Chest ACCP Member Benefits
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Guest Access | Sign In via User Name/Password
doi:10.1378/chest.06-1810
(Chest. 2007; 131:993-999)
© 2007 American College of Chest Physicians
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (5)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lee, Y.-C.
Right arrow Articles by Chang, Y.-L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lee, Y.-C.
Right arrow Articles by Chang, Y.-L.
Related Content
Right arrowRelated Editorial

Significance of Extranodal Extension of Regional Lymph Nodes in Surgically Resected Non-small Cell Lung Cancer*

Yung-Chie Lee, MD, PhD; Chen-Tu Wu, MD; Shuenn-Wen Kuo, MD; Yu-Ting Tseng, MD and Yih-Leong Chang, MD

* From the Departments of Surgery (Drs. Lee and Tseng), Pathology (Drs. Wu and Chang), and Traumatology (Dr. Kuo), National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan, Republic of China.

Correspondence to: Yih-Leong Chang, MD, 6F-1, 99, Section 3, Roosevelt Rd, Taipei 10646, Taiwan; e-mail: damu{at}ha.mc.ntu.edu.tw

Abstract

Study objectives: Regional lymph node (LN) involvement affects the prognosis of patients with surgically resected non-small cell lung cancer (NSCLC). The significance of extranodal extension in these groups of patients was prospectively studied to determine its clinicopathologic relationships and its influence on patient survival.

Methods: A total of 199 NSCLC patients who were proved to have regional LN involvement after resection were included. Histologic examinations including tumor cell type, grade of differentiation, vascular invasion, regional LN metastasis emphasizing the number and station of LN involvement, the presence or absence of extranodal extension, and the immunohistochemistry of p53 expression were obtained. The relationships between extranodal extension and histologic type, grade of differentiation, vascular invasion, tumor size, pathologic stage, p53 expression, or patient survival were analyzed.

Results: Extranodal extension was significantly higher in women, adenocarcinoma, advanced stage, tumors with vascular invasion, or p53 overexpression. The total number and positive rate of resected LNs with extranodal extension were significantly correlated with advanced stage, tumors with vascular invasion, or p53 overexpression. By multivariate analysis of survival, the presence or total number of LNs with extranodal extension, tumor stage, and p53 expression were significant prognostic factors. The 5-year survival rate of stage IIIA patients without extranodal extension (30.4%) was significantly better than that of stage II patients with extranodal extension (16.8%). No survival difference between extranodal positive stage II and IIIA patients was noted.

Conclusions: Extranodal extension of regional LNs is an important prognostic factor in patients with surgically resected NSCLC.

Key Words: extranodal extension • non-small cell lung cancer • prognosis • surgery

Lung cancer is one of the most common causes of cancer death in Taiwan.1 For non-small cell lung cancer (NSCLC), which comprises approximately 80% of all cases of lung cancer, surgery remains a mainstay of treatment if the tumor is resectable.2 The most important prognostic factor affecting patient survival after surgery is the TNM stage of the tumor. Furthermore, the degree of regional lymph node (LN) involvement mainly affects the prognosis if the tumor can be completely resected.234 According to the commonly used international staging system for lung cancer,5 LN staging is based on the location of LN involvement (ie, intrapulmonary, mediastinal, or contralateral mediastinal). But clinical observation has noted that the character of LN involvement is rather heterogeneous. And beside the level and number of positive LNs that were variable, the character of the tumors ranged from microscopic invasion to grossly bulky LNs.467 Conventional LN staging was considered to be inadequate because of the lack of consideration of the severity of LN involvement. Consequently, patient survival might be quite different even in the group of patients with the same LN stage.89 Several reports101112131415 have shown that the subclassification of LN involvement is useful for predicting patient prognosis. The criteria applied to subclassification included clinical or minimal N2 stage, the number or percentage of involved LNs, and single-station or multiple-station involvement. In this report, a more objective method, using microscopic evidence of capsule invasion as the criterion of extranodal extension, was applied to study the impact on patient survival. And the influences of location, and the total number and percentage of extranodal extension were further analyzed.

Materials and Methods

Patients and Tumor Specimen
During the period from January 1990 to December 1999, 199 NSCLC patients underwent complete surgical resection and were proved to have regional or mediastinal LN involvement. The preoperative staging procedures included chest radiography; blood chemistry analysis; CT scanning of the chest, abdomen, and brain; and bone scanning. All patients did not receive neoadjuvant therapy before surgery. These resected LNs were prospectively studied for the extent of LN involvement. All patients had undergone systemic dissection of LNs, including hilar, interlobar, lobar, intralobar, and ipsilateral mediastinal LNs. All resected specimens including tumors and LNs were formalin-fixed and sectioned for microscopic examination after applying hematoxylin-eosin stain. Histologic diagnosis and pathologic features were obtained, including tumor cell type, grade of tumor differentiation, vascular invasion, and regional LN metastasis, emphasizing the number and stations of LN involvement and the presence or absence of extranodal extension seen microscopically. The sizes of every LN with cancer involvement were measured. The LNs were separated into two groups according to their sizes (ie, < 1.0 cm and ≥ 1.0 cm). The assessment of LN extension was made by serial section at intervals of 1 to 2 mm along the greatest diameter for each LN. All of the sections were examined by two pathologists for the presence of extranodal extension (Fig 1 ). Pathologic staging was performed according to the international staging system for lung cancer,5 which is based on tumor size, location, and involvement, and the presence of LN metastasis. Adenosquamous carcinomas were not included in the classification of histologic type and grade of differentiation due to the discrepancy in each tumor. After operation, no adjuvant therapy was given to these patients. They were regularly followed up at the outpatient clinic with a chest roentgenogram, serum carcinoembryonic antigen measurements, and CT or bone scanning, as needed. And the status of living in each patient was reviewed and registered at the end of June 2005. The follow-up period ranged from 63 to 168 months. The project of this study was approved by the Research Ethics Committee of this hospital.


Figure 1
View larger version (148K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 1.. Metastatic NSCLC in an LN with extranodal extension (hematoxylin-eosin, original x33).

 
Immunohistochemistry of p53 Expression
For immunohistochemical demonstration of the p53 protein in tumor tissue, deparaffinized 4-µm-thick sections were treated with 0.3% H2O2 in methanol, heated in a microwave oven for 20 min to block endogenous peroxidase, and incubated with normal nonimmune goat serum. After excessive goat serum had been blotted, the slides were incubated with a specific mouse anti-p53 protein antibody (p53 [Ab-6], pantropic; Oncogene Science; Cambridge, MA) [diluted 1:50] for 1 h at room temperature. After incubation with biotinylated goat antimouse antibody, the sections were incubated with peroxidase-conjugated streptavidin. As a chromogen, 3',3-diaminobenzidine tetrachloride was used, stained sections were evaluated by two independent pathologists (Y.-L.C. and C.-T.W.). Tumors were considered to be positive for p53 when there was moderate-to-strong staining of > 50% of neoplastic cells or they were categorized as being weakly positive or negative if ≤ 50% of the tumor cells were stained.

Characteristics of LN Involvement and Its Relation to Clinicopathologic Parameters
The site of LN involvement was separated into two groups, N1 and N2. The extent of LN invasion was classified microscopically into the following two categories: (1) intranodal invasion, in which cancer cells were noted within the capsule of the LN; and (2) extranodal extension, in which cancer cells invaded beyond the capsule of the LN. Furthermore, the number and percentage of LNs with extranodal extension in each patient were counted and recorded. The correlations between characteristics of LN involvement and histologic type, grade of differentiation, vascular invasion, tumor size, or pathologic stage of the tumor were investigated. The relationships between LN size groups and the presence of extranodal extension were also studied.

Analysis of Prognostic Factors
Several factors, which included age, gender, histologic type, tumor size, grade of differentiation, microscopically vascular invasion, pathologic stage, characteristics of LN involvement, and status of p53 expression, were analyzed to evaluate their influence on patient survival. Special emphasis was given to analyzing the impact of LN station, and number or percentage of extranodal extensions on patient survival.

Statistical Analysis
The correlations between various clinicopathologic parameters and the characteristics of LN invasion were analyzed by using Pearson {chi}2 test. Survival curves were estimated using the Kaplan-Meier method, and differences in survival were evaluated with the general Wilcoxon test. The multivariate relationships were analyzed with the Cox proportional hazards general linear model.

Results

Patient Demography
During the 10-year period studied, 199 surgically treated NSCLC patients were proven to have regional or mediastinal LN involvement after the pathologic examination of resected specimens. Of the 199 patients, 132 patients were men and 67 patients were women (age range, 32 to 82 years; mean age, 62.0 years). There were 115 adenocarcinomas, 72 squamous cell carcinomas, and 12 adenosquamous carcinomas. Fourteen tumors were stage IIA (T1N1M0), 61 tumors were stage IIB (T2N1M0), and 124 tumors were stage IIIA (T3N1M0 or T1–3N2M0).

Correlation of Extranodal Involvement With Other Clinicopathologic Parameters
Among the 199 patients with LN involvement, 126 (63.3%) had extranodal extension seen microscopically. Correlations of extranodal extension with several clinicopathologic parameters were shown in Table 1 . The percentage of extranodal extension was significantly higher in tumors in women, adenocarcinoma histologic type, advanced stage, tumors with vascular emboli, and p53 overexpression. In addition, the total number and positive rate of extranodal positive LNs in surgically dissected LNs were significantly correlated with advanced stage, tumor with vascular emboli, or p53 overexpression (Table 2 ). A total of 465 LNs were proved to have cancer involvement in these patients. Among them, 398 LNs were positive for extranodal extension, and 67 LNs were negative. The ranges (and mean ± SD) of LN sizes of extranodal positive and negative LNs were 0.2 to 3.3 cm (mean, 1.02 ± 0.61 cm) and 0.2 to 2.5 cm (mean, 1.16 ± 0.53 cm), respectively. By using the criterion of size ≥ 1.0 cm, which was commonly applied clinically to recognize enlarged LNs, the rates for extranodal positive and negative LNs were 79.6% and 20.4%, respectively. However, in the group with LN sizes < 1.0 cm, the rates for extranodal positive and negative LNs were 90.8% and 9.2%, respectively. The difference was significant (p = 0.001).


View this table:
[in this window]
[in a new window]

  		Table 1.. Correlation of Extranodal Extension With Other Clinicopathologic Parameters

 

View this table:
[in this window]
[in a new window]

  		Table 2.. Correlation of Total Number and Positive Rate of Extranodal Extension in Dissected LNs With Other Clinocopathologic Parameters*

 
Influence of Extranodal Involvement on Patient Survival
By univariate analysis of patient survival, the presence, or total number, and percentage of LNs with extranodal extension were significant prognostic factors, in addition to tumor stage, differentiation, presence of vascular invasion, and p53 overexpression. By multivariate analysis, the presence, or total number of LNs with extranodal extension, tumor stage, and p53 overexpression remained significant prognostic factors. The 5-year survival rates were 40.7% and 13.5%, respectively, for patients with negative and positive extranodal extension (p < 0.001) [Fig 2 ]. The survival curves in three groups with different total numbers of positive extranodal LNs (0, 1 to 3, and >3) was shown in Figure 3 , with the 5-year survival rates at 40.7%, 19.7%, and 2.3%, respectively (p < 0.001). The survival curves in three groups with different positive rates of extranodal extension (0%, ≤ 50%, and >50%) is shown in Figure 4 , with 5-year survival rates of 40.7%, 14.0%, and 8.3%, respectively (p < 0.001).


Figure 2
View larger version (15K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 2.. Comparison of survival curves between the presence and absence of extranodal extension (p < 0.001).

 

Figure 3
View larger version (18K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 3.. Survival curves in three groups with different total numbers of positive extranodal LN (ie, 0, 1 to 3, and >3) [p < 0.001].

 

Figure 4
View larger version (17K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 4.. Survival curves in three groups with different positive rates of extranodal extension (ie, 0%, ≤ 50%, and >50%) [p < 0.001].

 
Reappraisal for LN Staging System
The influence of tumor stage with consideration of extranodal extension on patient survival was shown in Figure 5 . The survival difference between positive and negative extranodal extension in the tumors with same pathologic stage was significant (p < 0.001). The 5-year survival rate of stage IIIA patients without extranodal extension (30.4%) was significantly better than that for stage II patients with extranodal extension (16.8%). There was no survival difference between patients who were in extranodal positive stage II and those in stage IIIA. And there was also no survival differences among either or both intrapulmonary and mediastinal LN with extranodal extension (Fig 6 ). Therefore, besides the location of LN metastasis, the status of extranodal extension played a significant role in affecting patient prognosis.


Figure 5
View larger version (21K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 5.. Survival curves in different tumor stages with consideration of extranodal extension. Significant difference between stage IIIA extranodal (–) and stage II extranodal (+) was noted (p < 0.001).

 

Figure 6
View larger version (17K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 6.. Survival curves in three groups with either or both intrapulmonary and mediastinal extranodal extension (p = 0.069).

 
Discussion

In patients with surgically resected NSCLC, regional LN metastasis was recognized as one of the most important prognostic factors.234 The conventional international staging system5 classifies different stages of LN involvement according to the location or level of positive LN, irrespective of characteristics, or the number and multiplicity of LN involvement. Several investigations6789 have raised the heterogenicities of LN involvement, and these heterogenicities usually affect the prognosis of the patient significantly.

The concept of defining the severity of LN involvement was proposed for > 20 years.6 The commonly used description of a positive LN was clinical or microscopic invasion, which was defined by CT scan or mediastinoscopic findings of the LNs.10 The definition of clinically positive LN was subjectively measured, usually depending on one certain size of the LN. However, several studies161718 have shown that the existence and extent of LN involvement does not always correlate with the size of the LN. Using an LN size of ≥ 1.0 cm as a criterion for predicting cancer involvement, the accuracy rates ranged from 60 to approximately 80%.161718 In this study, the severity of LN involvement was defined by extranodal extension, which could be accurately decided by microscopic examination of serial sections of each dissected LN. Our observation also found that even small LNs (ie, < 1.0 cm) could have cancer involvement with extranodal extension.

In this study, the histologic type of adenocarcinoma had a higher frequency of extranodal extension, which is correlated with the findings of several previous studies619 that adenocarcinoma is more predisposed to regional LN metastasis than squamous cell carcinoma. Because 76.1% of female patients in this study had adenocarcinoma, female patients consequently had a higher rate of extranodal extension. The correlation of microscopic vascular or lymphatic invasion with the presence of extranodal extension can be explained by the sequence of pathogenesis of LN invasion.2021 The result of p53 overexpression correlating with extranodal extension indicated that p53 expression is an indicator of tumor invasiveness, which is similar to the findings of our study and several previous studies.2223

The impact of extranodal extension, including presence, total number, and positive rate, on patient survival was demonstrated in this study. The previous subclassifications of LN metastasis, which largely depended on the size of the LNs, were not always correct because LN size was influenced by several inflammatory processes, such as tuberculosis and anthracosis.2425 Meticulous discrimination for microscopic extranodal extension to subclassify the status of regional LN metastasis was mandatory and important to predict patient prognosis.

Several studies12131415 have shown that the level of LN metastasis was an important prognostic factor in patients with surgically resected NSCLC. The drawback in these studies was that they took no consideration of the heterogeneous character of LN involvement. In this study, we have demonstrated that extranodal extension was a worse prognostic factor, irrespective of the level of LN involvement. Even more, the prognosis of stage II extranodal-positive patients was significantly worse than that for stage III extranodal-negative patients. These observations also point out the limitations of the conventional LN staging system.

In conclusion, this study showed for the first time that the extranodal extension of LNs is an important prognostic factor in patients with surgically resected NSCLC. The total number and positive rate of extranodal extension also influence patient prognosis. It has been suggested that an evaluation of extranodal extension should be performed on dissected LNs. The status of extranodal extension might be considered in the LN staging system for more accurate prediction of patient prognosis.

Footnotes

Abbreviations: LN = lymph node; NSCLC = non-small cell lung cancer

This study was funded by research grant NSC-94–2314-B-002–007 from the National Science Council, Republic of China.

The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Received for publication July 27, 2006. Accepted for publication November 27, 2006.

References

  1. . Taiwan Department of Health. (2002) Vital statistics, 1971–2001. Department of Health. Taipei, Taiwan:
  2. Wigle, DA, Keshavjee, S, Ginsberg, RJ Lung cancer: surgical treatment. Sellke, FW Nido, PJD Swanson, SJ eds. Sabiston and Spencer surgery of the chest 7th ed. 2005,253-276 Elsevier Saunders. New York, NY:
  3. Naruke, T, Tsuchiya, R, Kondo, H, et al Prognosis and survival after resection for bronchogenic carcinoma based on the 1997 TNM-staging classification: the Japanese experience. Ann Thorac Surg 2001;71,1759-1764[Abstract/Free Full Text]
  4. Keller, SM, Adak, S, Wagner, H, et al Mediastinal lymph node dissection improves survival in patients with stage II and IIIA non-small cell lung cancer. Ann Thorac Surg 2000;70,358-366[Abstract/Free Full Text]
  5. Mountain, CF Revisions in the international system for staging lung cancer. Chest 1997;111,1710-1717[CrossRef][ISI][Medline]
  6. Martini, N, Flehinger, BJ, Zaman, MB, et al Results of resection in non-oat cell carcinoma of the lung with mediastinal lymph node metastases. Ann Surg 1983;198,386-397[ISI][Medline]
  7. Susuki, K, Nagai, K, Yoshida, Y, et al The prognosis of surgically resected N2 non-small cell lung cancer: the importance of clinical N status. J Thorac Cardiovasc Surg 1999;118,145-153[Abstract/Free Full Text]
  8. Grunenwald, D, Le Chavalier, T Stage IIIA category of non-small cell lung cancer: a new proposal. J Natl Cancer Inst 1997;89,88-89[Free Full Text]
  9. Pearson, G, Delarue, WC, Ilves, R, et al Significance of positive superior mediastinal nodes identified at mediastinoscopy in patients with resectable cancer of the lung. J Thorac Cardiovasc Surg 1982;83,1-11[ISI][Medline]
  10. Andre, F, Grunenwald, D, Pignon, JP, et al Survival of patients with resected N2 non-small-cell lung cancer: evidence for a subclassification and implications. J Clin Oncol 2000;18,2981-2989[Abstract/Free Full Text]
  11. Luzzi, L, Paladini, P, Ghiribelli, C, et al Assessing the prognostic value of the extent of mediastinal lymph node infiltration in surgically-treated non-small cell lung cancer (NSCLC). Lung Cancer 2000;30,99-105[CrossRef][ISI][Medline]
  12. Osaki, T, Nakashima, A, Yoshimatsu, T, et al Survival and characteristics of lymph node involvement in patients with N1 non-small cell lung cancer. Lung Cancer 2004;43,151-157[CrossRef][ISI][Medline]
  13. Okada, M, Sakamoto, T, Yuki, T, et al Border between N1 and N2 stations in lung carcinoma: lessons from lymph node metastatic patterns of lower lobe tumors. J Thorac Cardiovasc Surg 2005;129,825-830[Abstract/Free Full Text]
  14. Rea, F, Marulli, G, Callegaro, D, et al Prognostic significance of main bronchial lymph nodes involvement in non-small cell lung carcinoma: N1 or N2? Lung Cancer 2004;45,215-220[CrossRef][ISI][Medline]
  15. Marra, A, Hillejan, L, Zaboura, G, et al Pathologic N1 non-small cell lung cancer: correlation between pattern of lymphatic spread and prognosis. J Thorac Cardiovasc Surg 2003;125,543-553[Abstract/Free Full Text]
  16. Gould, MK, Kuschner, WG, Rydzak, CE, et al Test performance of positron emission tomography and computed tomography for mediastinal staging in patients with non-small-cell lung cancer: a meta-analysis. Ann Intern Med 2003;139,879-892[Abstract/Free Full Text]
  17. Prenzed, KL, Monig, SP, Sinning, JM, et al Lymph node size and metastatic infiltration in non-small cell lung cancer. Chest 2003;123,463-467[CrossRef][ISI][Medline]
  18. Fritscher-Ravens, A, Bohuslavizki, KH, Brandt, L, et al Mediastinal lymph node involvement in potentially resectable lung cancer: comparison of CT, positron emission tomography, and endoscopic ultrasonography with and without fine-needle aspiration. Chest 2003;123,442-451[CrossRef][ISI][Medline]
  19. Sagawa, M, Saito, Y, Takahashi, S, et al Clinical and prognostic assessment of patients with resected small peripheral lung cancer lesions. Cancer 1990;66,2653-2657[CrossRef][ISI][Medline]
  20. Ichinose, Y, Yano, T, Asoh, H, et al Prognostic factors obtained by a pathologic examination in completely resected non-small cell lung cancer. J Thorac Cardiovasc Surg 1995;110,601-605[Abstract/Free Full Text]
  21. Kessler, R, Grasser, B, Massard, G, et al Blood vessel invasion is a major prognostic factor in resected non-small cell lung cancer. Ann Thorac Surg 1996;62,1489-1493[Abstract/Free Full Text]
  22. Lee, YC, Chang, YL, Luh, SP, et al Significance of p53 and Rb protein expression in surgically treated non-small cell lung cancer. Ann Thorac Surg 1999;68,343-348[Abstract/Free Full Text]
  23. Marchetti, A, Buttitta, F, Merlo, G, et al P53 alteration in non-small cell lung cancers correlate with metastatic involvement of hilar and mediastinal lymph nodes. Cancer Res 1993;53,2846-2851[Abstract/Free Full Text]
  24. Murray, JG, O’Driscoll, M, Curtin, JJ Mediastinal lymph node size in an Asian population. Br J Radiol 1995;68,348-350[Abstract]
  25. Arita, T, Matsumoto, T, Kuramitsu, T, et al Is it possible to differentiate malignant mediastinal nodes from benign nodes by size? Reevaluation by CT, transesophageal echocardiography and nodal specimen. Chest 1996;110,1004-1008[ISI][Medline]

Related Editorial

The Staging System for Non-small Cell Lung Cancer: Time for an Overhaul?
David J. Barnes
Chest 2007 131: 948-949. [Full Text] [PDF]



This article has been cited by other articles:


Home page
 ChestHome page
A. M. Bell, B. R. DeYoung, J. Weydert, Y.-C. Lee, C.-T. Wu, and Y.-L. Chang
Extranodal Extension in Metastatic Non-small Cell Lung Cancer
Chest, December 1, 2007; 132(6): 2058 - 2060.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (5)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lee, Y.-C.
Right arrow Articles by Chang, Y.-L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lee, Y.-C.
Right arrow Articles by Chang, Y.-L.
Related Content
Right arrowRelated Editorial

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS