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We report here the sequencing and analysis of the genome of the thermophilic bacterium Carboxydothermus hydrogenoformans Z-2901. This species is a model for studies of hydrogenogens, which are diverse bacteria and archaea that grow anaerobically utilizing carbon monoxide (CO) as their sole carbon source and water as an electron acceptor, producing carbon dioxide and hydrogen as waste products. Organisms that make use of CO do so through carbon monoxide dehydrogenase complexes. Remarkably, analysis of the genome of C. hydrogenoformans reveals th e presence of at least five highly differentiated anaerobic carbon monoxide dehydrogenase complexes, which may in part explain how this species is able to grow so much more rapidly on CO than many other species. Analysis of the genome also has provided many general insights into the metabolism of this organism which should make it easier to use it as a source of biologically produced hydrogen gas. One surprising finding is the presence of many genes previously found only in sporulating species in the Firmicutes Phylum. Although this species is also a Firmicutes, it was not known to sporulate previously. Here we show that it does sporulate and because it is missing many of the genes involved in sporulation in other species, this organism may serve as a ''minimal'' model for sporulation studies. In addition, using phylogenetic profile analysis, we have identified many uncharacterized gene families found in all known sporulating Firmicutes, but not in any non-sporulating bacteria, including a sigma factor not known to be involved in sporulation previously. Copyright: ©2005 Wu et al.

Abstract Although internal seiches are ubiquitous in large, deep lakes, little is known about the effect of higher vertical-mode seiches on deepwater dynamics. Here, by combining entire summer season current and temperature observations and 3D numerical modeling, we demonstrate that previously undetected vertical mode-two and mode-three Poincaré waves in 309-meter deep Lake Geneva (Switzerland/France) generate bottom-boundary layer currents up to 4 cm s−1. Poincaré wave amphidromic patterns revealed three strong cells excited simultaneously. Weak hypolimnetic stratification (N 2 ≈ 10−6 s −2), typical of deep lakes, significantly modified the wave structure by shifting the lower vertical node in the lake’s center from ~75-meter depth (without stratification) to ~150-meter depth (with stratification). This shift induces shear in the middle of the hypolimnion and strengthens bottom currents, with important implications for hypolimnetic mixing and sediment-water exchange. Our findings demonstrate that classical concepts based on constant temperature layers cannot correctly characterize higher vertical-mode Poincaré seiches in deep lakes.

Osteosarcomas are the most common primary malignant bone tumors and mostly affect children, adolescents, and young adults. Despite current treatment options such as surgery and polychemotherapy, the survival of patients with metastatic disease remains poor. In recent studies, punicalagin has reduced the cell viability, angiogenesis, and invasion in cell culture trials. The aim of this study was to examine the effects of punicalagin on osteosarcomas in a 3D in vivo tumor model. Human osteosarcoma biopsies and SaOs-2 and MG-63 cells, were grown in a 3D in vivo chorioallantoic membrane (CAM) model. After a cultivation period of up to 72 h, the tumors received daily treatment with punicalagin for 4 days. Weight measurements of the CAM tumors were performed, and laser speckle contrast imaging (LSCI) and a deep learning-based image analysis software (CAM Assay Application v.3.1.0) were used to measure angiogenesis. HE, Ki-67, and Caspase-3 staining was performed after explantation. The osteosarcoma cell lines SaOs-2 and MG-63 and osteosarcoma patient tissue displayed satisfactory growth patterns on the CAM. Treatment with punicalagin decreased tumor weight, proliferation, and tumor-induced angiogenesis, and the tumor tissue showed pro-apoptotic characteristics. These results provide a robust foundation for the implementation of further studies and show that punicalagin offers a promising supplementary treatment option for osteosarcoma patients. The 3D in vivo tumor model represents a beneficial model for the testing of anti-cancer therapies.

Background/Objectives: One of the most important diagnostic tools in bone tumors is X-rays. Preliminary and, in the case of some benign lesions, definitive diagnoses are formed using this basic tool. Part of the decision making in this stage is based on statistical probability using the patient’s age, as well as the incidence and predilection sites of different entities. The information used today is based on older and fragmented data. To verify the underlying principles, we retrospectively evaluated all bone tumors in children and adolescents treated by our tertiary center in the last 20 years. Methods: For this retrospective study, patients under the age of 18 years suffering from histopathologically verified bone tumors were evaluated. Data were retrieved from our local musculoskeletal tumor database. Results: We were able to include 420 children treated for bone tumors in our tertiary center. The cohort consisted of 335 benign and 85 malignant lesions. The most common lesions were 137 osteochondromas; the malignant tumors consisted mainly of osteosarcomas (53) and Ewing’s sarcomas (28). The primary predilection sites were the metaphyses of long bones. Conclusions: We were able to confirm and supplement the fragmentary data of these rare diseases using our own cohort.

Background: Chondrosarcomas (CS) are a rare and heterogenic group of primary malignant bone tumors. In the literature, data on prognostic factors in chondrosarcomas are scarce, and most studies are limited by a short follow-up. The aim of this retrospective study was therefore to determine factors associated with the survival and local recurrence of chondrosarcomas and to compare the results with previous studies. Methods: We retrospectively evaluated 77 patients who were treated for chondrosarcoma of the extremities or pelvis at our tertiary sarcoma center between 1998 and 2007. Patient-related data (age, sex, etc.), tumor characteristics (localization, grading, presence of metastases, etc.), and treatment-related data (previous surgical treatment, type of local treatment, surgical margins, etc.) were evaluated and analyzed for possible correlation with patients’ outcomes. A statistical analysis was performed, including multivariate analysis. Results: The mean survival in our patients was 207 months, which resulted in a five-year survival rate of 76%. Negative prognostic factors for survival were histopathological grading, a patient aged over 70 years, and metastatic disease. The quality of the resection (clear or contaminated margins) negatively influenced both the development of local recurrence and survival too, at least in the univariate analysis. In contrast, factors such as tumor localization (extremities vs. pelvis), pathological fractures, or an initial inadequate resection elsewhere had no significant effect on survival. Conclusions: In accordance with results in the literature, the survival of patients with chondrosarcomas is mainly influenced by factors such as tumor grading, age, and metastases. However, complete resection remains paramount for the outcome in patients with chondrosarcoma—a primary malignant bone tumor with limited alternative treatment options.

Abstract Invasive lobular carcinoma (ILC) is a special breast cancer type characterized by noncohesive growth and E‐cadherin loss. Focal activation of P‐cadherin expression in tumor cells that are deficient for E‐cadherin occurs in a subset of ILCs. Switching from an E‐cadherin deficient to P‐cadherin proficient status (EPS) partially restores cell–cell adhesion leading to the formation of cohesive tubular elements. It is unknown what conditions control EPS. Here, we report on EPS in ILC metastases in the large bowel. We reviewed endoscopic colon biopsies and colectomy specimens from a 52‐year‐old female (index patient) and of 18 additional patients (reference series) diagnosed with metastatic ILC in the colon. EPS was assessed by immunohistochemistry for E‐cadherin and P‐cadherin. CDH1/E‐cadherin mutations were determined by next‐generation sequencing. The index patient's colectomy showed transmural metastatic ILC harboring a CDH1/E‐cadherin p.Q610* mutation. ILC cells displayed different growth patterns in different anatomic layers of the colon wall. In the tunica muscularis propria and the tela submucosa, ILC cells featured noncohesive growth and were E‐cadherin‐negative and P‐cadherin‐negative. However, ILC cells invading the mucosa formed cohesive tubular elements in the intercryptal stroma of the lamina propria mucosae. Inter‐cryptal ILC cells switched to a P‐cadherin‐positive phenotype in this microenvironmental niche. In the reference series, colon mucosa infiltration was evident in 13 of 18 patients, one of which showed intercryptal EPS and conversion to cohesive growth as described in the index patient. The large bowel is a common metastatic site in ILC. In endoscopic colon biopsies, the typical noncohesive growth of ILC may be concealed by microenvironment‐induced EPS and conversion to cohesive growth.

Background: An aberrant cellular microenvironment characterized by pathological cells or inflammation represents an added risk factor across various cancer types. While the significance of chronic inflammation in the development of most diffuse tumors has been extensively studied, an exception to this analysis exists in the context of chondrosarcomas. Chondrosarcomas account for 20–30% of all bone sarcomas, with an estimated global incidence of 1 in 100,000. The average age at diagnosis is 50, and over 70% of patients are over 40. This retrospective study aimed to examine the role of C-reactive protein (CRP) as a prognostic factor in relation to the histopathological findings in chondrosarcoma. Methods: In this retrospective study, 70 patients diagnosed with chondrosarcoma and treated between 2004 and 2019 were included. Preoperative CRP levels were measured in mg/dL, with non-pathological values defined as below 0.5 mg/dL. Disease-free survival time was calculated from the initial diagnosis to events such as local recurrence or metastasis. Follow-up status was categorized as death from disease, no evidence of disease, or alive with disease. Patients were excluded if they had insufficient laboratory values, missing follow-up information, or incomplete histopathological reports. Results: The calculated risk estimation of a reduced follow-up time was 2.25 timed higher in the patients with a CRP level >0.5 mg/dL (HR 2.25 and 95% CI 1.13–4.45) and 3 times higher in patients with a tumor size > pT2 (HR 3 and 95% CI 1.59–5.92). We can easily confirm that risk factors for reduced prognosis lie in chondrosarcoma high grading, preoperative pathological CRP- level, and a size > 8 cm. Conclusions: A pretreatment CRP value greater than 0.5 mg/dL can be considered a sensitive prognostic and risk factor for distant metastasis for chondrosarcoma patients.

Abstract Background Microsatellite instability (MSI) occurs in several cancer types and is commonly used for prognosis and as a predictive biomarker for immune checkpoint therapy. Methods We analyzed n = 263 formalin‐fixed paraffin‐embedded (FFPE) tumor specimens (127 colorectal cancer (CRC), 55 endometrial cancer (EC), 33 stomach adenocarcinoma (STAD), and 48 solid tumor specimens of other tumor types) with a capillary electrophoresis based multiplex monomorphic marker MSI‐PCR panel and an amplicon‐based NGS assay for microsatellite instability (MSI+). In total, n = 103 (39.2%) cases with a known defect of the DNA mismatch repair system (dMMR), determined by a loss in protein expression of MSH2/MSH6 (n = 48, 46.6%) or MLH1/PMS2 (n = 55, 53.4%), were selected. Cases with an isolated loss of MSH6 or PMS2 were excluded. Results The overall sensitivity and specificity of the NGS assay in comparison with the MSI‐PCR were 92.2% and 98.8%. With CRC cases a nearly optimal concordance was reached (sensitivity 98.1% and specificity 100.0%). Whereas EC cases only show a sensitivity of 88.6% and a specificity of 95.2%, caused by several cases with instability in less than five monomorphic markers, which could be difficult to analyze by NGS (subtle MSI+ phenotype). Conclusions MSI analysis of FFPE DNA by NGS is feasible and the results show a high concordance in comparison with the monomorphic marker MSI‐PCR. However, cases with a subtle MSI+ phenotype, most frequently manifest in EC, have a risk of a false‐negative result by NGS and should be preferentially analyzed by capillary electrophoresis.

Abstract Intrahepatic cholangiocarcinoma harbours druggable genetic lesions including FGFR2 gene fusions. Reliable and accurate detection of these fusions is becoming a critical component of the molecular work‐up, but real‐world data on the performance of fluorescence in situ hybridisation (FISH) and targeted RNA‐based next‐generation sequencing (NGS) are very limited. Bridging this gap, we report results of the first round robin test for FGFR2 fusions in cholangiocarcinoma and contextualise test data with genomic architecture. A cohort of 10 cholangiocarcinoma (4 fusion positive and 6 fusion negative) was tested by the Institute of Pathology, University Hospital Heidelberg, Germany. Data were validated by four academic pathology departments in Germany. Fusion‐positive cases comprised FGFR2::BICC1, FGFR2::DBP, FGFR2::TRIM8, and FGFR2::ATE1 fusions. In a second step, a round robin test involving 21 academic and non‐academic centres testing with RNA‐based NGS approaches was carried out; five participants performed FISH testing in addition. Thirteen of 16 (81%) centres successfully passed the NGS only and 3 of 5 (60%) centres passed the combined NGS + FISH round robin test. Identified obstacles were bioinformatic pipelines not optimised for the detection of FGFR2 fusions and assays not capable of detecting unknown fusion partners. This study shows the benefit of targeted RNA‐NGS for the detection of FGFR2 gene fusions. Due to the marked heterogeneity of the genomic architecture of these fusions, fusion partner agnostic (i.e. open) methodological approaches that are capable of identifying yet unknown fusion partners are superior. Furthermore, we highlight pitfalls in subsequent bioinformatic analysis and limitations of FISH‐based tests.

Theoretical studies on oceans and large lakes have shown that submesoscale instabilities in frontal zones tend to reduce horizontal density gradients and enhance vertical density gradients, thereby re-stratifying the Surface Mixed Layer (SML). Submesoscale filament dynamics are primarily studied using numerical models and remote sensing imagery. However, in large lakes, this concept remains without substantial field validation, mainly due to the difficulty in conducting the necessary high-resolution water column measurements. Using a procedure we recently developed to predict the time and location of mesoscale and submesoscale features generated by strong wind fields, this work presents direct field evidence demonstrating the role of submesoscale cold filaments in re-stratifying the SML under weakly stratified conditions in a large lake (Lake Geneva). The dynamics of the observed filaments were further investigated with a high-resolution three-dimensional (3D) numerical model and Lagrangian particle-tracking. The numerical model accurately captured the formation of these filaments. The enhancement of thermal stratification strength, N2, reached O(10-5) s-2 in areas adjacent to cold filaments under atmospheric cooling and heating conditions. In the pelagic zone (offshore), strong vertical velocities of O(100 m d-1) were associated with secondary circulation that rapidly transports and accumulates passive particles in the thermocline and hypolimnion layers, as confirmed by Acoustic Doppler Current Profiler (ADCP) backscattering intensity data. The field observations indicate that under weak stratification, Dissolved Oxygen (DO) variability reaches 0.5 mg l-1 near cold filaments. This documentation of strong vertical motions associated with submesoscale filaments is expected to contribute to the understanding of the vertical exchange of heat, contaminants and oxygen between the atmosphere and the pelagic zone of large lakes, as well as in oceans where carrying out such field measurements is very challenging.

Abstract Invasive lobular breast carcinoma (ILC) is the second most common breast carcinoma (BC) subtype and is mainly driven by loss of E‐cadherin expression. Correct classification of BC as ILC is important for patient treatment. This study assessed the degree of agreement among pathologists for the diagnosis of ILC. Two sets of hormone receptor (HR)‐positive/HER2‐negative BCs were independently reviewed by participating pathologists. In set A (61 cases), participants were provided with hematoxylin/eosin (HE)‐stained sections. In set B (62 cases), participants were provided with HE‐stained sections and E‐cadherin immunohistochemistry (IHC). Tumor characteristics were balanced. Participants classified specimens as non‐lobular BC versus mixed BC versus ILC. Pairwise inter‐observer agreement and agreement with a pre‐defined reference diagnosis were determined with Cohen's kappa statistics. Subtype calls were correlated with molecular features, including CDH1/E‐cadherin mutation status. Thirty‐five pathologists completed both sets, providing 4,305 subtype calls. Pairwise inter‐observer agreement was moderate in set A (median κ = 0.58, interquartile range [IQR]: 0.48–0.66) and substantial in set B (median κ = 0.75, IQR: 0.56–0.86, p

Abstract Background Whereas the genomic landscape of endocrine‐resistant breast cancer has been intensely characterized in previously treated cases with local or distant recurrence, comparably little is known about genomic alterations conveying primary non‐responsiveness to endocrine treatment in luminal early breast cancer. Methods In this study, 622 estrogen receptor‐expressing breast cancer cases treated with short‐term preoperative endocrine therapy (pET) from the WSG‐ADAPT trial (NCT01779206) were analyzed for genetic alterations associated with impaired endocrine proliferative response (EPR) to 3‐week pET with tamoxifen or aromatase inhibitors. EPR was categorized as optimal (post‐pET Ki67

As studying planning practices and planners’ motivations along the urban–rural gradient has not been common practice, we scrutinize the regional differences in the understanding of cycling planning of Austrian municipal administrators using three questions from a previous on-purpose survey. These questions serve as simple proxies for decisions that need to be made from the perspective of a climate change mitigation-driven transformation of transport planning. The administrators were asked (1) to rank the priorities for transport modes in the case of conflict of space allocation, (2) to name the quantity of bicycle parking provision in projects, and (3) to mark pictures of bicycle parking stands they consider fulfilling the needs of cyclists. The chosen priorities indicate that traditional understanding and mental barriers persist among administrators in an urban–rural gradient. In urban as well as rural areas administrators in charge of cycling planning, still prioritize cars (in terms of infrastructure and space) over bicycles. And up to one quarter of responses – from urban as well as rural municipalities – state that they don’t know if the amount of bicycle parking spaces provided meets legal requirements or exceeds them. These mental barriers need to be overcome for an improved and accelerated introduction of necessary cycling policies.

Background: Even after decades of intensive research, an ideal heart valve prosthesis remains elusive. Shortcomings of conventional devices include reduced durability of bioprostheses and the thrombogenicity of mechanical substitutes, necessitating anticoagulation and resulting in imperfect hemodynamics. Here we present in vivo results of a novel mechanical heart valve prosthesis aiming for freedom from anticoagulation. Methods: Four female sheep had their aortic valves replaced using the novel mechanical heart valve (size 21 mm), with no postoperative anticoagulation treatment. This trileaflet heart valve was designed with the pivots in the systolic central flow. Hemodynamics, biochemistry, hematology, and macroscopy and microscopy were studied at 90 days in 2 sheep and at 1 year in the other 2 sheep. Results: Mean (

Abstract Hepatocellular carcinoma (HCC) represents a global health challenge with limited therapeutic options. Anti-angiogenic immune checkpoint inhibitor-based combination therapy has been introduced for progressed HCC, but improves survival only in a subset of HCC patients. Tyrosine-kinase inhibitors (TKI) such as sorafenib represent an alternative treatment option but have only modest efficacy. Using different HCC cell lines and HCC tissues from various patients reflecting HCC heterogeneity, we investigated whether the sorafenib response could be enhanced by combination with pro-apoptotic agents, such as TNF-related apoptosis-inducing ligand (TRAIL) or the BH3-mimetic ABT-737, which target the death receptor and mitochondrial pathway of apoptosis, respectively. We found that both agents could enhance sorafenib-induced cell death which was, however, dependent on specific BH3-only proteins. TRAIL augmented sorafenib-induced cell death only in NOXA-expressing HCC cells, whereas ABT-737 enhanced the sorafenib response also in NOXA-deficient cells. ABT-737, however, failed to augment sorafenib cytotoxicity in the absence of BIM, even when NOXA was strongly expressed. In the presence of NOXA, BIM-deficient HCC cells could be in turn strongly sensitized for cell death induction by the combination of sorafenib with TRAIL. Accordingly, HCC tissues sensitive to apoptosis induction by sorafenib and TRAIL revealed enhanced NOXA expression compared to HCC tissues resistant to this treatment combination. Thus, our results suggest that BH3-only protein expression determines the treatment response of HCC to different sorafenib-based drug combinations. Individual profiling of BH3-only protein expression might therefore assist patient stratification to certain TKI-based HCC therapies.

River inflows have a major influence on lake water quality due to their input of sediments, nutrients and contaminants. After leaving the river channel, river waters form a plume and interact with ambient lake waters. Strong hydrodynamic changes take place in the nearfield. To determine the nearfield hydro-sedimentary dynamics of the negatively-buoyant Rhône River plume in thermally stratified Lake Geneva, field campaigns were carried out at high and intermediate river discharge. High-resolution full-depth Acoustic Doppler Current Profiler (ADCP) transects were taken at 400, 800, 1,200, and 1,500 m from the river mouth, combined with profiles of temperature, turbidity and particle size distribution. These measurements provided, for the first time in a lake, detailed velocity fields across the full-plume cross-section in each transect. Furthermore, the unique combination of measurement techniques allowed the quantification of entrainment, Suspended Particulate Matter (SPM) concentrations and fluxes. They revealed that the negatively buoyant river inflow intruded into the metalimnion as a laterally unconfined interflow and continued flowing straight out in the streamwise direction, since currents in the lake were weak. At the same time, it mainly spread laterally due to entrainment of ambient water. The size of the interflow core and its velocity progressively decreased with distance from the mouth, as did SPM concentrations and volumes of particles (by a factor of 2–3 within 1,500 m), due to sediment settling and entrainment. The interflow momentum flux remained constant along the pathway, but interflow cross sections and discharge increased 2–3 times (within 1,500 m). The entrainment coefficient was >2 at 400 m and further increased non-linearly along the pathway. These values are much higher than those reported for laterally confined laboratory studies. The particle size distribution in the interflow was dominated by fine particles (62 μm) almost completely settled out before reaching that distance. The above processes occurred independent of river discharge; their intensity, however, changed with discharge.

The spatial variability of lake surface water temperature (LSWT) between smooth and rough surface areas and its potential association with the natural surfactant distribution in the surface microlayer were investigated for the first time in a lake. In spring 2019, two different field campaigns were carried out in Lake Geneva to measure: i) the enrichment factor of fluorescent dissolved organic matter (FDOM) as a proxy for biogenic surfactants, and ii) LSWT and near-surface water temperature profiles while simultaneously monitoring water surface roughness in both cases. Results indicate that, under intense incoming short-wave radiation and intermittent light wind conditions, the atmospheric boundary layer (ABL) was stable and the accumulation of heat due to short-wave radiation in near-surface waters was greater than heat losses by surface cooling, thus creating a diurnal warm layer with strong thermal stratification in the water near-surface layer. A threshold wind speed of 1.5 m s-1 was determined as a transition between different dynamic regimes. For winds just above 1.5 m s-1, the lake surface became patchy, and smooth surface areas (slicks) were more enriched with FDOM than rough areas (non-slick) covered with gravity-capillary waves (GCW). Sharp thermal boundaries appeared between smooth and rough areas. LSWT in smooth slicks was found to be more than 1.5°C warmer than in rough non-slick areas, which differs from previous observations in oceans that reported a slight temperature reduction inside slicks. Upon the formation of GCW in non-slick areas, the near-surface stratification was destroyed and the surface temperature was reduced. Furthermore, winds above 1.5 m s-1 continuously fragmented slicks causing a rapid spatial redistribution of LSWT patterns mainly aligned with the wind. For wind speeds below 1.5 m s‑1 the surface was smooth, no well-developed GCW were observed, LSWT differences were small, and strong near-surface stratification was established. These results contribute to the understanding and the quantification of air-water exchange processes, which are presently lacking for stable Atmospheric Boundary Layer conditions in lakes.

Abstract Microglandular adenosis (MGA) represents a rare neoplasm of the mammary gland, which in a subset of cases may be associated with triple‐negative breast cancer (BC). The biology of MGA is poorly understood. In this study, eight MGA cases (n = 4 with and n = 4 without associated BC) were subjected to a comprehensive characterization using immunohistochemistry, genome‐wide DNA copy number (CN) profiling, fluorescence in situ hybridization (FISH), next‐generation sequencing (NGS), and DNA methylation profiling using 850 K arrays and bisulfite pyrosequencing. Median patient age was 61 years (range 57–76 years). MGA lesions were estrogen receptor (ER)‐negative, progesterone receptor‐negative, HER2‐negative, and S100‐positive. DNA CN alterations (CNAs) were complex or limited to few gains and losses. CN gain on chromosome 2q was the most common CNA and was validated by FISH in five of eight cases. NGS demonstrated an average of two mutations per case (range 0–5) affecting 10 different genes (ARID1A, ATM, CTNNB1, FBXW7, FGFR2, MET, PIK3CA, PMS2, PTEN, and TP53). CNAs and mutations were similar in MGA and adjacent BC, indicating clonal relatedness. DNA methylation profiling identified aberrant hypermethylation of CpG sites within GATA3, a key transcription factor required for luminal differentiation. Immunohistochemistry showed regular GATA3 protein expression in the normal mammary epithelium and in ER‐positive BC. Conversely, GATA3 was reduced or lost in all MGA cases tested (8/8). In conclusion, MGA is characterized by common CN gain on chromosome 2q and loss of GATA3. Epigenetic inactivation of GATA3 may provide a new clue to the peculiar biology of this rare neoplasia.

Abstract Background Small soft tissue masses are often falsely assumed to be benign and resected with failure to achieve tumor-free margins. Therefore, this study retrospectively investigated the distribution of histopathologic diagnosis to be encountered in small soft tissue tumors (≤ 5 cm) in a large series of a tertiary referral center. Methods Patients with a soft tissue mass (STM) with a maximum diameter of 5 cm presenting at our institution over a period of 10 years, who had undergone preoperative Magnetic resonance imaging and consequent biopsy or/and surgical resection, were included in this study. A final histopathological diagnosis was available in all cases. The maximum tumor diameter was determined on MR images by one radiologist. Moreover, tumor localization (head/neck, trunk, upper extremity, lower extremity, hand, foot) and depth (superficial / deep to fascia) were assessed. Results In total, histopathologic results and MR images of 1753 patients were reviewed. Eight hundred seventy patients (49.63%) showed a STM ≤ 5 cm and were therefore included in this study (46.79 +/− 18.08 years, 464 women). Mean maximum diameter of the assessed STMs was 2.88 cm. Of 870 analyzed lesions ≤ 5 cm, 170 (19.54%) were classified as superficial and 700 (80.46%) as deep. The malignancy rate of all lesions ≤ 5 cm was at 22.41% (superficial: 23.53% / deep: 22.14%). The malignancy rate dropped to 16.49% (20.79% / 15.32%) when assessing lesions ≤ 3 cm (p = 0.007) and to 15.0% (18.18% / 13.79%) when assessing lesions ≤ 2 cm (p = 0.006). Overall, lipoma was the most common benign lesion of superficial STMs (29.41%) and tenosynovial giant cell tumor was the most common benign lesion of deep STMs (23.29%). Undifferentiated pleomorphic sarcoma was the most common malignant diagnosis among both, superficial (5.29%) and deep (3.57%) STMs. Conclusions The rate of malignancy decreased significantly with tumor size in both, superficial and deep STMs. The distribution of entities was different between superficial and deep STMs, yet there was no significant difference found in the malignancy rate.

In 2010 a public debate emerged on the correctional education of children and adolescents during the second half of the twentieth century. People who had spent some years of their childhood and youth in reformatories described frequent experiences of massive violence. Subsequently, both western Austrian countries, Tyrol and Vorarlberg, provided research funds and made the relevant documents (particularly administrative records of the Welfare Service) available for scientific research. A number of these documents are the result of inventorying processes. Using a child welfare case file (Zöglingsakte) as an example, this paper analyses how the inventorying processes aimed to document the children’s bodies, their behaviour, and the objects with which they came into contact. These documentation processes were linked to the aims the welfare system tried to implement. In this sense, inventories appear as media of power discourses, which can be read as texts and narratives. Furthermore the lists, registers, and inventories included in the case files allow us to gain a deeper insight into the children’s lives.

As in oceans, large-scale coherent circulations such as gyres and eddies are ubiquitous features in large lakes that are subject to the Coriolis force. They play a crucial role in the horizontal and vertical distribution of biological, chemical and physical parameters that can affect water quality. In order to make coherent circulation patterns evident, representative field measurements of near-surface currents have to be taken. This, unfortunately, is difficult due to the high spatial and temporal variability of gyres/eddies. As a result, few complete field observations of coherent circulation in oceans/lakes have been reported. With the advent of high-resolution satellite imagery, the potential to unravel and improve the understanding of mesoscale and submesoscale processes has substantially increased. Features in the satellite images, however, must be verified by field measurements and numerical simulations. In the present study, Sentinel-1 SAR satellite imagery was used to detect gyres/eddies in a large lake (Lake Geneva). Comparing SAR images with realistic high-resolution numerical model results and in situ observations allowed for identification of distinct signatures of mesoscale gyres, which can be revealed through submesoscale current patterns. Under low wind conditions, cyclonic gyres manifest themselves in SAR images either through biogenic slicks that are entrained in submesoscale and mesoscale currents, or by pelagic upwelling that appears as smooth, dark elliptical areas in their centers. This unique combination of simultaneous SAR imagery, three-dimensional numerical simulations and field observations confirmed that SAR imagery can provide valuable insights into the spatial scales of thus far unresolved mesoscale and submesoscale processes in a lake. Understanding these processes is required for developing effective lake management concepts.

The differentiation between the atypical cartilaginous tumor (ACT) and the enchondromas is crucial as ACTs require a curettage and clinical as well as imaging follow-ups, whereas in the majority of cases enchondromas require neither a treatment nor follow-ups. Differentiating enchondromas from ACTs radiologically remains challenging. Therefore, this study evaluated imaging criteria in a combination of computed tomography (CT) and magnetic resonance (MR) imaging for the differentiation between enchondromas and ACTs in long bones. A total of 82 patients who presented consecutively at our institution with either an ACT (23, age 52.7 ±18.8 years; 14 women) or an enchondroma (59, age 46.0 ± 11.1 years; 37 women) over a period of 10 years, who had undergone preoperative MR and CT imaging and subsequent biopsy or/and surgical removal, were included in this study. A histopathological diagnosis was available in all cases. Two experienced radiologists evaluated several imaging criteria on CT and MR images. Likelihood of an ACT was significantly increased if either edema within the bone (p = 0.049), within the adjacent soft tissue (p = 0.006) or continuous growth pattern (p = 0.077) were present or if the fat entrapment (p = 0.027) was absent on MR images. Analyzing imaging features on CT, the likelihood of the diagnosis of an ACT was significantly increased if endosteal scalloping >2/3 (p < 0.001), cortical penetration (p < 0.001) and expansion of bone (p = 0.002) were present and if matrix calcifications were observed in less than 1/3 of the tumor (p = 0.013). All other imaging criteria evaluated showed no significant influence on likelihood of ACT or enchondroma (p > 0.05). In conclusion, both CT and MR imaging show suggestive signs which can help to adequately differentiate enchondromas from ACTs in long bones and therefore can improve diagnostics and consequently patient management. Nevertheless, these features are rare and a combination of CT and MR imaging features did not improve the diagnostic performance substantially.

The Hannover Unified Biobank (HUB) was established in 2012 as the central biobank of the Hannover Medical School (MHH) to provide an infrastructure for the standardised collection and storage of liquid biosamples and associated data in the context of research projects and clinical studies. For the comprehensive collection of tissue samples from the clinical routine the HUB cooperates with the MHH Institute of Pathology. All samples are connected with the associated clinical data stored in the ECRDW (Enterprise Clinical Research Data Warehouse) of the MHH. Headed by Prof. Dr. Thomas Illig the HUB developed into one of the biggest state of the art clinical biobanks in Germany and today stores about 2.88 Mio samples (mainly FFPE tissue and blood derived liquid samples) of a wide range of diseases.

Abstract The detection of IDH mutations in patients with diffusely infiltrating malignant astrocytomas resulted in substantial modifications in the concept of WHO classification of these tumors. An important underlying observation was that patients with anaplastic astrocytomas (AA) without IDH mutation had a clinical course similar to that of patients with glioblastomas (GBM). The underlying observations of the German Glioma Network and NOA-04, however, were based on mixed patient cohorts. While most GBM patients received combined radiochemotherapy, patients with AA usually had radiotherapy or chemotherapy only. This intrinsic shortcoming of the study raised the question of whether patients with AA, IDH wildtype, WHO grade III, might have better prognosis if treated with combined radiochemotherapy than patients with GBM receiving the same combination therapy. Thus, the question remains whether the established histopathological grading criteria for malignant astrocytomas in the absence of an IDH mutation are still important if neither vascular proliferation nor necrosis are detectable. All patients in the cohort investigated here with the diagnosis of AA or GBM were subjected to a combined radiochemotherapy according to the Stupp protocol independently of the histopathological diagnosis. Thus, the analysis of these patients allows to clarify whether patients with AA, IDH wildtype, WHO grade III have a prognosis similar to that of GBM, IDH wildtype, WHO grade IV, even under equivalent therapeutic conditions. We determined the IDH1 and IDH2 status by sequencing, the MGMT status by pyrosequencing after bisulfite treatment and the EGFR status of the patients by FISH. In fact, the patients with the histopathological diagnosis of an AA IDH wild-type under similar aggressive therapy showed a comparable and therefore no better prognosis (median overall survival (mOS) 16 months) than patients with a GBM (mOS 13 months). Instead, patients with an AA and an IDH mutation receiving the same therapy had a mOS of 54 months. Thus, it can be concluded that in the absence of an IDH mutation, the established histopathological grading criteria ‘necrosis’ and ‘vascular proliferation’ actually lose their prognostic significance. If, on the other hand, patients with malignant astrocytomas and an IDH mutation are examined, there is still a difference between patients with necrosis and/or vascular proliferation and those whose tumors do not show such characteristics. Accordingly, in patients with malignant astrocytomas with IDH mutation it can be concluded that a histological differentiation between AA IDH mutated and GBM IDH mutated remains beneficial from a prognostic perspective.

Abstract Background To evaluate the diagnostic value of MR imaging for the differentiation of lipomas and atypical lipomatous tumors (ALT) in comparison with histology and MDM2 amplification status. Methods Patients with well-differentiated lipomatous tumors (n = 113), of which 66 were diagnosed as lipoma (mean age 53 years (range, 13–82); 47% women) and 47 as atypical lipomatous tumor (ALT; mean age 60 years (range, 28–88); 64% women), were included into this study using histology and MDM2 amplification status by fluorescence in situ hybridization (FISH) as standard of reference. Preoperative MR images were retrospectively assessed by two radiologists for the following imaging features: maximum tumor diameter (mm) as well as the affected compartment (intramuscular, intermuscular or subcutaneous), septa (absent, thin ( 2 mm) with nodular components); contrast enhancing areas within the lipomatous tumor ( 1/3 of the tumor volume); Results Of the 47 patients with ALT, 40 (85.1%) presented thick septa (> 2 mm) and this finding significantly increased the likelihood of ALT (OR 6.24, 95% CI 3.36–11.59; P

Abstract Atypical chronic myeloid leukemia (aCML) and chronic myelomonocytic leukemia (CMML) represent two histologically and clinically overlapping myelodysplastic/myeloproliferative neoplasms. Also the mutational landscapes of both entities show congruencies. We analyzed and compared an aCML cohort (n = 26) and a CMML cohort (n = 59) by next‐generation sequencing of 25 genes and by an nCounter approach for differential expression in 107 genes. Significant differences were found with regard to the mutation frequency of TET2, SETBP1, and CSF3R. Blast content of the bone marrow revealed an inverse correlation with the mutation status of SETBP1 in aCML and TET2 in CMML, respectively. By linear discriminant analysis, a mutation‐based machine learning algorithm was generated which placed 19/26 aCML cases (73%) and 54/59 (92%) CMML cases into the correct category. After multiple correction, differential mRNA expression could be detected between both cohorts in a subset of genes (FLT3, CSF3R, and SETBP1 showed the strongest correlation). However, due to high variances in the mRNA expression, the potential utility for the clinic is limited. We conclude that a medium‐sized NGS panel provides a valuable assistance for the correct classification of aCML and CMML.

Purpose The entity ‘diffuse midline glioma, H3 K27M-mutant (DMG)’ was introduced in the revised 4th edition of the 2016 WHO classification of brain tumors. However, there are only a few reports on magnetic resonance imaging (MRI) of these tumors. Thus, we conducted a retrospective survey focused on MRI features of DMG compared to midline glioblastomas H3 K27M-wildtype (mGBM-H3wt). Methods We identified 24 DMG cases and 19 mGBM-H3wt patients as controls. After being retrospectively evaluated for microscopic evidence of microvascular proliferations (MVP) and tumor necrosis by two experienced neuropathologists to identify the defining histological criteria of mGBM-H3wt, the samples were further analyzed by two experienced readers regarding imaging features such as shape, peritumoral edema and contrast enhancement. Results The DMG were found in the thalamus in 37.5% of cases (controls 63%), in the brainstem in 50% (vs. 32%) and spinal cord in 12.5% (vs. 5%). In MRI and considering MVP, DMG were found to be by far less likely to develop peritumoral edema (OR: 0.13; 95%-CL: 0.02–0.62) (p = 0.010). They, similarly, were associated with a significantly lower probability of developing strong contrast enhancement compared to mGBM-H3wt (OR: 0.10; 95%-CL: 0.02–0.47) (P = 0.003). Conclusion Despite having highly variable imaging features, DMG exhibited markedly less edema and lower contrast enhancement in MRI compared to mGBM-H3wt. Of these features, the enhancement level was associated with evidence of MVP.

Patients with intrahepatic cholangiocarcinoma (iCCA) face a highly dismal prognosis, due to late stage diagnosis, the relative chemoresistance of the disease, and an overall limited portfolio of established therapeutic concepts. In recent years, a number of next generation sequencing studies have provided detailed information on the molecular landscape of biliary malignancies, and have laid the groundwork for the evaluation of novel, targeted therapeutic opportunities. Although nearly 40% of patients harbor genetic alterations for which targeted options exist, rapid translation into clinical trials is hampered by the overall low patient numbers. One of the most frequent genetic events in patients with iCCAs are fusions that involve the fibroblast growth factor receptor 2 ( FGFR2 ). Impressive results from pivotal phase II studies in pre-treated patients have confirmed that FGFR-inhibitors are a promising therapeutic option for this genetic subgroup, and the rapid pace with which these inhibitors are being clinically developed is clearly justified by the imminent benefit for the patients. However, the success of these agents should not blind us to key challenges that need to be addressed to optimize FGFR-directed therapies in the future. A better understanding of mechanisms that convey primary and secondary resistance will be crucial to improve up-front patient stratification, to prolong the duration of response, and to implement reasonable co-treatment approaches. In this review, we provide background information on the pathobiology of oncogenic FGFR fusions and selected genetic testing strategies, summarize the latest clinical data, and discuss future directions of FGFR-directed therapies in patients with iCCA.

Despite many years of research efforts and clinical trials the prognosis of patients diagnosed with glioblastoma remains very poor. The oligodendrocyte transcription factor 2 (Olig2) was identified as a marker for glioma stem cells, which are believed to be responsible for glioma recurrence and therapy resistance. In this retrospective analysis we assessed the prognostic value of oligodendroglial and glioma stem cell markers in 113 IDH-wildtype glioblastomas. Immunohistochemical staining for Olig2, NogoA, AQP4 and Nestin was performed in combination with sequencing of IDH1 and IDH2 as well as promotor methylation analysis of the MGMT gene. Even though differences in overall survival according to Olig2 expression were observed, univariate and multivariate survival analysis did not reveal a firm significant prognostic impact of Olig2, NogoA, AQP4 or Nestin expression. Additionally, no differences in the expression of these markers depending on clinical status, age or gender were found. The established independent prognostic factors age = 70 and methylated MGMT gene promoter were significant in the multivariate analysis. In conclusion expression of oligodendroglial and glioma stem cell markers do not have an independent prognostic effect in IDH-wildtype glioblastoma.

Summary: Differentiation events contribute to phenotypic cellular heterogeneity within tumors and influence disease progression and response to therapy. Here, we dissect mechanisms controlling intratumoral heterogeneity within triple-negative basal-like breast cancers. Tumor cells expressing the cytokeratin K14 possess a differentiation state that is associated with that of normal luminal progenitors, and K14-negative cells are in a state closer to that of mature luminal cells. We show that cells can transition between these states through asymmetric divisions, which produce one K14+ and one K14− daughter cell, and that these asymmetric divisions contribute to the generation of cellular heterogeneity. We identified several regulators that control the proportion of K14+ cells in the population. EZH2 and Notch increase the numbers of K14+ cells and their rates of symmetric divisions, and FOXA1 has an opposing effect. Our findings demonstrate that asymmetric divisions generate differentiation transitions and heterogeneity, and identify pathways that control breast cancer cellular composition. : Granit et al. study the sources of phenotypic cellular heterogeneity in triple-negative breast cancers. They find that cancer cells can undergo asymmetric divisions that produce K14+ and K14− daughters and thereby generate heterogeneity. K14+ cells possess a progenitor-associated, tumorigenic phenotype, and the authors identify regulators that control their relative numbers. Keywords: triple-negative breast cancer, basal-like breast cancer, tumor heterogeneity, asymmetric divisions, mammary progenitor cells, EZH2, Notch, FOXA1, NFIB, KLF5

Abstract Background Bone and soft tissue masses of the foot and ankle are not particularly rare but true neoplasia has to be strictly differentiated from pseudotumorous lesions. Diagnosis is often delayed as diagnostic errors are more common than in other regions. Awareness for this localization of musculoskeletal tumors is not very high and neoplasia is often not considered. The purpose of this study is to provide detailed information on the incidence and distribution patterns of foot and ankle tumors of a university tumor institute and propose a simple definition to facilitate comparison of future investigations. Methods As part of a retrospective, single-centre study, the data of patients that were treated for foot and ankle tumors between June 1997 and December 2015 in a musculoskeletal tumor centre were analyzed regarding epidemiologic information, entity and localization. Included were all cases with a true tumor of the foot and ankle. Exclusion criteria were incomplete information on the patient or entity (e.g. histopathological diagnosis) and all pseudotumoral lesions. Results Out of 7487 musculoskeletal tumors, 413 cases (5,52%) of tumors of the foot and ankle in 409 patients were included (215 male and 198 female patients). The average age of the affected patients was 36 ± 18y (min.3y, max.92y). Two hundred sixty-six tumors involved the bone (64%), among them 231 (87%) benign and 35 (13%) malignant. There were 147 soft tissue tumors (36%), 104 (71%) were benign, 43 (29%) malignant. The most common benign osseous tumor lesions included simple bone cysts, enchondroma and osteochondroma. By far the most common malignant bone tumor was chondrosarcoma. Common benign soft tissue tumors included pigmented villo-nodular synovitis, superifcial fibromatosis and schwannoma whereas the most common malignant members were synovial sarcoma and myxofibrosarcoma. Regarding anatomical localization, the hindfoot was affected most often. Conclusions Knowledge of incidence and distribution patterns of foot and ankle tumors will help to correctly assess unclear masses and initiate the right steps in further diagnostics and treatment. Unawareness can lead to delayed diagnosis and inadequate treatment with serious consequences for the affected patient.

Abstract Background Several surgical options for the reconstruction of massive bone defects have been described and include biologic methods with autografts and allografts, and the use of tumor endoprostheses (total femoral replacement, TFR). Several types of modular TFR are available, but nevertheless unpredictable outcomes and high complication rates have been described from most authors. The present study aims to compare results after TFR performed with modular total femur prosthesis MML (Fa. ESKA/Orthodynamics) in patients with and without malignant disease. Methods Retrospective chart review and functional investigation (Musculoskeletal Tumor Society (MSTS) score, Harris Hip Score (HHS), Oxford Knee Score (OKS), SF-12 Health Survey, and failure classification according to Henderson) of TFR cases from 1995 to 2011. Indications for TFR were malignant tumor resection from the femur (n = 9, Group A) or failure of a revision arthroplasty without history of malignant disease (n = 13, Group B). Results Thirty-six patients were treated during the study period, of whom 22 could be investigated clinically after a mean follow-up of 63 months. Overall failure rate for TFR was 59.1%, leading to 38 surgical revisions. The most common failure mechanisms were Type I (soft tissue), followed by Type IV (infection) and Type III (mechanical failure). Mean MSTS score out of 30 was 13 (range 1–25), with significantly higher scores in Group A (mean 19, range 3–25) than Group B (mean 9, range 1–15). Conclusion TFR is an established procedure to restore femoral integrity. However, complication rates are considerably high, and depend mainly on the age at initial reconstruction.

Urbanization is leading us to a more chaotic state where healthy living becomes a prime concern. The high-rise buildings influence the urban setting with a high shadow rate on surroundings that can have no positive impact on the general neighborhood. Nevertheless, shadows are the main factor of defeatist virtual settings, they are expensive to render in real-time. This paper investigates how the amount of sunlight varies by season and how seasons can indicate the time of year to understand how shadows vary in length at different times of the day and how they change over the seasons. We propose a novel efficient (fast and scalable) algorithm to calculate a 2.5D cast-shadow map from a given LiDAR-derived Digital Surface Model (DSM). We present a proof-of-concept demonstration to examine the technical practicability of the introduced algorithm. Tensor-based techniques such as singular value decomposition, tensor unfolding are examined and deployed to represent the multidimensional data. The proposed method exploits horizon mapping ideas and extends the method to a modern graphics algorithm (Bresenham’s line drawing algorithm) to account for the DSM’s underlying surface geometry. A proof-of-concept is developed utilizing Python’s TensorFlow library, exploring data flow graphs and the tensor data structure. The heavy computer graphics algorithm used in this paper is parallelized using PySpark. Results explicate significant enhancements in overall performance while preserving accuracy at negligible variations.

Abstract Background One-third of inflammatory bowel disease (IBD) patients show no response to infliximab (IFX) induction therapy, and approximately half of patients responding become unresponsive over time. Thus, identification of potential treatment response biomarkers are of great clinical significance. This study employs spectroscopy-based metabolic profiling of serum from patients with IBD treated with IFX and healthy subjects (1) to substantiate the use of spectroscopy as a semi-invasive diagnostic tool, (2) to identify potential biomarkers of treatment response and (3) to characterise the metabolic changes during management of patients with tumour necrosis factor-α inhibitors. Methods Successive serum samples collected during IFX induction treatment (weeks 0, 2, 6 and 14) from 87 IBD patients and 37 controls were analysed by 1H nuclear magnetic resonance (NMR) spectroscopy. Data were analysed with principal components analysis and orthogonal projection to latent structures discriminant analysis using SIMCA-P+ v12 and MATLAB. Results Metabolic profiles were significantly different between active ulcerative colitis and controls, active Crohn’s disease and controls, and quiescent Crohn’s disease and controls. Metabolites holding differential power belonged primarily to lipids and phospholipids with proatherogenic characteristics and metabolites in the pyruvate metabolism, suggestive of an intense inflammation-driven energy demand. IBD patients not responding to IFX were identified as a potentially distinct group based on their metabolic profile, although no applicable response biomarkers could be singled out in the current setting. Conclusion 1H NMR spectroscopy of serum samples is a powerful semi-invasive diagnostic tool in flaring IBD. With its use, we provide unique insights into the metabolic changes taking place during induction treatment with IFX. Of distinct clinical relevance is the identification of a reversible proatherogenic lipid profile in IBD patients with active disease, which partially explains the increased risk of cardiovascular disease associated with IBD.

Abstract Background The reconstruction of meta−/diaphyseal bone defects following bone tumour resection is challenging, and biological treatment options should be applied whenever possible, especially in benign lesions and early stage sarcomas. We aimed to evaluate the results of segmental (SR) and hemicortical reconstructions (HR) at the extremities using non-vascularised fibula grafts. Methods We retrospectively enrolled 36 patients who were treated with non-vascularised fibula reconstructions (15 SR, 21 HR) after bone tumour resection (15 malignant, 21 benign). All cases were evaluated regarding consolidation, hypertrophy at the graft-host junctions, and complications; moreover, the functional and oncological results were assessed. The mean follow-up was 8.3 years (2.1–26.6 years). Results Primary union was achieved in 94% (SR 87%, HR 100%) of patients, and 85% (SR 81%, HR 88%) showed hypertrophy at the graft-host junction. The overall complication rate was 36% with 4 patients (11%) developing local recurrence. There was a significant correlation between the development of mechanical complications (fracture, delayed-/non-union) and a defect size of ≥12 cm (p = 0.013), segmental defects (p = 0.013) and additional required treatment (p = 0.008). The functional outcome was highly satisfactory (mean MSTS score 86%). Conclusions Due to encouraging results and advantages (such as their remodelling capacity at the donor site), non-vascularised fibula reconstructions should be considered a valuable alternative treatment option for patients with hemicortical defects or segmental reconstructions of less than 12 cm in which no additional neo-/adjuvant treatment is necessary.

Abstract Background Soft tissue sarcomas are rare entities with over 50 histological subtypes. Liposarcoma (LS) is the most common neoplasm in this group; it is a complex neoplasm that is divided into different histological subtypes. Different therapy options, such as surgical resection, radiation, and chemotherapy, are available. Depending on the subtype, location, status of the resection margins and metastatic status, different therapy options are used. Therefore, the aim of this study was to determine the prognostic factors influencing the survival of patients affected by LS with consideration for the grading, histological subtype, state of the resection margin, size, location, metastases and local recurrence in a retrospective, single-centre analysis over 15 years. Methods We included 133 patients (male/female = 67/66) in this study. We recorded the histologic subtype, grade, TNM classification, localization, biopsy technique, tumour margins, number of operations, complications, radiation and dose, chemotherapy, survival, recrudescence, metastases and follow-up. Survivorship analysis was performed. Results We detected 56 (43%; 95%-CI 34.6–51.6%) atypical LS cases, 21 (16.2%; 95%-CI 9.8–22.5) dedifferentiated LS cases, 40 (30.8%; 95%-CI 22.8–38.7) myxoid LS cases and 12 (9.2%; 95%-CI 4.3–14.2) pleomorphic LS cases. G1 was the most common grade, which was followed by G3. Negative margins (R0) were detected in 67 cases (53.6%; 95%-CI 44.9–62.3) after surgical resection. Local recurrence was detected in 23.6% of cases. The presence of metastases and dedifferentiated LS subtype as well as negative margins, grade and tumour size are significant prognostic factors of the survival rates (p

Abstract Background The aim of this study was to compare the functional outcomes and complication rates after distal femoral replacement (DFR) performed with the modular Munich-Luebeck (MML) modular prosthesis (ESKA/Orthodynamics, Luebeck, Germany) in patients being treated for malignant disease or failed total knee arthroplasty. Methods A retrospective review of patient charts and a functional investigation (involving Musculoskeletal Tumor Society Score [MSTS], American Knee Society Score [AKSS], Oxford Knee Score [OKS], Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC], Toronto Extremity Salvage Score [TESS], the 12-Item Short-Form [SF-12] Health Survey, and a failure classification system developed by Henderson et al.) of DFR cases from 2002 to 2015 were conducted. The indications for DFR were malignant tumor resection in the femur (n = 20, group A) or failure of revision total knee arthroplasty without a history of malignant disease (n = 16, group B). Results One-hundred and twenty-nine patients were treated during the study period. Of these, 82 were analyzed for complications and implant-survival. Further, 36 patients were available for functional assessment after a mean follow-up of 86 months (range: 24–154). There were 75 complications in total. The overall failure rate for DFR was 64.6% (53/82 patients). The most common failure mechanisms were type III (mechanical failure), followed by type I (soft tissue) and type II (aseptic loosening). The mean MSTS score (out of 30) was 17 for group A and 12 for group B. All the clinical outcome scores revealed an age-dependent deterioration of function. Conclusion DFR is an established procedure to restore distal femoral integrity. However, complication rates are high. Post-procedure functionality depends mainly on the patient’s age at initial reconstruction.

Presents a study which examined the influence of concomitant drug therapy on the efficacy of atrial overdrive stimulation for prevention of atrial tachyarrhythmias. Methods; Results and discussion; Conclusions.

PURPOSE Extra-abdominal desmoid tumours are benign and rare, and lead to a persistent treatment dilemma because of their high recurrence rate and their heterogeneous behaviour. The goal of this retrospective study was to evaluate the results of different treatment modalities for extra-abdominal desmoid tumours at four sarcoma treatment centres. METHODS The mean follow-up time for the 96 patients included in the study (63.5% female; mean age 38.9 years) was 8.4 years (2.0–40.5 years). The initial treatments were surgery (n = 44), surgery with radiation (n = 16), watchful waiting (n = 15), radiation only (n = 9), or systemic treatment (n = 12). Patient demographics, tumour sites, and the follow-up status of all patients were reviewed and evaluated for each of the treatment modalities. RESULTS The local recurrence rate was 45.5% in patients with primary surgical treatment and 37.5% following surgery combined with irradiation. Patients who were treated with radiation alone showed regressive (33.3%) or stable disease (66.6%). Systemic treatment alone resulted in disease progression in 41.7% of our patients. In the watchful waiting group, 73.3% showed stable disease, 20.0% showed spontaneous regression, and 6.7% showed progression after a mean follow-up of 4.1 years (2.0–11.5 years). CONCLUSIONS Our results suggest that a watchful waiting approach should be the first line treatment in asymptomatic desmoid tumours. However, radiation can help improve local control rates in patients who have undergone surgery. Progression and local recurrence rates following systemic treatment were comparable to those observed in surgery combined with radiation.

Reactivation of interspersed repetitive sequences due to loss of methylation is associated with genomic instability, one of the hallmarks of cancer cells. LINE-1 hypomethylation is a surrogate marker for global methylation loss and is potentially a new diagnostic and prognostic biomarker in tumors. However, the correlation of LINE-1 hypomethylation with clinicopathological parameters and the CpG island methylator phenotype (CIMP) in patients with liver tumors is not yet well defined, particularly in Caucasians who show quite low rates of HCV/HBV infection and a higher incidence of liver steatosis. Therefore, quantitative DNA methylation analysis of LINE-1, RASSF1A, and CCND2 using pyrosequencing was performed in human hepatocellular carcinomas (HCC, n = 40), hepatocellular adenoma (HCA, n = 10), focal nodular hyperplasia (FNH, n = 5), and corresponding peritumoral liver tissues as well as healthy liver tissues (n = 5) from Caucasian patients. Methylation results were correlated with histopathological findings and clinical data. We found loss of LINE-1 DNA methylation only in HCC. It correlated significantly with poor survival (log rank test, p = 0.007). An inverse correlation was found for LINE-1 and RASSF1A DNA methylation levels (r2 = -0.47, p = 0.002). LINE-1 hypomethylation correlated with concurrent RASSF1/CCND2 hypermethylation (Fisher's exact test, p = 0.02). Both LINE-1 hypomethylation and RASSF1A/CCND2 hypermethylation were not found in benign hepatocellular tumors (HCA and FNH). Our results show that LINE-1 hypomethylation and RASSF1A/CCND2 hypermethylation are epigenetic aberrations specific for the process of malignant liver transformation. In addition, LINE-1 hypomethylation might serve as a future predictive biomarker to identify HCC patients with unfavorable overall survival.

Two complementary measurement systems-built upon an autonomous floating craft and a tethered balloon-for lake research and monitoring are presented. The autonomous vehicle was assembled on a catamaran for stability, and is capable of handling a variety of instrumentation for in situ and near-surface measurements. The catamaran hulls, each equipped with a small electric motor, support rigid decks for arranging equipment. An electric generator provides full autonomy for about 8 h. The modular power supply and instrumentation data management systems are housed in two boxes, which enable rapid setup. Due to legal restrictions in Switzerland (where the craft is routinely used), the platform must be observed from an accompanying boat while in operation. Nevertheless, the control system permits fully autonomous operation, with motion controlled by speed settings and waypoints, as well as obstacle detection. On-board instrumentation is connected to a central hub for data storage, with real-time monitoring of measurements from the accompanying boat. Measurements from the floating platform are complemented by mesoscale imaging from an instrument package attached to a He-filled balloon. The aerial package records thermal and RGB imagery, and transmits it in real-time to a ground station. The balloon can be tethered to the autonomous catamaran or to the accompanying boat. Missions can be modified according to imagery and/or catamaran measurements. Illustrative results showing the surface thermal variations of Lake Geneva demonstrate the versatility of the combined floating platform/balloon imagery system setup for limnological investigations.

With the current widespread use of dolutegravir in low-income countries, the understanding of the impact of nucleoside reverse transcriptase inhibitor (NRTI-) associated mutations on the efficacy of dolutegravir-containing antiretroviral therapy (ART) is of utmost importance. We describe a rare case of a patient with pre-existing M184V/I mutation and virological failure on a dolutegravir/lamivudine/abacavir regimen with the emergence of integrase strand transfer inhibitor resistance mutations. Additional risk factors, which may have triggered the virological failure, included suboptimal adherence and low nadir CD4+ cell count. This case illustrates that dolutegravir-containing triple-therapy should be prescribed with caution to patients with pre-existing M184V/I mutation and poor efficacy of the reverse transcriptase inhibitor backbone. In addition, this case highlights the need for viral load monitoring in patients on dolutegravir-containing regimens in settings with a high prevalence of the M184V/I mutation such as in low-income countries.

Therapies targeting programmed death 1-(PD-1) or its ligand (PD-L1), promoting antitumor T-cell activity have been successfully introduced into clinical practice. Clinical response correlates with PD-L1 expression by tumor cells or immune cells within the tumor microenvironment. The PD-L1/PD-1 axis and tumor microenvironment has been rarely studied in high-grade sarcomas of soft tissue (hSTS), a group of rare, genetically heterogenous and clinically aggressive tumors. We examined PD-L1 protein and CD274/PD-L1 gene copy number variations in 128 primary resected, therapy-naive hSTS using immunohistochemistry and fluorescence-in-situ hybridization. Frequency of tumoral PD-L1 expression varied widely in different disease subentities, with highest rates of positivity (40%) seen in undifferentiated pleomorphic sarcomas (UPS) and rare positivity detected in synovial sarcomas (6%). Amplification of the CD274/PD-L1 gene occurred in 14% of UPS and was rare in other subtypes. PD-L1 protein expression was significantly more frequent in CD274/PD-L1 amplified cases (p = 0.015). The subgroup of UPS was further characterized regarding the interaction between PD-L1 and the immunologic tumor microenvironment. High density of CD3+ and CD8+ tumor infiltrating lymphocytes (TILs) was significantly correlated with the presence of PD-L1 expression and seen more frequently in tumors with lower TNM stage (p = 0.024). Both, PD-L1 expression and high density lymphocytic infiltration were independent prognostic factors for a favorable overall (p = 0.001, HR 6.105 (2.041–8.258)), disease-specific (p = 0.003, HR 10.536 (2.186–50.774)) and disease-free survival (p = 0.020, HR 3.317 (1.209–9.106); values for CD8) in this particular subgroup of hSTS, whereas PD-L1 expression in TILs or CD274/PD-L1 gene amplification were not associated with outcome. These findings represent novel insights into the immune landscape of soft tissue sarcomas, in particular UPS and strengthen the rationale for immunotherapy, including targeting the PD-1/PD-L1 axis in these tumors.

Both unicameral bone cysts and intraosseous lipoma of the calcaneus are rare entities that are mostly diagnosed because of unspecific heel pain, pathologic fracture, or as incidental finding. Minimally invasive ossoscopy with endoscopic resection of the tumor followed by grafting can potentially minimize risks of open surgery and speed up convalescence. We present our modifications to previously described techniques of endoscopic curettage with a particular focus on intraosseous lipoma and allogenic grafting. The key point for grafting is the use of a funnel-shaped ear speculum facilitating the plombage with allogenic cancellous bone chips. Compared with its alternatives, grafting with allogenic cancellous bone might prove favorable in this localization for several reasons: osteointegration, handling, availability, and costs. The objective of this technical note is to present a simple, safe, and cost-effective surgical technique for endoscopic surgical treatment of benign osteolytic lesions of the calcaneus.

In patients with osteoarthritis (OA), intraarticular injection of hyaluronic acid (HA) frequently results in reduced pain and improved function for prolonged periods of time, i.e. more than 6 months. However, the mechanisms underlying these effects are not fully understood. Our underlying hypothesis is that HA modifies the enzymatic breakdown of joint tissues.To test this hypothesis, we examined osteochondral cylinders from 12 OA patients. In a bioreactor, these samples were stimulated by interleukin 1β (Il1ß) (2 ng/ml) plus mechanical load (2.0 Mpa at 0.5 Hz horizontal and 0.1 Hz vertical rotation), thus the experimental setup recapitulated both catabolic and anabolic clues of the OA joint.Upon addition of HA at either 1 or 3 mg/ml, we observed a significant suppression of expression of metalloproteinase (MMP)-13. A more detailed analysis based on the Kellgren and Lawrence (K&L) OA grade, showed a much greater degree of suppression of MMP-13 expression in grade IV as compared to grade II OA. In contrast to the observed MMP-13 suppression, treatment with HA resulted in a suppression of MMP-1 expression only at 1 mg/ml HA, while MMP-2 expression was not significantly affected by either HA concentration.Together, these data suggest that under concurrent catabolic and anabolic stimulation, HA exhibits a pronounced suppressive effect on MMP-13. In the long-run these findings may benefit the development of treatment strategies aimed at blocking tissue degradation in OA patients.

This paper presents an introduction to meso-scale transport modeling and issues of human behaviour in transport systems. Along with other examples of the human ability to learn in transport systems we look at the comparison of real life data and the prediction of modeling tools for the closure of Vienna’s inner ring road during the 2008 European Football Championship (EURO 2008). Some light is shed on the scientific question, whether currently used modeling tools are able to adequately reproduce the real-life behaviour of human beings in the transport system and should be used for transport policy decision making.

Traditional methods of measuring the capacities of infrastructures are usually based on indicators like passenger car units (PCU). It is quite clear that these methods of capacity evaluation (categories of roads, calculation procedures, capacity limits, e.g. defined in the HCM – Highway Capacity Manual) cannot be used to picture the intermodality of the traffic system. The first step has to include the intermodality (modal split) in the cross section of a road (pedestrians, bicycles, public transport, private vehicles), and in a further step it is necessary to account for all alternatives within the corridor, like parallel routed railways or public transport lines, to reach an intermodal point of view. Finally it is also necessary to include the effects on the settlement structure. Beside intermodality, any new method also has to consider cost effectiveness, a comprehensive consideration of feedbacks in the traffic system, as well as compatibility to CBA. As a result it is necessary to find new indicators (instead of car units) to define passenger and freight flows. There are guidelines in progress auditing transport operations and infrastructure conditions of roadways. A revision of these guidelines aims to integrate different modes of transport by changing the key-indicators (e.g. incline, curviness, roadway width, capacity utilisation) and to use a system approach which includes indicators like modal split, car occupancy or utilised capacity of lorries. The procedure presented in this paper can be seen as one building block to meet the demands of future assessments within corridors.

The pressure on a flat plate suspended over a submerged detonation is measured and simulated. Calculation and experiment are in relatively good agreement, although there is variation in experimental results and simulations are sensitive, near the centerline, to the computational details. This sensitivity is linked to the instability of the accelerating plume, typical of a Richtmyer-Meshkov instability. The plate loading features an initial force at plate center, followed by an expanding circular loading pattern. The initial load is due to plume impact, while the circular load arises from the impact of water transported up the edges of the explosion cavity.