William J. Kostis

Three-dimensional segmentation and growth-rate estimation of small pulmonary nodules in helical CT images

Small pulmonary nodules are a common radiographic finding that presents an important diagnostic challenge in contemporary medicine. While pulmonary nodules are the major radiographic indicator of lung cancer, they may also be signs of a variety of benign conditions. Measurement of nodule growth rate over time has been shown to be the most promising tool in distinguishing malignant from nonmalignant pulmonary nodules. In this paper, we describe three-dimensional (3-D) methods for the segmentation, analysis, and characterization of small pulmonary nodules imaged using computed tomography (CT). Methods for the isotropic resampling of anisotropic CT data are discussed. 3-D intensity and morphology-based segmentation algorithms are discussed for several classes of nodules. New models and methods for volumetric growth characterization based on longitudinal CT studies are developed. The results of segmentation and growth characterization methods based on in vivo studies are described. The methods presented are promising in their ability to distinguish malignant from nonmalignant pulmonary nodules and represent the first such system in clinical use.

On measuring the change in size of pulmonary nodules

The pulmonary nodule is the most common manifestation of lung cancer, the most deadly of all cancers. Most small pulmonary nodules are benign, however, and currently the growth rate of the nodule provides for one of the most accurate noninvasive methods of determining malignancy. In this paper, we present methods for measuring the change in nodule size from two computed tomography image scans recorded at different times; from this size change the growth rate may be established. The impact of partial voxels for small nodules is evaluated and isotropic resampling is shown to improve measurement accuracy. Methods for nodule location and sizing, pleural segmentation, adaptive thresholding, image registration, and knowledge-based shape matching are presented. The latter three techniques provide for a significant improvement in volume change measurement accuracy by considering both image scans simultaneously. Improvements in segmentation are evaluated by measuring volume changes in benign or slow growing nodules. In the analysis of 50 nodules, the variance in percent volume change was reduced from 11.54% to 9.35% (p=0.03) through the use of registration, adaptive thresholding, and knowledge-based shape matching.

Meta-analysis of statin effects in women versus men.

OBJECTIVES The aim of this study was to evaluate the effect of statins in decreasing cardiovascular events in women and men. BACKGROUND Published data reviews have suggested that statins might not be as effective in women as in men in decreasing cardiovascular events. METHODS Published data searches and contacts with investigators identified 18 randomized clinical trials of statins with sex-specific outcomes (N = 141,235, 40,275 women, 21,468 cardiovascular events). Odds ratios (ORs) and 95% confidence intervals (CIs) for cardiovascular events were calculated for women and men separately with random effects meta-analyses. RESULTS The cardiovascular event rate was lower among those randomized to statin intervention than in those randomized to control (low-dose statin in 4 studies, placebo in 11 studies, usual care in 3 studies) and similar in women and men (OR: 0.81, 95% CI: 0.75 to 0.89; p < 0.0001, and OR: 0.77, 95% CI: 0.71 to 0.83, p < 0.0001, respectively). The benefit of statins was statistically significant in both sexes, regardless of the type of control, baseline risk, or type of endpoint and in both primary and secondary prevention. All-cause mortality was also lower with statin therapy both in women and men without significant interaction by sex (p for interaction = 0.4457). CONCLUSIONS Statin therapy is associated with significant decreases in cardiovascular events and in all-cause mortality in women and men. Statin therapy should be used in appropriate patients without regard to sex.

Statin Therapy and the Risk of Intracerebral Hemorrhage: A Meta-Analysis of 31 Randomized Controlled Trials

Background and Purpose— Statin therapy decreases the risk of ischemic stroke. An increased risk of intracerebral hemorrhage (ICH) has been observed in some studies. To investigate this issue, we performed a meta-analysis of randomized controlled trials using statins that reported ICH. Methods— We performed a literature search of Medline, Web of Science, and The Cochrane Library through January 25, 2012, and identified additional randomized controlled trials by reviewing reference lists of retrieved studies and prior meta-analyses. All randomized controlled trials of statin therapy that reported ICH or hemorrhagic stroke were included. The primary outcome variable was ICH. Thirty-one randomized controlled trials were included. All analyses used random effects models and heterogeneity was not observed in any of the analyses. Results— A total of 91 588 subjects were included in the active group and 91 215 in the control group. There was no significant difference in incidence of ICH observed in the active treatment group versus control (OR, 1.08; 95% CI, 0.88–1.32; P=0.47). ICH risk was not related to the degree of low-density lipoprotein reduction or achieved low-density lipoprotein cholesterol. Total stroke (OR, 0.84; 95% CI, 0.78–0.91; P<0.0001) and all-cause mortality (OR, 0.92; CI, 0.87–0.96; P=0.0007) were significantly reduced in the active therapy group. There was no evidence of publication bias. Conclusions— Active statin therapy was not associated with significant increase in ICH in this meta-analysis of 31 randomized controlled trials of statin therapy. A significant reduction in all stroke and all-cause mortality was observed with statin therapy.

Trends in Mortality of Acute Myocardial Infarction After Discharge From the Hospital

Background—We assessed trends in the prognosis of patients with acute myocardial infarction hospitalized in New Jersey hospitals. In recent decades, in-hospital mortality has declined markedly but the decline in longer-term mortality is less pronounced, implying that mortality after discharge has worsened. Methods and Results—Using the Myocardial Infarction Data Acquisition System (MIDAS), we examined the outcomes of 285 397 patients hospitalized for a first acute myocardial infarction between 1986 and 2007. Mortality at discharge decreased by 9.4% from 16.9% to 7.5% (annual change, −0.44; 95% confidence interval, −0.49 to −0.40), but the decrease at 1 year was less pronounced (6.4%) because of an increase in mortality from discharge to 1 year after discharge (from 12.1% to 13.9%; annual change, +0.15; 95% confidence interval, +0.10 to +0.20). Mortality from 30 days after discharge to 1 year, a measure not affected by length of stay, increased by 1.2% (annual change, +0.10; 95% confidence interval, +0.06 to +0.23). The effect was more evident in the older age groups and was due to noncardiovascular mortality, especially from respiratory and renal diseases, septicemia, and cancer. All effects remained statistically significant (P<0.0001) after adjustment for demographics, comorbidities, infarction type, complications, and interventions. Piecewise linear regressions confirmed these trends. Conclusions—Postdischarge mortality of patients with acute myocardial infarction is increasing, primarily because of higher noncardiovascular mortality in the older age groups.

Meta-Analysis of Selective Serotonin Reuptake Inhibitor–Associated QTc Prolongation

OBJECTIVE To evaluate the association between selective serotonin reuptake inhibitors (SSRIs) and corrected QT interval (QTc) prolongation via meta-analysis of prospective studies. DATA SOURCES PubMed/MEDLINE database (January 1, 1975-August 15, 2012), with additional reports identified using hand searches of reference lists of relevant articles. Key words searched were QT, torsades de pointes, and sudden cardiac death, combined with antidepressants, citalopram, escitalopram, fluoxetine, sertraline, paroxetine, and fluvoxamine. English-, Spanish-, and German-language articles were included. STUDY SELECTION Two reviewers independently identified prospective controlled studies in adults that reported data related to QTc intervals prior to and following treatment with SSRIs. DATA EXTRACTION AND SYNTHESIS Three reviewers independently extracted study-level data including population characteristics, method of QTc measurement and treatment and outcome data. Two independent reviewers critiqued study quality. Publication bias was assessed visually using a funnel plot and quantitatively. Heterogeneity was measured using Cochran Q statistic. RESULTS Sixteen articles (with 25 distinct data subsets) involving 4,292 patients were included. SSRIs were associated with a dose-dependent increase in QTc interval compared to placebo (+6.10 milliseconds; 95% CI, 3.47-8.73; P < .001). Tricyclic antidepressants (TCAs) were associated with a significantly greater QTc increase than SSRIs (TCA prolongation, 7.05 milliseconds; 95% CI, 3.84-10.27 greater than SSRIs; P < .001). With respect to specific SSRI agents, citalopram was associated with significantly greater QTc prolongation than sertraline, paroxetine, and fluvoxamine. CONCLUSIONS SSRIs were associated with a modest but statistically significant increase in the QTc interval, although to a lesser extent than TCAs; this finding was not limited to any single study. Citalopram was associated with more QTc prolongation than most other SSRIs.

COMPUTER-AIDED DIAGNOSIS FOR LUNG CANCER

CAD methods may provide radiologists with tools to obtain more accurate diagnoses for lung cancer. Considerable effort has been devoted to developing CAD tools for CXR; however, these are limited by the fundamental constraints of the projective CXR modality. CT provides far more detailed information that can be exploited better by CAD systems. There has been very little work done in this area to date, although the basic technology has already been developed through the more extensive research in the computer vision areas supported by industry and the military. Initial prototype CT CAD systems have been described that are highly effective in detecting small pulmonary nodules and in predicting malignancy of nodules. CT is now achieving momentum in the study of lung cancer. It has taken time for this modality to gain acceptance because of several factors: higher radiation dose, higher cost, and the novelty of use in this application. It is important to note that the technology for CT scanners is still rapidly evolving. As the speed, resolution, and cost of CT scanners continue to improve, computer techniques for the measurement and analysis of nodules will also achieve corresponding improvements in accuracy and diagnostic utility. Future knowledge-based CT CAD systems will provide detailed analysis of the related conditions of the lungs, such as emphysema, and diagnostic analysis of nodules. The issue is not whether CAD will improve the performance and capabilities of the radiologist, but at what rate their development and the corresponding improvement will occur. Current prototype CAD systems may be considered as tools. As such they will improve the performance of the user/radiologist if they are well engineered and if the user understands their capabilities and limitations. These systems need to be improved by knowledge-based engineering, which is notoriously difficult to implement robustly and requires model refinement and optimization based on a large database of cases. Research should be directed at developing these methods rather than comparing prototype systems with current practices. Future performance should be expected to exceed that of todays grand masters.

Association of increased pulse pressure with the development of heart failure in shep

The aim of this study was to assess the relationship between pulse pressure (PP) and the occurrence of heart failure (HF) in older persons with isolated systolic hypertension. Data from a prospective, multicenter, randomized, double-blind, placebo-controlled clinical trial were analyzed. A total of 4736 persons aged > or = 60 years with systolic blood pressure (SBP) between 160 and 219 mm Hg and diastolic blood pressure (DBP) < 90 mm Hg who participated in the Systolic Hypertension in the Elderly Program (SHEP) were studied. The main outcome measures were fatal and nonfatal HF. During 4.5 years average follow-up, fatal or nonfatal HF occurred in 160 of 4736 patients. The SBP, PP, and mean arterial pressure (MAP) were strong predictors of the development of HF (P < .0002). Cox proportional hazards regression using time-dependent covariates and controlling for MAP indicated that HF was inversely related to DBP (P = 0.002) and was directly related to pulse pressure (P = 0.002). Data were similar when patients who developed myocardial infarction during follow up were excluded. These data indicate that, in older persons with isolated systolic hypertension, high pulse pressure is associated with increased risk of heart failure independently of MAP and of the occurrence of acute myocardial infarction during follow-up.

Fiber architecture in remodeled myocardium revealed with a quantitative diffusion CMR tractography framework and histological validation.

BackgroundThe study of myofiber reorganization in the remote zone after myocardial infarction has been performed in 2D. Microstructural reorganization in remodeled hearts, however, can only be fully appreciated by considering myofibers as continuous 3D entities. The aim of this study was therefore to develop a technique for quantitative 3D diffusion CMR tractography of the heart, and to apply this method to quantify fiber architecture in the remote zone of remodeled hearts.MethodsDiffusion Tensor CMR of normal human, sheep, and rat hearts, as well as infarcted sheep hearts was performed ex vivo. Fiber tracts were generated with a fourth-order Runge-Kutta integration technique and classified statistically by the median, mean, maximum, or minimum helix angle (HA) along the tract. An index of tract coherence was derived from the relationship between these HA statistics. Histological validation was performed using phase-contrast microscopy.ResultsIn normal hearts, the subendocardial and subepicardial myofibers had a positive and negative HA, respectively, forming a symmetric distribution around the midmyocardium. However, in the remote zone of the infarcted hearts, a significant positive shift in HA was observed. The ratio between negative and positive HA variance was reduced from 0.96 ± 0.16 in normal hearts to 0.22 ± 0.08 in the remote zone of the remodeled hearts (p<0.05). This was confirmed histologically by the reduction of HA in the subepicardium from −52.03° ± 2.94° in normal hearts to −37.48° ± 4.05° in the remote zone of the remodeled hearts (p < 0.05).ConclusionsA significant reorganization of the 3D fiber continuum is observed in the remote zone of remodeled hearts. The positive (rightward) shift in HA in the remote zone is greatest in the subepicardium, but involves all layers of the myocardium. Tractography-based quantification, performed here for the first time in remodeled hearts, may provide a framework for assessing regional changes in the left ventricle following infarction.

Microstructural Impact of Ischemia and Bone Marrow–Derived Cell Therapy Revealed With Diffusion Tensor Magnetic Resonance Imaging Tractography of the Heart In Vivo

Background— The arrangement of myofibers in the heart is highly complex and must be replicated by injected cells to produce functional myocardium. A novel approach to characterize the microstructural response of the myocardium to ischemia and cell therapy, with the use of serial diffusion tensor magnetic resonance imaging tractography of the heart in vivo, is presented. Methods and Results— Validation of the approach was performed in normal (n=6) and infarcted mice (n=6) as well as healthy human volunteers. Mice (n=12) were then injected with bone marrow mononuclear cells 3 weeks after coronary ligation. In half of the mice the donor and recipient strains were identical, and in half the strains were different. A positive response to cell injection was defined by a decrease in mean diffusivity, an increase in fractional anisotropy, and the appearance of new myofiber tracts with the correct orientation. A positive response to bone marrow mononuclear cell injection was seen in 1 mouse. The response of the majority of mice to bone marrow mononuclear cell injection was neutral (9/12) or negative (2/12). The in vivo tractography findings were confirmed with histology. Conclusions— Diffusion tensor magnetic resonance imaging tractography was able to directly resolve the ability of injected cells to generate new myofiber tracts and provided a fundamental readout of their regenerative capacity. A highly novel and translatable approach to assess the efficacy of cell therapy in the heart is thus presented.