Stereotactic ultrahypofractionated MR-guided radiotherapy for localized prostate cancer - Acute toxicity and patient-reported outcomes in the prospective, multicenter SMILE phase II trial.

Background: Due to superior image quality and daily adaptive planning, MR-guided stereotactic body radiation therapy (MRgSBRT) has the potential to further widen the therapeutic window in radiotherapy of localized prostate cancer. This study reports on acute toxicity rates and patient-reported outcomes after MR-guided adaptive ultrahypofractionated radiotherapy for localized prostate cancer within the prospective, multicenter phase II SMILE trial. Materials and methods: A total of 69 patients with localized prostate cancer underwent MRgSBRT with daily online plan adaptation. Inclusion criteria comprised a tumor stage ≤ T3a, serum PSA value ≤ 20 ng/ml, ISUP Grade group ≤ 4. A dose of 37.5 Gy was prescribed to the PTV in five fractions on alternating days with an optional simultaneous boost of 40 Gy to the dominant intraprostatic lesion defined by multiparametric MRI. Acute genitourinary (GU-) and gastrointestinal (GI-) toxicity, as defined by CTCAE v. 5.0 and RTOG as well as patient-reported outcomes according to EORTC QLQ-C30 and -PR25 scores were analyzed at completion of radiotherapy, 6 and 12 weeks after radiotherapy and compared to baseline symptoms. Results: There were no toxicity-related treatment discontinuations. At the 12-week follow-up visit, no grade 3 + toxicities were reported according to CTCAE. Up until the 12-week visit, in total 16 patients (23 %) experienced a grade 2 GU or GI toxicity. Toxicity rates peaked at the end of radiation therapy and subsided within the 12-week follow-up period. At the 12-week follow-up visit, no residual grade 2 GU toxicities were reported and 1 patient (1 %) had residual grade 2 enteritic symptoms. With exception to a significant improvement in the emotional functioning score following MRgSBRT, no clinically meaningful changes in the global health status nor in relevant subscores were reported. Conclusion: Daily online-adaptive MRgSBRT for localized prostate cancer resulted in an excellent overall toxicity profile without any major negative impact on quality of life.

Sedation, sleep-promotion, and non-verbal and verbal communication techniques in critically ill intubated or tracheostomized patients: results of a survey.

BACKGROUND: The aim of this survey was to describe, on a patient basis, the current practice of sedation, pharmacologic and non-pharmacologic measures to promote sleep and facilitation of communication in critically ill patients oro-tracheally intubated or tracheostomized. METHODS: Cross-sectional online-survey evaluating sedation, sleep management and communication in oro-tracheally intubated (IP) or tracheostomized (TP) patients in intensive care units on a single point. RESULTS: Eighty-one intensive care units including 447 patients (IP: n = 320, TP: n = 127) participated. A score of ≤ -2 on the Richmond Agitation Sedation Scale (RASS) was prevalent in 58.2% (IP 70.7% vs. TP 26.8%). RASS -1/0 was present in 32.2% (IP 25.9% vs. TP 55.1%) of subjects. Propofol and alpha-2-agonist were the predominant sedatives used while benzodiazepines were applied in only 12.1% of patients. For sleep management, ear plugs and sleeping masks were rarely used (< 7%). In half of the participating intensive care units a technique for phonation was used in the tracheostomized patients. CONCLUSIONS: The overall rate of moderate and deep sedation appears high, particularly in oro-tracheally intubated patients. There is no uniform sleep management and ear plugs and sleeping masks are only rarely applied. The application of phonation techniques in tracheostomized patients during assisted breathing is low. More efforts should be directed towards improved guideline implementation. The enhancement of sleep promotion and communication techniques in non-verbal critically ill patients may be a focus of future guideline development.

Precision dosing software to optimize antimicrobial dosing: a systematic search and follow-up survey of available programs.

BACKGROUND: Precision dosing programs are promising tools for optimising antimicrobial dosing. Selecting the ideal program for local application may be challenging due to the large variety of available programs with differing characteristics. OBJECTIVES: The objectives of this study were to systematically identify available precision dosing software programs to optimize antimicrobial dosing and describe the characteristics of each program. Details on the ability of programs to provide beta-lactam dosing support was also gathered. SOURCES: A systematic review search strategy was used to identify candidate software programs described in the literature in Embase and PubMed. A detailed survey was then developed to identify characteristics of programs, including details on the underlying methodology driving dosing software recommendations, interface characteristics, costs and regulatory affairs. Software developers from all identified programs were invited to participate in the survey. CONTENT: The systematic search results identified 18 programs. Fifteen developers responded to the survey (83%) and 11 programs provide dosing support for at least one beta-lactam. Fourteen programs can utilize measured drug concentrations to generate dosing recommendations, with 13 able to generate empiric dosing recommendations. Six programs integrate with local electronic health records and four are registered with at least one regulatory agency. Pharmacokinetic models in combination with Bayesian statistics is the most common methodology used to generate dosing recommendations, with 14 programs utilizing this method. IMPLICATIONS: There was significant variability in the available antimicrobial profiles and characteristics among dosing software programs. As healthcare providers will differ in their requirements within their local settings, clinicians should use these findings to identify potential candidate programs and, if feasible, trial these to ensure they meet their specific requirements.

[Generations Y and Z-New challenges for hospital leadership]. / Die Generationen Y und Z ­ Neue Herausforderungen für Führungskräfte im Krankenhaus.

BACKGROUND AND OBJECTIVE: In this study medical students of the generations Y and Z at the Georg-August University Göttingen were asked about their preferences in the workplace and the choice of an employer. MATERIAL AND METHODS: In 2016, the survey was sent to 2637 students at the University Medical Center Göttingen using an online questionnaire via EvaSys and was answered by 742 (response rate: 28.1%). RESULTS: Regardless of the generation, with 89.5% the respondents felt predominantly "well" and "not so well" prepared for the transition from university to professional life. The most common fears were a lot of work/little free time, lack of time in patient care, lack of experience, stress, excessive technical demands and poor familiarization. In both groups almost 60% obtained information about future employers via the hospital's website. It was important for the students to have a particularly good education and a structured induction/advanced training curriculum. CONCLUSION: The further development of a structured induction concept for young professionals, a binding and structured further training curriculum, the establishment or further development of a mentoring program, the further development of leadership skills and the design of an appealing and updated website are essential prerequisites for future success in the highly competitive skilled labor market.

Surveillance of surgical site infections: methodical comparison of the IQTIG and KISS strategies.

Aim: In 2017, the Institute for Quality Assurance and Transparency in Healthcare (IQTIG) introduced a quality assurance system for the surveillance of surgical site infections (SSI) on behalf the Federal Joint Committee. The establishment of the new system was made in parallel to existing methods, such as the "Krankenhaus-Infektions-Surveillance-System" (KISS). The aim of this work was to perform a comparative analysis. Methods: All 2,233 cases at the University Medical Center Goettingen requiring an assessment of the presence of SSI as part of the IQTIG procedure in 2018 and 2019 were evaluated retrospectively according to the KISS protocol. Results: In total, 2,050 patients were included in the comparative evaluation. Overall, 1,779 (79.7%) had a surgical anamnesis (surgery during the stay or in the past), and 1,716 (83.7%) showed identical results for both surveillance strategies. Different results were found for 334 patients (16.3%), with 160 of these (7.8%) positive for SSI according to IQTIG and 174 (8.5%) positive for KISS. Risk factors were identified for a discordant assessment between the methods. Conclusion: The congruence of the two strategies was consistently high over the study period. There is evidence that the efficiency of the documentation algorithm can be increased without the loss of documentation of SSI, while preserving the precision of the documentation through training.

Stability and reproducibility of 6013 deep inspiration breath-holds in left-sided breast cancer.

PURPOSE: Patients with left-sided breast cancer frequently receive deep inspiration breath-hold (DIBH) radiotherapy to reduce the risk of cardiac side effects. The aim of the present study was to analyze intra-breath-hold stability and inter-fraction breath-hold reproducibility in clinical practice. MATERIAL AND METHODS: Overall, we analyzed 103 patients receiving left-sided breast cancer radiotherapy using a surface-guided DIBH technique. During each treatment session the vertical motion of the patient was continuously measured by a surface guided radiation therapy (SGRT) system and automated gating control (beam on/off) was performed using an audio-visual patient feedback system. Dose delivery was automatically triggered when the tracking point was within a predefined gating window. Intra-breath-hold stability and inter-fraction reproducibility across all fractions of the entire treatment course were analyzed per patient. RESULTS: In the present series, 6013 breath-holds during beam-on time were analyzed. The mean amplitude of the gating window from the baseline breathing curve (maximum expiration during free breathing) was 15.8 mm (95%-confidence interval: [8.5-30.6] mm) and had a width of 3.5 mm (95%-CI: [2-4.3] mm). As a measure of intra-breath-hold stability, the median standard deviation of the breath-hold level during DIBH was 0.3 mm (95%-CI: [0.1-0.9] mm). Similarly, the median absolute intra-breath-hold linear amplitude deviation was 0.4 mm (95%-CI: [0.01-2.1] mm). Reproducibility testing showed good inter-fractional reliability, as the maximum difference in the breathing amplitudes in all patients and all fractions were 1.3 mm on average (95%-CI: [0.5-2.6] mm). CONCLUSION: The clinical integration of an optical surface scanner enables a stable and reliable DIBH treatment delivery during SGRT for left-sided breast cancer in clinical routine.

B-Lines for the assessment of extravascular lung water: Just focused or semi-quantitative?

BACKGROUND: B-lines as typical artefacts of lung ultrasound are considered as surrogate measurement for extravascular lung water. However, B-lines develop in the sub-pleural space and do not allow assessment of the whole lung. Here, we present data from the first observational multi-centre study focusing on the correlation between a B-lines score and extravascular lung water in critically ill patients suffering from a variety of diseases. PATIENTS AND METHODS: In 184 adult patients, 443 measurements were obtained. B-lines were counted and expressed in a score which was compared to extravascular lung water, measured by single-indicator transpulmonary thermodilution. Appropriate correlation coefficients were calculated and receiver operating characteristics (ROC-) curves were plotted. RESULTS: Overall, B-lines score was correlated with body weight-indexed extravascular lung water characterized by r = .59. The subgroup analysis revealed a correlation coefficient in patients without an infection of r = .44, in those with a pulmonary infection of r = .75 and in those with an abdominal infection of r = .23, respectively. Using ROC-analysis the sensitivity and specificity of B-lines for detecting an increased extravascular lung water (>10 mL/kg) was 63% and 79%, respectively. In patients with a P/F ratio <200 mm Hg, sensitivity and specificity to predict an increased extravascular lung water was 71% and 93%, respectively. CONCLUSIONS: Assessment of B-lines does not accurately reflect actual extravascular lung water. In presence of an impaired oxygenation, B-lines may reliably indicate increased extravascular lung water as cause of the oxygenation disorders.

The time course of muscle-tendon properties and function responses of a five-minute static stretching exercise.

The purpose of this study was to investigate the time course of the changes of muscle-tendon mechanical properties and the function responses of the plantar flexor muscles following 5 × 60 s of static stretching. Fourteen healthy volunteers were tested on four separate days in a random order with three different rest times (0, 5, 10 min) after 5 × 60 s of stretching or following a control period without stretching. During each test, the dorsiflexion range of motion (RoM), passive resistive torque (PRT), and maximum voluntary contraction (MVC) were measured with a dynamometer. Ultrasonography of the gastrocnemius medialis (GM) muscle-tendon junction displacement and motion capture allowed us to determine the length changes in the tendon and muscle, respectively, and hence to calculate their stiffness. We observed an increase in RoM and decrease in MVC at 0, 5, and 10 min post-stretching. This could be attributed to an increase in muscle elongation which lasted at least 10 min. A decrease in muscle-tendon stiffness was observed immediately, but not 5 or 10 min after the stretching. A decrease in PRT and muscle stiffness was observed up to 5 min after the stretching. No changes were detected in tendon stiffness or in any variable in the control group. The effects of a 5 × 60 s static stretching exercise changes the muscle-tendon functions (RoM, MVC), which are related to mechanical changes of the muscle but not the tendon structure, respectively. Although the functional changes last for at least 10 min, changes in muscle stiffness were only observed up to 5 min after the stretching exercise.

Tumour Necrosis Factor-α Inhibition Improves Stroke Outcome in a Mouse Model of Rheumatoid Arthritis.

Rheumatoid Arthritis (RA) is a chronic inflammatory disorder where incidence and severity of myocardial infarction are increased. Data on the incidence and outcome of stroke are conflicting. Thus, we investigated outcome after Ischemia/Reperfusion (I/R) brain injury in a mouse model of RA and assessed for the role of the tumour necrosis factor-α (TNF-α) inhibitor Infliximab herein. We used a TNF-α reliant mouse model of RA. RA and wildtype (WT) animals were treated with vehicle (RA/WT) or Infliximab (RA Infliximab) for 4 weeks, before undergoing I/R brain injury. RA-animals displayed larger strokes and poorer neurological performance. Immunohistochemistry on brain sections revealed increased numbers of resident and peripheral innate immune cells (microglia and macrophages); increased Blood-Brain-Barrier (BBB)-disruption; decreased levels of the tight junction proteins (TJPs) claudin-5 and occludin; increased expression of matrix-metalloproteinases (MMP)-3 and -9 and enhanced lipid peroxidation. Treatment with Infliximab corrected these alterations. We show that RA associates to worse stroke-outcome via exacerbated BBB degradation by decrease of the TJPs claudin-5 and occludin. We identified MMPs-3 and -9 and increased oxidative stress as potential mediators thereof. Increased numbers of resident and peripheral innate immune cells (microglia and macrophages) may in turn contribute to all these effects. Infliximab-treatment restored the phenotype of RA-mice to baseline. Our data provide evidence clearly linking RA to adverse stroke-outcome in mice and indicate an approved TNF-α inhibitor as a potential strategy to reduce stroke-burden in this setting.

Optical Surface Scanning for Patient Positioning in Radiation Therapy: A Prospective Analysis of 1902 Fractions.

PURPOSE/OBJECTIVE: Reproducible patient positioning remains one of the major challenges in modern radiation therapy. Recently, optical surface scanners have been introduced into clinical practice in addition to well-established positioning systems, such as room laser and skin marks. The aim of this prospective study was to evaluate setup errors of the optical surface scanner Catalyst HD (C-RAD AB) in different anatomic regions. MATERIAL/METHODS: Between October 2016 and June 2017 a total of 1902 treatment sessions in 110 patients were evaluated. The workflow of this study included conventional setup procedures using laser-based positioning with skin marks and an additional registration of the 3-dimensional (3D) deviations detected by the Catalyst system. The deviations of the surface-based method were then compared to the corrections of cone beam computed tomography alignment which was considered as gold standard. A practical Catalyst setup error was calculated between the translational deviations of the surface scanner and the laser positioning. Two one-sided t tests for equivalence were used for statistical analysis. RESULTS: Data analysis revealed total deviations of 0.09 mm ± 2.03 mm for the lateral axis, 0.07 mm ± 3.21 mm for the longitudinal axis, and 0.44 mm ± 3.08 mm vertical axis for the Catalyst system, compared to -0.06 ± 3.54 mm lateral, 0.53 ± 3.47 mm longitudinal, and 0.19 ± 3.49 mm vertical for the laser positioning compared to cone beam computed tomography. The lowest positional deviations were found in the cranial region, and larger deviations occurred in the thoracic and abdominal sites. A statistical comparison using 2 one-sided t tests showed a general concordance of the 2 methods ( P ≤ 0.036), excluding the vertical direction of the abdominal region ( P = 0.198). CONCLUSION: The optical surface scanner Catalyst HD is a reliable and feasible patient positioning system without any additional radiation exposure. From the head to the thoracic and abdominal region, a decrease in accuracy was observed within a comparable range for Catalyst and laser-assisted positioning.

Real-time intra-fraction motion management in breast cancer radiotherapy: analysis of 2028 treatment sessions.

BACKGROUND: Intra-fraction motion represents a crucial issue in the era of precise radiotherapy in several settings, including breast irradiation. To date, only few data exist on real-time measured intra-fraction motion in breast cancer patients. Continuous surface imaging using visible light offers the capability to monitor patient movements in three-dimensional space without any additional radiation exposure. The aim of the present study was to quantify the uncertainties of possible intra-fractional motion during breast radiotherapy. MATERIAL AND METHODS: One hundred and four consecutive patients that underwent postoperative radiotherapy following breast conserving surgery or mastectomy were prospectively evaluated during 2028 treatment sessions. During each treatment session the patients' motion was continuously measured using the Catalyst™ optical surface scanner (C-RAD AB, Sweden) and compared to a reference scan acquired at the beginning of each session. The Catalyst system works through an optical surface imaging with light emitting diode (LED) light and reprojection captured by a charge coupled device (CCD) camera, which provide target position control during treatment delivery with a motion detection accuracy of 0.5 mm. For 3D surface reconstruction, the system uses a non-rigid body algorithm to calculate the distance between the surface and the isocentre and using the principle of optical triangulation. Three-dimensional deviations and relative position differences during the whole treatment fraction were calculated by the system and analyzed statistically. RESULTS: Overall, the maximum magnitude of the deviation vector showed a mean change of 1.93 mm ± 1.14 mm (standard deviation [SD]) (95%-confidence interval: [0.48-4.65] mm) and a median change of 1.63 mm during dose application (beam-on time only). Along the lateral and longitudinal axis changes were quite similar (0.18 mm ± 1.06 mm vs. 0.17 mm ± 1.32 mm), on the vertical axis the mean change was 0.68 mm ± 1.53 mm. The mean treatment session time was 154 ± 53 (SD) seconds and the mean beam-on time only was 55 ± 16 s. According to Friedman's test differences in the distributions of the three possible directions (lateral, longitudinal and vertical) were significant (p < 0.01), in post-hoc analysis there were no similarities between any two of the three directions. CONCLUSION: The optical surface imaging system is an accurate and easy tool for real-time motion management in breast cancer radiotherapy. Intra-fraction motion was reported within five millimeters in all directions. Thus, intra-fraction motion in our series of 2028 treatment sessions seems to be of minor clinical relevance in postoperative radiotherapy of breast cancer.

Low Altitude Solar Magnetic Reconnection, Type III Solar Radio Bursts, and X-ray Emissions.

Type III solar radio bursts are the Sun's most intense and frequent nonthermal radio emissions. They involve two critical problems in astrophysics, plasma physics, and space physics: how collective processes produce nonthermal radiation and how magnetic reconnection occurs and changes magnetic energy into kinetic energy. Here magnetic reconnection events are identified definitively in Solar Dynamics Observatory UV-EUV data, with strong upward and downward pairs of jets, current sheets, and cusp-like geometries on top of time-varying magnetic loops, and strong outflows along pairs of open magnetic field lines. Type III bursts imaged by the Murchison Widefield Array and detected by the Learmonth radiospectrograph and STEREO B spacecraft are demonstrated to be in very good temporal and spatial coincidence with specific reconnection events and with bursts of X-rays detected by the RHESSI spacecraft. The reconnection sites are low, near heights of 5-10 Mm. These images and event timings provide the long-desired direct evidence that semi-relativistic electrons energized in magnetic reconnection regions produce type III radio bursts. Not all the observed reconnection events produce X-ray events or coronal or interplanetary type III bursts; thus different special conditions exist for electrons leaving reconnection regions to produce observable radio, EUV, UV, and X-ray bursts.

3D faces are recognized more accurately and faster than 2D faces, but with similar inversion effects.

Recognition of faces typically occurs via holistic processing where individual features are combined to provide an overall facial representation. However, when faces are inverted, there is greater reliance on featural processing where faces are recognized based on their individual features. These findings are based on a substantial number of studies using 2-dimensional (2D) faces and it is unknown whether these results can be extended to 3-dimensional (3D) faces, which have more depth information that is absent in the typical 2D stimuli used in face recognition literature. The current study used the face inversion paradigm as a means to investigate how holistic and featural processing are differentially influenced by 2D and 3D faces. Twenty-five participants completed a delayed face-matching task consisting of upright and inverted faces that were presented as both 2D and 3D stereoscopic images. Recognition accuracy was significantly higher for 3D upright faces compared to 2D upright faces, providing support that the enriched visual information in 3D stereoscopic images facilitates holistic processing that is essential for the recognition of upright faces. Typical face inversion effects were also obtained, regardless of whether the faces were presented in 2D or 3D. Moreover, recognition performances for 2D inverted and 3D inverted faces did not differ. Taken together, these results demonstrated that 3D stereoscopic effects influence face recognition during holistic processing but not during featural processing. Our findings therefore provide a novel perspective that furthers our understanding of face recognition mechanisms, shedding light on how the integration of stereoscopic information in 3D faces influences face recognition processes.

Omega-3 fatty acids predict recurrent venous thromboembolism or total mortality in elderly patients with acute venous thromboembolism.

Essentials The role of omega-3 fatty acids (n-3 FAs) in recurrent venous thromboembolism (VTE) is unknown. Association of n-3 FAs with recurrent VTE or total mortality was investigated in 826 patients. Whole blood n-3 FAs were inversely correlated with recurrent VTE or total mortality. Major and non-major bleeding was not increased in patients with higher levels of n-3 FAs. SUMMARY: Background The role of omega-3 fatty acids (n-3 FAs) in recurrent venous thromboembolism (VTE) remains unknown. Objectives To investigate the association of n-3 FAs with recurrent VTE or total mortality at 6 months and 3 years. Methods N-3 FAs were assessed in 826 patients aged ≥ 65 years, categorized into low, medium and high based on the 25th and 75th percentile. Mean follow-up was 29 months. Results At 6 months, subjects with medium (adjusted hazard ratio [HR], 0.37; 95% confidence interval [CI], 0.22-0.62) and high n-3 FA levels (adjusted HR, 0.36; 95% CI, 0.20-0.67) were less likely to develop recurrent VTE or total mortality, compared with those with low n-3 FAs. At 3 years, medium levels (adjusted HR, 0.67; 95% CI, 0.47-0.96) were associated with lower risk of recurrent VTE or total mortality. As compared with low n-3 FAs, the adjusted sub-hazard ratio [SHR] of recurrent VTE was 0.39 (95% CI, 0.15-0.99) in patients with medium and 0.17 (95% CI, 0.03-0.82) in patients with high n-3 FAs. The cumulative incidence of recurrent VTE was lower in the medium and high n-3 FA groups as compared with the low n-3 FA groups, but seems to have worn off after 3 years. The incidence of major and non-major bleeding was not greater in the high n-3 FA group. Conclusion Higher levels of n-3 FAs were associated with a lower risk of recurrent VTE or total mortality in elderly patients with VTE, but not with greater bleeding risk.

Right frontal gamma and beta band enhancement while solving a spatial puzzle with insight.

Solving a problem with an "a-ha" effect is known as insight. Unlike incremental problem solving, insight is sudden and unique, and the question about its distinct brain activity, intrigues many researchers. In this study, electroencephalogram signals were recorded from 12 right handed, human participants before (baseline) and while they solved a spatial puzzle known as the '10 coin puzzle' that could be solved incrementally or by insight. Participants responded as soon as they reached a solution and reported whether the process was incremental or by sudden insight. EEG activity was recorded from 19 scalp locations. We found significant differences between insight and incremental solvers in the Gamma and Beta 2 bands in frontal areas (F8) and in the alpha band in right temporal areas (T6). The right-frontal gamma indicates a process of restructuring which leads to an insight solution, in spatial problems, further suggesting a universal role of gamma in restructuring. These results further suggest that solving a spatial puzzle via insight requires exclusive brain areas and neurological-cognitive processes which may be important for meta-cognitive components of insight solutions, including attention and monitoring of the solution.

WEB as part of a multimodality treatment in complex, large, and partially thrombosed intracranial aneurysms: a single-center observational study of technical success, safety, and recurrence.

INTRODUCTION: Complex, large, wide-neck aneurysms, but particularly partially thrombosed intracranial aneurysms (PTIAs), have a greater tendency to recanalize after coil occlusion. The Woven Endovascular Bridge (WEB) combines shape memory wires braided to a relatively uniform, dense surface, which may limit its compaction and its incorporation into an existing aneurysm clot and may thus reduce PTIA recurrence. OBJECTIVE: To carry out a retrospective analysis of our experience with the WEB as part of a complex treatment in conjunction with other implants to assess the efficacy and safety of this technique. METHODS: Among 43 aneurysms treated with the WEB in our center, eight complex, large, wide-neck aneurysms were treated in conjunction with other implants (additional WEBs, coils, stents, flow diverters). Six of these eight aneurysms were PTIAs. All patients were followed up by DSA between 3½ and 38 months. RESULTS: All eight (100%) of the complex, large, wide-neck aneurysms were treated successfully and without periprocedural adverse events (0%). At follow-up, the two non-thrombosed aneurysms were completely occluded, but all six PTIAs recurred (75%) and were re-treated. There was no morbidity or mortality in these eight patients. CONCLUSIONS: Treatment of large, complex aneurysms with the WEB in conjunction with other implants was technically successful and safe but did not prevent recurrence of partially thrombosed aneurysms in our center. PTIA re-treatment was possible and not limited by the previously placed WEB.

Risk factors for bone pain among patients with cancer receiving myelosuppressive chemotherapy and pegfilgrastim.

PURPOSE: The purpose of this study was to evaluate risk factors for bone pain in patients receiving myelosuppressive chemotherapy and pegfilgrastim. METHODS: Individual patient data from 22 pegfilgrastim clinical trials were analyzed. Multivariable logistic regression models were used to evaluate risk factors associated with grade ≥2 bone pain and any grade bone pain in the first chemotherapy cycle and across cycles 1-6. RESULTS: Of the 1949 patients analyzed, 19 and 36 % had grade ≥2 and any grade bone pain, respectively, in cycle 1, and 28 and 51 % had grade ≥2 and any grade bone pain, respectively, across cycles 1-6. In cycle 1, history of bone pain (odds ratio (OR), 1.51; 95 % confidence interval (CI), 1.09-2.07) was associated with increased risk of grade ≥2 bone pain; age ≥65 years (versus <45 years; OR, 0.64; 95 % CI, 0.42-0.98), the European Union region (versus the USA region; OR, 0.32; 95 % CI, 0.20-0.52), colorectal cancer (versus breast cancer; OR, 0.14; 95 % CI, 0.05-0.41), and small-cell lung cancer (OR, 0.34; 95 % CI, 0.12-0.98) were associated with reduced risk of grade ≥2 bone pain. CONCLUSIONS: Potential risk factors for bone pain in patients receiving myelosuppressive chemotherapy and primary prophylactic pegfilgrastim identified in this study are younger age and history of bone pain. No other association with clinical factors and risk of bone pain was detected. Better understanding of risk factors for bone pain would be useful in identifying patients who may benefit from pain prevention strategies.

Post-ischaemic silencing of p66Shc reduces ischaemia/reperfusion brain injury and its expression correlates to clinical outcome in stroke.

AIM: Constitutive genetic deletion of the adaptor protein p66(Shc) was shown to protect from ischaemia/reperfusion injury. Here, we aimed at understanding the molecular mechanisms underlying this effect in stroke and studied p66(Shc) gene regulation in human ischaemic stroke. METHODS AND RESULTS: Ischaemia/reperfusion brain injury was induced by performing a transient middle cerebral artery occlusion surgery on wild-type mice. After the ischaemic episode and upon reperfusion, small interfering RNA targeting p66(Shc) was injected intravenously. We observed that post-ischaemic p66(Shc) knockdown preserved blood-brain barrier integrity that resulted in improved stroke outcome, as identified by smaller lesion volumes, decreased neurological deficits, and increased survival. Experiments on primary human brain microvascular endothelial cells demonstrated that silencing of the adaptor protein p66(Shc) preserves claudin-5 protein levels during hypoxia/reoxygenation by reducing nicotinamide adenine dinucleotide phosphate oxidase activity and reactive oxygen species production. Further, we found that in peripheral blood monocytes of acute ischaemic stroke patients p66(Shc) gene expression is transiently increased and that this increase correlates with short-term neurological outcome. CONCLUSION: Post-ischaemic silencing of p66(Shc) upon reperfusion improves stroke outcome in mice while the expression of p66(Shc) gene correlates with short-term outcome in patients with ischaemic stroke.

The effect of filgrastim or pegfilgrastim on survival outcomes of patients with cancer receiving myelosuppressive chemotherapy.

BACKGROUND: Primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) is associated with higher chemotherapy relative dose intensity, which may lead to improved outcomes; however, the association between G-CSF primary prophylaxis and overall survival (OS) is not well characterized. This study assessed the effect of G-CSF primary prophylaxis on patient outcomes in randomized, controlled, registrational clinical trials of filgrastim and pegfilgrastim. PATIENTS AND METHODS: Three placebo-controlled and two non-inferiority clinical trials of filgrastim and/or pegfilgrastim in patients receiving myelosuppressive chemotherapy for lung, breast, or colorectal cancer were included. The median OS, 6- and 12-month survival rates, and hazard ratios [HRs; unadjusted Cox model with 95% confidence intervals (CIs)] were estimated for patients receiving ≥1 dose of filgrastim, pegfilgrastim, or placebo. Comparisons were based on a log-rank test. A fixed-effect meta-analysis assessed the effect of primary prophylaxis with filgrastim/pegfilgrastim on OS in the placebo-controlled trials. RESULTS: In patients with lung cancer receiving filgrastim versus placebo, the median OS was 14.1 versus 11.1 months (HR, 0.81; 95% CI 0.48-1.35; P = 0.412); in patients who crossed over to filgrastim from placebo after cycle 1, the median OS was 16.9 months (HR, 0.75; 95% CI 0.43-1.28; P = 0.286). The median OS was inestimable in at least one treatment arm in the other studies because of the small number of OS events. Where estimable, 6- and 12-month survival rates were generally greater among patients receiving filgrastim/pegfilgrastim versus placebo. In the meta-analysis of placebo-controlled studies comparing G-CSF primary prophylaxis with placebo in the as-treated analysis sets, the HR (95% CI) for OS was 0.77 (0.58-1.03). CONCLUSIONS: In this retrospective analysis, OS point estimates were greater among patients receiving filgrastim versus placebo, but the differences were not statistically significant. Further studies evaluating patient outcomes with G-CSF prophylaxis are warranted. CLINICAL TRIAL REGISTRATION: NCT00035594, NCT00094809.

Candidemia in the intensive care unit: analysis of direct treatment costs and clinical outcome in patients treated with echinocandins or fluconazole.

Direct treatment costs caused by candidemia in German intensive care unit (ICU) patients are currently unknown. We analyzed treatment costs and the impact of antifungal drug choice. Comprehensive data of patients who had at least one episode of candidemia while staying in the ICU between 01/2005 and 12/2010 were documented in a database using the technology of the Cologne Cohort of Neutropenic Patients (CoCoNut). A detailed analysis of all disease-associated treatment costs was performed. Patients treated with echinocandins (i.e., anidulafungin, caspofungin, micafungin) or fluconazole were analyzed separately and compared. Forty-one and 64 patients received echinocandins and fluconazole, respectively. The mean Acute Physiology and Chronic Health Evaluation (APACHE) IV score was 114 (95 % confidence interval [CI]: 106-122) vs. 95 (95 % CI: 90-101, p = <0.001). Twenty-three (56 %) and 33 (52 %, p = 0.448) patients survived hospitalization, while 17 (41 %) and 22 (34 %, p = 0.574) survived one year after diagnosis. In the echinocandin and fluconazole groups, the mean costs per patient of ICU treatment were 20,338 (95 % CI: 12,893-27,883) vs. 11,932 (95 % CI: 8,016-15,849, p = 0.110), and the total direct treatment costs per patient were 37,995 (95 % CI: 26,614-49,376) vs. 22,305 (95 % CI: 16,817-27,793, p = 0.012), resulting in daily costs per patient of 1,158 (95 % CI: 1,036-1,280) vs. 927 (95 % CI: 828-1,026, p = 0.001). Our health economic analysis shows the high treatment costs of patients with candidemia in the ICU. Sicker patients had a prolonged hospitalization and were more likely to receive echinocandins, leading to higher treatment costs. Outcomes were comparable to those achieved in less sick patients with fluconazole.