Value of infliximab (Remicade®) in patients with low-risk myelodysplastic syndrome: final results of a randomized phase II trial (EORTC trial 06023) of the EORTC Leukemia Group

Tumor-necrosis factor alpha activity has been correlated to ineffective erythropoiesis in lower risk myelodysplastic syndromes. Infliximab (Remicade^®) is an anti-tumor necrosis factor alpha chimeric antibody that is used in the treatment of patients with rheumatoid arthritis or Crohn’s disease. Forty-six patients with myelodysplastic syndromes and a relatively low risk of developing acute leukemia were included in a randomized phase II study assessing the therapeutic activity of two dosages of infliximab administration (3 mg/kg vs. 5 mg/kg). The primary end point was the response rate. Responses were observed in 3 of 22 patients (13.1%) randomized to the 3 mg/kg arm, versus 0 of 21 patients randomized in the 5 mg/kg arm. According to the statistical design of the current study, neither of the two infliximab dose schedules tested showed sufficient activity as a single agent in this cohort of unselected patients with early myelodysplastic syndrome.     

Cytokine secretion and NK cell activity in human ADAM17 deficiency

Genetic deficiencies provide insights into gene function in humans. Here we describe a patient with a very rare genetic deficiency of ADAM17. We show that the patient''s PBMCs had impaired cytokine secretion in response to LPS stimulation, correlating with the clinical picture of severe bacteremia from which the patient suffered. ADAM17 was shown to cleave CD16, a major NK killer receptor. Functional analysis of patient''s NK cells demonstrated that his NK cells express normal levels of activating receptors and maintain high surface levels of CD16 following mAb stimulation. Activation of individual NK cell receptors showed that the patient''s NK cells are more potent when activated directly by CD16, albeit no difference was observed in Antibody Depedent Cytotoxicity (ADCC) assays. Our data suggest that ADAM17 inhibitors currently considered for clinical use to boost CD16 activity should be cautiously applied, as they might have severe side effects resulting from impaired cytokine secretion.     

Selective inhibition of EGFR downstream signaling reverses the irradiation-enhanced migration of HNSCC cells

Irradiation, which is one of the standard therapies used to treat squamous cell carcinoma of the head and neck (HNSCC), has been linked to enhanced tumor migration in carcinomas. In this study, we demonstrated that irradiation induced the phosphorylation of AKT, p38 MAPK and ERK. The combined activation of these pathways caused inactivation of GSK3β kinase, resulting in enhanced tumor cell migration. Here, we describe that the exclusive and specific inhibition of just one of the aforementioned key signaling molecules is sufficient to restore GSK3β activity and to reduce radiation-induced migration in HNSCC. These data indicate that pharmacological inhibition of pathways targeting GSK3β could decrease radiation-induced cell migration in HNSCC and thus potentially reduce metastasis and locoregional recurrence in patients.     

Lipopolysaccharide-binding protein: A valuable biomarker in the differentiation between periprosthetic joint infection and aseptic loosening?

Purpose

The pre-operative differentiation between periprosthetic joint infection (PJI) and aseptic loosening after total hip (THA) or knee (TKA) arthroplasty is essential for successful therapy and relies in part on the use of molecular markers. The objective of this study was to assess serum levels of lipopolysaccharide-binding protein (LBP) as a diagnostic tool for PJI and to compare its accuracy with standard tests.

Methods

One hundred and twenty patients presenting with a painful TKA or TKA with indication for surgical revision were included in this prospective, controlled, clinical trial at a single centre. Pre-operative blood and serum samples were collected and analysed for white blood cell (WBC) count, C-reactive protein (CRP) and LBP. The definite diagnosis of periprosthetic joint infection was determined on the basis of clinical, microbiological and histopathological examination.

Results

LBP showed significantly higher values in PJI compared with aseptic loosening (p?p?7 ng/ml. In combination with CRP, the positive predictive value for PJI was at 0.67; negative predictive value with both negative was at 0.77.

Discussion

Patients with PJI have elevated serum levels of LBP when compared with patients with aseptic loosening. The use of LBP in serum appears not to be a more accurate marker than CRP level in serum for detecting PJI. On the basis of these results, we cannot recommend the sole use of LBP for differentiating PJI and aseptic loosening following THA and TKA.     

A 13-year analysis from Switzerland of non-fatal sledging (sledding or tobogganing) injuries

Introduction

Winter sports have evolved from an upper class activity to a mass industry. Especially sledging regained popularity at the start of this century, with more and more winter sports resorts offering sledge runs. This study investigated the rates of sledging injuries over the last 13 years and analysed injury patterns specific for certain age groups, enabling us to make suggestions for preventive measures.

Methods

We present a retrospective analysis of prospectively collected data. From 1996/1997 to 2008/2009, all patients involved in sledging injuries were recorded upon admission to a Level III trauma centre. Injuries were classified into body regions according to the Abbreviated Injury Scale (AIS). The Injury Severity Score (ISS) was calculated. Patients were stratified into 7 age groups. Associations between age and injured body region were tested using the chi-squared test. The slope of the linear regression with 95% confidence intervals was calculated for the proportion of patients with different injured body regions and winter season.

Results

4956 winter sports patients were recorded. 263 patients (5%) sustained sledging injuries. Sledging injury patients had a median age of 22 years (interquartile range [IQR] 14–38 years) and a median ISS of 4 (IQR 1–4). 136 (51.7%) were male. Injuries (AIS ≥ 2) were most frequent to the lower extremities (n = 91, 51.7% of all AIS ≥ 2 injuries), followed by the upper extremities (n = 48, 27.3%), the head (n = 17, 9.7%), the spine (n = 7, 4.0%). AIS ≥ 2 injuries to different body regions varied from season to season, with no significant trends (p > 0.19). However, the number of patients admitted with AIS ≥ 2 injuries increased significantly over the seasons analysed (p = 0.031), as did the number of patients with any kind of sledging injury (p = 0.004). Mild head injuries were most frequent in the youngest age group (1–10 years old). Injuries to the lower extremities were more often seen in the age groups from 21 to 60 years (p < 0.001).

Conclusion

Mild head trauma was mainly found in very young sledgers, and injuries to the lower extremities were more frequent in adults. In accordance with the current literature, we suggest that sledging should be performed in designated, obstacle-free areas that are specially prepared, and that children should always be supervised by adults. The effect of routine use of helmets and other protective devices needs further evaluation, but it seems evident that these should be obligatory on official runs.     

Laser-induced drug release for local tumor control—a proof of concept

Background

The systemic palliative chemotherapy of locally extended gastrointestinal and hepatobiliary tumors is associated with a considerable burden for the patient. The aim of this project was to develop a new drug release system to improve the local stent therapy in these patients as a proof of concept study. For this purpose, polymer filaments were modified with drug-loaded polymer microgels that allow selective release of the active substance by photochemical triggering using laser radiation. Integrated into a stent system, the better local tumor control could thus contribute to a significant increase in the quality of life of patients.

Methods

A standard mammalian cell line and two carcinoma cell lines were established. By Fluorescence activated cell sorting (FACS), the cytotoxicity of the different materials was determined in vitro before and after drug loading with the chemotherapeutic agent 5-Fluorouracil (5-FU). For this purpose, the locally applied 5-FU concentration was previously determined by Bromdesoxyuridin assay. 5-FU dimer was synthesized by photo-induced dimerization of 5-FU in the presence of benzophenone in methanol. The chemical structure of 5-FU dimer was confirmed with Hydrogen-1 nuclear magnetic resonance and Fluorine-19 nuclear magnetic resonance. 5-FU dimer is nonsoluble in water and can be easily incorporated in polymer microgels modified with hydrophobic binding domains (cyclodextrin). After laser irradiation, 5-FU dimer decomposes and 5-FU can be released from microgels. Finally, the measurements were repeated after this laser-induced drug release.

Results

In FACS analysis, neither the microgels nor the microgel cumarin complexes showed a significant difference in comparison with the negative control with H₂O and therefore no toxic effect on the cell lines. After loading with the 5-FU dimer, there was no significant cell death (contrary to the pure 5-FU monomer, which dose had been previously tested as highly toxic). After laser-induced dissociation back to monomer and the associated drug release, FACS analysis showed cytotoxicity.

Conclusions

It was possible to develop 5-FU dimerloaded microgels, which show no cytotoxic effect on cell lines before laser irradiation. After dissociation back to 5-FU monomer by selective photochemical triggering using laser irradiation, the active substance was released. Thus, a new drug release system has been created and tested in vitro. For further development, integration into a stent system and for in vivo follow-up evaluation more studies need to be conducted.     

The neural underpinnings of an optimal exploitation of social information under uncertainty

Social information influences decision-making through an integration of information derived from individual experience with that derived from observing the actions of others. This raises the question as to which extent one should utilize social information. One strategy is to make use of uncertainty estimates, leading to a copy-when-uncertain strategy that weights information from individual and social sources based on their respective reliabilities. Here, we investigate this integration process by extending models of Bayes optimal integration of sensory information to a social decision context. We then use a key parameter of our behavioral model in conjunction with functional magnetic resonance imaging to identify the neural substrate that is specifically linked to the fidelity of this integration process. We show that individuals behave near Bayes optimal when integrating two distinct sources of social information but systematically deviate from Bayes optimal choice when integrating individual with social information. This systematic behavioral deviation from optimality is linked to activity of left inferior frontal gyrus. Thus, an ability to optimally exploit social information depends on processes that overcome an egocentric bias, and this regulatory role involves the left inferior prefrontal cortex. The findings provide a mechanistic explanation for observations wherein individuals neglect the benefits from exploiting social information.