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Girschikofsky M.,Ctr. of Hematology An Stem Cell Transplantation | Arico M.,Azienda Ospedaliero Universitaria A. Meyer | Castillo D.,Hospital de la Santa Creu i Sant Pau | Chu A.,Imperial College London | And 12 more authors.
Orphanet Journal of Rare Diseases

Langerhans Cell Histiocytosis (LCH) is an orphan disease of clonal dendritic cells which may affect any organ of the body. Most of the knowledge about the diagnosis and therapy is based on pedriatic studies. Adult LCH patients are often evaluated by physicians who focus on only the most obviously affected organ without sufficient evaluation of other systems, resulting in patients being underdiagnosed and/or incompletely staged. Furthermore they may be treated with pediatric-based therapies which are less effective and sometimes more toxic for adults. The published literature on adult LCH cases lacks a comprehensive discussion on the differences between pediatric and adult patients and there are no recommendations for evaluation and comparative therapies. In order to fill this void, a number of experts in this field cooperated to develop the first recommendations for management of adult patients with LCH. Key questions were selected according to the clinical relevance focusing on diagnostic work up, therapy, and follow up. Based on the available literature up to December 2012, recommendations were established, drafts were commented by the entire group, and redrafted by the executive editor. The quality of evidence of the recommendations is predominantly attributed to the level of expert opinion. Final agreement was by consensus. © 2013 Girschikofsky et al.; licensee BioMed Central Ltd. Source

Toulis K.A.,424 General Military Hospital | Anastasilakis A.D.,424 General Military Hospital | Polyzos S.A.,Aristotle University of Thessaloniki | Makras P.,251 Hellenic Air Force and VA General Hospital

Targeting osteoblast may be the means of effectively improving both bone quality and mass, thus offering an intriguing alternative in the treatment of osteoporosis. Aside from injectable parathyroid hormone (PTH) and its novel preparations, PTH-related peptide (PTHrP), calcilytics, beta-adrenergic receptors, enhancement of Wnt signaling (mainly via sclerostin and Dickkopf-1 neutralization), regulation of low-density lipoprotein receptor-related protein (LPR) 5/osteoblast axis, activin, IGF-1, and bone morphogenic proteins (BMPs) are reviewed for their basic rationale and evidence of bone anabolic potential. Sclerostin neutralizing antibody, teriparatide transdermal patch, and PTHrP (1-36) are currently at an advanced stage of research. Safety and tissue specificity are the prerequisites in the development of a novel treatment, especially when addressing a chronic condition such as osteoporosis. Source

Anastasilakis A.D.,424 General Military Hospital | Polyzos S.A.,Aristotle University of Thessaloniki | Gkiomisi A.,424 General Military Hospital | Bisbinas I.,424 General Military Hospital | And 2 more authors.
Journal of Clinical Endocrinology and Metabolism

Context: Decreased bone formation due to a coupling effect limits bone mass increases after antiresorptive treatment. Objective: The purpose of this study was to compare the effects of 2 potent antiresorptive agents with different mechanism of action on serum levels of Wnt antagonists, sclerostin and dickkopf-1 (Dkk-1). Design: This was an interventional, parallel assignment, open-label, randomized clinical trial. Setting: The study was conducted at the outpatient clinics for metabolic bone diseases of 424 General Military Hospital, Thessaloniki, Greece. Patients and Interventions: Naive postmenopausal women with low bone mass were assigned to zoledronic acid infusion (n = 46) or denosumab injection (n = 46). One woman in the zoledronic acid group was lost to follow-up. Main Outcome Measures: Serum sclerostin and Dkk-1 levels were the main outcomes. Secondary measurements were serum osteoprotegerin, receptor activator of nuclear factor κB ligand, procollagen type 1 N-terminal propeptide, and C-terminal cross-linking telopeptide of type 1 collagen. Results: Serum sclerostin levels significantly decreased in the zoledronic acid (P < .001) but increased in the denosumab group (P = .003). Dkk-1 levels significantly decreased in the zoledronic acid group (P = .006) but did not change in the denosumab group (P = .402). Serum osteoprotegerin remained essentially unchanged in either group, where as receptor activator of nuclear factorκBliganddecreased in the zoledronic acid group (P=.004) but increased in the denosumab group (P=.037). Bone markers (procollagentype1N- terminal propeptide, C-terminal cross-linking telopeptide oftype1collagen,and total serum alkaline phosphatase) decreased in both groups (all P < .001). Conclusions: Although they both decrease bone resorption, zoledronic acid and denosumab exert opposite effects on Wnt signaling: the former decreases serum levels of both sclerostin and Dkk-1, whereas the latter increases sclerostin and does not affect Dkk-1. Copyright © 2013 by The Endocrine Society. Source

Anastasilakis A.D.,424 General Military Hospital | Polyzos S.A.,Aristotle University of Thessaloniki | Makras P.,251 Hellenic Air Force and VA General Hospital | Sakellariou G.T.,424 General Military Hospital | And 7 more authors.

An acute phase response (APR) is frequently observed in patients treated with intravenous (i.v.) zoledronate (ZOL). We aimed to define clinical and laboratory parameters that may predict ZOL-induced APR in women with low bone mass. Fifty-one postmenopausal women with low bone mass were given a single i.v. infusion of ZOL 5. mg. APR was clinically defined by the visual analog pain scale (VAS) for the musculoskeletal symptoms and body temperature. White blood cell count (WBC), leucocyte subpopulations, C-reactive protein (CRP), parathyroid hormone (PTH), 25-hydroxyvitamin D [25(OH)D], interleukins (IL)-1b and -6, tumor necrosis factor (TNF)α and interferon (IFN)γ were measured before and 48 h following the infusion. Subsequently, patients were divided into those experiencing APR (APR+) or not (APR-). WBC, granulocytes, CRP, IL-1b and IL-6 were significantly increased, whereas lymphocytes, eosinophils, calcium, phosphate and 25(OH)D decreased 48. h after ZOL infusion. Twenty-eight of the 51 patients (54.9%) experienced an APR. APR+ patients were younger and had higher baseline lymphocytes compared to APR- patients. There was no difference (p= 0.405) in the development of APR between treatment-naive patients (19/32, 59.4%) and patients previously treated with another oral nitrogen-containing bisphosphonate (9/19, 47.4%). In conclusion, our data suggest that pre-treatment higher lymphocyte number increases the risk of APR while previous treatment with another nitrogen-containing bisphosphonate does not significantly reduce the risk. Serum 25(OH)D concentrations decrease significantly after the infusion, possibly as part of the inflammatory response to ZOL. © 2012 Elsevier Inc. Source

Anastasilakis A.D.,424 General Military Hospital | Polyzos S.A.,Aristotle University of Thessaloniki | Delaroudis S.,424 General Military Hospital | Bisbinas I.,424 General Military Hospital | And 5 more authors.
Clinical Endocrinology

Objective Patients treated with intravenous zoledronate frequently experience an acute phase reaction (APR) characterized by flu-like symptoms and increased levels of inflammatory cytokines. We aimed to define the role of various cytokines/adipocytokines in zoledronate-induced APR and develop a prognostic model for its prediction. Patients and Measurements Fifty-one postmenopausal women with low bone mass were subjected to zoledronate intravenous infusion. Patients were divided into those who experienced APR (APR+) and those who did not (APR-). APR was clinically defined by body temperature and the visual analogue pain scale for musculoskeletal symptoms. White blood cell count, leucocytic subpopulations, C-reactive protein, interleukin-6, tumour necrosis factor-alpha, visfatin, resistin and leptin were measured before and 48 h following the infusion. The quantitative insulin sensitivity check index (QUICKI) and homoeostasis model of assessment - insulin resistance (HOMA-IR) were calculated to assess insulin sensitivity and resistance, respectively. Results (APR+) patients were younger and had lower baseline visfatin and higher baseline lymphocytes and phosphate compared with APR- patients. QUICKI decreased and HOMA-IR increased in APR+ patients while remained unchanged in APR- patients. In binary logistic regression analysis, a model containing previous bisphosphonate treatment, age, body mass index, lymphocytes and visfatin, which predicted zoledronate-induced APR with 82·1% sensitivity and 73·9% specificity, was selected. In this model, lymphocytes (P = 0·010) and visfatin (P = 0·029) at baseline could independently predict APR. Conclusions Zoledronate-induced APR is associated with serum increases of pro-inflammatory cytokines and an increase of insulin resistance. Patients with higher lymphocytes and lower visfatin levels at baseline are at higher risk for APR. © 2012 Blackwell Publishing Ltd. Source

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