Duration of and time to response in oncology clinical trials from the perspective of the estimand framework.

Duration of response (DOR) and time to response (TTR) are typically evaluated as secondary endpoints in early-stage clinical studies in oncology when efficacy is assessed by the best overall response and presented as the overall response rate. Despite common use of DOR and TTR in particular in single-arm studies, the definition of these endpoints and the questions they are intended to answer remain unclear. Motivated by the estimand framework, we present relevant scientific questions of interest for DOR and TTR and propose corresponding estimand definitions. We elaborate on how to deal with relevant intercurrent events which should follow the same considerations as implemented for the primary response estimand. A case study in mantle cell lymphoma illustrates the implementation of relevant estimands of DOR and TTR. We close the paper with practical recommendations to implement DOR and TTR in clinical study protocols.

Propensity score stratified MAP prior and posterior inference for incorporating information across multiple potentially heterogeneous data sources.

Incorporation of external information is becoming increasingly common when designing clinical trials. Availability of multiple sources of information has inspired the development of methodologies that account for potential heterogeneity not only between the prospective trial and the pooled external data sources but also between the different external data sources themselves. Our approach proposes an intuitive way of handling such a scenario for the continuous outcomes setting by using propensity score-based stratification and then utilizing robust meta-analytic predictive priors for each stratum to incorporate the prior data to distinguish among different external data sources in each stratum. Through extensive simulations, our approach proves to be more efficient and less biased than the currently available methods. A real case study using clinical trials that study schizophrenia from multiple different sources is also included.

Pharmacometrics enhanced Bayesian borrowing approach to improve clinical trial efficiency: Case of empagliflozin in type 2 diabetes.

We report use of a pharmacometrics enhanced Bayesian borrowing (PEBB) approach to leverage historical clinical trial data on a drug product to build models, project the outcome of future clinical trials, and borrow information from these projections to improve the efficiency of future target trials. This design takes a two-stage approach. First, a design phase is performed before target trial data are available to determine the operating characteristics and an appropriate tuning parameter that will be used in the subsequent analysis phase of a chosen target trial. Second, once the target trial data are available, the analysis phase is performed with the determined tuning parameter. This step is where borrowing is applied from these projections to inform the results for the target trial. To illustrate how a PEBB could improve the efficiency of clinical trials, we apply our design to trials with empagliflozin for treating patients with type 2 diabetes. We performed a retrospective evaluation applying the method to a phase III target trial and a hypothetical smaller trial. The type I error could be kept below 10% while increasing the trial power and effective sample size. Our findings suggest that a PEBB has the potential to increase the power of clinical trials, while controlling for type I error, by leveraging the information from previous trials through population pharmacokinetic/pharmacodynamic modeling and simulation.

Real-world evidence for the effectiveness and safety of dupilumab in patients with CRSwNP after 1 year of therapy.

Objectives: For nearly 3 years, the monoclonal antibody dupilumab has been approved in Germany for the treatment of patients with chronic rhinosinusitis with nasal polyps (CRSwNP). Although efficacy has been demonstrated in large double-blind, placebo-controlled clinical trials, few reports of real-world data on this therapy have been published to date. Methods: Patients with an indication for treatment with dupilumab for CRSwNP were included in the study and followed up every 3 months for a period of 1 year. At the baseline visit, demographic data, medical history, comorbidities, nasal polyp score, disease-related quality of life (SNOT-22), nasal congestion, and sense of smell (VAS and Sniffin Sticks test) were recorded. In addition, total blood eosinophil counts and serum total IgE were measured. During follow-up, all of the described parameters and possible adverse events were recorded. Results: Eighty-one patients were enrolled in the study, of whom 68 patients were still receiving dupilumab after 1 year of follow-up. Eight patients discontinued therapy, with only 1 patient discontinuing due to severe side effects. The Polyp score decreased substantially during follow-up, and parameters for disease-related quality of life and sense of smell increased significantly. Total IgE levels decreased significantly, and eosinophils leveled off at baseline after an initial increase after three months of therapy. No clinical data could be identified to a priori predict a treatment response. Conclusions: Dupilumab shows effectiveness and safety in the treatment of CRSwNP under real-world conditions. More research on systemic biomarkers and clinical parameters to predict treatment response is necessary.

Nasal residence time and rheological properties of a new bentonite-based thixotropic gel emulsion nasal spray - AM-301.

OBJECTIVE: The present work provides characterization of rheological properties of a new bentonite-based thixotropic gel emulsion nasal spray (AM-301), its nasal residence time, distribution, safety and tolerability. SIGNIFICANCE: The nasal epithelium is a portal of entry for allergens and primary infection by airborne pathogens. Non-pharmacological interventions, which enhance physical and biological barriers, protect against allergens and pathogens without drug-related side effects. AM-301 has shown promising efficacy and safety in the nasal epithelium against viruses (in vitro) and pollen (clinical). METHODS: Technical part (i) spray characterization was performed with a validated droplet size distribution method; evaluation of the rheological properties of the formulation was performed by a validated amplitude sweep method and a validated oscillation, rotation, oscillation; Clinical part (ii) nasal and oropharyngeal endoscopy were used to provide a semi-quantitative evaluation of distribution and residence time of fluorescein-labelled AM-301 in the nose and oropharynx of healthy volunteers; (iii) tolerability and safety. RESULTS: (i) The non-Newtonian rheological properties of the formulation allow AM-301 to be sprayed and then to revert to a gel to prevent run-off from the nasal cavity; (ii) the formulation remains on the inferior turbinate, septum and oropharynx of volunteers for up to 210 min and on the middle turbinate for up to 60 min; two nasal sprays provide no substantial benefit over a single application with regards to coverage or retention; (iii) the spray is well tolerated. CONCLUSIONS: Single dose spray delivery of AM-301 provides extended coverage of the nasal mucosa up to the inferior turbinates.

A transfacet approach to the lumbar nerve root canal: technical note.

BACKGROUND: Intraforaminal and extraforaminal nerve root compressions caused by disk herniation or stenosis are relatively common causes of lumbar radiculopathy. Currently, the two available surgical treatment methods are decompression from the spinal canal or lateral decompression via the Wiltse approach. OBJECTIVE: To describe a novel transosseous approach to the lumbar nerve root canal. METHODS: Transfacet foraminotomy was performed in 11 patients with intraforaminal or extraforaminal disk herniation. The outcome was measured using the Patient Satisfaction Index (PSI), need for reoperation, radiographic criteria, and finite element analysis. RESULTS: We noted that at the time of dismissal, PSI scores of 1 and 3 were reported by 10 and one patients, respectively. At the last follow-up, 10 patients reported a PSI score of 1 or 2. Two patients required reoperation because of recurrent disk herniation. Two patients underwent computed tomography (CT) postoperatively, which showed the transfacet approach. Intriguingly, a second postoperative CT after one month showed that the hole through the facet joint had shrunk significantly. CONCLUSION: A posterior-anterior transfacet approach for intraforaminal or extraforaminal disk herniations using an ellipsoid facetectomy is safe and allows for fast and comfortable decompression of the nerve root without compromising the long-term strength of the facet joint.

Xenon-Enhanced Dynamic Dual-Energy CT Is Able to Quantify Sinus Ventilation Using Laminar and Pulsating Air-/Gas Flow Before and After Surgery: A Pilot Study in a Cadaver Model.

Background: Chronic rhinosinusitis is a common disease with a significant impact on the quality of life. Topical drug delivery to the paranasal sinuses is not efficient to prevent sinus surgery or expensive biologic treatment in a lot of cases as the affected mucosa is not reached. More efficient approaches for topical drug delivery are, therefore, necessary. In the current study, dual-energy CT (DECT) imaging was used to examine sinus ventilation before and after sinus surgery using a pulsating xenon gas ventilator in a cadaver head. Methods: Xenon gas was administered to the nasal cavity of a cadaver head with a laminar flow of 7 L/min and with pulsating xenon-flow (45 Hz frequency, 25 mbar amplitude). Nasal cavity and paranasal sinuses were imaged by DECT. This procedure was repeated after functional endoscopic sinus surgery (FESS). Based on the enhancement levels in the different sinuses, regional xenon concentrations were calculated. Results: Xenon-related enhancement could not be detected in most of the sinuses during laminar gas flow. By superimposing laminar flow with pulsation, DECT imaging revealed a xenon wash-in and wash-out in the sinuses. After FESS, xenon enhancement was immediately seen in all sinuses and reached higher concentrations than before surgery. Conclusion: Xenon-enhanced DECT can be used to visualize and quantify sinus ventilation. Pulsating air-/gas flow was superior to laminar flow for the administration of xenon to the paranasal sinuses. FESS leads to successful ventilation of all paranasal sinuses.

ENT Residents Benefit from a Structured Operation Planning Approach in the Training of Functional Endoscopic Sinus Surgery.

Background and Objectives: Preoperative planning utilizing computed tomographies (CT) is of utmost importance in functional endoscopic sinus surgery (FESS). Frequently, no uniform documentation and planning structures are available to residents in training. Consequently, overall completeness and quality of operation planning may vary greatly. The objective of the present study was to evaluate the impact of a structured operation planning (SOP) approach on the report quality and user convenience during a 4-day sinus surgery course. Materials and Methods: Fifteen participant were requested to plan a FESS procedure based on a CT scan of the paranasal sinuses that exhibited common pathological features, in a conventional manner, using a free text. Afterwards, the participants reevaluated the same scans by means of a specifically designed structured reporting template. Two experienced ENT surgeons assessed the collected conventional operation planning (COP) and SOP methods independently with regard to time requirements, overall quality, and legibility. User convenience data were collected by utilizing visual analogue scales. Results: A significantly greater time expenditure was associated with SOPs (183 s vs. 297 s, p = 0.0003). Yet, legibility (100% vs. 72%, p < 0.0001) and overall completeness (61.3% vs. 22.7%, p < 0.0001) of SOPs was significantly superior to COPs. Additionally, description of highly relevant variants in anatomy and pathologies were outlined in greater detail. User convenience data delineated a significant preference for SOPs (VAS 7.9 vs. 6.9, p = 0.0185). Conclusions: CT-based planning of FESS procedures by residents in training using a structured approach is more time-consuming while producing a superior report quality in terms of detailedness and readability. Consequently, SOP can be considered as a valuable tool in the process of preoperative evaluations, especially within residency.

Incidence and Outcome of Aneurysmal Subarachnoid Hemorrhage: The Swiss Study on Subarachnoid Hemorrhage (Swiss SOS).

BACKGROUND AND PURPOSE: The purpose of this study was to assess nationwide incidence and outcomes of aneurysmal subarachnoid hemorrhage (aSAH). The Swiss SOS (Swiss Study on Subarachnoid Hemorrhage) was established in 2008 and offers the unique opportunity to provide this data from the point of care on a nationwide level. METHODS: All patients with confirmed aneurysmal subarachnoid hemorrhage admitted between January 1, 2009 and December 31, 2014, within Switzerland were recorded in a prospective registry. Incidence rates were calculated based on time-matched population data. Admission parameters and outcomes at discharge and at 1 year were recorded. RESULTS: We recorded data of 1787 consecutive patients. The incidence of aneurysmal subarachnoid hemorrhage in Switzerland was 3.7 per 100 000 persons/y. The number of female patients was 1170 (65.5%). With a follow-up rate of 91.3% at 1 year, 1042 patients (58.8%) led an independent life according to the modified Rankin Scale (0-2). About 1 in 10 patients survived in a dependent state (modified Rankin Scale, 3-5; n=185; 10.4%). Case fatality was 20.1% (n=356) at discharge and 22.1% (n=391) after 1 year. CONCLUSIONS: The current incidence of aneurysmal subarachnoid hemorrhage in Switzerland is lower than expected and an indication of a global trend toward decreasing admissions for ruptured intracranial aneurysms. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03245866.

Long-Term Reduction of Sacroiliac Joint Pain With Peripheral Nerve Stimulation.

BACKGROUND: We recently demonstrated that 86% of the patients treated with peripheral nerve stimulation (PNS) for therapy-refractory sacroiliac joint (SIJ) pain were satisfied with the result after 1 year of treatment. OBJECTIVE: To investigate the long-term (up to 4 years) response rate of this novel treatment. METHODS: Sixteen consecutive patients with therapy-refractory SIJ pain were treated with PNS and followed for 4 years in 3 patients, 3 years in 6 patients, and 2 years in 1 patient. Quality of life, pain, and patient satisfaction were assessed using the Oswestry Disability Index 2.0, Visual Analog Scale (VAS), and International Patient Satisfaction Index. RESULTS: Patients reported a pain reduction from 8.8 to 1.6 (VAS) at 1 year ( P < .001), and 13 of 14 patients (92.9%) rated the therapy as effective (International Patient Satisfaction Index score ≤ 2). At 2 years, average pain score was 1.9 ( P < .001), and 9 of 10 patients (90.0%) considered the treatment a success. At 3 years, 8 of 9 patients (88.9%) were satisfied with the treatment results, reporting an average VAS of 2.0 ( P < .005). At 4 years, 2 of 3 patients were satisfied with the treatment results. CONCLUSION: We have shown for the first time that PNS is a successful long-term therapy for SIJ pain.

Neonatal hypoxia-ischemia in rat increases doublecortin concentration in the cerebrospinal fluid.

Doublecortin (DCX) is a microtubule-associated protein widely used as an indicator of neurogenesis in immunohistochemical analyses of the postmortem adult brain. A recent study reported that DCX can be quantified in the cerebrospinal fluid (CSF) from healthy rats between postnatal day 0 (P0) and P30. However, it is currently unclear whether the concentration of DCX in the CSF (CSF-DCX) may represent a measure of endogenous neurogenesis. To address this question, this study examined the impact of a neonatal hypoxic-ischemic (HI) brain injury, known to induce neurogenesis, on CSF-DCX. HI was elicited at P7 in Sprague-Dawley rat neonates, and CSF was collected serially from the cisterna magna at P5 and P10, or at P10 and P15. A sandwich immunoassay was used to measure CSF-DCX. Brains from P10 neonates were analyzed immunohistochemically for neurogenesis and cell death markers. Mean CSF-DCX was significantly higher in HI- than in sham-exposed animals, at both P10 and P15. In the HI group at P10, CSF-DCX and stroke severity correlated positively. DCX immunoreactivity was increased in the ipsilateral neurogenic niches from the P10 HI brains in comparison with that of shams. The number of proliferative DCX-positive cells was higher in the ipsilateral hippocampal subgranular zone (SGZ) than in the HI contralateral or sham SGZ. Thus, neonatal HI brain injury disrupts the developmental time-course of DCX levels in the CSF. Our data suggest that the increased concentration of DCX in the CSF after neonatal HI is the result of both cellular injury and increased neurogenesis.

Simulation-based adjustment after exploratory biomarker subgroup selection in phase II.

As part of the evaluation of phase II trials, it is common practice to perform exploratory subgroup analyses with the aim of identifying patient populations with a beneficial treatment effect. When investigating targeted therapies, these subgroups are typically defined by biomarkers. Promising results may lead to the decision to select the respective subgroup as the target population for a subsequent phase III trial. However, a selection based on a large observed treatment effect may potentially induce an upwards-bias leading to over-optimistic expectations on the success probability of the phase III trial. We describe how Approximate Bayesian Computation techniques can be used to derive a simulation-based bias adjustment method in this situation. Recommendations for the implementation of the approach are given. Simulation studies show that the proposed method reduces bias substantially compared with the maximum likelihood estimator. The procedure is illustrated with data from an oncology trial. Copyright © 2017 John Wiley & Sons, Ltd.

Probability of success for phase III after exploratory biomarker analysis in phase II.

The probability of success or average power describes the potential of a future trial by weighting the power with a probability distribution of the treatment effect. The treatment effect estimate from a previous trial can be used to define such a distribution. During the development of targeted therapies, it is common practice to look for predictive biomarkers. The consequence is that the trial population for phase III is often selected on the basis of the most extreme result from phase II biomarker subgroup analyses. In such a case, there is a tendency to overestimate the treatment effect. We investigate whether the overestimation of the treatment effect estimate from phase II is transformed into a positive bias for the probability of success for phase III. We simulate a phase II/III development program for targeted therapies. This simulation allows to investigate selection probabilities and allows to compare the estimated with the true probability of success. We consider the estimated probability of success with and without subgroup selection. Depending on the true treatment effects, there is a negative bias without selection because of the weighting by the phase II distribution. In comparison, selection increases the estimated probability of success. Thus, selection does not lead to a bias in probability of success if underestimation due to the phase II distribution and overestimation due to selection cancel each other out. We recommend to perform similar simulations in practice to get the necessary information about the risk and chances associated with such subgroup selection designs.

Reverse phase protein arrays enable glioblastoma molecular subtyping.

In the present study we investigated the phosphorylation status of the 12 most important signaling cascades in glioblastomas. More than 60 tumor and control biopsies from tumor center and periphery (based on neuronavigation) were subjected to selective protein expression analysis using reverse-phase protein arrays (RPPA) incubated with antibodies against posttranslationally modified cancer pathway proteins. The ratio between phosphorylated (or modified) and non-phosphorylated protein was assessed. All samples were histopathologically validated and proteomic profiles correlated with clinical and survival data. By RPPA, we identified three distinct activation patterns within glioblastoma defined by the ratios of pCREB1/CREB1, NOTCH-ICD/NOTCH1, and pGSK3ß/GSK3ß, respectively. These subclasses demonstrated distinct overall survival patterns in a cohort of patients from a single-institution and in an analysis of publicly available data. In particular, a high pGSK3ß/GSK3ß-ratio was associated with a poor survival. Wnt-activation/GSK3ß-inhibition in U373 and U251 cell lines halted glioma cell proliferation and migration. Gene expression analysis was used as an internal quality control of baseline proteomic data. The protein expression and phosphorylation had a higher resolution, resulting in a better class-subdivision than mRNA based stratification data. Patients with different proteomic profiles from multiple biopsies showed a worse overall survival. The CREB1-, NOTCH1-, GSK3ß-phosphorylation status correlated with glioma grades. RPPA represent a fast and reliable tool to supplement morphological diagnosis with pathway-specific information in individual tumors. These data can be exploited for molecular stratification and possible combinatorial treatment planning. Further, our results may optimize current glioma grading algorithms.

An Enzyme- and Serum-free Neural Stem Cell Culture Model for EMT Investigation Suited for Drug Discovery.

Epithelial to mesenchymal transition (EMT) describes the process of epithelium transdifferentiating into mesenchyme. EMT is a fundamental process during embryonic development that also commonly occurs in glioblastoma, the most frequent malignant brain tumor. EMT has also been observed in multiple carcinomas outside the brain including breast cancer, lung cancer, colon cancer, gastric cancer. EMT is centrally linked to malignancy by promoting migration, invasion and metastasis formation. The mechanisms of EMT induction are not fully understood. Here we describe an in vitro system for standardized isolation of cortical neural stem cells (NSCs) and subsequent EMT-induction. This system provides the flexibility to use either single cells or explant culture. In this system, rat or mouse embryonic forebrain NSCs are cultured in a defined medium, devoid of serum and enzymes. The NSCs expressed Olig2 and Sox10, two transcription factors observed in oligodendrocyte precursor cells (OPCs). Using this system, interactions between FGF-, BMP- and TGFß-signaling involving Zeb1, Zeb2, and Twist2 were observed where TGFß-activation significantly enhanced cell migration, suggesting a synergistic BMP-/TGFß-interaction. The results point to a network of FGF-, BMP- and TGFß-signaling to be involved in EMT induction and maintenance. This model system is relevant to investigate EMT in vitro. It is cost-efficient and shows high reproducibility. It also allows for the comparison of different compounds with respect to their migration responses (quantitative distance measurement), and high-throughput screening of compounds to inhibit or enhance EMT (qualitative measurement). The model is therefore well suited to test drug libraries for substances affecting EMT.

On confidence intervals for the hazard ratio in randomized clinical trials.

The log-rank test is widely used to compare two survival distributions in a randomized clinical trial, while partial likelihood (Cox, 1975) is the method of choice for making inference about the hazard ratio under the Cox (1972) proportional hazards model. The Wald 95% confidence interval of the hazard ratio may include the null value of 1 when the p-value of the log-rank test is less than 0.05. Peto et al. (1977) provided an estimator for the hazard ratio based on the log-rank statistic; the corresponding 95% confidence interval excludes the null value of 1 if and only if the p-value of the log-rank test is less than 0.05. However, Peto's estimator is not consistent, and the corresponding confidence interval does not have correct coverage probability. In this article, we construct the confidence interval by inverting the score test under the (possibly stratified) Cox model, and we modify the variance estimator such that the resulting score test for the null hypothesis of no treatment difference is identical to the log-rank test in the possible presence of ties. Like Peto's method, the proposed confidence interval excludes the null value if and only if the log-rank test is significant. Unlike Peto's method, however, this interval has correct coverage probability. An added benefit of the proposed confidence interval is that it tends to be more accurate and narrower than the Wald confidence interval. We demonstrate the advantages of the proposed method through extensive simulation studies and a colon cancer study.

Standard first-line chemotherapy with or without nintedanib for advanced ovarian cancer (AGO-OVAR 12): a randomised, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Angiogenesis is a target in the treatment of ovarian cancer. Nintedanib, an oral triple angiokinase inhibitor of VEGF receptor, platelet-derived growth factor receptor, and fibroblast growth factor receptor, has shown activity in phase 2 trials in this setting. We investigated the combination of nintedanib with standard carboplatin and paclitaxel chemotherapy in patients with newly diagnosed advanced ovarian cancer. METHODS: In this double-blind phase 3 trial, chemotherapy-naive patients (aged 18 years or older) with International Federation of Gynecology and Obstetrics (FIGO) IIB-IV ovarian cancer and upfront debulking surgery were stratified by postoperative resection status, FIGO stage, and planned carboplatin dose. Patients were randomly assigned (2:1) via an interactive voice or web-based response system to receive six cycles of carboplatin (AUC 5 mg/mL per min or 6 mg/mL per min) and paclitaxel (175 mg/m(2)) in addition to either 200 mg of nintedanib (nintedanib group) or placebo (placebo group) twice daily on days 2-21 of every 3-week cycle for up to 120 weeks. Patients, investigators, and independent radiological reviewers were masked to treatment allocation. The primary endpoint was investigator-assessed progression-free survival analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01015118. FINDINGS: Between Dec 9, 2009, and July 27, 2011, 1503 patients were screened and 1366 randomly assigned by nine study groups in 22 countries: 911 to the nintedanib group and 455 to the placebo group. 486 (53%) of 911 patients in the nintedanib group experienced disease progression or death compared with 266 (58%) of 455 in the placebo group. Median progression-free survival was significantly longer in the nintedanib group than in the placebo group (17·2 months [95% CI 16·6-19·9] vs 16·6 months [13·9-19·1]; hazard ratio 0·84 [95% CI 0·72-0·98]; p=0·024). The most common adverse events were gastrointestinal (diarrhoea: nintedanib group 191 [21%] of 902 grade 3 and three [<1%] grade 4 vs placebo group nine [2%] of 450 grade 3 only) and haematological (neutropenia: nintedanib group 180 [20%] grade 3 and 200 (22%) grade 4 vs placebo group 90 [20%] grade 3 and 72 [16%] grade 4; thrombocytopenia: 105 [12%] and 55 [6%] vs 21 [5%] and eight [2%]; anaemia: 108 [12%] and 13 [1%] vs 26 [6%] and five [1%]). Serious adverse events were reported in 376 (42%) of 902 patients in the nintedanib group and 155 (34%) of 450 in the placebo group. 29 (3%) of 902 patients in the nintedanib group experienced serious adverse events associated with death compared with 16 (4%) of 450 in the placebo group, including 12 (1%) in the nintedanib group and six (1%) in the placebo group with a malignant neoplasm progression classified as an adverse event by the investigator. Drug-related adverse events leading to death occurred in three patients in the nintedanib group (one without diagnosis of cause; one due to non-drug-related sepsis associated with drug-related diarrhoea and renal failure; and one due to peritonitis) and in one patient in the placebo group (cause unknown). INTERPRETATION: Nintedanib in combination with carboplatin and paclitaxel is an active first-line treatment that significantly increases progression-free survival for women with advanced ovarian cancer, but is associated with more gastrointestinal adverse events. Future studies should focus on improving patient selection and optimisation of tolerability. FUNDING: Boehringer Ingelheim.

Risk factors for postoperative CSF leakage after elective craniotomy and the efficacy of fleece-bound tissue sealing against dural suturing alone: a randomized controlled trial.

OBJECT: Cerebrospinal fluid leakage is an immanent risk of cranial surgery with dural opening. Recognizing the risk factors for this complication and improving the technique of dural closure may reduce the associated morbidity and its surgical burden. The aim of this paper was to investigate whether the addition of TachoSil on top of the dural suture reduces postoperative CSF leakage compared with dural suturing alone and to assess the frequency and risk factors for dural leakage and potentially related complications after elective craniotomy. METHODS: The authors conducted a prospective, randomized, double-blinded single-center trial in patients undergoing elective craniotomy with dural opening. They compared their standard dural closure by running suture alone (with the use of a dural patch if needed) to the same closure with the addition of TachoSil on top of the suture. The primary end point was the incidence of CSF leakage, defined as CSF collection or any open CSF fistula within 30 days. Secondary end points were the incidence of infection, surgical revision, and length of stay in the intensive care unit (ICU) or intermediate care (IMC) unit. The site of craniotomy, a history of diabetes mellitus, a diagnosis of meningioma, the intraoperative need of a suturable dural substitute, and blood parameters were assessed as potential risk factors for CSF leakage. RESULTS: The authors enrolled 241 patients, of whom 229 were included in the analysis. Cerebrospinal fluid leakage, mostly self-limiting subgaleal collections, occurred in 13.5% of patients. Invasive treatment was performed in 8 patients (3.5%) (subgaleal puncture in 6, lumbar drainage in 1, and surgical revision in 1 patient). Diabetes mellitus, a higher preoperative level of C-reactive protein (CRP), and the intraoperative need for a dural patch were positively associated with the occurrence of the primary end point (p = 0.014, 0.01, and 0.049, respectively). Cerebrospinal fluid leakage (9.7% vs 17.2%, OR 0.53 [95% CI 0.23-1.15], p = 0.108) and infection (OR 0.18 [95% CI 0.01-1.18], p = 0.077) occurred less frequently in the study group than in the control group. TachoSil significantly reduced the probability of staying in the IMC unit for 1 day or longer (OR 0.53 [95% CI 0.27-0.99], p = 0.048). Postoperative epidural hematoma and empyema occurred in the control group but not in the study group. CONCLUSIONS: Dural leakage after elective craniotomy/durotomy occurs more frequently in association with diabetes mellitus, elevated preoperative CRP levels, and the intraoperative need of a dural patch. This randomized controlled trial showed no statistically significant reduction of postoperative CSF leakage and surgical site infections upon addition of TachoSil on the dural suture, but there was a significant reduction in the length of stay in the IMC unit. Dural augmentation with TachoSil was safe and not related to adverse events. Clinical trial registration no. NCT00999999 ( http://www.ClinicalTrials.gov ).

Current practice in neuropsychological outcome reporting after aneurysmal subarachnoid haemorrhage.

BACKGROUND: Neuropsychological deficits (NPD) are common in patients with aneurysmal subarachnoid haemorrhage (aSAH). NPD are one of the major limiting factors for patients with an otherwise acceptable prognosis for sustained quality of life. There are only a few studies reporting outcome after aSAH, which used a standardized neuropsychological test battery as a primary or secondary outcome measure. Aim of this study was to determine the current practice of reporting NPD following aSAH in clinical studies. METHODS: A MEDLINE analysis was performed using the search term "subarachnoid haemorrhage outcome". The latest 1,000 articles were screened. We recorded study design, number of patients, and the presence of neuropsychological outcome report. Additionally, the time of testing after aSAH, the neuropsychological tests administered, as well as the percentage of patients with NPD were analyzed. RESULTS: A total of 324 publications between 2009 and 2012 were selected for further review. Of those, 21 studies (6.5%) reported neuropsychological outcome, in 2,001 of 346,666 patients (0.6%). The assessment of NPD differed broadly using both subjective and objective cognitive evaluation, and a large variety of tests were used. CONCLUSION: Neuropsychological outcome is underreported, and there is great variety in assessment in currently published clinical articles on aSAH. Prospective randomized trials treating aSAH may benefit from implementing more comprehensive and standardized neuropsychological outcome measures. This approach might identify otherwise unnoticed treatment effects in future interventional studies of aSAH patients.