human populations and has been linked to immune dysfunction. Here we explored the effects of cholecalciferol supplementation on circulating cytokines in severely vitamin D deficient [blood 25(OH)D << 30 nmol/L] adolescents aged 12-15 from Mongolia. The study included 28 children receiving 800 IU daily cholecalciferol for 6 months spanning winter and spring, and 30 children receiving placebo during the same period. The levels of 25(OH)D were assessed at baseline, 3 and 6 months. Twenty-one cytokines were measured in serum at baseline and at 6 months. Changes in 25(OH)D and cytokines were assessed using paired parametric tests. The median blood 25(OH)D concentration at baseline was 13.7 nmol/L (IQR = 10.0-21.7). Supplementation tripled blood 25(OH)D levels (p < 0.001) and was associated with elevated interleukin (IL)-6 (p = 0.043). The placebo group had reduced macrophage inflammatory protein (MIP)-1 alpha (p = 0.007) and IL-8 (p = 0.034) at 6 months. Although limited by a small sample size, these findings suggest that cholecalciferol supplementation and seasonality may impact systemic immunity in adolescents, identifying chemokines as potentially important biomarkers of vitamin D status in this Northeast Asian population. Larger clinical trials are warranted to validate these results

Receipt of definitive therapy in elderly patients with unfavorable‐risk prostate cancer

BACKGROUND Conservative management of aggressive prostate cancer in the elderly without definitive therapy has been associated with a 10‐year prostate cancer‐specific mortality of approximately 50%. The authors examined the prevalence of definitive therapy in elderly patients with intermediate‐risk or high‐risk disease. METHODS 411,343 patients who were diagnosed from 2004 through 2012 with intermediate‐risk or high‐risk prostate cancer were identified in the National Cancer Database. Multivariable logistic regression adjusting for sociodemographic characteristics and comorbidity was used to examine the association between age and receipt of definitive therapy, defined as radical prostatectomy or radiotherapy, and of primary androgen deprivation therapy (ADT) among patients who did not receive definitive therapy. RESULTS In total, 87.1% of high‐risk patients and 91.9% of intermediate‐risk patients received definitive therapy. When stratified by age, 93.7%, 92.1%, 90.8%, 87.6%, 80.9%, and 55.2% of high‐risk patients and 96.1%, 94.7%, 93.4%, 89.7%, 82.7%, and 62.8% of intermediate‐risk patients ages <60, 60 to 64, 65 to 69, 70 to 74, 75 to 79, and ≥80 years received definitive therapy, respectively. For both high‐risk and intermediate‐risk patients, increasing age was significantly associated with a decreased likelihood of receiving definitive therapy overall (both P < .001) and a greater likelihood of receiving primary ADT among those who did not receive definitive therapy (both P < .001). CONCLUSIONS Older age was significantly associated with a decreased likelihood of receiving definitive therapy and an increased likelihood of receiving primary ADT in this national cohort of patients with intermediate‐risk or high‐risk prostate cancer. Notably, approximately 40% to 45% of patients aged ≥80 years did not receive definitive therapy. These findings are alarming given the dismal outcomes of conservatively managed unfavorable‐risk prostate cancer. Cancer 2017;123:4832‐40. © 2017 American Cancer Society. In a national cohort of patients with intermediate‐risk or high‐risk prostate cancer, age is significantly associated with decreased receipt of definitive therapy. 40% to 45% of patients aged 80 years and older do not receive definitive therapy despite a high risk of cancer‐specific mortality from the conservative management of aggressive prostate cancer

Vitamin D supplementation and growth in urban Mongol school children: Results from two randomized clinical trials

<div><p>Background</p><p>Symptomatic vitamin D deficiency is associated with slowed growth in children. It is unknown whether vitamin D repletion in children with asymptomatic serum vitamin D deficiency can restore normal growth.</p><p>Objective</p><p>We tested the impact of vitamin D-supplementation on serum concentrations of 25-hydroxyvitamin D [25(OH)D] and short-term growth in Mongol children, with very low serum vitamin D levels in winter.</p><p>Design</p><p>We conducted two randomized, double-blind, placebo-controlled trials in urban school age children without clinical signs of rickets. The Supplementation Study was a 6-month intervention with an 800 IU vitamin D₃ supplement daily, compared with placebo, in 113 children aged 12–15 years. A second study, the Fortification Study, was a 7-week intervention with 710 ml of whole milk fortified with 300 IU vitamin D₃ daily, compared with unfortified milk, in 235 children aged 9–11 years.</p><p>Results</p><p>At winter baseline, children had low vitamin D levels, with a mean (±SD) serum 25-hydroxyvitamin D [25(OH)D] concentration of 7.3 (±3.9) ng/ml in the Supplementation Study and 7.5 (±3.8) ng/ml in the Fortification Study. The serum levels increased in both vitamin D groups—by 19.8 (±5.1) ng/ml in the Supplementation Study, and 19.7 (±6.1) ng/ml in the Fortification Study. Multivariable analysis showed a 0.9 (±0.3 SE) cm greater increase in height in the vitamin-D treated children, compared to placebo treated children, in the 6-month Supplementation Study (p = 0.003). Although the children in the 7-week Fortification Study intervention arm grew 0.2 (±0.1) cm more, on average, than placebo children this difference was not statistically significant (p = 0.2). There were no significant effects of vitamin D supplements on differences in changes in weight or body mass index in either trial. For the Fortification Study, girls gained more weight than boys while taking vitamin D 3 (p-value for interaction = 0.03), but sex was not an effect modifier of the relationship between vitamin D3 and change in either height or BMI in either trial.</p><p>Conclusions</p><p>Correcting vitamin D deficiency in children with very low serum vitamin D levels using 800 IU of vitamin D3 daily for six months increased growth, at least in the short-term, whereas, in a shorter trial of 300 IU of D fortified milk daily for 7 weeks did not.</p></div

Change in vitamin D and growth characteristics by study and intervention arm.

<p>Change in vitamin D and growth characteristics by study and intervention arm.</p

Participant flow (Supplementation Study).

<p>Participant flow (Supplementation Study).</p

Baseline characteristics of participants by study and intervention arm.

<p>Baseline characteristics of participants by study and intervention arm.</p

Change in height by quartile of vitamin D at follow-up by study.

<p>Change in height by quartile of vitamin D at follow-up by study.</p

Impact of percent positive biopsy cores on cancer-specific mortality for patients with high-risk prostate cancer

•The impact of positive biopsy cores (PBC) in high-risk prostate cancer is unclear.•We examined ≥50% PBC and prostate cancer-specific mortality (PCSM).•≥50% PBC was prognostic of a 2-fold risk of PCSM in a cohort of high-risk patients. A high percent positive biopsy cores (PBC), typically dichotomized at ≥50% is prognostic of worse cancer-specific outcomes for patients with low- and intermediate-risk prostate cancer (CaP). The clinical significance of ≥50% PBC for patients with high-risk disease is poorly understood. We examined the association between ≥50% PBC, compared to <50% PBC, and prostate cancer-specific mortality (PCSM) for patients with high-risk disease. We identified 7,569 men from the Surveillance, Epidemiology, and End Results program who were diagnosed with high-risk CaP (Gleason score of 8–10, prostate-specific antigen >20 ng/mL, or cT3-T4 stage) in 2010–2011 and had 6 to 24 cores sampled at biopsy. Multivariable Fine and Gray competing risks regression was utilized to examine the association between ≥50% PBC and PCSM. Median follow-up was 3.8 years. 56.2% of patients (4,253) had ≥50% PBC. On competing risks regression, ≥50% PBC was associated with a significantly higher risk of PCSM compared to <50% PBC (adjusted hazard ratio [AHR] 2.00, 95% confidence interval [CI] 1.48–2.70, P < 0.001). On subgroup analyses, ≥50% PBC was associated with a significantly higher risk of PCSM only for cT1–T2 disease (AHR 2.23, 95% CI 1.62–3.07) but not cT3–T4 disease (AHR 0.83, 95% CI 0.39–1.76), with a significant interaction (Pinteraction = 0.016). No significant interactions by Gleason score, prostate-specific antigen level, use of definitive therapy, or number of biopsy cores sampled were observed. In this large cohort of patients with high-risk CaP, ≥50% PBC was independently associated with an approximately 2-fold increased risk of PCSM for patients with cT1–T2, but not cT3–T4, tumors. Percent PBC, which is a widely available clinical value, should be routinely used to risk stratify men with high-risk disease and identify patients whom may benefit from treatment intensification

Mean difference (standard error, SE) in growth parameter change between study arms.

<p>Mean difference (standard error, SE) in growth parameter change between study arms.</p

Low rates of androgen deprivation therapy use with salvage radiation therapy in patients with prostate cancer after radical prostatectomy

The RTOG 9601 and GETUG-AFU 16 randomized controlled trials demonstrated that the addition of androgen deprivation therapy (ADT) to salvage radiation therapy (SRT) improves progression-free and, for RTOG 9601, overall survival. We examined national trends in the use of ADT with SRT. Of the 484,009 patients in the National Cancer Database from 2004 to 2012 with localized or locally advanced prostate cancer treated with radical prostatectomy (RP), 4,200 men received SRT (≥6mo after surgery). We used Pearson’s chi-squared test to evaluate changes in ADT use, and multiple logistic regression to examine predictors of ADT use. Overall, 32.1% of SRT patients received ADT, which increased after initial results of RTOG 9601 showed an improvement in metastasis-free survival in 2010 (28.5% in 2008/2009 vs. 34.5% in 2011/2012, P = 0.006). Predictors of ADT use include presurgery prostate-specific antigen>20ng/ml vs.<10ng/ml (adjusted odds ratio [AOR] = 1.34, P = 0.002; 36.7% vs. 29.6%); positive vs. negative margins (AOR = 1.29, P = 0.001; 34.9% vs. 27.8%); Gleason 3+4 (AOR = 1.53; 21.3%), Gleason 4+3 (AOR = 2.40; 32.0%), or Gleason 8 to 10 (AOR = 4.49; 49.2%) vs. Gleason 2 to 6 (P≤0.005 for all; 13.2%); and pathologic T3a (AOR = 1.46; 30.9%), T3b (AOR = 2.50; 47.6%), or T4 (AOR = 4.14; 60.9%) vs. T2 (P<0.001 for all; 19.1%). Starting SRT 12 to 23.9 months (AOR = 0.69; 23.2%) or≥24 months (AOR = 0.25; 8.0%) after RP was associated with decreased odds of ADT use vs. starting SRT 6 to 8.9 months after RP (P≤0.002 for both; 35.0%). Although less than one-third of SRT patients from the study era received ADT, there is evidence that physicians and patients have begun slowly adopting this practice with the 2010 reporting of a decrease in the cumulative incidence of metastases with the addition of ADT to SRT. Given the newly reported survival benefit of RTOG 9601, additional work will be necessary to identify which patients benefit the most from the use of ADT with SRT to individualize treatment. •We studied trends in androgen deprivation therapy (ADT) use with salvage radiation.•From 2004 through 2012, 32.1% of salvage radiation patients received ADT.•ADT use rose to 6% with the 2010 reporting of a metastasis benefit by RTOG 9601.•Higher Gleason score, pT3–4 stage, and positive margins were predictors of ADT use