Neurofibromatosis type 1-associated plexiform neurofibromas of the neck: topography of lesions and surgical treatment data of 69 patients.

PURPOSE: Plexiform neurofibromas (PNF) are rare tumors arising from peripheral nerve sheath cells. PNF are a hallmark in patients with neurofibromatosis type 1 (NF1), a tumor predisposition syndrome. PNF often grow invasively and destructively, what may complicate surgical treatment. Data on frequency, location, and surgical procedures of patients with NF1-associated FPNF are scarce. This study provides treatment data of NF1 patients. METHODS: Localization and treatment data of 69 NF1 patients with neck PNF were analyzed. Frequency of lesions was recorded in coded colors on schematic neck drawings. RESULTS: The tumors showed no side preference, were located in the entire area under investigation, and did not respect anatomical units/dermatomes. However, the sternocleidomastoid region was particularly frequently affected. The mean number of surgical measures per patient was 1.33. Complications were extensive swelling, hematoma, and bleeding. Histological assessment usually confirmed the clinical assessment of neoplasm. However, histologic differentiation of PNST reveals differences in between tumors that have been unified in clinical assessment as PNF. CONCLUSION: The color-coded, schematic overview of the frequency distribution of surgical neck interventions in NF1 patients with PNF proved a useful tool to gain assessment of preferred treatment needs. The imaging procedure may be suitable for controlling the external aspect of natural tumor development (growth, effects of aging) in the same way as the documentation of the post-surgical course. Treatment plans for patients with these tumors should consider that repeated interventions may be necessary to achieve a longer-term stable result.

Unified risk analysis in radiation therapy.

PURPOSE: The increasing complexity of new treatment methods as well as the Information Technology (IT) infrastructure within radiotherapy require new methods for risk analysis. This work presents a methodology on how to model the treatment process of radiotherapy in different levels. This subdivision makes it possible to perform workflow-specific risk analysis and to assess the impact of IT risks on the overall treatment workflow. METHODS: A Unified Modeling Language (UML) activity diagram is used to model the workflows. The subdivision of the workflows into different levels is done with the help of swim lanes. The model created in this way is exported in an xml-compatible format and stored in a database with the help of a Python program. RESULTS: Based on an existing risk analysis, the workflows CT Appointment, Glioblastoma Multiforme, and Deep Inspiration Breath Hold (DIBH) were modeled in detail. Part of the analysis are automatically generated workflow-specific risk matrices including risks of medical devices incorporated into a specific workflow. In addition, SQL queries allow to quickly retrieve e.g., the details of the medical device network installed in a department. CONCLUSION: Activity diagrams of UML can be used to model workflows in radiotherapy. Through this, a connection between the different levels of the entire workflow can be established and workflow-specific risk analysis is possible.

Implementation of an antimicrobial stewardship programme in three regional hospitals in the south-east of Liberia: lessons learned.

Background: Antimicrobial stewardship (AMS) programmes can improve the use of antimicrobial agents. However, there is limited experience in the implementation of such programmes in low- and middle-income countries (LMICs). Objectives: To assess the effect of AMS measures in south-east Liberia on the quality of antimicrobial use in three regional hospitals. Methods: A bundle of three measures (local treatment guideline, training and regular AMS ward rounds) was implemented and quality indicators of antimicrobial use (i.e. correct compounds, dosage and duration) were assessed in a case series before and after AMS ward rounds. Primary endpoints were (i) adherence to the local treatment guideline; (ii) completeness of the microbiological diagnostics (according to the treatment guideline); and (iii) clinical outcome. The secondary endpoint was reduction in ceftriaxone use. Results: The majority of patients had skin and soft tissue infections (n = 108) followed by surgical site infections (n = 72), pneumonia (n = 64), urinary tract infection (n = 48) and meningitis (n = 18). After the AMS ward rounds, adherence to the local guideline improved for the selection of antimicrobial agents (from 34.5% to 61.0%, P < 0.0005), dosage (from 15.2% to 36.5%, P < 0.0005) and duration (from 13.2% to 31.0%, P < 0.0005). In total, 79.7% of patients (247/310) had samples sent for microbiological analysis. Overall, 92.3% of patients improved on Day 3 (286/310). The proportion of patients receiving ceftriaxone was significantly reduced after the AMS ward rounds from 51.3% to 14.2% (P < 0.0005). Conclusions: AMS measures can improve the quality of antimicrobial use in LMICs. However, long-term engagement is necessary to make AMS programmes in LMICs sustainable.

Risk analysis for radiotherapy at the Universitätsklinikum Erlangen.

PURPOSE: Risk analysis is required by various laws and regulations in Germany and has an impact on each department of a large clinic. We provide an overview of the relevant laws and regulations in Germany and present the technical and organizational experience of introducing risk analysis in the Department of Radiation Oncology at the Universitätsklinikum Erlangen. METHODS: Risk analysis was performed with an in-house developed extension of our intranet platform and ticketing system. Risks were classified according to occurrence and severity, each on a 5-level scale resulting into a risk matrix. An interdisciplinary team of six experienced members formed the core meeting weekly. RESULTS: A total of 38 risks and 50 measures have been identified in 41 1h-meetings corresponding to approx. 260 working hours. Risk was distributed 8/20/13 to the categories critical (n=8), monitoring (n=20), and conditionally acceptable (n=13). Risk analysis has been evaluated before and after introducing measures. CONCLUSION: The risk analysis method introduced has been successfully used in routine operations for over a year. Risk analysis takes time and effort. However, because experts from different disciplines meet each other every week, the overall workflow of the radiation oncology department can be improved efficiently and continuously.

Dosimetry, Optimization and FMEA of Total Skin Electron Irradiation (TSEI).

PURPOSE: Total Skin Electron Irradiation (TSEI) is a method for treating malignant cutaneous T-cell lymphomas. This work aims to implement and optimize the total skin technique established at Strahlenklinik Erlangen, Germany on two new linear accelerators and to quantify the risks using failure mode and effects (FMEA) analysis. MATERIAL AND METHODS: TSEI is performed at a VersaHD accelerator (Elekta, Stockholm) with 6MeV in the "high dose rate mode" HDRE and a nominal field size of 40×40cm2. To reach the entire skin surface, the patients perform 6 different body positions at a distance of 330cm behind an acrylic scatter plate, with two overlapping irradiation fields being radiated at 2 gantry angles per position. The irradiation technique was commissioned according to the recommendation of AAPM report 23. With the help of a reference profile at 270°, 2 gantry angles were calculated, which in total resulted in an optimal dose distribution. This was metrologically verified with ion-chamber measurements in the patient's longitudinal axis. The influence of the shape of the acrylic scatter plate and the distance between the acrylic scatter plate and patient was determined by measurements. The dose homogeneity was verified using an anthropomorphic disc phantom equipped with GafChromic films. The workflows and failure modes of the total skin technique were described in a process map and subsequently quantified with a FMEA analysis. RESULTS: An optimal dose distribution is achieved at a distance of SSD=330cm, using the gantry angles 289° and 251°. The previously used segmented acrylic scatter plate was replaced by a flat plate (200×120×0.5cm3), which is placed at a distance of 50cm in front of the patient. The densitometric evaluation of the GafChromic films in the anthropomorphic disc phantom revealed an expected dose distribution of 3Gy at a depth of up to 1.5cm below the skin surface, with a homogeneity of ±10% over the phantom's longitudinal axis. By FMEA a maximum risk priority number of 30 was determined. CONCLUSION: Based on the calculations and measurements performed on the new accelerators as well as the risk analysis, we concluded that total skin therapy can be implemented clinically.

Monoubiquitination of ancient ubiquitous protein 1 promotes lipid droplet clustering.

Lipid droplets, the intracellular storage organelles for neutral lipids, exist in a wide range of sizes and of morphologically distinct organization, from loosely dispersed lipid droplets to tightly packed lipid droplet clusters. We show that the lipid droplet protein AUP1 induces cluster formation. A fraction of AUP1 is monoubiquitinated at various lysine residues. This process depends on its internal CUE domain, which is a known ubiquitin-binding domain. AUP1 with a deleted or point mutagenized CUE domain, as well as a lysine-free mutant, are not ubiquitinated and do not induce lipid droplet clustering. When such ubiquitination deficient mutants are fused to ubiquitin, clustering is restored. AUP1 mutants with defective droplet targeting fail to induce clustering. Also, another lipid droplet protein, NSDHL, with a fused ubiquitin does not induce clustering. The data indicate that monoubiquitinated AUP1 on the lipid droplet surface specifically induces clustering, and suggest a homophilic interaction with a second AUP1 molecule or a heterophilic interaction with another ubiquitin-binding protein.

Tracing fatty acid metabolism by click chemistry.

Fatty acids are abundant constituents of all biological systems, and their metabolism is important for normal function at all levels of an organism. Aberrations in fatty acid metabolism are associated with pathological states and have become a focus of current research, particularly due to the interest in metabolic overload diseases. Here we present a click-chemistry-based method that allows tracing of fatty acid metabolism in virtually any biological system. It combines high sensitivity with excellent linearity and fast sample turnover. Since it is free of radioactivity, it can be combined with any other modern analysis technology and can be used in high-throughput applications. Using the new method, we provide for the first time an analysis of cellular fatty metabolism with high time resolution and a comprehensive comparison of utilization of a broad spectrum of fatty acids in hepatoma and adipose cell lines.

Ancient ubiquitous protein 1 (AUP1) localizes to lipid droplets and binds the E2 ubiquitin conjugase G2 (Ube2g2) via its G2 binding region.

Lipid droplets (LDs), the major intracellular storage sites for neutral lipids, consist of a neutral lipid core surrounded by a phospholipid monolayer membrane. In addition to their function in lipid storage, LDs participate in lipid biosynthesis and recently were implicated in proteasomal protein degradation and autophagy. To identify components of the protein degradation machinery on LDs, we studied several candidates identified in previous LD proteome analyses. Here, we demonstrate that the highly conserved and broadly expressed ancient ubiquitous protein 1 (AUP1) localizes to LDs, where it integrates into the LD surface in a monotopic fashion with both termini facing the cytosol. AUP1 contains a C-terminal domain with strong homology to a domain known as G2BR, which binds E2 ubiquitin conjugases. We show that AUP1, by means of its G2BR domain, binds to Ube2g2. This binding is abolished by deletion or mutation of the G2BR domain, although the LD localization of AUP1 is not affected. The presence of the AUP1-Ube2g2 complex at LDs provides a direct molecular link between LDs and the cellular ubiquitination machinery.

SLOW MOTION is required for within-plant auxin homeostasis and normal timing of lateral organ initiation at the shoot meristem in Arabidopsis.

The regular arrangement of leaves and flowers around a plant's stem is a fascinating expression of biological pattern formation. Based on current models, the spacing of lateral shoot organs is determined by transient local auxin maxima generated by polar auxin transport, with existing primordia draining auxin from their vicinity to restrict organ formation close by. It is unclear whether this mechanism encodes not only spatial information but also temporal information about the plastochron (i.e., the interval between the formation of successive primordia). Here, we identify the Arabidopsis thaliana F-box protein SLOW MOTION (SLOMO) as being required for a normal plastochron. SLOMO interacts genetically with components of polar auxin transport, and mutant shoot apices contain less free auxin. However, this reduced auxin level at the shoot apex is not due to increased polar auxin transport down the stem, suggesting that it results from reduced synthesis. Independently reducing the free auxin level in plants causes a similar lengthening of the plastochron as seen in slomo mutants, suggesting that the reduced auxin level in slomo mutant shoot apices delays the establishment of the next auxin maximum. SLOMO acts independently of other plastochron regulators, such as ALTERED MERISTEM PROGRAM1 or KLUH/CYP78A5. We propose that SLOMO contributes to auxin homeostasis in the shoot meristem, thus ensuring a normal rate of the formation of auxin maxima and organ initiation.