Clinical Nutrition

Statin Use and 25-Hydroxyvitamin D Blood Level Response to Vitamin D Treatment of Older Adults.

Bischoff-Ferrari HA1,2, Fischer K1,2, Orav EJ3, Dawson-Hughes B4, Meyer U1,2, Chocano-Bedoya PO1,2, Meyer OW1,2, Ernst R1,2, Schietzel S1,2, Eberli F5, Staehelin HB6, Freystätter G1,2, Roas S1, Theiler R1,2, Egli A1,2, Wilson NM1,2.

1. Department of Geriatrics and Aging Research, University Hospital Zurich, Zurich, Switzerland.

2. Centre on Aging and Mobility, University of Zurich and City Hospital Waid, Zurich, Switzerland.

3. Department of Biostatistics, School of Public Health, Harvard University, Boston, Massachusetts.

4. U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts.

5. Department of Cardiology, Triemli City Hospital, Zurich, Switzerland.

6. Department of Geriatrics, University of Basel, Basel, Switzerland.

Objectives

To determine whether statin use alters response of 25-hydroxyvitamin D (25(OH)D) level to vitamin D treatment.

Design

Pooled analysis.

Setting

Three double-blind randomized controlled trials that tested different doses of vitamin D.

Participants

Participants of three trials (N = 646; mean age 76.3 ± 8.4, 65% female).

Measurements

In all three trials, 25(OH)D status and statin use were assessed repeatedly over time (baseline, 6 and 12 months). Repeated-measures analysis was used to compare 25(OH)D response to vitamin D treatment at baseline and 6 and 12 months of statin users and nonusers, controlling for age, sex, body mass index, Charlson Comorbidity Index, vitamin D dose, trial, and season.

Results

At baseline, 17.5% were statin users, and 65% were vitamin D deficient (25(OH)D < 20 ng/mL). Baseline 25(OH)D levels did not differ significantly between groups at baseline (18.8 for statin users, 17.2 ng/mL for nonusers, P = .07), but according to the longitudinal analyses, the total increase over 12 months in 25(OH)D concentration was significantly lower in statin users (13.1 ng/L) than nonusers (15.9 ng/mL; 21.4% difference; P = .009).

Conclusion

Of persons aged 60 and older at high risk of vitamin D deficiency, statin users had a 21.4% smaller increase in 25(OH)D serum concentrations over time than nonusers, independent of vitamin D dose and other covariates.

J Am Geriatr Soc. 2017 Feb 27. doi: 10.1111/jgs.14784. [Epub ahead of print]

http://onlinelibrary.wiley.com/doi/10.1111/jgs.14784/abstract;jsessionid=5F6CEF2F9C66112DD3D63D73042DB09A.f02t02

Md. PhD. Patricia Chocano. Ex miembro del GII. 

Factores de crecimiento y Cancer

Oncogenic growth factor signaling mediating tumor escape from cellular immunity.

Concha-Benavente F1, Ferris RL2.

1.Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA; University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.

2. Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA; University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA. Electronic address: ferrisrl@upmc.edu.

Unrestrained growth factor signals can promote carcinogenesis, as well as other hallmarks of cancer such as immune evasion. Our understanding of the function and complex regulation of HER family of receptors has led to the development of targeted therapeutic agents that suppress tumor growth. However, these receptors also mediate escape from recognition by the host immune system. We discuss how HER family of oncogenic receptors downregulate tumor antigen presentation and upregulate suppressive membrane-bound or soluble secreted inhibitory molecules that ultimately lead to impaired cellular immunity mediated by cytotoxic T lymphocyte (CTL) recognition. Implementing this knowledge into new therapeutic strategies to enhance tumor immunogenicity may restore effector cell mediated immune clearance of tumors and clinical efficacy of tumor-targeted immunotherapy against HER receptor overexpression.

Curr Opin Immunol. 2017 Feb 13;45:52-59. doi: 10.1016/j.coi.2017.01.004. [Epub ahead of print]

http://www.sciencedirect.com/science/article/pii/S0952791517300092

Md. PhD. Fernando Concha. Ex-miembro del GII

CD137 y Cancer de Cabeza y Cuello

CD137 Stimulation Enhances Cetuximab-Induced Natural Killer: Dendritic Cell Priming of Antitumor T-Cell Immunity in Patients with Head and Neck Cancer

Srivastava RM1, Trivedi S1, Concha-Benavente F2, Gibson SP1, Reeder C1, Ferrone S3, Ferris RL4,2,5.

1. Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania.

2. Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania.

3. Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

4. Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania. ferrisrl@upmc.edu.

5. Cancer Immunology Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.

Abstract

PURPOSE:

Cetuximab, an EGFR-specific antibody (mAb), modestly improves clinical outcome in patients with head and neck cancer (HNC). Cetuximab mediates natural killer (NK) cell:dendritic cell (DC) cross-talk by cross-linking FcγRIIIa, which is important for inducing antitumor cellular immunity. Cetuximab-activated NK cells upregulate the costimulatory receptor CD137 (4-1BB), which, when triggered by agonistic mAb urelumab, might enhance NK-cell functions, to promote T-cell-based immunity.

EXPERIMENTAL DESIGN:

CD137 expression on tumor-infiltrating lymphocytes was evaluated in a prospective cetuximab neoadjuvant trial, and CD137 stimulation was evaluated in a phase Ib trial, in combining agonistic urelumab with cetuximab. Flow cytometry and cytokine release assays using NK cells and DC were used in vitro, testing the addition of urelumab to cetuximab-activated NK, DC, and cross presentation to T cells.

RESULTS:

CD137 agonist mAb urelumab enhanced cetuximab-activated NK-cell survival, DC maturation, and tumor antigen cross-presentation. Urelumab boosted DC maturation markers, CD86 and HLA DR, and antigen-processing machinery (APM) components TAP1/2, leading to increased tumor antigen cross-presentation. In neoadjuvant cetuximab-treated patients with HNC, upregulation of CD137 by intratumoral, cetuximab-activated NK cells correlated with FcγRIIIa V/F polymorphism and predicted clinical response. Moreover, immune biomarker modulation was observed in an open label, phase Ib clinical trial, of patients with HNC treated with cetuximab plus urelumab.

CONCLUSIONS:

These results suggest a beneficial effect of combination immunotherapy using cetuximab and CD137 agonist in HNC. Clin Cancer Res; 23(3); 707-16. ©2016 AACR.

Clin Cancer Res. 2017 Feb 1;23(3):707-716. doi: 10.1158/1078-0432.CCR-16-0879. Epub 2016 Aug 5.

http://clincancerres.aacrjournals.org/content/23/3/707.long

Md. PhD. Fernando Concha. Ex-miembro del GII