A Bayesian Approach for Measurements of Stray Neutrons at Proton Therapy Facilities: Quantifying Neutron Dose Uncertainty.

Bonner sphere measurements are typically analyzed using unfolding codes. It is well known that it is difficult to get reliable estimates of uncertainties for standard unfolding procedures. An alternative approach is to analyze the data using Bayesian parameter estimation. This method provides reliable estimates of the uncertainties of neutron spectra leading to rigorous estimates of uncertainties of the dose. We extend previous Bayesian approaches and apply the method to stray neutrons in proton therapy environments by introducing a new parameterized model which describes the main features of the expected neutron spectra. The parameterization is based on information that is available from measurements and detailed Monte Carlo simulations. The validity of this approach has been validated with results of an experiment using Bonner spheres carried out at the experimental hall of the OncoRay proton therapy facility in Dresden.

Data-intensive Undergraduate Research Project Informs to Advance Healthcare Analytics.

The overarching framework for incorporating informatics into the Wesley College (Wesley) undergraduate curriculum was to teach emerging information technologies that prepared undergraduates for complex high-demand work environments. Federal and State support helped implement Wesley's undergraduate Informatics Certificate and Minor programs. Both programs require project-based coursework in Applied Statistics, SAS Programming, and Geo-spatial Analysis (ArcGIS). In 2015, the State of Obesity listed the obesity ranges for all 50 US States to be between 21-36%. Yet, the Center for Disease Control and Prevention (CDC) mortality records show significantly lower obesity-related death-rates for states with very high obesity-rates. This study highlights the disparities in the reported obesity-related death-rates (specified by an ICD-10 E66 diagnosis code) and the obesity-rate percentages recorded for all 50 US States. Using CDC mortality-rate data, the available obesity-rate information, and ArcGIS, we created choropleth maps for all US States. Visual and statistical analysis shows considerable disparities in the obesity-related death-rate record-keeping amongst the 50 US States. For example, in 2015, Vermont with the sixth lowest obesity-rate had the highest reported obesity-related death-rate. In contrast, Alabama had the fifth highest adult obesity-rate in the nation, yet, it had a very low age-adjusted mortality-rate. Such disparities make comparative analysis difficult.

Requirements for a Compton camera for in vivo range verification of proton therapy.

To ensure the optimal outcome of proton therapy, in vivo range verification is highly desired. Prompt γ-ray imaging (PGI) is a possible approach for in vivo range monitoring. For PGI, dedicated detection systems, e.g. Compton cameras, are currently under investigation. The presented paper deals with substantial requirements regarding hardware and software that a Compton camera used in clinical routine has to meet. By means of GEANT4 simulations, we investigate the load on the detectors and the percentage of background expected in a realistic irradiation and we simulate γ-ray detections subsequently used as input data for the reconstruction. By reconstructing events from simulated sources of well-defined geometry, we show that large-area detectors are favourable. We investigate reconstruction results in dependence of the number of events. Finally, an end-to-end test for a realistic patient scenario is presented: starting with a treatment plan, the γ-ray emissions are calculated, the detector response is modelled, and the image reconstruction is performed. By this, the complexity of the system is shown, and requirements and limitations regarding precision and costs are determined.

Towards clinical application: prompt gamma imaging of passively scattered proton fields with a knife-edge slit camera.

Prompt γ-ray imaging with a knife-edge shaped slit camera provides the possibility of verifying proton beam range in tumor therapy. Dedicated experiments regarding the characterization of the camera system have been performed previously. Now, we aim at implementing the prototype into clinical application of monitoring patient treatments. Focused on this goal of translation into clinical operation, we systematically addressed remaining challenges and questions. We developed a robust energy calibration routine and corresponding quality assurance protocols. Furthermore, with dedicated experiments, we determined the positioning precision of the system to 1.1 mm (2σ). For the first time, we demonstrated the application of the slit camera, which was intentionally developed for pencil beam scanning, to double scattered proton beams. Systematic experiments with increasing complexity were performed. It was possible to visualize proton range shifts of 2-5 mm with the camera system in phantom experiments in passive scattered fields. Moreover, prompt γ-ray profiles for single iso-energy layers were acquired by synchronizing time resolved measurements to the rotation of the range modulator wheel of the treatment system. Thus, a mapping of the acquired profiles to different anatomical regions along the beam path is feasible and additional information on the source of potential range shifts can be obtained. With the work presented here, we show that an application of the slit camera in clinical treatments is possible and of potential benefit.

From prompt gamma distribution to dose: a novel approach combining an evolutionary algorithm and filtering based on Gaussian-powerlaw convolutions.

Range verification and dose monitoring in proton therapy is considered as highly desirable. Different methods have been developed worldwide, like particle therapy positron emission tomography (PT-PET) and prompt gamma imaging (PGI). In general, these methods allow for a verification of the proton range. However, quantification of the dose from these measurements remains challenging. For the first time, we present an approach for estimating the dose from prompt γ-ray emission profiles. It combines a filtering procedure based on Gaussian-powerlaw convolution with an evolutionary algorithm. By means of convolving depth dose profiles with an appropriate filter kernel, prompt γ-ray depth profiles are obtained. In order to reverse this step, the evolutionary algorithm is applied. The feasibility of this approach is demonstrated for a spread-out Bragg-peak in a water target.

Characterization of the microbunch time structure of proton pencil beams at a clinical treatment facility.

Proton therapy is an advantageous treatment modality compared to conventional radiotherapy. In contrast to photons, charged particles have a finite range and can thus spare organs at risk. Additionally, the increased ionization density in the so-called Bragg peak close to the particle range can be utilized for maximum dose deposition in the tumour volume. Unfortunately, the accuracy of the therapy can be affected by range uncertainties, which have to be covered by additional safety margins around the treatment volume. A real-time range and dose verification is therefore highly desired and would be key to exploit the major advantages of proton therapy. Prompt gamma rays, produced in nuclear reactions between projectile and target nuclei, can be used to measure the proton's range. The prompt gamma-ray timing (PGT) method aims at obtaining this information by determining the gamma-ray emission time along the proton path using a conventional time-of-flight detector setup. First tests at a clinical accelerator have shown the feasibility to observe range shifts of about 5 mm at clinically relevant doses. However, PGT spectra are smeared out by the bunch time spread. Additionally, accelerator related proton bunch drifts against the radio frequency have been detected, preventing a potential range verification. At OncoRay, first experiments using a proton bunch monitor (PBM) at a clinical pencil beam have been conducted. Elastic proton scattering at a hydrogen-containing foil could be utilized to create a coincident proton-proton signal in two identical PBMs. The selection of coincident events helped to suppress uncorrelated background. The PBM setup was used as time reference for a PGT detector to correct for potential bunch drifts. Furthermore, the corrected PGT data were used to image an inhomogeneous phantom. In a further systematic measurement campaign, the bunch time spread and the proton transmission rate were measured for several beam energies between 69 and 225 MeV as well as for variable momentum limiting slit openings. We conclude that the usage of a PBM increases the robustness of the PGT method in clinical conditions and that the obtained data will help to create reliable range verification procedures in clinical routine.

Experimental investigation of irregular motion impact on 4D PET-based particle therapy monitoring.

Particle therapy positron emission tomography (PT-PET) is an in vivo and non-invasive imaging technique to monitor treatment delivery in particle therapy. The inevitable patient respiratory motion during irradiation causes artefacts and inaccurate activity distribution in PET images. Four-dimensional (4D) maximum likelihood expectation maximisation (4D MLEM) allows for a compensation of these effects, but has up to now been restricted to regular motion for PT-PET investigations. However, intra-fractional motion during treatment might differ from that during acquisition of the 4D-planning CT (e.g. amplitude variation, baseline drift) and therefore might induce inaccurate 4D PET reconstruction results. This study investigates the impact of different irregular analytical one-dimensional (1D) motion patterns on PT-PET imaging by means of experiments with a radioactive source and irradiated moving phantoms. Three sorting methods, namely phase sorting, equal amplitude sorting and event-based amplitude sorting, were applied to manage the PET list-mode data. The influence of these sorting methods on the motion compensating algorithm has been analysed. The event-based amplitude sorting showed a superior performance and it is applicable for irregular motions with ⩽ 4 mm amplitude elongation and drift. For motion with 10 mm baseline drift, the normalised root mean square error was as high as 10.5% and a 10 mm range deviation was observed.

Detection of mixed-range proton pencil beams with a prompt gamma slit camera.

With increasing availability of proton and particle therapy centers for tumor treatment, the need for in vivo range verification methods comes more into the focus. Imaging of prompt gamma rays emitted during the treatment is one of the possibilities currently under investigation. A knife-edge shaped slit camera was recently proposed for this task and measurements proved the feasibility of range deviation detection in homogeneous and inhomogeneous targets. In the present paper, we concentrate on laterally inhomogeneous materials, which lead to range mixing situations when crossed by one pencil beam: different sections of the beam have different ranges. We chose exemplative cases from clinical irradiation and assembled idealized tissue equivalent targets. One-dimensional emission profiles were obtained by measuring the prompt gamma emission with the slit camera. It could be shown that the resulting range deviations can be detected by evaluation of the measured data with a previously developed range deviation detection algorithm. The retrieved value, however, strongly depends on the target composition, and is not necessarily in direct relation to the ranges of both parts of the beam. By combining the range deviation detection with an analysis of the slope of the distal edge of the measured prompt gamma profile, the origin of the detected range deviation, i.e. the mixed range of the beam, is also identified. It could be demonstrated that range mixed prompt gamma profiles exhibit less steep distal slopes than profiles from beams traversing laterally homogeneous material. For future application of the slit camera to patient irradiation with double scattered proton beams, situations similar to the range mixing cases are present and results could possibly apply.

Short-lived positron emitters in beam-on PET imaging during proton therapy.

The only method for in vivo dose delivery verification in proton beam radiotherapy in clinical use today is positron emission tomography (PET) of the positron emitters produced in the patient during irradiation. PET imaging while the beam is on (so called beam-on PET) is an attractive option, providing the largest number of counts, the least biological washout and the fastest feedback. In this implementation, all nuclides, independent of their half-life, will contribute. As a first step towards assessing the relevance of short-lived nuclides (half-life shorter than that of (10)C, T1/2 = 19 s) for in vivo dose delivery verification using beam-on PET, we measured their production in the stopping of 55 MeV protons in water, carbon, phosphorus and calcium The most copiously produced short-lived nuclides and their production rates relative to the relevant long-lived nuclides are: (12)N (T1/2 = 11 ms) on carbon (9% of (11)C), (29)P (T1/2 = 4.1 s) on phosphorus (20% of (30)P) and (38m)K (T1/2 = 0.92 s) on calcium (113% of (38g)K). No short-lived nuclides are produced on oxygen. The number of decays integrated from the start of an irradiation as a function of time during the irradiation of PMMA and 4 tissue materials has been determined. For (carbon-rich) adipose tissue, (12)N dominates up to 70 s. On bone tissue, (12)N dominates over (15)O during the first 8-15 s (depending on carbon-to-oxygen ratio). The short-lived nuclides created on phosphorus and calcium provide 2.5 times more beam-on PET counts than the long-lived ones produced on these elements during a 70 s irradiation. From the estimated number of (12)N PET counts, we conclude that, for any tissue, (12)N PET imaging potentially provides equal to superior proton range information compared to prompt gamma imaging with an optimized knife-edge slit camera. The practical implementation of (12)N PET imaging is discussed.

Measurement of prompt gamma profiles in inhomogeneous targets with a knife-edge slit camera during proton irradiation.

Proton and ion beam therapies become increasingly relevant in radiation therapy. To fully exploit the potential of this irradiation technique and to achieve maximum target volume conformality, the verification of particle ranges is highly desirable. Many research activities focus on the measurement of the spatial distributions of prompt gamma rays emitted during irradiation. A passively collimating knife-edge slit camera is a promising option to perform such measurements. In former publications, the feasibility of accurate detection of proton range shifts in homogeneous targets could be shown with such a camera. We present slit camera measurements of prompt gamma depth profiles in inhomogeneous targets. From real treatment plans and their underlying CTs, representative beam paths are selected and assembled as one-dimensional inhomogeneous targets built from tissue equivalent materials. These phantoms have been irradiated with monoenergetic proton pencil beams. The accuracy of range deviation estimation as well as the detectability of range shifts is investigated in different scenarios. In most cases, range deviations can be detected within less than 2 mm. In close vicinity to low-density regions, range detection is challenging. In particular, a minimum beam penetration depth of 7 mm beyond a cavity is required for reliable detection of a cavity filling with the present setup. Dedicated data post-processing methods may be capable of overcoming this limitation.

Simulation and experimental verification of prompt gamma-ray emissions during proton irradiation.

Irradiation with protons and light ions offers new possibilities for tumor therapy but has a strong need for novel imaging modalities for treatment verification. The development of new detector systems, which can provide an in vivo range assessment or dosimetry, requires an accurate knowledge of the secondary radiation field and reliable Monte Carlo simulations. This paper presents multiple measurements to characterize the prompt γ-ray emissions during proton irradiation and benchmarks the latest Geant4 code against the experimental findings. Within the scope of this work, the total photon yield for different target materials, the energy spectra as well as the γ-ray depth profile were assessed. Experiments were performed at the superconducting AGOR cyclotron at KVI-CART, University of Groningen. Properties of the γ-ray emissions were experimentally determined. The prompt γ-ray emissions were measured utilizing a conventional HPGe detector system (Clover) and quantitatively compared to simulations. With the selected physics list QGSP_BIC_HP, Geant4 strongly overestimates the photon yield in most cases, sometimes up to 50%. The shape of the spectrum and qualitative occurrence of discrete γ lines is reproduced accurately. A sliced phantom was designed to determine the depth profile of the photons. The position of the distal fall-off in the simulations agrees with the measurements, albeit the peak height is also overestimated. Hence, Geant4 simulations of prompt γ-ray emissions from irradiation with protons are currently far less reliable as compared to simulations of the electromagnetic processes. Deviations from experimental findings were observed and quantified. Although there has been a constant improvement of Geant4 in the hadronic sector, there is still a gap to close.

Mito-FLAG with Ara-C as bolus versus continuous infusion in recurrent or refractory AML--long-term results of a prospective randomized intergroup study of the East German Study Group Hematology/Oncology (OSHO) and the Study Alliance Leukemia (SAL).

BACKGROUND: For patients with primary refractory or relapsed acute myeloid leukemia (AML), no treatment of choice has until now been defined to date. Cytarabine (Ara-C) is a key drug in the treatment of AML patients, there is still uncertainly regarding its optimal dose and infusion schedule. The aim of this study is to examine the impact of the Ara-C infusion schedule used as part of an intensive salvage regimen, in patients with relapsed or refractory AML. PATIENTS AND METHODS: A total of 252 adult patients (median age 59 years) with relapsed or refractory AML were randomly allocated to receive either Mito-FLAG with Ara-C as bolus (B) (1000 mg/m(2) over 1 h, every 12 h, days 1-5), or continuous infusion (CI) (150 mg/m(2) over 24 h, days 1-5) in combination with mitoxantrone, fludarabine, and granulocyte colony-stimulating factor (G-CSF). Autologous or allogeneic hematopoietic stem-cell transplantation was offered as consolidation therapy. Primary end point was the rate of complete remissions (CRs) after the first cycle of Mito-FLAG. RESULTS: The CR rates after Mito-FLAG (B) and Mito-FLAG (CI) were 54% and 43%, respectively (P = 0.1). There was no statistical difference between rates of grade 3/4 neutropenia, thrombocytopenia, mucositis, renal, and liver toxicity. More infections occurred, however, after Mito-FLAG (B) compared with Mito-FLAG (CI) (80% versus 69%, P = 0.01). The early death rate by day 42 was 13% in both arms. Median disease-free survival was comparable in the two arms (7.8 versus 7.1 months, P = 0.53) as was overall survival (7.1 versus 6.6 months, P = 0.53). CONCLUSION: A 5-day course of Ara-C 2 × 1000 mg/m(2) administered as bolus versus Ara-C 150 mg/m(2) administered by CI (in combination with mitoxantrone, fludarabine, and G-CSF), resulted in a nonsignificant trend in response rates in favor of Mito-FLAG (B) at the selected dose levels, but no differences in the survival outcome in relapsed or refractory AML. CLINICAL TRIAL NUMBER: LN_NN_2004_39/EudraCT number 2014-000083-18.

Evaluation of resistive-plate-chamber-based TOF-PET applied to in-beam particle therapy monitoring.

Particle therapy is a highly conformal radiotherapy technique which reduces the dose deposited to the surrounding normal tissues. In order to fully exploit its advantages, treatment monitoring is necessary to minimize uncertainties related to the dose delivery. Up to now, the only clinically feasible technique for the monitoring of therapeutic irradiation with particle beams is Positron Emission Tomography (PET). In this work we have compared a Resistive Plate Chamber (RPC)-based PET scanner with a scintillation-crystal-based PET scanner for this application. In general, the main advantages of the RPC-PET system are its excellent timing resolution, low cost, and the possibility of building large area systems. We simulated a partial-ring scanner based on an RPC prototype under construction within the Fondazione per Adroterapia Oncologica (TERA). For comparison with the crystal-based PET scanner we have chosen the geometry of a commercially available PET scanner, the Philips Gemini TF. The coincidence time resolution used in the simulations takes into account the current achievable values as well as expected improvements of both technologies. Several scenarios (including patient data) have been simulated to evaluate the performance of different scanners. Initial results have shown that the low sensitivity of the RPC hampers its application to hadron-beam monitoring, which has an intrinsically low positron yield compared to diagnostic PET. In addition, for in-beam PET there is a further data loss due to the partial ring configuration. In order to improve the performance of the RPC-based scanner, an improved version of the RPC detector (modifying the thickness of the gas and glass layers), providing a larger sensitivity, has been simulated and compared with an axially extended version of the crystal-based device. The improved version of the RPC shows better performance than the prototype, but the extended version of the crystal-based PET outperforms all other options.

Experimental verification of a 4D MLEM reconstruction algorithm used for in-beam PET measurements in particle therapy.

In-beam positron emission tomography (PET) has been proven to be a reliable technique in ion beam radiotherapy for the in situ and non-invasive evaluation of the correct dose deposition in static tumour entities. In the presence of intra-fractional target motion an appropriate time-resolved (four-dimensional, 4D) reconstruction algorithm has to be used to avoid reconstructed activity distributions suffering from motion-related blurring artefacts and to allow for a dedicated dose monitoring. Four-dimensional reconstruction algorithms from diagnostic PET imaging that can properly handle the typically low counting statistics of in-beam PET data have been adapted and optimized for the characteristics of the double-head PET scanner BASTEI installed at GSI Helmholtzzentrum Darmstadt, Germany (GSI). Systematic investigations with moving radioactive sources demonstrate the more effective reduction of motion artefacts by applying a 4D maximum likelihood expectation maximization (MLEM) algorithm instead of the retrospective co-registration of phasewise reconstructed quasi-static activity distributions. Further 4D MLEM results are presented from in-beam PET measurements of irradiated moving phantoms which verify the accessibility of relevant parameters for the dose monitoring of intra-fractionally moving targets. From in-beam PET listmode data sets acquired together with a motion surrogate signal, valuable images can be generated by the 4D MLEM reconstruction for different motion patterns and motion-compensated beam delivery techniques.

4D particle therapy PET simulation for moving targets irradiated with scanned ion beams.

Particle therapy positron emission tomography (PT-PET) allows for an in vivo and in situ verification of applied dose distributions in ion beam therapy. Since the dose distribution cannot be extracted directly from the ß(+)-activity distribution gained from the PET scan the validation is done by means of a comparison between the reconstructed ß(+)-activity distributions from a PT-PET measurement and from a PT-PET simulation. Thus, the simulation software for generating PET data predicted from the treatment planning is an essential part of the dose verification routine. For the dose monitoring of intra-fractionally moving target volumes the PET data simulation needs to be upgraded by using time resolved (4D) algorithms to account correctly for the motion dependent displacement of the positron emitters. Moreover, it has to consider the time dependent relative movement between target volume and scanned beam to simulate the accurate positron emitter distribution generated during irradiation. Such a simulation program is presented which properly proceeds with motion compensated dose delivery by scanned ion beams to intra-fractionally moving targets. By means of a preclinical phantom study it is demonstrated that even the sophisticated motion-mitigated beam delivery technique of range compensated target tracking can be handled correctly by this simulation code. The new program is widely based on the 3D PT-PET simulation program which had been developed at the Helmholtz-Zentrum Dresden-Rossendorf, Germany (HZDR) for application within a pilot project to simulate in-beam PET data for about 440 patients with static tumor entities irradiated at the former treatment facility of the GSI Helmholtzzentrum für Schwerionenforschung, Darmstadt, Germany (GSI). A simulation example for a phantom geometry irradiated with a tracked (12)C-ion beam is presented for demonstrating the proper functionality of the program.

On the feasibility of automatic detection of range deviations from in-beam PET data.

In-beam PET is a clinically proven method for monitoring ion beam cancer treatment. The objective is predominantly the verification of the range of the primary particles. Due to different processes leading to dose and activity, evaluation is done by comparing measured data to simulated. Up to now, the comparison is performed by well-trained observers (clinicians, physicists). This process is very time consuming and low in reproducibility. However, an automatic method is desirable. A one-dimensional algorithm for range comparison has been enhanced and extended to three dimensions. System-inherent uncertainties are handled by means of a statistical approach. To test the method, a set of data was prepared. Distributions of ß(+)-activity calculated from treatment plans were compared to measurements performed in the framework of the German Heavy Ion Tumor Therapy Project at GSI Helmholtz Centre for Heavy Ion Research, Darmstadt, Germany. Artificial range deviations in the simulations served as test objects for the algorithm. Range modifications of different depth (4, 6 and 10 mm water equivalent path length) can be detected. Even though the sensitivity and specificity of a visual evaluation are higher, the method is feasible as the basis for the selection of patients from the data pool for retrospective evaluation of treatment and treatment plans and correlation with follow-up data. Furthermore, it can be used for the development of an assistance tool for a clinical application.

In-beam PET measurement of 7Li3+ irradiation induced beta+-activity.

At present positron emission tomography (PET) is the only feasible method of an in situ and non-invasive monitoring of patient irradiation with ions. At the experimental carbon ion treatment facility of the Gesellschaft für Schwerionenforschung (GSI) Darmstadt an in-beam PET scanner has been integrated into the treatment site and lead to a considerable quality improvement of the therapy. Since ions other than carbon are expected to come into operation in future patient treatment facilities, it is highly desirable to extend in-beam PET also to other therapeutic relevant ions, e.g. (7)Li. Therefore, by means of the in-beam PET scanner at GSI the beta(+)-activity induced by (7)Li(3+) ions has been investigated for the first time. Targets of PMMA, water, graphite and polyethylene were irradiated with monoenergetic, pencil-like beams of (7)Li(3+) with energies between 129.1 A MeV and 205.3 A MeV and intensities ranging from 3.0 x 10(7) to 1.9 x 10(8) ions s(-1). This paper presents the measured beta(+)-activity profiles as well as depth dependent thick target yields which have been deduced from the experimental data. The beta(+)-activity induced by (7)Li ions was found to be a factor of 1.76 higher than the one induced by (12)C ions at the same physical dose and particle range.

Effects of the selective endothelin A (ET(A)) receptor antagonist Clazosentan on cerebral perfusion and cerebral oxygenation following severe subarachnoid hemorrhage - preliminary results from a randomized clinical series.

OBJECTIVE: To study the effects of clazosentan, a new selective endothelin receptor subtype A antagonist, on cerebral perfusion and cerebral oxygenation following severe aneurysmal subarachnoid haemorrhage (aSAH). METHODS: All 12 patients treated at our institution in the context of a phase IIa, multicenter, randomized trial on clazosentan's safety and efficacy in reducing the incidence of angiographic cerebral vasospasm were included in this substudy. The phase IIa study (n = 34) consisted of two parts: a double-blind, randomized Part A (clazosentan 0.2 mg/kg/h versus placebo) and an open-label Part B (clazosentan 0.4 mg/kg/h for 12 h followed by 0.2 mg/kg/h) for patients with established vasospasm. In parallel to the phase IIa study protocol, which included assessment of vasospasm by angiography and transcranial Doppler sonography, we determined regional cerebral blood flow (rCBF), cerebrovascular resistance, and regional tissue oxygenation. RESULTS: Cerebral perfusion was comparable between treatment groups during the early post-bleeding period (rCBF placebo, 22.6 +/- 3.5 ml/100 g/min versus rCBF clazosentan, 23.9 +/- 1.1 ml/100 g/min). By the time of control angiography (day 8 after aSAH), rCBF decreased by 50% in the placebo group (11.3 +/- 6.7 ml/ 100 g/min) while it remained stable in the clazosentan group (23.5 +/- 12.9 ml/100 g/min). During Part B of the study, all 3 patients who developed haemodynamically relevant vasospasm during placebo treatment, showed a sustained improvement in rCBF upon conversion to clazosentan. CONCLUSIONS: These preliminary data suggest that clazosentan reduces the extent of vasospasm-associated impairment of cerebral perfusion following aSAH. Furthermore, clazosentan may exert beneficial actions on overt vasospasm-associated hypoperfusion.