Measurement setup for Nernst and Seebeck effect at high temperatures and magnetic fields tested on elemental bismuth and full-Heusler compounds.

In this work, a measurement setup to study the Seebeck and Nernst effect at high temperatures and high magnetic fields is introduced and discussed. The measurement system allows for simultaneous measurements of both thermoelectric effects up to 700 K and magnetic fields up to 12 T. Based on theoretical concepts, measurement equations are derived that counteract constant spurious offset voltages and, therefore, inhibit systematic errors in the measurement setup. The functionality is demonstrated on polycrystalline samples of elemental bismuth as well as various full-Heusler materials, exhibiting an anomalous Nernst effect. In all samples, the measured Seebeck and Nernst coefficients align excellently with the reported values. This allows future research to substantially extend the measured temperature and field intervals, commonly limited to temperatures below room temperature. For the first time, the thermoelectric and thermomagnetic properties of these materials are reported up to temperatures of 560 K.

2-Desaza-annomontine (C81) impedes angiogenesis through reduced VEGFR2 expression derived from inhibition of CDC2-like kinases.

Angiogenesis is a crucial process in the progression of various pathologies, like solid tumors, wet age-related macular degeneration, and chronic inflammation. Current anti-angiogenic treatments still have major drawbacks like limited efficacy in diseases that also rely on inflammation. Therefore, new anti-angiogenic approaches are sorely needed, and simultaneous inhibition of angiogenesis and inflammation is desirable. Here, we show that 2-desaza-annomontine (C81), a derivative of the plant alkaloid annomontine previously shown to inhibit endothelial inflammation, impedes angiogenesis by inhibiting CDC2-like kinases (CLKs) and WNT/ß-catenin signaling. C81 reduced choroidal neovascularization in a laser-induced murine in vivo model, inhibited sprouting from vascular endothelial growth factor A (VEGF-A)-activated murine aortic rings ex vivo, and reduced angiogenesis-related activities of endothelial cells in multiple functional assays. This was largely phenocopied by CLK inhibitors and knockdowns, but not by inhibitors of the other known targets of C81. Mechanistically, CLK inhibition reduced VEGF receptor 2 (VEGFR2) mRNA and protein expression as well as downstream signaling. This was partly caused by a reduction of WNT/ß-catenin pathway activity, as activating the pathway induced, while ß-catenin knockdown impeded VEGFR2 expression. Surprisingly, alternative splicing of VEGFR2 was not detected. In summary, C81 and other CLK inhibitors could be promising compounds in the treatment of diseases that depend on angiogenesis and inflammation due to their impairment of both processes.

Enhanced RBE of Particle Radiation Depends on Beam Size in the Micrometer Range.

High-linear energy transfer (LET) radiation, such as heavy ions is associated with a higher relative biological effectiveness (RBE) than low-LET radiation, such as photons. Irradiation with low- and high-LET particles differ in the interaction with the cellular matter and therefore in the spatial dose distribution. When a single high-LET particle interacts with matter, it results in doses of up to thousands of gray (Gy) locally concentrated around the ion trajectory, whereas the mean dose averaged over the target, such as a cell nucleus is only in the range of a Gy. DNA damage therefore accumulates in this small volume. In contrast, up to hundreds of low-LET particle hits are required to achieve the same mean dose, resulting in a quasi-homogeneous damage distribution throughout the cell nucleus. In this study, we investigated the dependence of RBE from different spatial dose depositions using different focused beam spot sizes of proton radiation with respect to the induction of chromosome aberrations and clonogenic cell survival. Human-hamster hybrid (AL) as well as Chinese hamster ovary cells (CHO-K1) were irradiated with focused low LET protons of 20 MeV (LET = 2.6 keV/µm) beam energy with a mean dose of 1.7 Gy in a quadratic matrix pattern with point spacing of 5.4 × 5.4 µm2 and 117 protons per matrix point at the ion microbeam SNAKE using different beam spot sizes between 0.8 µm and 2.8 µm (full width at half maximum). The dose-response curves of X-ray reference radiation were used to determine the RBE after a 1.7 Gy dose of radiation. The RBE for the induction of dicentric chromosomes and cell inactivation was increased after irradiation with the smallest beam spot diameter (0.8 µm for chromosome aberration experiments and 1.0 µm for cell survival experiments) compared to homogeneous proton radiation but was still below the RBE of a corresponding high LET single ion hit. By increasing the spot size to 1.6-1.8 µm, the RBE decreased but was still higher than for homogeneously distributed protons. By further increasing the spot size to 2.7-2.8 µm, the RBE was no longer different from the homogeneous radiation. Our experiments demonstrate that varying spot size of low-LET radiation gradually modifies the RBE. This underlines that a substantial fraction of enhanced RBE originates from inhomogeneous energy concentrations on the µm scale (mean intertrack distances of low-LET particles below 0.1 µm) and quantifies the link between such energy concentration and RBE. The missing fraction of RBE enhancement when comparing with high-LET ions is attributed to the high inner track energy deposition on the nanometer scale. The results are compared with model results of PARTRAC and LEM for chromosomal aberration and cell survival, respectively, which suggest mechanistic interpretations of the observed radiation effects.

Heat and shear stability of particle stabilised foams for application in gluten-free bread.

Bread forms an integral part of the daily diet in many cultures worldwide. At the same time, a significant number of people try to avoid wheat-based products for either health reasons or due to personal preferences. The absence of a protein network in gluten free bread affects its structure, taste, texture and shelf-life. This paper suggests a technological solution to this issue that uses a pre-foamed mass of gluten free raw materials which is mixed with the bread's ingredients, then kneaded and baked to form a high quality gluten free bread. To survive the high shear stresses during kneading and temperature increase during baking, the foam requires exceptional stability. This stability was achieved through particle stabilisation of the bubble interfaces. Both of the tested foams (with and without particles) exhibited thermal stability up to 80 °C. However, resistance to shear stresses was higher in the particle stabilised foams. Of all the tested particles, linseed press cake and banana powder led to the best results. In conclusion, particle stabilised foams seem very well suited to applications in gluten free baked goods. Further application potential is seen for vegan foamed desserts.

Abiotic factors influencing soil microbial activity in the northern Antarctic Peninsula region.

Microorganisms play a key role in the carbon (C) cycle through soil organic matter (SOM). The rate of SOM mineralization, the influence of abiotic factors on this rate and the potential behaviour of SOM are of particular interest in the northern Antarctic Peninsula and offshore islands. This is one of the most rapidly warming regions on Earth with numerous ice-free areas, some with abundant wildlife and with the greatest known soil organic carbon (SOC) storage in Antarctica. The latter implies extended Antarctic summer conditions promote increased terrestrial plant growth and soil microbial activity (SMA). SMA, determined by respirometry, is a measure of ecosystem function, and depends on microclimatic conditions and soil environmental properties. SMA and the effect of abiotic variables have been analysed in locations with different soil types, on Cierva Point (Antarctic Peninsula), Deception Island and Fildes Peninsula (King George Island). Soil microbial biomass carbon (SMBC) ranged from 5.66 to 196.6 mg SMBC kg-1and basal respiration (BR) from 2.86 to 160.67 mg CO2 kg-1 d-1. SMBC and BR values were higher in Cierva Point, followed by Fildes Peninsula and Deception Island, showing the same trend of SOM abundance. Except for Cierva Point, low nitrogen, phosphorus and C concentrations were observed. SMBC/total organic carbon (TOC) levels indicated that SOC was recalcitrant and SOM content was closely related to the extent of vegetation cover observed in situ. High metabolic quotient values obtained at Cierva Point and Deception Island (median values 7.27 and 6.53 mg C-CO2 g SMBC-1 h-1) and low SMBC/TOC in Cierva Point suggest a poor efficiency of the microbial populations in the consumption of the SOC. High SMBC/TOC values obtained in Deception Island indicates that SMBC may influence SOM stabilization. Mineralization rates were very low (negligible values to 1.44%) and sites with the lowest values had the highest SOM.

The inguinal region revisited: the surgical point of view : An anatomical-surgical mapping and sonographic approach regarding postoperative chronic groin pain following open hernia repair.

PURPOSE: Inguinodynia or chronic post-herniorrhaphy pain, defined as pain lasting longer than 3 months after open inguinal hernia repair, has become the most important complication after inguinal surgery and therefore compromises the patient´s quality of life. A major reason for inguinodynia might be the lack of neuroanatomical knowledge and suboptimal "management" of the nerves during surgery. METHODS: We present a detailed neuroanatomic mapping of the inguinal region by dissection including the most important surgical landmarks with all nerves confirmed by immunohistochemistry, ultrasound guided visualization of the iliohypogastric, ilio-inguinal, and genital branch of the genitofemoral nerve, and a practical (preoperative) algorithm for clinical management. RESULTS: Surgically and ultrasonographically relevant structures ("landmarks") in open hernia repair are the anterior-superior iliac spine, pubic tubercle, Camper´s fascia (superficial layer of the superficial abdominal fascia), External oblique aponeurosis, Internal oblique muscle, Transversus abdominis muscle, superficial inguinal ring, external spermatic fascia, cremasteric fascia with cremaster muscle fibers, internal spermatic fascia, cremasteric vein (=external spermatic vein = "blue line"), ductus deferens, pampiniform plexus, inguinal ligament and the inferior epigastric vessels. CONCLUSION: A detailed understanding of inguinal anatomy is an indispensable basic requirement for all surgeons to perform inguinal ultrasonography as well as open inguinal hernia repair, avoiding complications, especially postoperative inguinodynia.

Responses to genotoxicity in mouse testicular germ cells and epididymal spermatozoa are affected by increased age.

The increased number of cell divisions undergone by spermatogonia of older fathers cannot fully account for the observed increase in germline genetic damage. Studies have shown that the mechanisms induced in germ cells in response to oxidative damage varies with age, that DNA repair efficiency declines, and both sperm DNA damage and spontaneous mutations increase. However, it is not known whether the altered response with age is a cause, or consequence, of an age-associated change in cell susceptibility to genetic damage. Following a single 150 mg/kg dose of cyclophosphamide (CP), young (8-weeks old) and aged (17-month old) male mice were examined 24 h later for induced genetic damage in epididymal spermatozoa using the alkaline comet and sperm chromatin stability assays. Apoptosis among testicular cells was examined on tissue cross-sections using the TUNEL assay. Sperm showed no significant increase in DNA strand breaks with age (detected by the comet assay) and no change in sperm chromatin stability (detected by the SCSA assay). Following CP treatment, there was no effect on DNA-strand breakage but sperm chromatin instability was significantly higher. Furthermore, it was also significantly elevated in old treated, compared with young treated, animals suggesting that increased age affects the sensitivity of epididymal sperm to chromatin damage. There was no difference in apoptosis in testicular germ cells from either young or old control animals, while CP administration resulted in a significant increase in apoptosis among young animals but not old animals. Following genotoxin exposure, an increase in chromatin instability in the spermatozoa of old animals and a decrease in the ability of their testicular germ cells undergo apoptosis suggests an age-related decrease in genome protection mechanisms. Since those germ cells are only transiently present in the testis, it is likely that this age-related deterioration originates in the spermatogonial stem cells. The findings are also evidence that the safety evaluation of reproductive genotoxins should consider young and old individuals separately.

MODELING STUDIES ON DICENTRICS INDUCTION AFTER SUB-MICROMETER FOCUSED ION BEAM GRID IRRADIATION.

The biophysical simulation tool PARTRAC contains modules for DNA damage response representing non-homologous end joining of DNA double-strand breaks (DSB) and the formation of chromosomal aberrations. Individual DNA ends from the induced DSB are followed regarding both their enzymatic processing and spatial mobility, as is needed for chromosome aberrations to arise via ligating broken ends from different chromosomes. In particular, by tracking the genomic locations of the ligated fragments and the positions of centromeres, the induction of dicentrics can be modeled. In recent experiments, the impact of spatial clustering of DNA damage on dicentric yields has been assessed in AL human-hamster hybrid cells: Defined numbers of 20 MeV protons (linear energy transfer, LET 2.6 keV/µm), 45 MeV Li ions (60 keV/µm) and 55 MeV C ions (310 keV/µm) focused to sub-µm spot sizes were applied with the ion microbeam SNAKE in diverse grid modes, keeping the absorbed dose constant. The impact of the µm-scaled spatial distribution of DSB (focusing effect) has thus been separated from nm-scaled DSB complexity (LET effect). The data provide a unique benchmark for the model calculations. Model and parameter refinements are described that enabled the simulations to largely reproduce both the LET-dependence and the focusing effect as well as the usual biphasic rejoining kinetics. The predictive power of the refined model has been benchmarked against dicentric yields for photon irradiation.

Observation of Rydberg Blockade Induced by a Single Ion.

We study the long-range interaction of a single ion with a highly excited ultracold Rydberg atom and report on the direct observation of an ion-induced Rydberg excitation blockade mediated over tens of micrometer distances. Our hybrid ion-atom system is directly produced from an ultracold atomic ensemble via near-threshold photoionization of a single Rydberg excitation, employing a two-photon scheme that is specifically suited for generating a very low-energy ion. The ion's motion is precisely controlled by small electric fields, which allows us to analyze the blockade mechanism for a range of principal quantum numbers. Finally, we explore the capability of the ion as a high-sensitivity, single-atom-based electric field sensor. The observed ion-Rydberg-atom interaction is of current interest for entanglement generation or studies of ultracold chemistry in hybrid ion-atom systems.

Overcoming resistance in a BRAF V600E-mutant adenocarcinoma of the lung.

We report on a patient with an adenocarcinoma of the lung harbouring a BRAF V600E mutation who benefited from combination therapy with dabrafenib-trametinib after developing resistance to vemurafenib. To our knowledge, our report shows, for the first time, that combination therapy with dabrafenib-trametinib can overcome vemurafenib resistance in a BRAF V600E-mutated adenocarcinoma of the lung.

Evaluation of radiation-related invasion in primary patient-derived glioma cells and validation with established cell lines: impact of different radiation qualities with differing LET.

PURPOSE: Glioblastoma multiforme (GBM) is the most common primary brain tumor and has a very poor overall prognosis. Multimodal treatment is still inefficient and one main reason is the invasive nature of GBM cells, enabling the tumor cells to escape from the treatment area causing tumor progression. This experimental study describes the effect of low- and high-LET irradiation on the invasion of primary GBM cells with a validation in established cell systems. METHODS: Seven patient derived primary GBM as well as three established cell lines (LN229, LN18 and U87) were used in this study. Invasion was investigated using Matrigel® coated transwell chambers. Irradiation was performed with low- (X-ray) and high-LET (alpha particles) radiation. The colony formation assay was chosen to determine the corresponding alpha particle dose equivalent to the X-ray dose. RESULTS: 4 Gy X-ray irradiation increased the invasive potential of six patient derived GBM cells as well as two of the established lines. In contrast, alpha particle irradiation with an equivalent dose of 1.3 Gy did not show any effect on the invasive behavior. The findings were validated with established cell lines. CONCLUSION: Our results show that in contrast to low-LET irradiation high-LET irradiation does not enhance the invasion of established and primary glioblastoma cell lines. We therefore suggest that high-LET irradiation could become an alternative treatment option. To fully exploit the benefits of high-LET irradiation concerning the invasion of GBM further molecular studies should be performed.

Rydberg Molecules for Ion-Atom Scattering in the Ultracold Regime.

We propose a novel experimental method to extend the investigation of ion-atom collisions from the so far studied cold, essentially classical regime to the ultracold, quantum regime. The key aspect of this method is the use of Rydberg molecules to initialize the ultracold ion-atom scattering event. We exemplify the proposed method with the lithium ion-atom system, for which we present simulations of how the initial Rydberg molecule wave function, freed by photoionization, evolves in the presence of the ion-atom scattering potential. We predict bounds for the ion-atom scattering length from ab initio calculations of the interaction potential. We demonstrate that, in the predicted bounds, the scattering length can be experimentally determined from the velocity of the scattered wave packet in the case of ^{6}Li^{+}-^{6}Li and from the molecular ion fraction in the case of ^{7}Li^{+}-^{7}Li. The proposed method to utilize Rydberg molecules for ultracold ion-atom scattering, here particularized for the lithium ion-atom system, is readily applicable to other ion-atom systems as well.

Local application of a gentamicin-loaded thermo-responsive hydrogel allows for fracture healing upon clearance of a high Staphylococcus aureus load in a rabbit model.

Antibiotic-loaded biomaterials (ALBs) have emerged as a potential useful adjunctive antimicrobial measure for the prevention of infection in open fracture care. A biodegradable thermo-responsive poly(N-isopropylacrylamide) grafted hyaluronic acid (HApN) hydrogel loaded with gentamicin has recently been shown to prevent implant-related infection in a rabbit osteosynthesis model. The primary aim of this study was to determine the influence of this HApN hydrogel on bone healing at an early stage (4 weeks). A rabbit humeral osteotomy model with plating osteosynthesis was used to compare fracture healing in rabbits receiving the hydrogel as compared with control animals. The secondary aim was to observe fracture healing in groups treated with and without antibiotic-loaded hydrogel in the presence of bacterial contamination. In all groups, outcome measures were mechanical stability and histological score, with additional quantitative bacteriology in the inoculated groups. Application of the HApN hydrogel in non-inoculated rabbits did not significantly influence humeral stiffness or histological scores for fracture healing in comparison to controls. In the inoculated groups, animals receiving the bacterial inoculum without hydrogel were culture-positive at euthanasia and found to display lower humeral stiffness values and higher histopathological scores for bacterial presence in comparison with equivalents receiving the gentamicin-loaded HApN hydrogel, which were also infection-free. In summary, our data showed that HApN was an effective antibiotic carrier that did not affect fracture healing. This data supported its suitability for application in fracture care. Addition of osteopromotive compounds could provide further support for accelerating fracture healing in addition to successful infection prophylaxis.

New insights in the relative radiobiological effectiveness of proton irradiation.

BACKGROUND: Proton radiotherapy is a form of charged particle therapy that is preferentially applied for the treatment of tumors positioned near to critical structures due to their physical characteristics, showing an inverted depth-dose profile. The sparing of normal tissue has additional advantages in the treatment of pediatric patients, in whom the risk of secondary cancers and late morbidity is significantly higher. Up to date, a fixed relative biological effectiveness (RBE) of 1.1 is commonly implemented in treatment planning systems with protons in order to correct the physical dose. This value of 1.1 comes from averaging the results of numerous in vitro experiments, mostly conducted in the middle of the spread-out Bragg peak, where RBE is relatively constant. However, the use of a constant RBE value disregards the experimental evidence which clearly demonstrates complex RBE dependency on dose, cell- or tissue type, linear energy transfer and biological endpoints. In recent years, several in vitro studies indicate variations in RBE of protons which translate to an uncertainty in the biological effective dose delivery to the patient. Particularly for regions surrounding the Bragg peak, the more localized pattern of energy deposition leads to more complex DNA lesions. These RBE variations of protons bring the validity of using a constant RBE into question. MAIN BODY: This review analyzes how RBE depends on the dose, different biological endpoints and physical properties. Further, this review gives an overview of the new insights based on findings made during the last years investigating the variation of RBE with depth in the spread out Bragg peak and the underlying differences in radiation response on the molecular and cellular levels between proton and photon irradiation. Research groups such as the Klinische Forschergruppe Schwerionentherapie funded by the German Research Foundation (DFG, KFO 214) have included work on this topic and the present manuscript highlights parts of the preclinical work and summarizes the research activities in this context. SHORT CONCLUSION: In summary, there is an urgent need for more coordinated in vitro and in vivo experiments that concentrate on a realistic dose range of in clinically relevant tissues like lung or spinal cord.

Intensify production, transform biomass to energy and novel goods and protect soils in Europe-A vision how to mobilize marginal lands.

The rapid increase of the world population constantly demands more food production from agricultural soils. This causes conflicts, since at the same time strong interest arises on novel bio-based products from agriculture, and new perspectives for rural landscapes with their valuable ecosystem services. Agriculture is in transition to fulfill these demands. In many countries, conventional farming, influenced by post-war food requirements, has largely been transformed into integrated and sustainable farming. However, since it is estimated that agricultural production systems will have to produce food for a global population that might amount to 9.1 billion by 2050 and over 10 billion by the end of the century, we will require an even smarter use of the available land, including fallow and derelict sites. One of the biggest challenges is to reverse non-sustainable management and land degradation. Innovative technologies and principles have to be applied to characterize marginal lands, explore options for remediation and re-establish productivity. With view to the heterogeneity of agricultural lands, it is more than logical to apply specific crop management and production practices according to soil conditions. Cross-fertilizing with conservation agriculture, such a novel approach will provide (1) increased resource use efficiency by producing more with less (ensuring food security), (2) improved product quality, (3) ameliorated nutritional status in food and feed products, (4) increased sustainability, (5) product traceability and (6) minimized negative environmental impacts notably on biodiversity and ecological functions. A sustainable strategy for future agriculture should concentrate on production of food and fodder, before utilizing bulk fractions for emerging bio-based products and convert residual stage products to compost, biochar and bioenergy. The present position paper discusses recent developments to indicate how to unlock the potentials of marginal land.

Endoscopic anterior component separation: a novel technical approach.

PURPOSE: Open anterior release of the external oblique fascia to enable midline closure of large abdominal wall defects is associated with relevant morbidity due to extensive subcutaneous dissection. Using endoscopic techniques, wound complications can be minimized. However, identification of the correct entry point (e.g. for balloon trocar insertion) can be challenging especially in adipose patients. We therefore present a technical modification facilitating the entire procedure. METHODS: A novel technique for endoscopic anterior component separation using a trocar system allowing blunt and sharp dissection under direct vision is described. This brief communication also contains our initial experience and learning curve with this novel approach. RESULTS: Endoscopic release of the external oblique fascia was successfully performed 29 times in a total of 15 patients. Body mass index accounted for 30.8 kg/m2 (median; range 21.6-42.5). Transverse width of midline defect accounted for 7 cm (median; range 4-12). Subsequent hernia repair was successfully done using sublay mesh reinforcement (n = 13) or a laparoscopic intraperitoneal onlay mesh procedure (n = 2) with midline closure in all cases. One hematoma was seen at site of release managed conservatively. CONCLUSIONS: Using a trocar system allowing blunt and sharp dissection under direct vision may be a viable option for the endoscopic anterior component separation.

A large animal model for a failed two-stage revision of intramedullary nail-related infection by methicillin-resistant Staphylococcus aureus.

The treatment of chronic orthopaedic device-associated infection (ODRI) often requires multiple surgeries and prolonged antibiotic therapy. Despite this extensive treatment protocol, the procedure is associated with significant failure rates. Currently, no large animal model is available that recapitulates a failed revision. Therefore, our aim was to establish a large animal model for failed treatment of an ODRI in order to serve as a testbed for future interventional strategies. Adult Swiss Alpine sheep received an intramedullary nail in the tibia and a localised inoculum of either a methicillin-sensitive or methicillin-resistant Staphylococcus aureus (MSSA, MRSA respectively). After 8 weeks, when chronic infection had been established, the animals underwent a staged revision with debridement and temporary placement of an antibiotic-loaded cement spacer. Antibiotics were delivered systemically in a standard or pathogen-adapted manner. Debridement and implant exchange alone failed to treat the MSSA infection. Neither local therapy alone nor systemic therapy alone were effective in resolving infection with MSSA, but a combination of local and systemic therapy was effective against it. MRSA infection was not resolved by the combination of local and systemic antibiotics (standard or pathogen-adapted). A model for failed revision of MRSA infection is described despite the use of local and systemic antibiotics. Novel interventions may be assessed using this model, including antibiotic and non-antibiotic interventions.

The Pararectus approach provides secure access to the deep circumflex iliac vessel for harvest of a large sized and vascularized segment of the iliac crest.

BACKGROUND: The feasibility of harvesting a vascularized iliac crest utilizing the Pararectus approach was assessed in cadavers and then this new technique was implemented in a clinical case. METHODS: Bilaterally in five cadavers the branches of both external iliac arteries were injected with colored silicone to assess their position to each other and to harvest a bone graft vascularized by the deep circumflex iliac artery (DCIA) through the Pararectus approach. This technique was implemented in a 68-years-old female patient, initially admitted to a level-I-trauma center after sustaining multiple injuries by falling from great height. For definitive treatment of a severely contaminated medially open (Gustilo-Anderson Type 3A) calcaneal luxation fracture (Sanders type IIIBC) in this patient a vascularized iliac crest autograft harvest by the Pararectus approach was used for reconstructive surgery. RESULTS: The DCIA and the deep inferior epigastric vessels (DIEV: vascularizing the rectus abdominis muscle and main pedicle of the inferiorly based rectus abdominis myocutaneous flap) are very close on the lateral and medial border of the external iliac artery, respectively. As a consequence, the retrograde dissection of the DIEV towards the DCIA through the Pararectus approach made the dissection of the vascularized iliac crest more amenable, preserving both the lateral femoral cutaneous and the genitofemoral nerves. Four months after the surgery the patient was able to fully weight-bear in orthopedic shoes. Radiographs and CT scans showed correct hind foot alignment and bony integration of the vascularized iliac crest graft into the residual calcaneal body. CONCLUSION: The Pararectus approach allowed for secure collection of large vascularized iliac grafts. The presented technique was successful as a salvage procedure in a clinical case with substantial bone loss after an open calcaneal fracture.

BioXmark for high-precision radiotherapy in an orthotopic pancreatic tumor mouse model : Experiences with a liquid fiducial marker.

BACKGROUND AND PURPOSE: High-precision radiotherapy (RT) requires precise positioning, particularly with high single doses. Fiducial markers in combination with onboard imaging are excellent tools to support this. The purpose of this study is to establish a pancreatic cancer mouse model for high-precision image-guided RT (IGRT) using the liquid fiducial marker BioXmark (Nanovi, Kongens Lyngby, Denmark). METHODS: In an animal-based cancer model, different volumes of BioXmark (10-50 µl), application forms, and imaging modalities-cone-beam computer tomography (CBCT) incorporated in either the Small Animal Radiation Research Platform (SARRP) or the small-animal micro-CT Scanner (SkyScan; Bruker, Brussels, Belgium)-as well as subsequent RT with the SARRP system were analyzed to derive recommendations for BioXmark. RESULTS: Even small volumes (10 µl) of BioXmark could be detected by CBCT (SARRP and Skyscan). Larger volumes (50 µl) led to hardening artefacts. The position of BioXmark was monitored at least weekly by CBCT and was stable over 4 months. BioXmark was shown to be well tolerated; no changes in physical condition or toxic side effects were observed in comparison to control mice. BioXmark enabled an exact fusion with the original treatment plan with less hardening artefacts, and minimized the application of contrast agent for fractionated RT. CONCLUSION: An orthotopic pancreatic tumor mouse model was established for high-precision IGRT using a fiducial marker. BioXmark was successfully tested and provides the perfect basis for improved imaging in high-precision RT. BioXmark enables a unique application method and optimal targeted precision in fractionated RT. Therefore, preclinical trials evaluating novel fractionation regimens and/or combination treatment with high-end RT can be performed.

Neurotoxicity from immune-checkpoint inhibition in the treatment of melanoma: a single centre experience and review of the literature.

Background: Treatment with immune checkpoint inhibitors (ICPi) has greatly improved survival for patients with advanced melanoma in recent years. Anti-CTLA-4 and anti-PD1 antibodies have been approved following large Phase III trials. Immune-related neurological toxicity of varying severity has been reported in the literature. The cumulative incidence of neurotoxicity among ipilimumab, nivolumab and pembrolizumab is reported as <1% in published clinical trials. We aimed to identify the incidence of neurotoxicity in our institution across anti-CTLA4 and anti-PD-1 antibodies, including the combination of ipilimumab with nivolumab. We also review the existing literature and propose an investigation and management algorithm. Methods: All patients with advanced melanoma treated with ipilimumab, nivolumab, pembrolizumab or the combination of ipilimumab and nivolumab (ipi + nivo), managed at the Royal Marsden Hospital between September 2010 and December 2015, including patients on (published) clinical trials were included. Medical records for each patient were reviewed and information on neurotoxicity recorded. A systematic search strategy was performed to collate existing reports of neurological toxicity. Results: In total, 413 immunotherapy treatment episodes in 352 patients were included, with median follow-up of 26.7 months. Ten cases of neurotoxicity were recorded, affecting 2.8% of patients overall, ranging from grade 1 to 4, affecting both central and peripheral nervous systems. A rate of 14% was noted with ipi + nivo. Three of five patients commenced on corticosteroids responded to these. Six patients had made a full recovery at the time of reporting. A favorable radiological response was found in 7 of the 10 cases. Unusual presentations are described in detail. Conclusions: Neurological toxicity is not uncommon, and may be more frequent in patients treated with combination ipi + nivo. Patterns of presentation and response to treatment are varied. A prompt and considered approach is required to optimize outcomes in this group of patients.