Nilotinib as frontline and second-line therapy in chronic myeloid leukemia: open questions

Nilotinib is a second generation ABL tyrosine kinase inhibitor (TKI) that exerts major anti-leukemic effects in newly diagnosed patients with chronic myeloid leukemia (CML) as well as in most patients with imatinib-resistant CML. In freshly diagnosed patients, the anti-leukemic activity of nilotinib exceeds the efficacy of imatinib, and although long-term data for nilotinib are not available yet, the drug has recently been approved for firstline treatment of chronic phase CML in various countries. Still however, several questions concerning the optimal dose, follow-up parameters, long-term safety, and patient selection remain open. Likewise, it remains uncertain whether both Sokal low-risk and high-risk patients should receive nilotinib as frontline therapy in the future. Another question is whether nilotinib can completely eradicate CML in a subset of patients. Furthermore, it remains unclear whether and what comorbidity must be regarded as relative or absolute contra-indication for this TKI. To discuss these issues, the Austrian CML Working Group organized a series of meetings in 2010. In the current article, the outcomes from these discussions are summarized and presented together with recommendations for frontline use of TKIs in various groups of patients with CML. These recommendations should assist in daily practice as well as in the preparation and conduct of clinical trials.     

Antithymocyte globulin induction therapy improves survival in lung transplantation for cystic fibrosis

Cystic fibrosis (CF) is an inherited condition that leads to respiratory failure and is the third most common indication for adult bilateral lung transplantation (LuTX). In contrast to other lung diseases, the immune system of CF patients is up‐regulated and we therefore hypothesized that these patients would benefit from induction therapy. In the current study, we investigated the impact of antithymocyte globulin (ATG) induction therapy in CF patients after LuTX. One hundred and forty six patients who underwent LuTX for CF at our centre between January 1999 and December 2010 were included in the study and retrospectively analysed. They were divided into two groups according to the immunosuppressive protocol: group‐A (n = 103) with and group‐B (n = 43) without induction therapy on top of the basic calcineurin inhibitor based triple immunosuppression with mycophenolate mofetil and steroids. Perioperative survival was significantly better in the ATG group, a benefit sustained for the entire follow‐up. ATG induction resulted in a significantly lower incidence of acute rejections without an increase in infectious complications. Taken together, our results indicate that ATG induction therapy confers a significant survival benefit in CF patients undergoing LuTX and reduces rejection. We advocate the use of induction therapy in this patient cohort.     

Polypropylene meshes coated with a polysaccharide based bioadhesive for intra-abdominal mesh fixation in a rabbit model

Background

In this study, we evaluate a new bioadhesive for intra-abdominal onlay mesh fixation of a polypropylene–polyvinylchloride graft.

Methods

Three pieces of a commercially available polypropylene/polyvinylfluoride mesh, each 3 × 3 cm in size, and three pieces of the same mesh coated with a polysaccharide bioadhesive were fixated to the surface of the anterior abdominal wall of 30 New Zealand white rabbits. The fixation was performed either by using four transabdominal Prolene^® 4/0 sutures, four spiral tacks (Protack 5 mm Tyco), or cyanoacrylate glue (Glubran^® GEM, Viareggio, Italy). Each mesh position and the according kind of fixation were randomized before implantation. The animals were sacrificed 12 weeks postoperatively. After determining the extent of intra-abdominal adhesions, the meshes were excised en bloc with the anterior abdominal wall for tensile strength measurements and histological analysis.

Results

All meshes coated with the bioadhesive adhered to the intact peritoneum without extra fixation. Irrespective of the fixation technique coated meshes led to more and stronger adhesions. Mesh shrinkage by scarring was increased in coated meshes fixed with glue and low in uncoated meshes fixed with tacks. Testing the tensile strength, coated meshes fixed with transfascial sutures achieved the best results (16.14 ± 6.1 N), whereas coated meshes fixed with glue showed the lowest strength (10.39 ± 4.81 N). The foreign body reaction was considerably more distinctive using coated mesh. The mesh ingrowth was not influenced by this reaction.

Conclusions

All meshes coated with the new bioadhesive were self-adhesive in that way; they stayed in position when attached to the peritoneum. Although this may facilitate intra-operative mesh fixation, the bioadhesive displayed several disadvantages, such as stronger adhesions and an increased shrinkage of the implant. The tensile strength was not influenced by the use of the bioadhesive. At present, we see no major advantage for polysaccharide bioadhesive applied in this study.     

Plasma clots gelled by different amounts of calcium for stem cell delivery

Purpose

Freshly prepared autologous plasma clots may serve as a carrier matrix for expanded multipotent mesenchymal stromal cells (MSCs) or bone marrow cells. By varying the calcium concentration, plasma clots with different properties can be produced. The purpose of this in vitro study was to determine the optimal calcium concentrations for the clotting process, intra-clot cell viability, and clot lysis.

Methods

Different plasma clots were prepared by adding an equal volume of RPMI1640 (with or without MSCs) to citrate plasma (either containing platelets or platelet-free). Clotting was initiated by the addition of CaCl₂ (10 g/100 ml H₂O, 10 % solution). The final concentration of CaCl₂ ranged from 1 to 10 % by volume of plasma. Viability and distribution of the MSCs were analysed by calcein-AM/propidium iodide staining. MSC-embedded plasma clots were dissolved with trypsin (0.25 %), and recovered cells were further incubated for 1 week under cell culture conditions.

Results

The viability of MSCs embedded in clots formed by the addition of 1–8 % by volume CaCl2 was not affected by incubation of up to 1 week. In contrast, clots produced by higher volumes of CaCl₂ solutions (9–10 % by volume of plasma) showed decreased numbers of viable cells. Intra-clot cell proliferation was highest in clots produced by addition of 5 % CaCl₂ by plasma volume. Osteocalcin release was not influenced in platelet-free plasma but decreased in platelet-containing plasma. Morphological analysis of stained recovered MSCs revealed that lysis of the plasma clot did not affect cell morphology or subsequent spontaneous proliferation.

Conclusions

Clot formation and clot stability can be controlled by changing the concentration of CaCl₂ added to plasma. The addition of 5 % CaCl₂ produced a plasma clot with optimal results for stem cell delivery.     

Gaze direction affects linear self‐motion heading discrimination in humans

We investigated the effect of eye‐in‐head and head‐on‐trunk direction on heading discrimination. Participants were passively translated in darkness along linear trajectories in the horizontal plane deviating 2° or 5° to the right or left of straight‐ahead as defined by the subject's trunk. Participants had to report whether the experienced translation was to the right or left of the trunk straight‐ahead. In a first set of experiments, the head was centered on the trunk and fixation lights directed the eyes 16° either left or right. Although eye position was not correlated with the direction of translation, rightward reports were more frequent when looking right than when looking left, a shift of the point of subjective equivalence in the direction opposite to eye direction (two of the 38 participants showed the opposite effect). In a second experiment, subjects had to judge the same trunk‐referenced trajectories with head‐on‐trunk deviated 16° left. Comparison with the performance in the head‐centered paradigms showed an effect of the head in the same direction as the effect of eye eccentricity. These results can be qualitatively described by biases reflecting statistical regularities present in human behaviors such as the alignment of gaze and path. Given the known effects of gaze on auditory localization and perception of straight‐ahead, we also expect contributions from a general influence of gaze on the head‐to‐trunk reference frame transformations needed to bring motion‐related information from the head‐centered otoliths into a trunk‐referenced representation.