Transcatheter Aortic Valve Implantation by Intercostal Access: Initial Experience with a No-Touch Technique.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) is now a well-established therapeutic option in an elderly high-risk patient cohort with aortic valve disease. Although most commonly performed via a transfemoral route, alternative approaches for TAVI are constantly being improved. Instead of the classical mini-sternotomy, it is possible to achieve a transaortic access via a right anterior mini-thoracotomy in the second intercostal space. We describe our experience with this sternum- and rib-sparing technique in comparison to the classical transaortic approach. METHODS: Our retrospective study includes 173 patients who were treated in our institution between January 2017 and April 2020 with transaortic TAVI via either upper mini-sternotomy or intercostal thoracotomy. The primary endpoint was 30-day mortality, and secondary endpoints were defined as major postoperative complications that included admission to the intensive care unit and overall hospital stay, according to the Valve Academic Research Consortium 3. RESULTS: Eighty-two patients were treated with TAo-TAVI by upper mini-sternotomy, while 91 patients received the intercostal approach. Both groups were comparable in age (mean age: 82 years) and in the proportion of female patients. The intercostal group had a higher rate of peripheral artery disease (41% vs. 22%, p = 0.008) and coronary artery disease (71% vs. 40%, p < 0.001) with a history of percutaneous coronary intervention or coronary artery bypass grafting, resulting in significantly higher preinterventional risk evaluation (EuroScore II 8% in the intercostal vs. 4% in the TAo group, p = 0.005). Successful device implantation and a reduction of the transvalvular gradient were achieved in all cases with a significantly lower rate of trace to mild paravalvular leakage in the intercostal group (12% vs. 33%, p < 0.001). The intercostal group required significantly fewer blood transfusions (0 vs. 2 units, p = 0.001) and tended to require less reoperation (7% vs. 15%, p = 0.084). Hospital stays (9 vs. 12 d, p = 0.011) were also shorter in the intercostal group. Short- and long-term survival in the follow-up showed comparable results between the two approaches (30-day, 6-month- and 2-year mortality: 7%, 23% and 36% in the intercostal vs. 9%, 26% and 33% in the TAo group) with acute kidney injury (AKI) and reintubation being independent risk factors for mortality. CONCLUSIONS: Transaortic TAVI via an intercostal access offers a safe and effective treatment of aortic valve stenosis.

Enzymatic activity of extracellular circulating proteasome in the CSF of patients with malignant Intrinsic and metastatic brain tumors: proof of concept.

BACKGROUND: Malignant intrinsic brain tumors are a hazardous disease with limited life expectancy despite intensive research in new targeted treatment options. Lately, proteasome inhibitors have been identified as potent agents causing death in glioma cell lines. It is the aim of the present study to identify proteasomal activity in the CSF of patients suffering from malignant brain tumors. METHODS: A total of 24 patients with histological confirmed brain tumors (12 malignant gliomas, 12 metastases) were included and CSF probes preoperatively analyzed for concentration and enzymatic activity of free circulating proteasome. Tumor volumina were assessed using the preoperative MRI and correlated with the CSF findings. Statistical analyses were performed using SPSS (18.0.3; SPSS Inc., Chicago, IL, USA). RESULTS: Extracellular proteasomes were found in all CSF samples showing enzymatic activity. Proteasome concentrations (28 ng/mL and 23 ng/mL, resp.) were elevated compared to a historical control group. Proteasomal enzymatic chymotrypsin-like activity was significantly raised in patients with gliomas (mean 31 fkat/ mL) compared to controls (P<0.049), whereas the enzymatic activity was not significantly elevated in metastases (P=0.109). In gliomas, neither concentration nor enzymatic activity correlated with the preoperative assessed tumor volume. CONCLUSIONS: This pilot study clearly showed that the proteasomal activity in the CSF is significantly elevated in patients with intrinsic brain tumors. Further studies need to identify the proteasomal concentration and enzymatic activity as a potential biomarker for the effectiveness of any treatment and for the early diagnosis of a possible recurrence of the disease.

Neurotrauma Emergencies during the SARS-CoV2 Pandemic at a Tertiary Medical Center: Analysis of Incidence and Outcome.

BACKGROUND: We assess the impact of lockdown in Germany due to the COVID-19 pandemic on the incidence and outcome of neurotrauma emergencies at a tertiary medical center. METHODS: All neurosurgical emergencies from March 16, 2020 (first lockdown in Germany) to January 31, 2021 were included and compared with a longitudinal case-cohort. Cases were descriptively recorded and retrospectively analyzed with respect to incidence and outcome. RESULTS: All emergencies defined as polytrauma referred to our center decreased by 10% during the pandemic (n = 226), whereas neurosurgical emergencies increased by 18.4% (764 vs. 905 cases). The number of specific neurotrauma emergencies increased by 44.4% (63 vs. 91 cases), yet statistically not significant (p = 0.245). The duration of treatment in the intensive care unit (ICU) extended from 621 to 1,056 days (p = 0.34). CONCLUSION: The reasons for the increase in the number of neurotrauma emergencies were the following: (1) many surrounding smaller care providers were canceled during this time and (2) there was a lack of free intensive care capacities in other hospitals, urging primarily maximum care providers to deal with more referrals. Both these facts and the prolonged treatment on ICUs strengthen the necessity for maximum care providers to keep ICU capacities for non-COVID patients. Specialized neurosurgical expertise should maintain in tertiary medical centers, even or particularly in exceptional circumstances such as the current pandemic.

Disposition Decision Support by Laboratory Based Outcome Prediction.

Disposition is one of the main tasks in the emergency department. However, there is a lack of objective and reliable disposition criteria, and diagnosis-based risk prediction is not feasible at early time points. The aim was to derive a risk score (TRIAL) based on routinely collected baseline (TRIage level and Age) and Laboratory data-supporting disposition decisions by risk stratification based on mortality. We prospectively included consecutive patients presenting to the emergency department over 18 weeks. Data sets of routinely collected baseline (triage level and age) and laboratory data were used for multivariable logistic regression to develop the TRIAL risk score predicting mortality. Routine laboratory variables and disposition cut-offs were chosen beforehand by expert consensus. Risk stratification was based on low risk (<1%), intermediate risk (1-10%), and high risk (>10%) of in-hospital mortality. In total, 8687 data sets were analyzed. Variables identified to develop the TRIAL risk score were triage level (Emergency Severity Index), age, lactate dehydrogenase, creatinine, albumin, bilirubin, and leukocyte count. The area under the ROC curve for in-hospital mortality was 0.93. Stratification according to the TRIAL score showed that 67.5% of all patients were in the low-risk category. Mortality was 0.1% in low-risk, 3.5% in intermediate-risk, and 26.2% in high-risk patients. The TRIAL risk score based on routinely available baseline and laboratory data provides prognostic information for disposition decisions. TRIAL could be used to minimize admission in low-risk and to maximize observation in high-risk patients.

Resection of cerebellar tumours causes widespread and functionally relevant white matter impairments.

Several diffusion tensor imaging studies reveal that white matter (WM) lesions are common in children suffering from benign cerebellar tumours who are treated with surgery only. The clinical implications of WM alterations that occur as a direct consequence of cerebellar disease have not been thoroughly studied. Here, we analysed structural and diffusion imaging data from cerebellar patients with chronic surgical lesions after resection for benign cerebellar tumours. We aimed to elucidate the impact of focal lesions of the cerebellum on WM integrity across the entire brain, and to investigate whether WM deficits were associated with behavioural impairment in three different motor tasks. Lesion symptom mapping analysis suggested that lesions in critical cerebellar regions were related to deficits in savings during an eyeblink conditioning task, as well as to deficits in motor action timing. Diffusion imaging analysis of cerebellar WM indicated that better behavioural performance was associated with higher fractional anisotropy (FA) in the superior cerebellar peduncle, cerebellum's main outflow path. Moreover, voxel-wise analysis revealed a global pattern of WM deficits in patients within many cerebral WM tracts critical for motor and non-motor function. Finally, we observed a positive correlation between FA and savings within cerebello-thalamo-cortical pathways in patients but not in controls, showing that saving effects partly depend on extracerebellar areas, and may be recruited for compensation. These results confirm that the cerebellum has extended connections with many cerebral areas involved in motor/cognitive functions, and the observed WM changes likely contribute to long-term clinical deficits of posterior fossa tumour survivors.

Validation of a German version of the Cerebellar Cognitive Affective/ Schmahmann Syndrome Scale: preliminary version and study protocol.

BACKGROUND: Traditionally, cerebellar disorders including ataxias have been associated with deficits in motor control and motor learning. Since the 1980's growing evidence has emerged that cerebellar diseases also impede cognitive and affective processes such as executive and linguistic functions, visuospatial abilities and regulation of emotion and affect. This combination of non-motor symptoms has been named Cerebellar Cognitive Affective/ Schmahmann Syndrome (CCAS). To date, diagnosis relies on non-standardized bedside cognitive examination and, if available, detailed neuropsychological test batteries. Recently, a short and easy applicable bedside test (CCAS Scale) has been developed to screen for CCAS. It has been validated in an US-American cohort of adults with cerebellar disorders and healthy controls. As yet, the CCAS Scale has only been available in American English. We present a German version of the scale and the study protocol of its ongoing validation in a German-speaking patient cohort. METHODS: A preliminary German version has been created from the original CCAS Scale using a standardized translation procedure. This version has been pre-tested in cerebellar patients and healthy controls including medical experts and laypersons to ensure that instructions are well understandable, and that no information has been lost or added during translation. This preliminary German version will be validated in a minimum of 65 patients with cerebellar disease and 65 matched healthy controls. We test whether selectivity and sensitivity of the German CCAS Scale is comparable to the original CCAS Scale using the same cut-off values for each of the test items, and the same pass/ fail criteria to determine the presence of CCAS. Furthermore, internal consistency, test-retest and interrater reliability will be evaluated. In addition, construct validity will be tested in a subset of patients and controls in whom detailed neuropsychological testing will be available. Secondary aims will be examination of possible correlations between clinical features (e.g. disease duration, clinical ataxia scores) and CCAS scores. PERSPECTIVE: The overall aim is to deliver a validated bedside test to screen for CCAS in German-speaking patients which can also be used in future natural history and therapeutic trials. STUDY REGISTRATION: The study is registered at the German Clinical Study Register (DRKS-ID: DRKS00016854).

Nonadiabatic coupling of the dynamical structure to the superconductivity in YSr2Cu2.75Mo0.25O7.54 and Sr2CuO3.3.

A crucial issue in cuprates is the extent and mechanism of the coupling of the lattice to the electrons and the superconductivity. Here we report Cu K edge extended X-ray absorption fine structure measurements elucidating the internal quantum tunneling polaron (iqtp) component of the dynamical structure in two heavily overdoped superconducting cuprate compounds, tetragonal YSr2Cu2.75Mo0.25O7.54 with superconducting critical temperature, Tc = 84 K and hole density p = 0.3 to 0.5 per planar Cu, and the tetragonal phase of Sr2CuO3.3 with Tc = 95 K and p = 0.6. In YSr2Cu2.75Mo0.25O7.54 changes in the Cu-apical O two-site distribution reflect a sequential renormalization of the double-well potential of this site beginning at Tc, with the energy difference between the two minima increasing by ∼6 meV between Tc and 52 K. Sr2CuO3.3 undergoes a radically larger transformation at Tc, >1-Šdisplacements of the apical O atoms. The principal feature of the dynamical structure underlying these transformations is the strongly anharmonic oscillation of the apical O atoms in a double-well potential that results in the observation of two distinct O sites whose Cu-O distances indicate different bonding modes and valence-charge distributions. The coupling of the superconductivity to the iqtp that originates in this nonadiabatic coupling between the electrons and lattice demonstrates an important role for the dynamical structure whereby pairing occurs even in a system where displacements of the atoms that are part of the transition are sufficiently large to alter the Fermi surface. The synchronization and dynamic coherence of the iqtps resulting from the strong interactions within a crystal would be expected to influence this process.

Diagnosis of COVID-19 by analysis of breath with gas chromatography-ion mobility spectrometry - a feasibility study.

BACKGROUND: There is an urgent need to rapidly distinguish COVID-19 from other respiratory conditions, including influenza, at first-presentation. Point-of-care tests not requiring laboratory- support will speed diagnosis and protect health-care staff. We studied the feasibility of using breath-analysis to distinguish these conditions with near-patient gas chromatography-ion mobility spectrometry (GC-IMS). METHODS: Independent observational prevalence studies at Edinburgh, UK, and Dortmund, Germany, recruited adult patients with possible COVID-19 at hospital presentation. Participants gave a single breath-sample for VOC analysis by GC-IMS. COVID-19 infection was identified by transcription polymerase chain reaction (RT- qPCR) of oral/nasal swabs together with clinical-review. Following correction for environmental contaminants, potential COVID-19 breath-biomarkers were identified by multi-variate analysis and comparison to GC-IMS databases. A COVID-19 breath-score based on the relative abundance of a panel of volatile organic compounds was proposed and tested against the cohort data. FINDINGS: Ninety-eight patients were recruited, of whom 21/33 (63.6%) and 10/65 (15.4%) had COVID-19 in Edinburgh and Dortmund, respectively. Other diagnoses included asthma, COPD, bacterial pneumonia, and cardiac conditions. Multivariate analysis identified aldehydes (ethanal, octanal), ketones (acetone, butanone), and methanol that discriminated COVID-19 from other conditions. An unidentified-feature with significant predictive power for severity/death was isolated in Edinburgh, while heptanal was identified in Dortmund. Differentiation of patients with definite diagnosis (25 and 65) of COVID-19 from non-COVID-19 was possible with 80% and 81.5% accuracy in Edinburgh and Dortmund respectively (sensitivity/specificity 82.4%/75%; area-under-the-receiver- operator-characteristic [AUROC] 0.87 95% CI 0.67 to 1) and Dortmund (sensitivity / specificity 90%/80%; AUROC 0.91 95% CI 0.87 to 1). INTERPRETATION: These two studies independently indicate that patients with COVID-19 can be rapidly distinguished from patients with other conditions at first healthcare contact. The identity of the marker compounds is consistent with COVID-19 derangement of breath-biochemistry by ketosis, gastrointestinal effects, and inflammatory processes. Development and validation of this approach may allow rapid diagnosis of COVID-19 in the coming endemic flu seasons. FUNDING: MR was supported by an NHS Research Scotland Career Researcher Clinician award. DMR was supported by the University of Edinburgh ref COV_29.

Local lattice distortions and dynamics in extremely overdoped superconducting YSr2Cu2.75Mo0.25O7.54.

A common characteristic of many "overdoped" cuprates prepared with high-pressure oxygen is Tc values ≥ 50 K that often exceed that of optimally doped parent compounds, despite O stoichiometries that place the materials at the edge or outside of the conventional boundary between superconducting and normal Fermi liquid states. X-ray absorption fine-structure (XAFS) measurements at 52 K on samples of high-pressure oxygen (HPO) YSr2Cu2.75Mo0.25O7.54, Tc = 84 K show that the Mo is in the (VI) valence in an unusually undistorted octahedral geometry with predominantly Mo neighbors that is consistent with its assigned substitution for Cu in the chain sites of the structure. Perturbations of the Cu environments are minimal, although the Cu X-ray absorption near-edge structure (XANES) differs from that in other cuprates. The primary deviation from the crystal structure is therefore nanophase separation into Mo- and Cu-enriched domains. There are, however, indications that the dynamical attributes of the structure are altered relative to YBa2Cu3O7, including a shift of the Cu-apical O two-site distribution from the chain to the plane Cu sites. Another effect that would influence Tc is the possibility of multiple bands at the Fermi surface caused by the presence of the second phase and the lowering of the Fermi level.

Local structure of Sr2CuO3.3, a 95 K cuprate superconductor without CuO2 planes.

The local structure of the highly "overdoped" 95 K superconductor Sr2CuO3.3 determined by Cu K X-ray absorption fine structure (XAFS) at 62 K in magnetically oriented samples shows that 1) the magnetization is perpendicular to the c axis; 2) at these levels of precision the Cu sublattice is tetragonal in agreement with the crystal structure; the O sublattice has 3) continuous -Cu-O- chains that orient perpendicular to an applied magnetic field; 4) approximately half-filled -Cu-O- chains that orient parallel to this field; 5) a substantial number of apical O vacancies; 6) O ions at some apical positions with expanded Cu-O distances; and 7) interstitial positions that imply highly displaced Sr ions. These results contradict the universally accepted features of cuprates that require intact CuO2 planes, magnetization along the c axis, and a termination of the superconductivity when the excess charge on the CuO2 Cu ions exceeds 0.27. These radical differences in charge and structure demonstrate that this compound constitutes a separate class of Cu-O-based superconductors in which the superconductivity originates in a different, more complicated structural unit than CuO2 planes while retaining exceptionally high transition temperatures.

Palladium oxidation leads to methane combustion activity: Effects of particle size and alloying with platinum.

Pd- and Pt-based catalysts are highly studied materials due to their widespread use in emissions control catalysis. However, claims continue to vary regarding the active phase and oxidation state of the metals. Different conclusions have likely been reached due to the heterogeneous nature of such materials containing various metal nanoparticle sizes and compositions, which may each possess unique redox features. In this work, using uniform nanocrystal catalysts, we study the effect of particle size and alloying on redox properties of Pd-based catalysts and show their contribution to methane combustion activity using operando quick extended x-ray absorption fine structure measurements. Results demonstrate that for all studied Pd sizes (3 nm-16 nm), Pd oxidation directly precedes CH4 combustion to CO2, suggesting Pd oxidation as a prerequisite step to methane combustion, and an oxidation pretreatment shows equal or better catalysis than a reduction pretreatment. Results are then extended to uniform alloyed PtxPd1-x nanoparticles, where oxidative pretreatments are shown to enhance low-temperature combustion. In these uniform alloys, we observe a composition-dependent effect with Pt-rich alloys showing the maximum difference between oxidative and reductive pretreatments. In Pt-rich alloys, we initially observe that the presence of Pt maintains Pd in a lower-activity reduced state. However, with time on stream, PdO eventually segregates under oxidizing combustion conditions, leading to a slowly increasing activity. Overall, across particle sizes and alloy compositions, we relate increased catalytic activity to Pd oxidation, thus shedding light on previous contrasting results related to the methane combustion activity of these catalysts.

Trust in socially assistive robots: Considerations for use in rehabilitation.

Incorporation of social robots into rehabilitation calls for understanding what factors affect user motivation and success of the interaction. Trust between the user and the robot has been identified as important in human-robot interaction and in human-human interactions in therapy. Trust has been studied in the context of automation technology, (e.g., autonomous cars), but not in the context of social robots for rehabilitation. In this narrative review, we address the unique patient-clinician-robot triad, and argue that this context calls for specific design features in order to foster trust with the users. We review pertinent methods for measuring trust, and studies demonstrating that culture, prior experience and propensity-to-trust affect to what extent users trust robots. We suggest design guidelines for fostering trust and methods for measuring trust in human-robot interactions in rehabilitation. We stress the need to create measures of trust that are accessible to people who suffer from speech or cognitive impairments. This review is pertinent to researchers, roboticists, and clinicians interested in designing and using social robots for rehabilitation.

Association of Surgical Resection, Disability, and Survival in Patients with Glioblastoma.

OBJECTIVE: Extent of resection (EOR) and Karnofsky Performance Status (KPS) are at odds in glioblastoma (GBM) surgery, that is, the anticipated postoperative disability limits the EOR. This study analyzes the correlation of different surgical modalities with the resulting physical status and survival of patients with GBM. METHODS: A total of 565 patients with primary GBM were operated on in a single institution between 2006 and 2014. Possible surgical modalities comprised supratotal resection (SLR), gross total resection (GTR; ≥ 95% by volume), tumor debulking (TDB; ≤ 95% by volume), and stereotactic biopsy (SB). Pre- and postoperative KPS before and up to 4 weeks after surgery as well as overall survival (OS) rate were determined retrospectively. Hazard ratio (HR) and 95% confidence intervals were calculated using a Cox proportional hazards model. RESULTS: Median postoperative KPS was ≥ 70, irrespective of surgical modality. Mean OS was 12.5 months. Multivariate analysis revealed age ≥ 70 years (HR: 1.93), preoperative KPS < 70 (HR: 2.15), and unmethylation in MGMT promoter (HR: 1.27) as independent factors for worse OS. Regarding surgical modality, SB was associated with the worst survival (HR: 2.3) followed by TDB (HR: 1.36). SLR was inferior to GTR (HR: 1.27). CONCLUSION: Higher EOR in patients with GBM does not seem inevitably correlated with increasing functional impairment, but better survival, provided there is a balanced preoperative indication. Nevertheless, SLR does not seem to be superior to GTR. Whenever possible, maximal safe resection should be considered in patients with GBM, even if an EOR ≥ 95% is not possible.

Use of ambiguous detections to improve estimates from species distribution models.

As large carnivores recover throughout Europe, their distribution needs to be studied to determine their conservation status and assess the potential for human-carnivore conflicts. However, efficient monitoring of many large carnivore species is challenging due to their rarity, elusive behavior, and large home ranges. Their monitoring can include opportunistic sightings from citizens in addition to designed surveys. Two types of detection errors may occur in such monitoring schemes: false negatives and false positives. False-negative detections can be accounted for in species distribution models (SDMs) that deal with imperfect detection. False-positive detections, due to species misidentification, have rarely been accounted for in SDMs. Generally, researchers use ad hoc data-filtering methods to discard ambiguous observations prior to analysis. These practices may discard valuable ecological information on the distribution of a species. We investigated the costs and benefits of including data types that may include false positives rather than discarding them for SDMs of large carnivores. We used a dynamic occupancy model that simultaneously accounts for false negatives and positives to jointly analyze data that included both unambiguous detections and ambiguous detections. We used simulations to compare the performances of our model with a model fitted on unambiguous data only. We tested the 2 models in 4 scenarios in which parameters that control false-positive detections and true detections varied. We applied our model to data from the monitoring of the Eurasian lynx (Lynx lynx) in the European Alps. The addition of ambiguous detections increased the precision of parameter estimates. For the Eurasian lynx, incorporating ambiguous detections produced more precise estimates of the ecological parameters and revealed additional occupied sites in areas where the species is likely expanding. Overall, we found that ambiguous data should be considered when studying the distribution of large carnivores through the use of dynamic occupancy models that account for misidentification.

Social robots in rehabilitation: A question of trust.

Social robots can help meet the growing need for rehabilitation assistance; measures for creating and maintaining trust in human-robot interactions should be priorities when designing social robots for rehabilitation.

Cerebral arterio-venous malformations in the paediatric population: Angiographic characteristics, multimodal treatment strategies and outcome.

OBJECTIVES: Cerebral arterio-venous malformations (AVM) are considered congenital lesions, emerging as an important cause of haemorrhagic stroke in children. The potential influence of age on clinical presentation and angio-architecture have been analysed extensively in the last years. Yet, comparative studies comprising ascending age groups may be limited in their conclusions, especially when comparing young children and adults. It is the aim of this study to evaluate characteristic clinical and angiographic features of AVM within a paediatric subgroup and their correlation to age at presentation. PATIENTS AND METHODS: Between 1990-2015, 46 children harbouring AVMs were treated at our institution. Clinical presentation, radiological data, treatment strategies and outcome were evaluated retrospectively. RESULTS: Of 46 consecutive patients, 18 were male and 28 female patients. Mean age was 11.6±4.3years, ranging from 2 to 17 years. 35 patients (76%) presented with haemorrhage. Seizures were found in 6 patients (13%) and progressive or transient focal neurological deficits in 4 individuals (9%). There was one incidental patient, only. Mean age of children presenting with haemorrhage was significantly lower as compared to those without a history of intracranial bleeding (p=0.1). The size of the AVM was small (n=27, 59%), corresponding a grade I AVM in the majority of patients (N=28, 61%). 41 patients (89%) underwent treatment of their AVM by an interdisciplinary approach achieving complete elimination of the lesion in 34 patients (83%). 34 patients (83%) showed at least a favourable outcome (mRS≤2) at last follow-up. An excellent recovery (mRS 0-1) was noted in 28 patients (68%). CONCLUSION: From our data we suggest that patients' age impacts the clinical presentation. Particularly young children seem to bear a higher risk for haemorrhage from their AVM. Treatment of paediatric AVMs can be achieved safely in experienced hands with a high rate of complete elimination and good clinical outcome.

Study of angiogenic signaling pathways in hemangioblastoma.

Hemangioblastoma (HB) is mainly located in the brain and the spinal cord. The tumor is composed of two major components, namely neoplastic stromal cells and abundant microvessels. Thus, hyper-vascularization is the hallmark of this tumor. Despite the identification of germline and/or epigenetic mutations of Von Hippel Lindau (VHL) gene as an important pathogenic mechanism of HB, little is known about the molecular signaling involved in this highly vascularized tumor. The present study investigated the key players of multiple angiogenic signaling pathways including VEGF/VEGFR2, EphB4/EphrinB2, SDF1α/CXCR4 and Notch/Dll4 pathways in surgical specimens of 22 HB. The expression of key angiogenic factors was detected by RT2 -PCR and Western blot. Immunofluorescent staining revealed the cellular localization of these proteins. We demonstrated a massive upregulation of mRNA levels of VEGF and VEGFR2, CXCR4 and SDF1α, EphB4 and EphrinB2, as well as the main components of Dll4-Notch signaling in HB. An increase in the protein expression of VEGF, CXCR4 and the core-components of Dll4-Notch signaling was associated with an activation of Akt and Erk1/2 and accompanied by an elevated expression of PCNA. Immuofluorescent staining revealed the expression of VEGF and CXCR4 in endothelial cells as well as in tumor cells. Dll4 protein was predominantly found in tumor cells, whereas EphB4 immunoreactivity was exclusively detected in endothelial cells. We conclude that multiple key angiogenic pathways were activated in HB, which may synergistically contribute to the abundant vascularization in this tumor. Identification of these aberrant pathways provides potential targets for a possible future application of anti-angiogenic therapy for this tumor, particularly when a total surgical resection becomes difficult due to the localization or multiplicity of the tumor.

Evaluation of the application of rhino-septal splints in endoscopic transsphenoidal skull base surgery.

The endoscopic transnasal route for the surgical removal of tumors in the sellar region is frequently associated with nasal complications such as synechiae or impaired nasal breathing. In this study, we investigated the impact of septal splints on avoiding surgery-related co-morbidities. 49 patients in whom endoscopic transnasal, transsphenoidal surgery for sellar tumors was performed between 2012 and 2014 were studied. In 30 of these, nasal septal splints were applied at the end of surgery to both sides of the septum and left in situ for 10 days (group 1), 19 patients received no splints (group 2). A standardized postsurgical follow-up investigation with endoscopic nasal examination, rhinomanometry and olfactory testing was performed on average 2 months postoperatively. Patients' subjective nose-related discomfort at follow-up was assessed descriptively using a set of standardized self-rating statements on nasal problems. Synechias occurred less likely with nasal septal splints (n = 15; 50 %) than without (n = 16; 84.2 %). Moreover, multiple synechiae were predominantly observed in the group without septal splints (n = 10 vs. n = 2). Rhinomanometry showed improved flow-V150-inspiration scores when splints were used (with significant differences between groups for the left nostril: p = 0.039 and p = 0.022, resp.). In accordance, impaired nasal breathing after surgery was reported more frequently by 76.9 % of patients without splints, but only 56 % of patients with splints. Our results provide support for the application of nasal septal splints when operating endoscopically on tumors in the sellar region to reduce postoperative synechias and to improve nasal breathing.

Critical analysis of anatomical landmarks within the sphenoid sinus for transsphenoidal surgery.

The transsphenoidal approach to the sellar region has been introduced more than a 100 years ago. It is the accepted standard operative corridor to pathologies of the pituitary gland and surrounding structures. There are anatomical landmarks within the sphenoid sinus that are used for orientation directing to the sella floor or the cavernous sinus. Yet, little data can be found on the consistency of these landmarks. It is the aim of this study to evaluate the reliability of these anatomical landmarks for the surgeon's orientation. A total of 245 computed tomography (CT) volume data sets of the cranium performed according to a standardized protocol were analyzed for study purposes. CT scans of the cranium of 125 patients admitted to the emergency room of our hospital receiving a trauma spiral according to the local protocol were employed as a control group when no pathology in the sellar region was observed. In addition, preoperative CT scans of a group of 120 patients diagnosed with pituitary adenomas between 2009 and 2013 were analyzed. Image analysis of the anatomical landmarks included the minimal intercarotid distance (ICD), diameter of the sphenoid sinus (DSS), direction of the septum sinuum sphenoidalium (SSS), and the distance between vomer and clivus (VCD). The overall mean ICD was 16.2 mm, with patients suffering from adenomas showing a mean ICD of 15.8 mm compared with an average 16.5 mm in the control group. DSS was equal for both groups (adenoma group: mean 31.5 mm; controls: mean 31.3 mm). Mean VCD was 27.9 mm in patients with pituitary adenomas compared with 26.7 mm in controls. A septum of the sphenoid sinus located in the midline was found in overall 23 % only. SSS was directed into the bony shield of the internal carotid artery in 28 % of underlying tumors and in 37 % of the control group. This is the first detailed description of landmarks of the sphenoid sinus based on a large radiologic-anatomical analysis of CT scans yielding a wide variation and high inconsistency of these landmarks. From out data, we suggest that the surgeon approaching the sphenoid sinus should handle the anatomical landmarks with care bearing their inconsistency in mind. A thorough planning of the procedure up front is highly recommended. Usage of a navigation system considering the bony structures might as well facilitate as steady the approach to the sellar region in some cases for the patient's sake.

Activation of multiple angiogenic signaling pathways in hemangiopericytoma.

Hemangiopericytoma (HPC) is a highly vascularized mesenchymal tumor. Local recurrence and distant metastasis are common features of HPC. Considering the remarkable hyper-vasculature phenotype of HPC, we assumed that dysregulated angiogenic signaling pathways were involved in HPC. The key components of angiogenic signaling pathways including VEGF-VEGF-R2, EphrinB2-EphB4 and DLL4-Notch were examined by real-time RT-PCR, Western blotting and immunostaining in 17 surgical specimens of HPC patients and in 6 controls. A significant upregulation of VEGF and VEGF-R2 associated with elevated levels of p-Akt and proliferating cell nuclear antigen (PCNA) was detected in HPC. Moreover, a dramatic increase in the mRNA and protein expression of EphB4 and its downstream factor p-Erk1/2 was found in HPC. A massive activation of core-components of DLL4-Notch signaling was detected in HPC. Double-immunofluorescent staining confirmed the expression of these upregulated key factors in the endothelial cells of tumor vessels. The present study identified the activation of multiple and crucial angiogenic signaling pathways, which could function individually and/or synergistically to stimulate angiogenesis in HPC and eventually contribute to tumor growth and progression. Our findings emphasize the importance to target multiple angiogenic signaling pathways when an anti-angiogenic therapy is considered for this highly vascularized tumor.