McSART: an iterative model-based, motion-compensated SART algorithm for CBCT reconstruction.

4D cone beam computed tomography (CBCT) images of the thorax and abdomen can have reduced quality due to the limited number of projections per respiratory bin used in gated image reconstruction. In this work, we present a new algorithm to reconstruct high quality CBCT images by simultaneously reconstructing images and generating an associated respiratory motion model. This is done by updating model parameters to compensate for motion during the iterative image reconstruction process. CBCT image acquisition was simulated using the digital eXternal CArdiac Torso (XCAT) phantom, simulating breathing motion using four patient breathing traces. 4DCBCT images were reconstructed using the simultaneous algebraic reconstruction technique (SART), and compared to the proposed motion-compensated SART (McSART) algorithm. McSART used a motion model that describes tissue position as a function of diaphragm amplitude and velocity. The McSART algorithm alternately updated the motion model and image reconstruction, increasing the number of projections used for image reconstruction with every iteration. The model was able to interpolate and extrapolate deformations according to the magnitude of the surrogate signal. Without noise, the final iteration McSART images had HU errors at 31%, 34%, and 44% of their SART-reconstructed counterparts compared to ground truth XCAT images, with corresponding root-mean-square (RMS) motion model errors of 0.75 mm, 1.08 mm, and 1.17 mm respectively. With added image noise, McSART's HU error was 31% of the SART-reconstructed 4DCBCT error, with a 1.43 mm RMS motion model error. Qualitatively, blurring and streaking artifacts were reduced in all the reconstructed images compared to 3D or SART-reconstructed 4DCBCT. The output of the algorithm was a high quality reference image and a corresponding motion model, that could be used to deform the reference image to any other point in a breathing cycle.

A prospective gating method to acquire a diverse set of free-breathing CT images for model-based 4DCT.

Breathing motion modeling requires observation of tissues at sufficiently distinct respiratory states for proper 4D characterization. This work proposes a method to improve sampling of the breathing cycle with limited imaging dose. We designed and tested a prospective free-breathing acquisition protocol with a simulation using datasets from five patients imaged with a model-based 4DCT technique. Each dataset contained 25 free-breathing fast helical CT scans with simultaneous breathing surrogate measurements. Tissue displacements were measured using deformable image registration. A correspondence model related tissue displacement to the surrogate. Model residual was computed by comparing predicted displacements to image registration results. To determine a stopping criteria for the prospective protocol, i.e. when the breathing cycle had been sufficiently sampled, subsets of N scans where 5 ⩽ N ⩽ 9 were used to fit reduced models for each patient. A previously published metric was employed to describe the phase coverage, or 'spread', of the respiratory trajectories of each subset. Minimum phase coverage necessary to achieve mean model residual within 0.5 mm of the full 25-scan model was determined and used as the stopping criteria. Using the patient breathing traces, a prospective acquisition protocol was simulated. In all patients, phase coverage greater than the threshold necessary for model accuracy within 0.5 mm of the 25 scan model was achieved in six or fewer scans. The prospectively selected respiratory trajectories ranked in the (97.5 ± 4.2)th percentile among subsets of the originally sampled scans on average. Simulation results suggest that the proposed prospective method provides an effective means to sample the breathing cycle with limited free-breathing scans. One application of the method is to reduce the imaging dose of a previously published model-based 4DCT protocol to 25% of its original value while achieving mean model residual within 0.5 mm.

3D fluoroscopic image estimation using patient-specific 4DCBCT-based motion models.

3D fluoroscopic images represent volumetric patient anatomy during treatment with high spatial and temporal resolution. 3D fluoroscopic images estimated using motion models built using 4DCT images, taken days or weeks prior to treatment, do not reliably represent patient anatomy during treatment. In this study we developed and performed initial evaluation of techniques to develop patient-specific motion models from 4D cone-beam CT (4DCBCT) images, taken immediately before treatment, and used these models to estimate 3D fluoroscopic images based on 2D kV projections captured during treatment. We evaluate the accuracy of 3D fluoroscopic images by comparison to ground truth digital and physical phantom images. The performance of 4DCBCT-based and 4DCT-based motion models are compared in simulated clinical situations representing tumor baseline shift or initial patient positioning errors. The results of this study demonstrate the ability for 4DCBCT imaging to generate motion models that can account for changes that cannot be accounted for with 4DCT-based motion models. When simulating tumor baseline shift and patient positioning errors of up to 5 mm, the average tumor localization error and the 95th percentile error in six datasets were 1.20 and 2.2 mm, respectively, for 4DCBCT-based motion models. 4DCT-based motion models applied to the same six datasets resulted in average tumor localization error and the 95th percentile error of 4.18 and 5.4 mm, respectively. Analysis of voxel-wise intensity differences was also conducted for all experiments. In summary, this study demonstrates the feasibility of 4DCBCT-based 3D fluoroscopic image generation in digital and physical phantoms and shows the potential advantage of 4DCBCT-based 3D fluoroscopic image estimation when there are changes in anatomy between the time of 4DCT imaging and the time of treatment delivery.

Review article: prescribing medications in patients with cirrhosis - a practical guide.

BACKGROUND: Most drugs have not been well studied in cirrhosis; recommendations on safe use are based largely on experience and/or expert opinion, with dosing recommendations often based on pharmacokinetic (PK) changes. AIM: To provide a practical approach to prescribing medications for cirrhotic patients. METHODS: An indexed MEDLINE search was conducted using keywords cirrhosis, drug-induced liver injury, pharmacodynamics (PDs), PKs, drug disposition and adverse drug reactions. Unpublished information from the Food and Drug Administration and industry was also reviewed. RESULTS: Most medications have not been adequately studied in cirrhosis, and specific prescribing information is often lacking. Lower doses are generally recommended based on PK changes, but data are limited in terms of correlating PD effects with the degree of liver impairment. Very few drugs have been documented to have their hepatotoxicity potential enhanced by cirrhosis; most of these involve antituberculosis or antiretroviral agents used for HIV or viral hepatitis. Paracetamol can be used safely when prescribed in relatively small doses (2-3 g or less/day) for short durations, and is recommended as first-line treatment of pain. In contrast, NSAIDs should be used cautiously (or not at all) in advanced cirrhosis. Proton pump inhibitors have been linked to an increased risk of spontaneous bacterial peritonitis (SBP) in cirrhosis and should be used with care. CONCLUSIONS: Most drugs can be used safely in cirrhosis, including those that are potentially hepatotoxic, but lower doses or reduced dosing frequency is often recommended, due to altered PKs. Drugs that can precipitate renal failure, gastrointestinal bleeding, SBP and encephalopathy should be identified and avoided.

SU-E-J-210: Lung Tumor Target Volume Contours on EPID Cine Mode Images.

PURPOSE: While real time imaging of treatment through an electronic portal imaging device (EPID) is a powerful tool to monitor treatment, limited field of view and lower contrast from an MV beam can make assessment difficult for physicians. This work will develops a method to register and project contour outlines for the internal target volume (ITV) and planning target volume (PTV) of lung tumor cases onto cine mode EPID images to help physicians in interpretation during treatment. METHODS: A sequence of EPID images, acquired during treatment, was registered to treatment planning computed tomography (CT) by machine geometry and patient setup with cone-beam computed tomography (CBCT). The planning CT was converted from Hounsfield scale to electron density by calibration curves of our CT simulator and digitally reconstructed radiographs (DRRs) were produced to match the EPID geometry, pixel for pixel. ITV and PTV structures as defined on the planning CT were then projected onto the DRRs. The DRRs were registered to the EPID images using cross correlation of a single template defined within the treatment aperture of each image. Once registered, the contours from the DRR were transferred to the EPID. RESULTS: We were able to successfully register MV DRRs to EPID images and display the projected target volumes. Without introduced motion, geometric registration and CBCT guided patient setup up were sufficient to register the contours within a single pixel, as normalized cross correlations produced no additional shift. We expect the DRR/EPID registration to be an important step when looking at cases with substantial tumor movement. CONCLUSIONS: The visualization of target volumes provides a tool for physicians to interpret EPID images and assess treatment, especially in cases with tumor movement. The methods developed will serve as the basis for a clinical tool providing real time contours.

Utility of the Roussel Uclaf Causality Assessment Method (RUCAM) to analyze the hepatic findings in a clinical trial program: evaluation of the direct thrombin inhibitor ximelagatran.

AIMS: Causality assessment in drug-induced liver injury is often based on circumstantial evidence rather than a formal, systematic review. The Roussel Uclaf Causality Assessment Method (RUCAM) provides a more objective means of assessing causality of a suspected hepatotoxin but, to our knowledge, has never been used in the assessment of a single drug with unknown hepatotoxic potential in a clinical trial setting. METHODS: We studied the utility of RUCAM in assessing the hepatic events during the long-term clinical trials of the oral direct thrombin inhibitor ximelagatran, which has been associated with an increased incidence of alanine aminotransferase (ALT) elevations. A total of 233 subjects with elevated ALT values signalling possibly severe hepatic injury were eligible for RUCAM analysis (198 ximelagatran and 35 comparator anticoagulants). RESULTS: RUCAM scores, calculated independently by the assessors, using the existing numerical criteria provided in its methodology, suggested a possible or probable causal relationship between ALT and ximelagatran in 37 and 27% of cases, respectively. Causality was excluded or unlikely in the remaining 36% of cases. However, in the course of utilizing RUCAM, several limitations to the methodology came to light, including awarding additional points for age > 55 years, an unspecified use of alcohol, and a latency period of < 90 days, which may have had the unintentional effect of raising the overall score. Moreover, rechallenge is highly rewarded by RUCAM but is seldom done in clinical practice or in clinical trials. We also found ambiguities in the extent to which other causes of liver injury were excluded, what constitutes a significant hepatotoxic concomitant medication, and whether a clinical trial drug should be considered as having an unknown hepatotoxic potential for purposes of RUCAM scoring. Increasing familiarity with the RUCAM over the course of the study allowed for only a slight improvement in concordance between and among the assessors regarding the scoring. CONCLUSIONS: While the results indicate that RUCAM can provide for an objective assessment of causality of the hepatotoxicity of a drug under development in the clinical trial setting, this study highlights a number of problems with the current scoring system that should be addressed by future enhancements of the methodology.

Review article: The use of potentially hepatotoxic drugs in patients with liver disease.

BACKGROUND: Misconceptions surround the use of hepatotoxic drugs in chronic liver disease. While many prescription and over-the-counter (OTC) agents can be used safely, this often runs counter to labelled warnings/contraindications, especially for the statins and other commonly used agents. AIM: To evaluate published data on the use of hepatotoxic drugs in chronic liver disease including pharmacokinetic changes in cirrhosis and drug interactions, where available, to formulate recommendations on their use. METHODS: Using a combination of PubMed searches, review texts, the Physicians' Desk Reference and expert opinion, drugs considered at higher risk of hepatotoxicity in chronic liver disease were evaluated. RESULTS: Most drugs and OTC products including herbals have not been formally studied in chronic liver disease, but available data suggest that several of the most commonly used agents, especially the statins, can be used safely. While there is an increased risk of drug-induced liver injury for drugs used in the treatment of tuberculosis and HIV patients with hepatitis B or C, recommendations for their safe use are emerging. CONCLUSIONS: Although many clinicians remain hesitant to use hepatotoxic drugs in chronic liver disease, the database supporting this view is limited to just a few agents. Most medications can be used safely in patients with chronic liver disease with appropriate monitoring.

Percutaneous liver biopsy: what is the current approach? Results of a questionnaire survey.

The technique of performing liver biopsy varies among physicians, even within the same practice. In an attempt to determine whether gastroenteroogists/hepatologists differ in their approach compared to radiologists, we surveyed a nearly equal number of physicians in the Washington, DC, USA, metropolitan area with respect to 26 variables. While the technique can vary considerably, relatively few differences were seen between the groups. Only about half of gastroenterologists and hepatologists use ultrasound guidance, a biopsy, gun, and conscious sedation; radiologists routinely used a biopsy gun and conscious sedation and rarely require an overnight stay.

Management of drug-induced liver disease.

The treatment and prevention of drug-induced liver injury starts with the recognition of hepatotoxicity at the earliest possible time so that the suspected drug can be discontinued expeditiously. Both liver enzyme monitoring and vigilance for signs of hypersensitivity involving the liver are useful strategies for many agents known to cause hepatocellular necrosis leading to liver failure. Specific antidotes to prevent or limit hepatic damage exist for only a few drugs, the most important being N-acetylcysteine for the treatment of acetaminophen hepatotoxicity. Corticosteroids are of unproven benefit in the setting of fulminant failure. Ursodiol may be helpful in instances of cholestatic injury. For other agents, supportive measures and the increasing use of liver-assist devices as well as emergency liver transplantation are available when drug injury evolves into irreversible liver failure. It is hoped that a better understanding of hepatotoxicity mechanisms will lead to the development of more specific and effective forms of therapy in the near future.

Urine drug screens in overdose patients do not contribute to immediate clinical management.

A prospective study assessed whether routine urine drug screens might alter the management of overdose patients. Urine was collected from 107 patients with a diagnosis of deliberate self-poisoning seen in the emergency department (ED) of a teaching hospital. The mean age of patients was 36 years (range 13-86 years) and 64% were female. All patients recovered after standard investigations and management, which did not include knowledge of urinary drug screen results. Two hundred ninety-seven compounds were detected in the 107 urine samples. Twenty percent were drugs administered in the ED. Sixty-five percent of patients were found to have taken more than one drug. Benzodiazepines were detected in 18% of samples, paracetamol in 10%, and alcohol in 8%. Sixty-one drugs, in 35 people, were identified that the patients did not report taking. Of these, paracetamol (10), benzodiazepines (9), and tetrahydrocannabinol (8) were the most common. All patients in whom paracetamol was found had already had paracetamol detected in blood and appropriate management instituted. If the results of urine screening had been immediately available this would not have affected the management or outcome of any patient.

Management of partial segmental priapism.

We report the cases of 2 patients with partial segmental priapism. The patients presented with pain, a perineal mass, and proximal segmental corporal thrombosis. Treatment consisted of a proximal corpus cavernosal-spongiosum shunt. Diagnostic considerations, literature review, and treatment options are discussed.

Measuring the incremental cost of clinical cancer research.

PURPOSE: To summarize evidence on the costs of treating patients in clinical trials and to describe the Cost of Cancer Treatment Study, an ongoing effort to produce generalizable estimates of the incremental costs of government-sponsored cancer trials. METHODS: A retrospective study of costs will be conducted with 1,500 cancer patients recruited from a randomly selected sample of institutions in the United States. Patients accrued to either phase II or phase III National Cancer Institute-sponsored clinical trials during a 15-month period will be asked to participate in a study of their health care utilization (n = 750). Costs will be measured approximately 1 year after their trial enrollment from a combination of billing records, medical records, and an in-person survey questionnaire. Similar data will be collected for a comparable group of cancer patients not in trials (n = 750) to provide an estimate of the incremental cost. RESULTS: Evidence suggests insurers limit access to trials because of cost concerns. Public and private efforts are underway to change these policies, but their permanent status is unclear. Previous studies found that treatment costs in clinical trials are similar to costs of standard therapy. However, it is difficult to generalize from these studies because of the unique practice settings, insufficient sample sizes, and the exclusion of potentially important costs. CONCLUSION: Denials of coverage for treatment in a clinical trial limit patient access to trials and could impede clinical research. Preliminary estimates suggest changes to these policies would not be expensive, but these results are not generalizable. The Cost of Cancer Treatment Study is an ongoing effort to provide generalizable estimates of the incremental treatment cost of phase II and phase III cancer trials. The results should be of great interest to insurers and the research community as they consider permanent ways to finance cancer trials.

Drug-induced liver disease.

This year's review is divided into several sections: the first describes drug withdrawals and new general reviews of drug-induced liver disease (DILD), including a review of a classification of drug injury. We review agents newly described as causing DILD, and new reports of DILD from established agents appearing in the year 2000. New aspects regarding the treatment of acetaminophen toxicity are included, and in the final section we deal with prevention of DILD as well as issues surrounding the use of potentially hepatotoxic medications in patients with underlying chronic disease.

Drug-induced liver disease.

The incidence of drug-induced liver disease appears to be increasing, reflecting the increasing number of new agents that have been introduced into clinical use over the past several decades. Among the topics covered, the author discusses incidence, diagnosis, risk factors, clinical presentations, hepatitis, and vascular injury. The author also reviews the hepatic injury seen with commonly prescribed drugs, emphasizing newer developments in the field and recent publications and reports.

Gastrointestinal and hepatic disorders in end-stage renal disease and renal transplant recipients.

Gastrointestinal and hepatic disorders are commonly associated with end-stage renal disease, hemodialysis, and renal transplantation. Recent studies indicate that the prevalence of dyspepsia, ulcer disease, and Helicobacter pylori gastritis is not significantly different from the general population. Bleeding from angiodysplasia, however, is more common in chronic renal failure, as is gastroparesis. The prevalence of chronic hepatitis B has been dramatically reduced among hemodialysis patients since the advent of universal precautions. Response rates to hepatitis B vaccine in noninfected patients, however, are lower in these individuals. Chronic hepatitis C is found in 20% to 25% of HD patients worldwide and accounts for approximately 1% of all infected individuals. Levels of alanine aminotransferase and aspartase aminotransferase are often within normal limits but may be elevated compared with a patient's preinfection levels. Dialysis has been shown to reduce the level of hepatitis C virus viremia. Treatment is similar to non-renal failure patients, although interferon is generally not used in renal transplant recipients owing to concerns of graft failure.

The role of the NP in the diagnosis and management of erectile dysfunction.

Erectile dysfunction (ED) affects approximately 30 million men, significantly affecting their quality of life and relationships. More and more men are seeking help for this problem due to the advent of simpler, less-invasive treatment options. Inevitably, nurse practitioners (NPs) in primary care will encounter patients with ED. The assessment and diagnosis of ED can be facilitated by using a structured decision-making approach, which will promote comprehensive patient care. Some primary care NPs may need to increase their own comfort level with taking a sexual history, evaluating sexual problems, and knowing when to refer to a specialist.