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Papers by Bruce Hollis

Purpose:Previous studies have suggested that higher circulating 25-hydroxyvitamin D [25(OH)D] lev... more Purpose:Previous studies have suggested that higher circulating 25-hydroxyvitamin D [25(OH)D] levels are associated with decreased colorectal cancer risk and improved survival. However, the influence of vitamin D status on disease progression and patient survival remains largely unknown for patients with advanced or metastatic colorectal cancer.Experimental Design:We prospectively collected blood samples in 1,041 patients with previously untreated advanced or metastatic colorectal cancer participating in a randomized phase III clinical trial of first-line chemotherapy plus biologic therapy. We examined the association of baseline plasma 25(OH)D levels with overall survival (OS) and progression-free survival (PFS). Cox proportional hazards models were used to calculate hazard ratios (HRs) and confidence intervals (CIs), adjusted for prognostic factors and confounders.Results:At study entry, 63% of patients were vitamin D deficient (<20 ng/mL) and 31% were vitamin D insufficient (20–<30 ng/mL). Higher 25(OH)D levels were associated with an improvement in OS and PFS (Ptrend = 0.0009 and 0.03, respectively). Compared with patients in the bottom quintile of 25(OH)D (≤10.8 ng/mL), those in the top quintile (≥24.1 ng/mL) had a multivariable-adjusted HR of 0.66 (95% CI, 0.53–0.83) for OS and 0.81 (95% CI, 0.66–1.00) for PFS. The improved survival associated with higher 25(OH)D levels was consistent across patient subgroups of prognostic patient and tumor characteristics.Conclusions:In this large cohort of patients with advanced or metastatic colorectal cancer, higher plasma 25(OH)D levels were associated with improved OS and PFS. Clinical trials assessing the benefit of vitamin D supplementation in patients with colorectal cancer are warranted.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclo... more AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Bruce W. Hollis, DiaSorin (C) Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None

Higher total 25-hydroxyvitamin D [25(OH)D] levels are associated with an improvement in survival ... more Higher total 25-hydroxyvitamin D [25(OH)D] levels are associated with an improvement in survival among colorectal cancer (CRC) patients, but the relationships between plasma vitamin D binding protein (VDBP), bioavailable or free 25(OH)D, and CRC survival remain unknown. In two prospective cohort studies, the Health Professionals Follow-Up Study and the Nurses’ Health Study, we examined the association between prediagnostic plasma levels of VDBP, bioavailable 25(OH)D, and free 25(OH)D and survival among 604 participants diagnosed with CRC between 1991 and 2011. Plasma 25(OH)D and VDBP were directly measured, while bioavailable and free 25(OH)D were calculated using a validated formula based on total 25(OH)D, VDBP, and albumin levels. Cox proportional hazards models were used to estimate hazard ratios (HRs) for overall and CRC-specific mortality, adjusted for other prognostic markers and potential confounders. During the follow-up, there were 279 deaths, 177 of which were due to CRC (63%). Higher VDBP levels were associated with a significant improvement in overall and CRC-specific survival (Ptrend=0.005 and 0.02, respectively). Compared to patients in the lowest quartile, those in the highest quartile of VDBP had a multivariable-adjusted HR of 0.61 (95% confidence interval [CI], 0.42-0.89) for overall mortality and 0.56 (95% CI, 0.35-0.92) for CRC-specific mortality. The results remained similar after further adjustment for total 25(OH)D levels. In contrast, no association with overall or CRC-specific mortality was observed for bioavailable or free 25(OH)D levels. In conclusion, higher prediagnostic plasma VDBP levels were associated with improved survival among CRC patients. The clinical utility of VDBP as a prognostic marker warrants further exploration, as well as research into underlying mechanisms of action. Citation Format: Chen Yuan, Mingyang Song, Brian M. Wolpin, Jeffrey A. Meyerhardt, Shuji Ogino, Bruce W. Hollis, Andrew T. Chan, Charles S. Fuchs, Kana Wu, Molin Wang, Stephanie A. Smith-Warner, Edward L. Giovannucci, Kimmie Ng. Prediagnostic circulating concentrations of vitamin D binding protein and survival among colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3297.

Supplementary Figure and Table

Clinical Cancer Research, Dec 13, 2019

Hypertension, Apr 1, 2013

Log Change of PTH (Month 3-Month 0) by Vitamin D Dose/day. Figure S2. Change in PTH (Month 3- Mon... more Log Change of PTH (Month 3-Month 0) by Vitamin D Dose/day. Figure S2. Change in PTH (Month 3- Month 0) by Vitamin D Dose/day. (PDF 201 kb)

Epidemiology, 2019

Journal of Clinical Oncology, 2011

Purpose Previous studies have suggested that higher plasma 25-hydroxyvitamin D3 [25(OH)D] levels ... more Purpose Previous studies have suggested that higher plasma 25-hydroxyvitamin D3 [25(OH)D] levels are associated with decreased colorectal cancer risk and improved survival, but the prevalence of vitamin D deficiency in advanced colorectal cancer and its influence on outcomes are unknown. Patients and Methods We prospectively measured plasma 25(OH)D levels in 515 patients with stage IV colorectal cancer participating in a randomized trial of chemotherapy. Vitamin D deficiency was defined as 25(OH)D lower than 20 ng/mL, insufficiency as 20 to 29 ng/mL, and sufficiency as ≥ 30 ng/mL. We examined the association between baseline 25(OH)D level and selected patient characteristics. Cox proportional hazards models were used to calculate hazard ratios (HR) for death, disease progression, and tumor response, adjusted for prognostic factors. Results Among 515 eligible patients, 50% of the study population was vitamin D deficient, and 82% were vitamin D insufficient. Plasma 25(OH)D levels were...

Journal of Clinical Oncology, Jun 1, 2022

Antioxidants, 2021

N-acetylcysteine (NAC) and vitamin D provide effective neuroprotection in animal models of severe... more N-acetylcysteine (NAC) and vitamin D provide effective neuroprotection in animal models of severe or inflammation-sensitized hypoxic ischemic encephalopathy (HIE). To translate these FDA-approved drugs to HIE neonates, we conducted an early phase, open-label trial of 10 days of NAC (25, 40 mg/kg q12h) + 1,25(OH)2D (calcitriol 0.05 mg/kg q12h, 0.03 mg/kg q24h), (NVD), for pharmacokinetic (PK) estimates during therapeutic hypothermia and normothermia. We paired PK samples with pharmacodynamic (PD) targets of plasma isoprostanoids, CNS glutathione (GSH) and total creatine (tCr) by serial MRS in basal ganglia (BG) before and after NVD infusion at five days. Infants had moderate (n = 14) or severe HIE (n = 16), funisitis (32%), and vitamin D deficiency (75%). NVD resulted in rapid, dose-responsive increases in CNS GSH and tCr that correlated positively with plasma [NAC], inversely with plasma isofurans, and was greater in infants with lower baseline [GSH] and [tCr], suggesting increases ...

eLife, 2022

The placenta plays an important role in how vitamin D is metabolized and supplied to the fetus.

For decades, vitamin D has been recognized only for its ability to correct skeletal abnormalities... more For decades, vitamin D has been recognized only for its ability to correct skeletal abnormalities. This point is made clear by recent recommendations by the Institute of Medicine (IOM). This organization has only recognized vitamin D to have a role in skeletal homeostasis and thus recommended a minimal amount, 400-600 IU/d (1). Part of the problem here is that vitamin D has long been thought to be a teratogenic substance and thus feared by the obstetrics community (2). However, these fears are no longer valid and vitamin D not only is not a teratogen, significant amounts are required during pregnancy to avert a wide range of problems including complications of birth, preeclampsia, gestational diabetes, neurodevelopment and asthma incidence in the newborn child (3-4). Surely more roles of vitamin D will be uncovered in the future in the area of autoimmune function involving type 1 diabetes and multiple sclerosis. How does vitamin D alter all these systems in utero ? Our resear...

Antioxidants, 2021

Therapeutic hypothermia does not improve outcomes in neonatal hypoxia ischemia (HI) complicated b... more Therapeutic hypothermia does not improve outcomes in neonatal hypoxia ischemia (HI) complicated by perinatal infection, due to well-described, pre-existing oxidative stress and neuroinflammation that shorten the therapeutic window. For effective neuroprotection post-injury, we must first define and then target CNS metabolomic changes immediately after endotoxin-sensitized HI (LPS-HI). We hypothesized that LPS-HI would acutely deplete reduced glutathione (GSH), indicating overwhelming oxidative stress in spite of hypothermia treatment in neonatal rats. Post-natal day 7 rats were randomized to sham ligation, or severe LPS-HI (0.5 mg/kg 4 h before right carotid artery ligation, 90 min 8% O2), followed by hypothermia alone or with N-acetylcysteine (25 mg/kg) and vitamin D (1,25(OH)2D3, 0.05 μg/kg) (NVD). We quantified in vivo CNS metabolites by serial 7T MR Spectroscopy before, immediately after LPS-HI, and after treatment, along with terminal plasma drug concentrations. GSH was signifi...

Current Developments in Nutrition, 2020

Objectives VitD status is important during pregnancy and lactation as maternal status is linked w... more Objectives VitD status is important during pregnancy and lactation as maternal status is linked with fetal and neonatal outcomes: Maternal vitD status during pregnancy predicts neonatal vitD status; similarly, maternal vitD status during lactation predicts infant vitD status as mother is the sole source of vitD to the unsupplemented lactating infant. The best indicator of vitD status is measurement of circulating 25(OH)D concentration; however, results may be delayed and add to health care costs. A prediction model taking into account certain factors would assist health care providers in identifying those individuals most at risk for vitD deficiency. OBJ: Develop and test a prediction model for vitD status that utilizes information readily available to any health care provider in the primary care setting. Methods Three existing datasets (2 pregnancy, n = 405; and 1 lactation, n = 451; total n = 856 women) were combined for development of this prediction model. Variables included in ...

Clinical Chemistry, 2000

Background: Measurement of circulating 25-hydroxyvitamin D [25(OH)D] is important in the manageme... more Background: Measurement of circulating 25-hydroxyvitamin D [25(OH)D] is important in the management of metabolic bone disease. The aim of this study was to compare two widely used methods for the quantification of circulating 25(OH)D with attention to their abilities to measure 25-hydroxylated ergocalciferol (vitamin D2) [25(OH)D2] and cholecalciferol (vitamin D3) [25(OH)D3]. Methods: We used two commercially available, Food and Drug Administration-approved, radioiodine (125I)-based RIA kits for the detection of 25(OH)D (DiaSorin, Stillwater, MN and IDS Ltd, Tyne and Wear, United Kingdom). These methods were tested for general assay performance, including antibody specificity. Results were compared with those of an HPLC-based direct ultraviolet detection method. Results: Within- and between-run CVs were ≤10%. Both methods quantitatively recovered 25(OH)D3 added to serum, but only the DiaSorin kit quantitatively recovered 25(OH)D2. The primary antibody in the IDS kit had unequal reac...

Background. Among the causative factors of obesity, a rather newly proposed theory is viral infec... more Background. Among the causative factors of obesity, a rather newly proposed theory is viral infections. The association of ADV-36 infection and obesity has been reported by some research groups in children. We hypothesized that the association between ADV-36 infection and adiposity may be mediated by sub-optimal vitamin D status of the host. To examine this hypothesis, we conducted a case control study on children and adolescents with normal weight, over weight and obesity. Methods. In total, 91 (normal weight: 33, overweight: 33, obese: 25) apparently healthy children aged 5-18 years were randomly selected from the registered population at National Food and Nutrition Surveillance Program (NFNS). The groups were matched based on age and sex. Anthropometric, biochemical and serological assessments were performed. Results. The amount of anti-ADV36-Ab increased whereas circulating concentrations of calcidiol decreased across BMI categories with higher amounts in normal weight than in o...

Current Developments in Nutrition, 2019

Objectives We have previously found that vitamin D supplementation may slow down epigenetic aging... more Objectives We have previously found that vitamin D supplementation may slow down epigenetic aging in young adults. Recently, new epigenetic clocks have been developed to estimate gestational age in newborn babies. We tested the hypothesis that vitamin D supplementation would slow down the epigenetic gestational aging. Methods A total of 92 participants (51% whites, 21% blacks, 28% Hispanics) were randomly selected from 450 pregnant women who were enrolled in a randomized controlled trial. Each mother was randomized to receive either 4000 IU/day vitamin D3 or placebo plus the standard prenatal vitamins containing 400 IU vitamin D3. Cord blood genome-wide methylation analyses were performed on the Illumina Infinium MethylationEPIC Beadchip. DNA methylation gestational age (DNAmGA) was calculated based on two methods developed by Knight and Bohlin. The effects of vitamin D3 supplementation on DNA methylation-based gestational age acceleration (∆DNAmGA) were estimated in linear regressi...

Nutrients, 2019

The objective of this investigation was to compare bioavailability between single oral dose Vitam... more The objective of this investigation was to compare bioavailability between single oral dose Vitamin D3 (vitD3) gummies vs. tablets in healthy adults. An initial crossover, randomized clinical trial involving healthy adults (n = 9) was conducted followed by a larger, confirmatory study (n = 31). Healthy participants aged 18–45 years with body mass index (BMI) 18–30 without anemia or vitD deficiency were randomized to receive 20,000 international units (IU) vitD3 as single dose gummies or tablets with serial samples obtained to measure plasma vitD3 at baseline, 3, 6, 10, 24, and 48 h followed by a 2-week washout period. The same participants then crossed over to receive 20,000 IU vitD3 in the form not previously given, with sampling at the same time points. Deidentified blood samples were analyzed for vitD3 concentration by liquid chromatography (LC)-mass spectroscopy. In Study 1, results suggested bioavailability was greater with gummies compared with tablets, (effect size 1.08 at 24...

Supplementary Figure and Table

Clinical Cancer Research, Dec 13, 2019

Hypertension, Apr 1, 2013

Epidemiology, 2019

Journal of Clinical Oncology, 2011

Journal of Clinical Oncology, Jun 1, 2022

Antioxidants, 2021

eLife, 2022

The placenta plays an important role in how vitamin D is metabolized and supplied to the fetus.

Antioxidants, 2021

Current Developments in Nutrition, 2020

Clinical Chemistry, 2000

Current Developments in Nutrition, 2019

Nutrients, 2019