Fluence-modulated proton CT optimized with patient-specific dose and variance objectives for proton dose calculation.

Particle therapy treatment planning requires accurate volumetric maps of the relative stopping power, which can directly be acquired using proton computed tomography (pCT). With fluence-modulated pCT (FMpCT) imaging fluence is concentrated in a region-of-interest (ROI), which can be the vicinity of the treatment beam path, and imaging dose is reduced elsewhere. In this work we present a novel optimization algorithm for FMpCT which, for the first time, calculates modulated imaging fluences for joint imaging dose and image variance objectives. Thereby, image quality is maintained in the ROI to ensure accurate calculations of the treatment dose, and imaging dose is minimized outside the ROI with stronger minimization penalties given to imaging organs-at-risk. The optimization requires an initial scan at uniform fluence or a previous x-ray CT scan. We simulated and optimized FMpCT images for three pediatric patients with tumors in the head region. We verified that the target image variance inside the ROI was achieved and demonstrated imaging dose reductions outside of the ROI of 74% on average, reducing the imaging dose from 1.2 to 0.3 mGy. Such dose savings are expected to be relevant compared to the therapeutic dose outside of the treatment field. Treatment doses were re-calculated on the FMpCT images and compared to treatment doses re-recalculated on uniform fluence pCT scans using a 1% criterion. Passing rates were above 98.3% for all patients. Passing rates comparing FMpCT treatment doses to the ground truth treatment dose were above 88.5% for all patients. Evaluation of the proton range with a 1 mm criterion resulted in passing rates above 97.5% (FMpCT/pCT) and 95.3% (FMpCT/ground truth). Jointly optimized fluence-modulated pCT images can be used for proton dose calculation maintaining the full dosimetric accuracy of pCT but reducing the required imaging dose considerably by three quarters. This may allow for daily imaging during particle therapy ensuring a safe and accurate delivery of the therapeutic dose and avoiding excess dose from imaging.

Animal tissue-based quantitative comparison of dual-energy CT to SPR conversion methods using high-resolution gel dosimetry.

Dual-energy computed tomography (DECT) has been shown to allow for more accurate ion therapy treatment planning by improving the estimation of tissue stopping power ratio (SPR) relative to water, among other tissue properties. In this study, we measured and compared the accuracy of SPR values derived using both dual- and single-energy CT (SECT) based on different published conversion algorithms. For this purpose, a phantom setup containing either fresh animal soft tissue samples (beef, pork) and a water reference or tissue equivalent plastic materials was designed and irradiated in a clinical proton therapy facility. Dosimetric polymer gel was positioned downstream of the samples to obtain a three-dimensional proton range distribution with high spatial resolution. The mean proton range in gel for each tissue relative to the water sample was converted to a SPR value. Additionally, the homogeneous samples were probed with a variable water column encompassed by two ionization chambers to benchmark the SPR accuracy of the gel dosimetry. The SPR values measured with both methods were consistent with a mean deviation of 0.2%, but the gel dosimetry captured range variations up to 5 mm within individual samples.Across all fresh tissue samples the SECT approach yielded significantly greater mean absolute deviations from the SPR deduced using gel range measurements, with an average difference of 1.2%, compared to just 0.3% for the most accurate DECT-based algorithm. These results show a significant advantage of DECT over SECT for stopping power prediction in a realistic setting, and for the first time allow to compare a large set of methods under the same conditions.

Beam characterization and feasibility study for a small animal irradiation platform at clinical proton therapy facilities.

A deeper understanding of biological mechanisms to promote more efficient treatment strategies in proton therapy demands advances in preclinical radiation research. However this is often limited by insufficient availability of adequate infrastructures for precision image guided small animal proton irradiation. The project SIRMIO aims at filling this gap by developing a portable image-guided research platform for small animal irradiation, to be used at clinical facilities and allowing for a precision similar to a clinical treatment, when scaled down to the small animal size. This work investigates the achievable dosimetric properties of different lowest energy clinical proton therapy beams, manipulated by a dedicated portable beamline including active focusing after initial beam energy degradation and collimation. By measuring the lateral beam size in air close to the beam nozzle exit and the laterally integrated depth dose in water, an analytical beam model based on the beam parameters of the clinical beam at the Rinecker Proton Therapy Center was created for the lowest available clinical beam energy. The same approach was then applied to estimate the lowest energy beam model of different proton therapy facilities, Paul Scherrer Institute, Centre Antoine Lacassagne, Trento Proton Therapy Centre and the Danish Centre for Particle Therapy, based on their available beam commissioning data. This comparison indicated similar beam properties for all investigated sites, with emittance values of a few tens of mm·mrad. Finally, starting from these beam models, we simulated propagation through a novel beamline designed to manipulate the beam energy and size for precise small animal irradiation, and evaluated the resulting dosimetric properties in water. For all investigated initial clinical beams, similar dosimetric results suitable for small animal irradiation were found. This work supports the feasibility of the proposed SIRMIO beamline, promising suitable beam characteristics to allow for precise preclinical irradiation at clinical treatment facilities.

Dosimetric impact of the low-dose envelope of scanned proton beams at a ProBeam facility: comparison of measurements with TPS and MC calculations.

Due to the low-dose envelope of scanned proton beams, the dose output depends on the size of the irradiated field or volume. While this field size dependence has already been extensively investigated by measurements and Monte Carlo (MC) simulations for single pencil beams or monoenergetic fields, reports on the relevance of this effect for analytical dose calculation models are limited. Previous studies on this topic only exist for specific beamline designs. However, the amount of large-angle scattered primary and long-range secondary particles and thus the relevance of the low-dose envelope can considerably be influenced by the particular design of the treatment nozzle. In this work, we therefore addressed the field size dependence of the dose output at the commercially available ProBeam(®) beamline, which is being built in several facilities worldwide. We compared treatment planning dose calculations with ionization chamber (IC) measurements and MC simulations, using an experimentally validated FLUKA MC model of the scanning beamline. To this aim, monoenergetic square fields of three energies, as well as spherical target volumes were studied, including the investigation on the influence of the lateral spot spacing on the field size dependence. For the spherical target volumes, MC as well as analytical dose calculation were found in excellent agreement with the measurements in the center of the spread-out Bragg peak. In the plateau region, the treatment planning system (TPS) tended to overestimate the dose compared to MC calculations and IC measurements by up to almost 5% for the smallest investigated sphere and for small monoenergetic square fields. Narrower spot spacing slightly enhanced the field size dependence of the dose output. The deviations in the plateau dose were found to go in the clinically safe direction, i.e. the actual deposited dose outside the target was found to be lower than predicted by the TPS. Thus, the moderate overestimation of dose to normal tissue by the TPS is likely to result in no severe consequences in clinical cases, even for the most critical cases of small target volumes.

Investigation of EBT2 and EBT3 films for proton dosimetry in the 4-20 MeV energy range.

Radiochromic films such as Gafchromic EBT2 or EBT3 films are widely used for dose determination in radiation therapy because they offer a superior spatial resolution compared to any other digital dosimetric 2D detector array. The possibility to detect steep dose gradients is not only attractive for intensity-modulated radiation therapy with photons but also for intensity-modulated proton therapy. Their characteristic dose rate-independent response makes radiochromic films also attractive for dose determination in cell irradiation experiments using laser-driven ion accelerators, which are currently being investigated as future medical ion accelerators. However, when using these films in ion beams, the energy-dependent dose response in the vicinity of the Bragg peak has to be considered. In this work, the response of these films for low-energy protons is investigated. To allow for reproducible and background-free irradiation conditions, the films were exposed to mono-energetic protons from an electrostatic accelerator, in the 4-20 MeV energy range. For comparison, irradiation with clinical photons was also performed. It turned out that in general, EBT2 and EBT3 films show a comparable performance. For example, dose-response curves for photons and protons with energies as low as 11 MeV show almost no differences. However, corrections are required for proton energies below 11 MeV. Care has to be taken when correction factors are related to an average LET from depth-dose measurements, because only the dose-averaged LET yields similar results as obtained in mono-energetic measurements.

Comparison of Gafchromic EBT2 and EBT3 films for clinical photon and proton beams.

PURPOSE: Dose verification in highly conformal radiation therapy such as IMRT or proton therapy can benefit from the high spatial resolution offered by radio-chromic films such as Gafchromic EBT or EBT2. Recently, a new generation of these films, EBT3, has become available. The composition and thickness of the sensitive layer are the same as for the previous EBT2 films. The most important change is the symmetric layer configuration to eliminate side orientation dependence, which is reported for EBT2 films. METHODS: The general film characteristics such as sensitivity to read-out orientation and postexposure darkening evolution of the new EBT3 film are evaluated. Film response has been investigated in clinical photon and proton beams and compared to former EBT2 films. Quenching effects in the proton Bragg peak region have been studied for both, EBT2 and EBT3 films. RESULTS: The general performance of EBT3 is comparable to EBT2, and the orientation dependence with respect to film side is completely eliminated in EBT3 films. Response differences of EBT2 and EBT3 films are of the same order of magnitude as batch-to-batch variations observed for EBT2 films. No significant difference has been found for both generations of EBT films between photon and proton exposure. Depth dose measurements of EBT2 and EBT3 show an excellent agreement, though underestimating dose by up to 20% in the Bragg peak region. CONCLUSIONS: The symmetric configuration of EBT3 presents a major improvement for film handling. EBT3 has similar dosimetric performance as its precursor EBT2 and can, thus, be applied to dose verification in IMRT in the same way. For dose verification in proton therapy the underresponse in the Bragg peak region has to be taken into account.

Serum cholesterol concentrations and mood states in violent psychiatric patients: an experience sampling study.

The well-documented negative association between serum cholesterol and aggressive behavior has led Kaplan to propose a cholesterol-serotonin hypothesis of aggression. According to this hypothesis, low dietary cholesterol intake leads to depressed central serotonergic activity, which itself has been reported in numerous studies of violent individuals. In the present study, 25 violent psychiatric patients participated in a microbehavioral experience sampling procedure to examine differences in self-reports of affective and cognitive experiences as a function of serum cholesterol concentrations. For 7 days, they wore signaling devices that emitted an average of seven signals a day. Following each signal, patients filled out a mood questionnaire. Total serum cholesterol (TSC) concentration was positively associated with measures of affect, cognitive efficiency, activation, and sociability, suggesting a link between low TSC and dysphoria. These findings are consistent with the cholesterol-serotonin hypothesis and with the substantive literature linking both aggression and depression to depressed central serotonergic activity.

Medication adherence failure in schizophrenia: a forensic review of rates, reasons, treatments, and prospects.

Forensic patients with schizophrenia who fail to adhere to prescribed antipsychotic medication risk recidivism, which continues to be a serious concern. It affects all stages of trial proceedings and impacts on the treaters' liability. Although much remains unchanged since the authors reviewed the subject in 1986, significant advances have occurred. A patient's insight can be assessed with greater precision. Risks posed by past noncompliance, substance abuse, and a dysphoric response to medication are more clearly documented. Clinical and laboratory methods for assessing compliance have improved. Major advances in the effective amelioration of adverse effects can be applied to promote adherence. New augmentation strategies enable adequate treatment at lower doses. The development of atypical antipsychotic agents makes compliance easier to achieve and maintain. Other advances apply to the containment of relapse when it does occur. This review organizes the literature documenting these trends for use in both treatment and consultation.

Creatine kinase elevations and aggressive behavior in hospitalized forensic patients.

The relationship between creatine kinase (CK) and aggressive behavior was tested in 195 males consecutively admitted to a forensic hospital. Among patients receiving antipsychotic medication, the most violent patients had higher CK levels than less violent patients. This was not the case in patients who did not receive antipsychotic medication. CK levels were not influenced by age, ethnicity, or clinical diagnosis. CK levels were however influenced by prior assaultiveness and restraints. When these two factors were controlled for, CK levels remained strongly associated with subsequent violence. CK appears to be a potential predictor of violent behavior. It has the advantage of easy availability in comparison to other biological markers of aggression (e.g., 5-HIAA). Prospective studies are needed to confirm the validity of this biobehavioral association.

Ethnicity, aggression and serum creatine kinase in hospitalized male forensic patients.

OBJECTIVE: This study examined the relationship of serum creatine kinase (CK) levels with aggressive behavior as a function of psychosis and ethnicity in a sample of violent forensic patients. DESIGN: CK levels were determined on admission in a sample of 195 males consecutively admitted to a forensic hospital. The patients' aggressive behavior during their hospital stay was monitored using the Overt Aggression Scale (OAS). All data for this study was archival and gathered from hospital records. METHODS: Multivariate analysis of variance was used to examine whether African-American and Caucasian patients differed in serum CK levels and severity, frequency, and type (verbal vs physical) of aggression. T-tests were performed to compare ethnic groups in terms of age, weight, height, systolic and diastolic blood pressure. All patients who had been in restraints, had been administered intramuscular medications, had a history of drug or alcohol abuse, and were classified as schizophrenic were compared using chi-square analysis. For each of these variables further comparisons were made of CK levels between African-American and Caucasian patients. RESULTS: Mean serum CK in African-American patients was 64% higher than in Caucasians. African Americans displayed significantly greater physical aggression than Caucasian patients. In addition, African-American patients with a diagnosis of schizophrenia had significantly higher CK levels than African Americans with other diagnoses, with no significant differences related to schizophrenia noted within the Caucasian group. No significant differences in aggressive behavior related to schizophrenia were found in African-American patients. CONCLUSIONS: This study confirms the findings of previous reports which observed higher CK levels in African Americans than in Caucasians. It is also proposed that a confluence of physiologic and psychosocial factors may affect biological marker presentation, particularly as manifest in CK differences between ethnic groups.

Characteristics and cost of staff injuries in a forensic hospital.

At a maximum-security forensic hospital over a three-year period, 79 patients (35 percent of all patients) were involved in 157 staff injuries. Staff members' average postinjury absence from work was 85 days, at a cost equivalent to about 2 percent of the hospital's budget. Nursing staff, particularly psychiatric technicians, had the highest injury rate. Male staff were about twice as likely to be injured as female staff. More injuries occurred on the second shift. Patients who injured staff were younger than those who did not. Florid psychotic behavior, nonpsychotic agitation, and the recent use of restraints were the most common prodromal signs.

Recurrent self-injurious behavior in forensic patients.

A high prevalence of self-injurious behavior has been reported in the forensic psychiatric population and the correctional psychiatric population. Severely and recurrently self-destructive patients pose great therapeutic challenges. The present study examined forensic patients who engaged in multiple acts of self-injury while hospitalized and compared them to forensic patients who engaged in a single act of self-injury. The groups did not differ on demographic or diagnostic measures, but the recurringly self-injurious patients were more frequently and more severely aggressive against others (verbally as well as physically), and required longer hospitalization. The results are interpreted to suggest that the high cost of recurring self-injury in human and financial terms may be reduced by a strategy of early and vigorous intervention.

Aggression against self and aggression against others in violent psychiatric patients.

In spite of recent calls for the study of the comorbidity among behavior disorders, little is known about the coexistence of aggression against self and aggression against others. In this article, the relationship between indices of these 2 types of aggression is examined retrospectively in a sample of 103 male forensic inpatients during a 3-year period. Patients with both self-destructiveness during hospitalization and suicidal behavior before hospitalization engaged in the highest frequency of aggression against others. The implications of these findings for the assessment, prediction, and treatment of violence and self-destructiveness are discussed.

Serum cholesterol and aggression in hospitalized male forensic patients.

Human studies of the link between serum cholesterol and aggression have yielded equivocal results. Depending on the type of aggression studied (e.g., criminal violence or Type A hostility), investigators have found either a negative or a positive association between cholesterol and aggressive behavior. We conducted a retrospective analysis of aggressive incidents in a sample of hospitalized male forensic patients. The whole sample had lower cholesterol levels than the general population. Patients with low cholesterol levels (< 200 mg/dl) engaged in more frequent aggressive behavior but showed no difference in severity of aggression. They also showed no difference in verbal vs physical aggression. The relationship between cholesterol and frequency of aggression was curvilinear, with the most frequent acts of aggression committed by patients with moderately low cholesterol levels. Current research findings regarding the cholesterol-aggression association suggest the need for further clarification of the behavioral parameters under investigation.