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.

Spatial localization of the K+ channel selectivity filter by mutant cycle-based structure analysis.

The structurally well-characterized scorpion toxin Agitoxin2 inhibits ion permeation through Shaker K+ channels by binding to the external pore entryway. Scanning mutagenesis identified a set of inhibitor residues critical for making energetic contacts with the channel. Using thermodynamic mutant cycle analysis, we have mapped channel residues relative to the known inhibitor structure. This study constrains the position of multiple channel residues within the pore-forming loops; in one stretch, we have been able to map five out of seven contiguous residues to the inhibitor interaction surface, including those involved in ion selectivity. One interaction in particular, that of K27M on the inhibitor with Y445F on the channel, is unique in that it depends on the K+ ion concentration. These results reveal a shallow vestibule formed by the pore loops at the K+ channel entryway. The selectivity filter is located at the center of the vestibule close to (approximately 5 A) the extracellular solution.

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.

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.

Alpha-1-antitrypsin-Pittsburgh. A potent inhibitor of human plasma factor XIa, kallikrein, and factor XIIf.

Alpha-1-antitrypsin-Pittsburgh is a human variant that resulted from a point mutation in the plasma protease inhibitor, alpha 1-antitrypsin (358 Met----Arg). This defect in the alpha 1-antitrypsin molecule causes it to have greatly diminished anti-elastase activity but markedly increased antithrombin activity. In this report, we demonstrate that this variant protein also has greatly increased inhibitory activity towards the arginine-specific enzymes of the contact system of plasma proteolysis (Factor XIa, kallikrein, and Factor XIIf), in contrast to normal alpha 1-antitrypsin, which has modest to no inhibitory activity towards these enzymes. We determined the second-order-inactivation rate constant (k'') of purified, human Factor XIa by purified alpha 1-antitrypsin-Pittsburgh and found it to be 5.1 X 10(5) M-1 s-1 (23 degrees C), which is a 7,700-fold increase over the k'' for Factor XIa by its major inhibitor, normal purified alpha 1-antitrypsin (i.e., 6.6 X 10(1) M-1 s-1). Human plasma kallikrein, which is poorly inhibited by alpha 1-antitrypsin (k'' = 4.2 M-1 s-1), exhibited a k'' for alpha 1-antitrypsin-Pittsburgh of 8.9 X 10(4) M-1 s-1 (a 21,000-fold increase), making it a more efficient inhibitor than either of the naturally occurring major inhibitors of kallikrein (C-1-inhibitor and alpha 2-macroglobulin). Factor XIIf, which is not inhibited by normal alpha 1-antitrypsin, displayed a k'' for alpha 1-antitrypsin-Pittsburgh of 2.5 X 10(4) M-1 s-1. This enhanced inhibitory activity is similar to the effect of alpha 1-antitrypsin-Pittsburgh that has been reported for thrombin. In addition to its potential as an anticoagulant, this recently cloned protein may prove to be clinically valuable in the management of septic shock, hereditary angioedema, or other syndromes involving activation of the surface-mediated plasma proteolytic system.

Circulating proalbumin associated with a variant proteinase inhibitor.

The unique finding of normal proalbumin in human plasma provides an insight into the mechanism of propeptide cleavage. Proalbumin, present as 1-5% of the total albumin, was found in a boy whose prime problem was the presence of a mutant proteinase inhibitor, alpha 1-antitrypsin Pittsburgh (358 Met----Arg) [2]. The inferred structure of human proalbumin was confirmed as Arg-Gly-Val-Phe-Arg-Arg-Alb. On incubation with various enzymes (trypsin, tryptase, thrombin, chymotrypsin, chymase and cathepsin B), only trypsin was capable of converting proalbumin to albumin. There was no conversion when proalbumin was incubated with whole blood, plasma or serum. However, intravenous injection of proalbumin into a rat resulted in complete conversion to albumin, the half-life of this process being 6 h. We conclude that propeptide cleavage is dependent on a serine proteinase which is inhibited intracellularly, by the mutant inhibitor, and that all the albumin in the boy was secreted as proalbumin, but was subjected to a separate cleavage process after export from the hepatocyte.

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.

Treatment of gastric ulcer. What is old and what is new.

The rational treatment of gastric ulcer (GU) requires both an understanding of the various causative factors responsible for what is best considered a spectrum of disorders, as well as a familiarity with the newer antisecretory and cytoprotective therapies that are available. Gastric ulcers that fulfill the criteria to be peptic ulcers (ie, occur in the antrum in the presence of excess luminal acid, with or without a coexisting duodenal ulcer) are best treated with a histamine H2-receptor antagonist. For GUs that develop in the setting of normal or reduced acid output, or those that occur as a result of direct (ie, drug-induced or bile acid-related) mucosal injury, use of a cytoprotective agent (eg, sucralfate) is the treatment of choice. Any GU that fails to heal within 12 to 15 weeks should be carefully examined to exclude the presence of a malignant neoplasm and should be considered for surgical resection.

Diagnostic yield of a positive fecal occult blood test found on digital rectal examination. Does the finger count?

The value of a positive fecal occult blood test (FOBT) found at the time of digital rectal examination is disputed. To determine the significance of a positive FOBT obtained in this manner, the records of 270 patients who underwent colonoscopy for any positive FOBT were retrospectively reviewed. Occult blood was found in 144 patients at the time of digital rectal examination and in 126 individuals after they submitted three spontaneously passed stool specimens. Of the patients with a positive FOBT on rectal examination, 77% were hospitalized at the time compared with only 17% of those with positive FOBTs from spontaneously passed stools. The frequency of colonic abnormalities was similar with both stool collection methods in inpatients and outpatients. No statistically significant differences in neoplastic polyp or colon cancer detection rates, nor in the finding of hemorrhoids or other anorectal abnormalities, were apparent. Therefore, the belief that a positive FOBT found at the time of digital examination can or should be discounted as a false positive (because of the presence of hemorrhoids or other lesions prone to trauma at the time of digital examination) was not substantiated by this study.

Efficacy and safety of ibuprofen for hemophilic arthropathy.

The safety and usefulness of ibuprofen (Motrin) were evaluated in 15 patients suffering from hemophilic arthropathy via a double-blind protocol with individual crossover. No significant increase in hemorrhagic episodes or alteration in platelet function was observed. A decrease in morning stiffness was noted in nine patients, and three decreased markedly their use of other pain medications. We conclude that ibuprofen represents a relatively safe agent for the management of discomfort caused by hemophilic arthropathy in a select group of hemophilic patients.

Water-insoluble paraproteins with anticoagulant properties.

A 78-year-old woman, who had received steroid therapy for four years, had strikingly prolonged prothrombin time (PT) and partial thromboplastin time (PTT). The presumptive diagnosis was chronic hemolytic anemia. Platelet count and functions, fibrinogen, and factor XIII assays were all normal, but other factors assayed abnormally low; Sia water-dilution test was positive. When water-insoluble protein was removed by centrifugation, coagulation factors became normal. Dissolution of this precipitate in normal plasma caused marked prolongation of PT and PTT and lower factor assays. Serum electrophoresis showed a homogeneous M spike and an anomalous IgM, lambda-antigenic type in the gamma-globulin zone at point of origin. Ultracentrifugation of serum and of the precipitate showed 10% S17 and almost 100% S17 components, respectively. Five other patients with water-insoluble paraproteins were tested; two were clot-inhibitory.

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.

Intravenous gamma globulin in the treatment of chronic idiopathic thrombocytopenic purpura in adults.

Eight adult patients with chronic idiopathic thrombocytopenic purpura have been treated with an intravenous gamma globulin preparation. All patients received at least one "induction" course of intravenous gamma globulin for five consecutive days at a dose of 400 mg/kg per day. There were a total of 12 induction treatments. In five instances, patients also received single "maintenance" infusions of intravenous gamma globulin at the same dose. The mean peak increment in platelet count (X 10(3)/microliters) after induction was 87.3 +/- 42.37; after maintenance therapy it was 62.2 +/- 12.99. In only one instance was the platelet count increment less than 50 X 10(3)/microliters. In 13 of 17 intravenous gamma globulin treatments (both induction and maintenance), the platelet count returned to baseline or near-baseline levels within one to two weeks. In four instances, more prolonged remissions were observed. Measurements of platelet-associated IgG demonstrated the following: when platelet-associated IgG was greater than 100 ng/10(6) platelets, platelet-associated IgG usually decreased markedly after intravenous gamma globulin therapy. When platelet-associated IgG was less than 20 ng/10(6) platelets, platelet-associated IgG usually increased with therapy. There was no correlation between starting platelet-associated IgG levels or changes in platelet-associated IgG levels with therapy and the increment in the patient's platelet count.

Decreased helper/suppressor cell ratios after treatment with factor VIII and IX concentrates and fresh frozen plasma.

The immunologic status of three groups of multiply transfused asymptomatic patients was evaluated. These included five with acquired inhibitors to factor VIII treated with both factor VIII and factor IX concentrates (Group A), seven with hemophilia B treated with factor IX concentrate (Group B), and six with hemophilia B treated with fresh frozen plasma (Group C). Mean helper/suppressor T cell ratios (+/- SEM) for the three groups were 0.72 +/- 0.09, 1.35 +/- 0.18, and 1.37 +/- 0.12, respectively. All three differed significantly (p less than 0.01) from the control mean ratio of 2.22 +/- 0.16. In addition, the mean ratio of Group A patients was significantly different (p less than 0.01) from those of Groups B and C. An inverted ratio (less than 1.00) was found in all Group A patients and only one Group B patient. Increased IgG levels were found in 80, 57, and 50 percent of each group, respectively. These immunologic findings bear a striking resemblance to those of the acquired immunodeficiency syndrome (AIDS) of homosexuals, intravenous-drug abusers, Haitian immigrants, and factor VIII concentrate-treated hemophiliacs. Transmission via a blood-borne infectious agent seems likely.

The relation of preoperative coagulation findings to diagnosis, blood usage, and survival in adult liver transplantation.

A group of 70 adults with end-stage liver disease received 87 homologous liver transplants from 7/11/81 and 7/11/83. The recipients fell into the following diagnostic categories: postnecrotic cirrhosis (PNC) in 22, primary biliary cirrhosis (PBC) in 18, cancer or neoplasia (CA) in 11, sclerosing cholangitis (SC) in 8 and miscellaneous (MISC) in 11. Survival for six months or longer was 46%: survival by group was PBC = 67%, CA = 55%, PNC = 45%, SC = 25%, and MISC = 18%. Preoperative coagulation profiles were evaluated on 64 of the 70 first transplant patients by assigning a score derived from one point per abnormality in each of 8 tests. Mean coagulation abnormality scores (CAS) were strikingly elevated in the PNC and MISC groups. Mean intraoperative blood product usage was 43 units of RBCs, 40 units of fresh frozen plasma (FFP), 21 units of platelets, and 9 bags of cryoprecipitate. Direct correlations were found between CAS and RBC usage (+0.454, P = less than .001), CAS, and survival of 6 months or longer (-0.281, P = less than .02), and RBC usage and survival (-0.408, P = less than .001). These findings indicate that the degree of coagulation abnormality and the type of liver disease may be predictive of intraoperative blood usage and survival in liver transplantation in adults.

Systemic effects of tissue plasminogen activator-associated fibrinolysis and its relation to thrombin generation in orthotopic liver transplantation.

Orthotopic liver transplantation is frequently associated with hyperfibrinolysis, the origin and clinical relevance of which is largely unknown. In 20 orthotopic liver transplantations, we studied the occurrence and systemic effects of hyperfibrinolysis. Severe fibrinolysis was defined to be present when the euglobulin-clot lysis time and the whole-blood-clot lysis time, as measured by thrombelastography, were shorter than 60 and 90 min, respectively, at some time during the operation. Based on these criteria, 7 patients had minimal fibrinolysis (group I), and 13 patients had severe fibrinolysis (group II). In group II a gradual increase of tissue-type plasminogen activator (t-PA) activity was seen during the anhepatic stage, followed by an "explosive" increase immediately after graft reperfusion (P = 0.0004, compared with group I), and a reduction of plasminogen activator inhibitor (PAI) activity. Plasma degradation products of fibrinogen and fibrin increased parallel to t-PA activity, and levels were significantly higher at 45 min after graft reperfusion in group II compared with group I (P less than 0.04). Thrombin-antithrombin III complexes showed an identical steady increase in both groups, indicating that increased t-PA activity was not related to thrombin formation. A combination of increased endothelial release and reduced hepatic clearance may have caused the increased t-PA activity. The t-PA-associated destruction of fibrinogen and fibrin after graft reperfusion is consistent with the clinical signs of severe oozing often seen in this period. These observations may have important clinical implications for the treatment of bleeding in patients undergoing orthotopic liver transplantation.

Disseminated intravascular coagulation. Findings in 346 patients.

An analysis was made of 346 cases of disseminated intravascular coagulation (DIC) diagnosed by utilizing a combination of laboratory tests which reflect the pathophysiology of the syndrome. The goals of the study were three fold: 1) to compare our clinical disease categories with those of other investigators, 2) to re-evaluate the diagnostic tests and, 3) most importantly, to report the results of tests infrequently performed when evaluating DIC. The patients fell into the following groups: 1) infection -- 26%, 2) malignancy -- 24%, 3) surgery and trauma -- 19%, 4) liver disease -- 8%, 5) miscellaneous -- 23%. Of the diagnostic tests, those for fibrin split products (FSP), fibrin monomer and antithrombin III were the most valuable. Of the clotting proteins, factors II, V, VII and X were the most frequently decreased. The factor VIII: C levels were in conflict with the prevailing dogma. Factor VIII:C levels were decreased in only 9% of patients studied and, in fact, were increased in the majority of cases. Factor VIIIR:Ag and F VIIIR:vW were elevated in 80% of the patients evaluated. An overall mortality of 68% further confirms the dismal prognosis previously associated with DIC.

Treatment of amyloidosis associated factor X deficiency.

This is the tenth patient in thirteen years to be reported with the findings of an isolated factor X deficiency associated with primary amyloidosis. A favorable response to factor IX concentrate was manifested by temporary clinical and laboratory correction of her diathesis. This mode of treatment, therefore, provides an approach to therapy for bleeding complications in this group of patients who have previously failed to response to fresh frozen plasma.

Plasma fibronectin levels in clinical disease states and after cryoprecipitate infusion.

Fibronectin levels were measured in 151 hospitalized patients with liver disease, sepsis, malignancy, leukemia, and following trauma or surgery, using heterologous precipitating antibody in an immunoassay. The mean (+/- S.E.M.) in 25 controls was 0.95 +/- 0.06 U/ml, with females, 0.83 +/- 0.07 U/ml, lower than males, 1.09 +/- 0.09 U/ml. Mean fibronectin levels were decreased in all disease groups except in obstructive liver disease. The reduced levels in hepatocellular disease and the restoration of levels to normal after orthotopic liver transplantation in patients with hepatocellular disease supports the theory that hepatic synthesis contributes significantly to plasma fibronectin levels. Following cryoprecipitate infusion in four hemophiliac patients, plasma fibronectin levels rose to 32% to 45% of the levels predicted. In patients with reduced fibronectin and poor clinical response to standard treatment (antibiotics, chemotherapy), cryoprecipitate infusions may raise the levels of fibronectin and, perhaps, contribute to clinical improvement.

Indexes of intravascular hemolysis, quantification of coagulation factors, and platelet survival in patients with porcine heterograft valves.

Ten patients with porcine heterograft valves who were not receiving anticoagulant agents were evaluated to determine the effect of the valve on red blood cell survival and on platelet activation and consumption as measured by (1) quantification of the coagulation mechanism, (2) platelet function studies, and (3) 51-chromium platelet survival time. There was no evidence of significant intravascular hemolysis as determined by the reticulocyte count, serum iron and iron binding capacity, serum bilirubin level, or lactic dehydrogenase activity. The coagulation profile and the platelet function studies were normal. No statistically significant difference was found in the platelet survival time in the 10 patients with porcine heterograft valves (half-life 3.2 +/- 0.8 days) and the 11 normal control subjects (half-life 3.6 +/- 0.6 days) (p greater than 0.2). The finding of a normal platelet survival time in patients with porcine heterograft valves is consistent with clinical experience indicating that this device is associated with a low incidence of systemic embolization, approximating 3% per year.