Multiple foreign body granulomas after mastectomy with intraoperative application of tissue adhesive vs. surgical drainage - sonographic finding.

PURPOSE: The use of tissue adhesive instead of a drain following mastectomy was a point of interest for many breast surgeons. Postoperative formation of multiple unusual sonographic lesions was observed in patients that underwent mastectomy with TissuGlu. The aim of this study was to describe the sonographic features of these lesions and, when possible, to examine them histologically. MATERIALS AND METHODS: This study includes 98 patients, 49 underwent mastectomy with the application of TissuGlu and 49 with drain insertion. Unusual postoperative sonographic findings were thoroughly described. A histological examination was carried out according to the guideline recommendations. RESULTS: Unusual sonographic findings were detected in 87.8% of patients in the TissuGlu group and in only 4% of the patients in the drain group. These lesions were detectable between 6 and 59 months postoperatively. 47 breasts of the TissuGlu group were classified as category 3, while only 2 breasts as category 4. Lesions were on average 7.5 mm in diameter, echogenic or isoechoic with posterior shadowing, an irregular and ill circumscribed marginal contour, and a horizontal axis. All histologically examined lesions (n=29) were benign. Granulomatous tissue was histologically proven in 63% of those lesions (n=17), while residual adhesive material could be detected in 18.5% of lesions (n=5). CONCLUSION: The use of TissuGlu adhesive after mastectomy may cause the formation of unusual palpable granulomas, with or without residual adhesive materials. Sonographic description of lesions will help physicians to differentiate between granulomas and local relapse.

A Single Domain Shark Antibody Targeting the Transferrin Receptor 1 Delivers a TrkB Agonist Antibody to the Brain and Provides Full Neuroprotection in a Mouse Model of Parkinson's Disease.

Single domain shark antibodies that bind to the transferrin receptor 1 (TfR1) on brain endothelial cells have been used to shuttle antibodies and other cargos across the blood brain barrier (BBB) to the brain. For these studies the TXB4 brain shuttle was fused to a TrkB neurotrophin receptor agonist antibody. The TXB4-TrkB fusion retained potent agonist activity at its cognate receptor and after systemic administration showed a 12-fold increase in brain levels over the unmodified antibody. Only the TXB4-TrkB antibody fusion was detected within the brain and localized to TrkB positive cells in the cortex and tyrosine hydroxylase (TH) positive dopaminergic neurons in the substantia nigra pars compacta (SNc), where it was associated with activated ERK1/2 signaling. When tested in the 6-hydroxydopamine (6-OHDA) mouse model of Parkinson's disease (PD), TXB4-TrkB, but not the unmodified antibody, completely prevented the 6-OHDA induced death of TH positive neurons in the SNc. In conclusion, the fusion of the TXB4 brain shuttle allows a TrkB agonist antibody to reach neuroprotective concentrations in the brain parenchyma following systemic administration.

Myostatin as a therapeutic target in Amyotrophic lateral sclerosis.

Amyotrophic Lateral Sclerosis is a devastating neurological disease that is inevitably fatal after 3-5years duration. Treatment options are minimal and as such new therapeutic modalities are required. In this review, we discuss the role of the myostatin pathway as a modulator of skeletal muscle mass and therapeutic approaches using biological based therapies. Both monoclonal antibodies to myostatin and a soluble receptor decoy to its high affinity receptor have been used in clinical trials of neuromuscular diseases and while there have been efficacy signals with the latter approach there have also been safety issues. Our approach is to target the high affinity receptor-binding site on myostatin and to develop a next generation set of therapeutic reagents built on a novel protein scaffold. This is the natural single domain VNAR found in sharks which is extremely versatile and has the ability to develop products with superior properties compared to existing therapeutics.

Missing steps in the STAIR case: a Translational Medicine perspective on the development of NXY-059 for treatment of acute ischemic stroke.

The continued failure in approving new drugs for treatment of acute stroke has been recently set back by the failure of the NXY-059 (Stroke-Acute Ischemic NXY Treatment (SAINT) II) trial. The disappointment was heightened by the latter study being viewed as a most promising compound for stroke drug development program based on the preclinical data. Since the SAINT I/II development program included many of the STAIR (Stroke Therapy Academic Industry Round table) guidelines, yet have still failed to achieve the expected efficacy, there is a clear need to continue and analyze the path forward for stroke drug discovery. To this end, this review calls for a consortium approach including academia, government (FDA/NIH), and pharmaceutical industry partnerships to define this path. It is also imperative that more attention is given to the evolving discipline of Translational Medicine. A key issue in this respect is the need to devote more attention to the characteristics of the drug candidate nature-target interaction, and its relationship to pharmacodynamic treatment end points. It is equally important that efforts are spent to prove that phenotypic outcomes are linked to the purported mechanism of action of the compound. Development of technologies that allows a better assessment of these parameters, especially in in vivo models are paramount. Finally, rational patient selection and new outcome scales tailored in an adaptive design model must be evaluated.