| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1 Department of Radiology and Institute of Radiation Medicine, Seoul National
University Hospital, 28 Yongon-dong, Chongno-gu, Seoul 110-744, South
Korea.
2 Department of Preventive Medicine, Seoul National University College of
Medicine, Seoul, South Korea.
Received June 1, 2004;
accepted after revision August 10, 2004.
Address correspondence to J. M. Lee
(leejm{at}radcom.snu.ac.kr).
Abstract
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
MATERIALS AND METHODS. Contrast-enhanced sonography using 4 g of Levovist at a concentration of 300 mg/mL was performed on 75 focal hepatic lesions in 75 patients with diffuse liver disease. Interval reviews for both baseline without and with contrast-enhanced sonography were performed independently by two radiologists. They were requested to determine the malignity of focal hepatic lesions using a 5-point confidence level and to record the specific diagnoses and the necessity for further imaging for lesion characterization. Radiologists' performances for lesion differentiation using baseline and contrast-enhanced sonography were evaluated using receiver operating characteristic (ROC) analysis. Interobserver agreement was also analyzed.
RESULTS. When contrast-enhanced sonography was used, ROC analysis
revealed a significant improvement for both reviewers (area under the receiver
operating characteristic curve [Az] = 0.753 and 0.830 and
0.971 and 0.974 at baseline sonography and contrast-enhanced sonography,
respectively; p < 0.002) for differentiating malignant and benign
focal liver lesions. Contrast-enhanced sonography also improved specificity
from 12% to 91% for reviewer 1 and from 26% to 85% for reviewer 2 compared
with baseline sonography. Furthermore, excellent interobserver agreement was
achieved for contrast-enhanced sonography (weighted 
= 0.919), whereas
only good agreement was achieved for baseline sonography (weighted =
0.656). A better result for specific diagnosis was obtained by
contrast-enhanced sonography (79% and 75%) than by baseline sonography (37%
and 48%, p < 0.05). Contrast-enhanced sonography (72% and 63%)
outperformed baseline sonography (35% and 28%, p < 0.05) as a
confirmatory imaging technique.
CONCLUSION. Contrast-enhanced agent detection sonography can be used to characterize focal hepatic lesions in patients with diffuse liver disease reliably and with a higher diagnostic confidence than baseline sonography. Furthermore, contrast-enhanced sonography reduced the need for further diagnostic workups for focal hepatic lesion characterization.
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Although dysplastic nodules and hepatocellular carcinoma (HCC) are the most frequently observed focal hepatic lesions in the cirrhotic liver, other focal lesions such as hemangioma, cholangiocarcinoma, and metastasis may be concurrent [5-8]. However, HCC and dysplastic nodules often mimic hemangiomas on gray-scale sonography because of hyperechogenicity resulting from factors such as necrosis, fibrosis, fatty change, or sinusoid dilatation [9]. Moreover, hemangiomas in cirrhosis are likely to change in size and become more fibrotic, thus becoming more difficult to diagnose radiologically [4].
Agent detection imaging is a contrast-specific and multipulse technique that provides high-resolution images that detail the effect of microbubble emission and use the property of bubble emission to dramatically increase sensitivity for detecting microbubbles and to show regions where the contrast agent has localized. There is an increasing consensus that the use of contrast agents improves the ability of sonography to characterize focal hepatic lesions [10-12]. Moreover, the value of contrast-enhanced sonography for characterization of hepatic tumors can be maximized in patients with diffuse liver diseases, in which focal hepatic lesions may show atypical features on baseline sonography and, therefore, resist differential diagnosis. Nevertheless, no report is available on the diagnostic performance of contrast-enhanced sonography in such a special situation, to our knowledge. Thus, the purpose of our study was to assess the diagnostic performance of contrast-enhanced sonography for characterizing focal hepatic lesions in patients with diffuse liver diseases in comparison with baseline sonography and to determine whether agent detection imaging can reduce the necessity of further diagnostic workup for lesion characterization.
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Diffuse liver disease in these 75 patients was as follows: liver cirrhosis in 30, steatosis in 23, chronic hepatitis in 16, and both steatosis and chronic liver disease or liver cirrhosis in six. Hepatic steatosis was diagnosed when sonographic findings met all or part of the following criteria for fatty liver: echogenicity of hepatic parenchyma that increased more than that of the renal cortex; or poor or nonvisualization of the portal vein borders, the diaphragm, or the posterior portion of the right lobe [13]. Fatty change of the liver was confirmed in three patients by percutaneous biopsy, in seven patients using CT attenuation values on unenhanced CT scans (at least 10 H lower than those in the spleen) [14], and in four patients by a difference between the MRI signal intensity on in- and out-of-phase sequences [15]. Chronic hepatitis or cirrhosis was diagnosed by percutaneous liver biopsy in 15 patients (hepatitis in nine and cirrhosis in six) and by clinical course, sonographic findings, and laboratory data (including liver function test) in 37. The causes of chronic hepatitis or cirrhosis were viral infection (hepatitis B [n = 28], hepatitis C [n = 12], or both [n = 3]), biliary cirrhosis (n = 3), alcoholism (n = 4), or alcoholism combined with hepatitis B (n = 2).
A diagnosis of HCC was based on histopathologic findings in five. In the
remaining 26 HCCs, the following strict diagnostic criteria were met: a level
of 
-fetoprotein greater than 400 ng/mL at the time of diagnosis,
hypervascular staining at angiography, and the presence of Lipiodol ([iodized
oil], Guerbet) retention in the mass on Lipiodol CT performed 2 weeks after
transarterial chemoembolization. Hemangiomas were proven by characteristic
imaging findings, which included nodular peripheral enhancement and
isoattenuation to blood vessels with high signal intensity on T2-weighted MR
images (by dual-phase enhanced CT in 19 or by dynamic enhanced MRI in seven)
and lack of an interval increase in size for a minimum of 1 year
[16,
17]. All metastatic lesions,
cholangiocarcinomas, and dysplastic nodules were confirmed by histopathology.
Metastatic hepatic disease had spread from gastric carcinoma (n = 4),
colorectal carcinoma (n = 1), pancreatic carcinoma (n = 1),
or breast cancer (n = 1). All hepatic abscesses were verified by
percutaneous aspiration.
Approval for this study was obtained from the appropriate committee at our institution. Written informed consent was obtained from all patients before contrast-enhanced sonography.
Image Acquisition
All baseline and contrast-enhanced sonographic examinations were performed
by one of two abdominal radiologists (with 6 or 7 years of experience) using a
Sequoia 512 scanner (Acuson) equipped with a convex 3-5-MHz transducer and
agent detection imaging software. Before receiving a sonographic contrast
agent, all patients underwent baseline examinations including gray-scale and
color or power Doppler examinations with or without spectral Doppler
sonography. When a lesion was localized by gray-scale imaging, machine
settings such as depth, focal zone, and time-gain compensation were adjusted.
A single focal zone was located at the bottom or at the center of a lesion,
depending on its size. Unenhanced scanning including Doppler sonography
scanning was then performed during suspended respiration in the optimal
visualization plane.
The sonographic contrast agent used in the present study was SH U 508A (Levovist), which consists of galactose microparticles (99.9%) and palmitic acid (0.1%). Before administration, this agent was prepared by shaking the granules with 11 mL of sterile distilled water for 10 sec. A milky suspension of galactose microparticles and microbubbles was created by disaggregation of the granules. After standing to equilibrate for 2 min, Levovist was injected IV as a bolus in a 4-g dose at a concentration of 300 mg/mL, followed by a 10-mL saline flush using an 18- or 20-gauge peripheral IV cannula.
After engaging the agent detection imaging function, we readjusted the machine settings, such as box covering the lesion, depth, focus, and time-gain compensation. The default settings of the other machine parameters for agent detection imaging were the following: maximum mechanical index (1.9), a low level of line density and frame rate (9 Hz), and no frame averaging (persistence). We used the same contrast agent and scanning protocol as was used during our previous studies [12, 18] and obtained serial agent detection images for 3 or 5 min. Even if newer contrast agents from which low mechanical index imaging could be obtained had been recently developed, we could not use them because they had not gained regulatory approval in our country.
Four rapid breath-hold scans were performed to obtain four serial
phases—that is, early arterial (7 sec after the first arrival of
contrast material), late arterial (30 sec after contrast injection), portal
(90 sec), and delayed (3 or 5 min). In agent detection imaging, color
components representing the signal from the microbubble can be isolated from
the gray-scale images representing the signal from the tissue so that each
component (contrast, tissue, and combined mode of display) can be separately
displayed. All contrast-enhanced sonographic examinations were performed in
combined mode because the default setting and images were immediately
converted to contrast and tissue mode at the end of scans. All baseline and
contrast-enhanced scans were obtained as cine loops, stored on a
magnetooptical disk, and transferred to an IBM-compatible computer, with a
DICOM viewer (
-viewer, version 2.7, INFINITT).
Image Analysis
Randomized sonographic examinations were reviewed on a 19 x 19 inch
IBM-compatible computer monitor by two independent radiologists (with 10 and
12 years of experience in contrast-enhanced sonography) who were unaware of
the final diagnosis or the results of other imaging studies. Two
interpretation sessions with a 1-week interval were held for each radiologist
to review baseline sonography with and without contrast-enhanced sonography.
Both radiologists were asked the three questions under each of the two
interpretations: First, on a 5-point confidence scale (1, definitely benign;
2, probably benign; 3, indeterminate; 4, probably malignant; 5, definitely
malignant), what is your confidence that this lesion is malignant? Second,
could you characterize the lesion with a specific diagnosis, if any, and
record the diagnosis? Finally, is there any necessity for a further imaging
study to characterize this lesion? At the second interpretation session, the
radiologists were provided with all baseline and contrast-enhanced sonograms.
This interpretation method is appropriate for our evaluation because it mimics
the clinical situation.
A subjective evaluation was used to analyze the lesion at both interpretation sessions. At each session, both radiologists were asked to provide a diagnosis according to previously published established criteria [10-12, 19-22]. For baseline sonograms, the diagnostic criteria used for focal hepatic lesions were as follows: Homogeneous echogenic lesions or lesions with an echogenic peripheral rim without intralesional vascular flow were considered to be hemangiomas. Lesions with a thick irregular wall or septation containing echogenic debris or fluid, posterior enhancement, hypervascularity in the thickened wall, and the absence of central vessels were considered to be abscesses. Lesions having a hypoechoic rim regardless of echogenicity were suspected of being malignant. Of these, heterogeneous echogenic lesions with a hypoechoic rim and a hypervascular flow signal surrounding or penetrating a lesion were classified as HCCs. Heterogeneous echogenic lesions with a hypoechoic rim and bile duct dilatation at the periphery were considered to be cholangiocarcinomas. Multiple lesions with a hypoechoic halo or a target appearance without an intralesional flow signal were classified as metastases [19-21].
For contrast-enhanced sonography, lesions with delayed homogeneous enhancement, regardless of an enhancement pattern during the early phases, were rated as benign. Specifically, lesions showing early peripheral nodular enhancement and delayed centripetal filling-in were considered to be hemangiomas. Isoechoic septumlike enhancement compared with adjacent liver parenchyma in all phases and with an internal contrast-free component was considered to be the contrast-enhanced sonographic characteristic of hepatic abscesses. Solid lesions without enhancement or with inhomogeneous enhancement were given higher scores for malignancy. A pattern of early enhancement and washout led to a diagnosis of HCC. Lesions showing peripheral enhancement during the early phase and a heterogeneous defect without centripetal progression of the enhancement during the delayed phase were classified as metastases or cholangiocarcinomas [10-12, 22]. Further lesion differentiation was made using baseline sonography. Lesions that could not be classified as either benign or malignant using baseline or contrast-enhanced sonography were given a score of 3.
In addition to lesion differentiation, we analyzed how many lesions were given a specific diagnosis or correctly diagnosed using sonography with and without contrast enhancement by each radiologist. We also noted the number of lesions for which sonography played a role as a confirmatory imaging technique and the number of cases for which the radiologists incorrectly classified a lesion but stated that no further imaging was necessary. We defined sonography as a confirmatory imaging technique when radiologists decided that no further imaging for lesion characterization was needed and when the lesion concerned had been correctly diagnosed.
Statistical Analysis
A biostatistician participated in the study design and statistical
analysis. Interobserver agreement between two reviewers for each sonographic
interpretation without and with contrast enhancement was evaluated using
weighted kappa statistics. For the kappa statistics of 3 x 3 tables,
scores from 1 to 5 were classified into three grades: grade 1 for a score of 2
or lower, 2 for a score of 3, and 3 for a score of 4 or higher.
The individual performance of each radiologist with respect to differentiating benign and malignant lesions for both interpretation sessions was evaluated and compared using areas under the receiver operating characteristic (ROC) curve (Az), which was calculated using a nonparametric method of MedCalc software for Windows (Microsoft). This comparison indicated the effect of contrast-enhanced sonography on the radiologist's performance with respect to differentiating benignity and malignancy. In addition, sensitivity and specificity were calculated using only those lesions allocated a rating of 3 or higher. Sensitivity and specificity are presented with a 95% confidence interval and were compared using the McNemar test, a nonparametric test for two related dichotomous variables using SPSS version 11.0 (Statistical Package for the Social Sciences) for Windows (Microsoft) [23]. A p value of less than 0.05 was considered to indicate a statistically significant difference.
In terms of the number of correctly characterized cases, the number of cases in which sonography played a confirmatory diagnostic role and the number of cases for which the radiologists incorrectly classified a lesion but stated that no further imaging was necessary, the significances of differences between the results obtained with and without contrast-enhanced sonography for each radiologist were assessed using Fisher's exact test or the chisquare test.
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
|
|
|
|
|
|
|
|
Lesions correctly characterized at the two interpretation sessions varied for benign and malignant lesions, as shown in Table 2. The total number of correctly characterized lesions increased from 28 (37.3%) to 59 (78.7%) for radiologist 1 and from 36 (48%) to 56 (74.7%) for radiologist 2 when combined sonographic examinations were interpreted (p < 0.001). Adding contrast-enhanced sonography increased the number of benign and malignant lesions correctly classified, but Fisher's exact or the chi-square test failed to show a statistically significant increase in correctly classified malignant lesions (p > 0.05). In the case of malignant lesions, an additional one or seven lesions were correctly revealed by each radiologist by combined sonographic examinations than by baseline sonography, whereas for benign lesions, an additional 19 or 24 lesions were correctly depicted by combined sonography.
|
Contrast-enhanced sonography combined with baseline sonography played a successful role as a confirmatory imaging technique in 54 (72%) and 47 (63%) cases for the two radiologists, whereas baseline sonography played a role in 26 (35%) and 21 cases (28%) (Table 3). The role of sonography as a confirmatory imaging technique was markedly improved by combined sonographic examinations (p < 0.001). The increasing numbers of cases in which combined sonographic examinations played a confirmatory diagnostic role versus baseline sonography was achieved in both benign and malignant lesions; however, findings with Fisher's exact or chi-square test failed to show that this was significant for malignant lesions.
|
The numbers of cases for which the radiologists incorrectly classified but stated no further imaging was necessary were also decreased in combined sonographic examinations (two for radiologist 1 and one for radiologist 2) compared with in baseline sonography (four for both radiologists). However, the difference between baseline and combined sonographic examinations was not statistically significant (p > 0.05).
On a 5 x 5 table of grading, interobserver agreement for combined
sonographic examinations (baseline with contrast-enhanced sonography) improved
markedly (weighted = 0.881) versus baseline sonography (weighted
= 0.161). On a 3 x 3 table of grading (a score of 1 or 2 was
classified as 1, a score of 3 as 2, and a score of 4 or 5 as 3), an almost
perfect interobserver agreement was achieved for combined sonographic
examinations (weighted = 0.919), whereas substantial agreement was
achieved for baseline sonography (weighted = 0.656). Our rationale for
reclassifying the grades in this manner was that radiologists showed a wide
variance for grading of 1 and 2 on the one hand and of 4 and 5 on the other
and that shifts between 1 and 2 or 4 and 5 are not so important in the
clinical situation.
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Our results also show that contrast-enhanced sonography aids hepatic lesion characterization and the differentiation of benign and malignant focal hepatic lesions. In fact, many reports have been issued on the value of contrast-enhanced sonography for the characterization of focal hepatic lesions. However, this is the first report on the use of contrast-enhanced sonography for focal hepatic lesion characterization in fairly confusing clinical settings like diffuse liver diseases.
In our study, the findings of focal liver lesions on contrast-enhanced sonography in most cases were very characteristic and typical as shown (Figs. 2A, 2B, 3, 4). Nevertheless, some lesions with nonspecific and atypical features on contrast-enhanced sonography could not be correctly differentiated. Specifically, in our study, hepatic abscesses were frequently misinterpreted as malignant lesions—especially as metastases with necrosis—even on contrast-enhanced sonography (Fig. 5). Several authors have reported that the differentiation of hepatic abscesses and malignant hepatic tumors on CT, MRI, and sonography is difficult because there is a considerable overlap between their clinical presentations and radiologic appearances [24-26]. Moreover, few reports have detailed the contrast-enhanced sonographic findings of hepatic abscesses [12]. In our study, in three of the four abscesses that were misinterpreted, the patients presented with fever and leukocytosis on admission. However, our reviewers did not have any clinical or laboratory information. These facts might explain the poor diagnostic performance of contrast-enhanced sonography for hepatic abscesses. Therefore, when necrotic lesions with internal septumlike enhancement are encountered, clinical findings and sonographic features should be considered to differentiate abscesses and malignant tumors.
With respect to the other false-positive case in which a benign lesion was incorrectly classified as a malignant one, a 1.5-cm hemangioma in a patient with alcoholic hepatitis was tentatively diagnosed as a benign lesion on baseline sonography. On contrast-enhanced images, this lesion showed a subtle rimlike enhancement during the late arterial phase and appeared as an echo-defective lesion during the portal phase instead of showing the typical enhancement pattern of hemangioma and was therefore misinterpreted as a metastasis by both radiologists. Several studies have described typical enhancement patterns for hemangiomas on contrast-enhanced sonography, despite the use of different techniques [10-12, 22, 27]. Of hemangiomas, the lesions that had atypical pathologic characteristics such as sclerosing or sclerosed hemangiomas could show such atypical enhancement patterns. We cannot obtain the pathologic specimen of this case to prove this unusual pathology. In addition, deep-seated lesions could show such an atypical feature because of weak enhancement related to little simulated acoustic emission effect as in our case.
As for a false-negative case in which a malignant lesion was incorrectly classified as a benign one, an HCC was incorrectly interpreted as a hemangioma on contrast-enhanced sonography because it showed peripheral globular enhancement in all phases except the early arterial phase (Fig. 6). However, this lesion was determined to be malignant on baseline sonography because of its indeterminate nature. It is unclear why the contrast-enhanced sonographic findings of this HCC resembled those of a hemangioma. A previous study showed that HCCs with a large vascular spacelike peliosis or consisting of a large acinar formation could produce a hemangioma-like enhancement pattern [28]. In our study, only two specimens were obtained by sonographically guided percutaneous needle biopsy and such atypical pathologic features were not proven.
We also found that contrast-enhanced sonography improved interobserver agreement in terms of differentiating benign and malignant lesions. Interobserver agreement was observed to be fair or substantial with respect to the interpretation of baseline sonography and almost perfect when contrast-enhanced sonography was added. This finding correlates well with the findings of a previous study by von Herbay et al. [27], who performed late-phase pulse-inversion sonography in patients with focal hepatic lesions.
Finally, the necessity of a further imaging workup for lesion characterization was markedly reduced for both radiologists when the contrast-enhanced sonography was added. In 63-72% of cases, contrast-enhanced sonography played a successful role as a confirmatory imaging technique, whereas baseline sonography played a successful role in only 28-35%. The significant increase in numbers attributed to combined sonographic examinations was achieved in benign rather than in malignant lesions. This result might be explained by the large number of hemangiomas in our study. Contrast-enhanced sonography is known to be especially useful for the specific diagnosis of hemangiomas that show characteristic patterns of peripheral globular or rimlike enhancement with progressive centripetal fill-in [11, 12, 22]. If a patient with diffuse liver disease, especially liver cirrhosis, has nodules for which baseline sonography could not exclude HCC but whose nodules have the characteristic enhancement features of hemangioma on contrast-enhanced sonography, more expensive imaging studies for the purpose of characterization may be avoided. Indeed, in our hospital, if patients, especially those with liver cirrhosis, are shown to have an indeterminate lesion on baseline sonography, they are recommended for further CT or MRI study; then for practical reasons, the diagnosis is delayed for approximately 2 weeks. On the other hand, contrast-enhanced sonography could be performed with baseline sonography in 1 day. Moreover, if characteristic features are observed on contrast-enhanced sonography, further imaging workup may be avoided and the management plan can also be changed.
Despite these advantages, contrast-enhanced agent detection imaging has several inherent limitations. First, because the scanning plane should not be changed during the examination, it is not possible to evaluate multiple lesions after bolus administration of Levovist. Second, in addition to operator dependence, contrast-enhanced sonography is dependent on the patient's ability to regulate breathing during the intervals between scan phases. Thus, patient training may be essential for achieving acceptable image sets. Our study is also limited because criteria for the diagnosis of hepatic tumors were not applied prospectively. Thus, a prospective study of this enhancement pattern-based characterization in a large population with diffuse liver disease is needed. Other study limitations are the relatively small number of cases involved and the limited number of cases with pathologic proof. However, we believe that this limitation does not create result bias because confident diagnoses were made on the basis of well-established imaging criteria and follow-up. Finally, the proportion of hemangiomas in our study appears to be relatively high. Therefore, the ability of contrast-enhanced sonography to differentiate and characterize focal hepatic lesions could have been overestimated.
To our knowledge, this observer-based study is the first in which radiologists were requested to differentiate focal hepatic lesions in patients with diffuse liver disease using contrast-enhanced sonography. On the basis of our results, we conclude that contrast-enhanced sonography improves the performances of radiologists in terms of differentiating benign and malignant lesions in the presence of diffuse liver diseases, as indicated by statistically significant improvements in Az and specificity. We also found less interobserver variability for contrast-enhanced sonography than for baseline sonography. In addition, our results show that the use of contrast-enhanced sonography reduces the necessity for a further diagnostic workup to characterize focal hepatic lesions.
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  E. Quaia, M. D'Onofrio, P. Cabassa, F. Vecchiato, S. Caffarri, F. Pittiani, K. M. Wittkowski, and M. A. Cova Diagnostic Value of Hepatocellular Nodule Vascularity After Microbubble Injection for Characterizing Malignancy in Patients with Cirrhosis Am. J. Roentgenol., December 1, 2007; 189(6): 1474 - 1483. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Tarantino Utility of Sonography in Diagnosing Hepatocellular Carcinoma Am. J. Roentgenol., May 1, 2007; 188(5): W494 - W494. [Full Text] [PDF]
|
|
|
|
|
|
J. M. Lee Reply Am. J. Roentgenol., May 1, 2007; 188(5): W495 - W495. [Full Text] [PDF]
|
|
|
|
|
|
S. H. Kim, J. M. Lee, J. Y. Lee, J. K. Han, and B. I. Choi Contrast-Enhanced Sonography of Intrapancreatic Accessory Spleen in Six Patients Am. J. Roentgenol., February 1, 2007; 188(2): 422 - 428. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-X. Xu, G.-J. Liu, M.-D. Lu, X.-Y. Xie, Z.-F. Xu, Y.-L. Zheng, and J.-Y. Liang Characterization of Small Focal Liver Lesions Using Real-time Contrast-Enhanced Sonography: Diagnostic Performance Analysis in 200 Patients. J. Ultrasound Med., March 1, 2006; 25(3): 349 - 361. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
