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First Published Online July 9, 2008
The Oncologist, Vol. 13, No. 7, 751-760, July 2008; doi:10.1634/theoncologist.2007-0246
© 2008 AlphaMed Press

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Breast Cancer

The CYP19 TTTA Repeat Polymorphism Is Related to the Prognosis of Premenopausal Stage I–II and Operable Stage III Breast Cancers

Chiun-Sheng Huanga, Sung-Hsin Kuob,d,e, Huang-Chun Lienc, Shi-Yi Yangf, San-Lin Youf, Chen-Yang Sheng, Ching-Hung Linb,d, Yen-Sen Lub,d, King-Jeng Changa

Departments of aSurgery, bOncology, and cPathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; dCancer Research Center, National Taiwan University College of Medicine, Taipei, Taiwan; eDepartment of Oncology, National Taiwan University Hospital Yun-Lin Branch, Yunlin, Taiwan; fGraduate Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei, Taiwan; gInstitute of Biomedical Sciences and Life Science Library, Academia Sinica, Taipei, Taiwan

Key Words. CYP19 genetic polymorphism • Breast cancer • Prognostic factor • Survival • Adjuvant chemotherapy

Correspondence: Chiun-Sheng Huang, M.D., Ph.D., M.P.H., Department of Surgery, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, Taiwan. Telephone: 886-2-87339036; Fax: 886-2-23635227; e-mail: huangcs{at}ntu.edu.tw

Received December 17, 2008; accepted for publication June 4, 2008; first published online in THE ONCOLOGIST Express on July 9, 2008.

Disclosure: The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors, planners, independent peer reviewers, or staff managers.


   Learning Objectives
Top
 Learning Objectives
Abstract
 Introduction
 Methods
 Results
 Discussion
 Author Contributions
 Acknowledgments
 References
 
After completing this course, the reader should be able to:

  1. Describe why premenopausal women with the long allele of the CYP19 TTTA repeat polymorphism have a greater survival rate and may not gain benefit from adjuvant chemotherapy.
  2. Assess whether we need to revisit the routine use of adjuvant chemotherapy in high-risk premenopausal patients with the long allele of the CYP19 polymorphism.
  3. Explain why further validation in a randomized study with a large sample size is needed to determine whether the CYP19 TTTA repeat polymorphism can serve as a predictor in hormone receptor–positive premenopausal patients.

This article is available for continuing medical education credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Methods
 Results
 Discussion
 Author Contributions
 Acknowledgments
 References
 
Purpose. Given the critical role of the CYP19 gene, encoding aromatase, in estrogen synthesis and the association of the estrogen level with its TTTA repeat polymorphism, the potential influence of this polymorphism on breast cancer survival, and hence management, deserves further study.

Methods. Genotyping for the CYP19 TTTA repeat polymorphism was performed on 482 stage I–II and operable stage III Taiwanese breast cancer patients. Patients with more than seven TTTA repeats in either allele of CYP19 were defined as having the long allele. We correlated clinical variables and CYP19 genotypic polymorphism with outcome.

Results. In hormone receptor (HR)-positive breast cancers, premenopausal patients with the long allele of the CYP19 polymorphism had a significantly higher overall survival (OS) rate (8-year, 89% versus 68%; p = .003) than those without it. This difference was further demonstrated by a multivariate analysis (OS hazard ratio, 1.53; p = .041). In postmenopausal women or patients with HR-negative breast cancer, there was no significant difference in OS between patients with or without the long allele. In premenopausal women with HR-positive cancers, adequate intensity adjuvant chemotherapy did not achieve a greater OS rate than suboptimal chemotherapy in patients with the long allele, but it resulted in a significantly higher OS rate (p = .011) than suboptimal chemotherapy in women without the long allele.

Conclusions. The CYP19 TTTA repeat polymorphism is associated with survival in premenopausal women, but not in postmenopausal women, with HR-positive breast cancers. Premenopausal women with the long allele have a greater survival rate and may not gain benefit from adjuvant chemotherapy.


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Methods
 Results
 Discussion
 Author Contributions
 Acknowledgments
 References
 
Hormonal therapy for breast cancer is aimed at lowering estrogen levels or blocking estrogen receptors (ERs). Five years of adjuvant hormonal therapy after surgery with tamoxifen, an ER antagonist, reduces the risk for recurrence and death in pre- and postmenopausal patients with early breast cancers [1–3]. Ovarian ablation, as an adjuvant therapy, has been demonstrated to lead to longer survival in premenopausal patients [4]. Aromatase inhibitors have also shown efficacy in reducing the risk for recurrence and/or death in postmenopausal patients with hormone-responsive early breast cancers [5–9].

Aromatase catalyzes the final step of the conversion of androgens to estrogens [10]. In premenopausal women, estrogen is mainly produced by the ovary, with a small proportion being produced by aromatization of adrenal and ovarian androgen in extragonadal tissue, including adipose tissue, muscle, and liver. In postmenopausal women, the ovary ceases to function and aromatization of androgen in extragonadal tissue becomes the main source of estrogen.

Aromatase is encoded by the gene CYP19 [11–14]. Several germline genotypic polymorphisms of CYP19, including a TTTAn tetranucleotide repeat polymorphism within intron 4, have been examined for an association with breast cancer risk [11–13]. In a British population-based study, a higher repeat number of the TTTA repeat polymorphism was found to be associated with longer survival in breast cancer patients [15]. No analysis related to clinical management was performed in that study [15]. A study by Haiman et al. [13] also demonstrated that women with the 7-repeat allele have lower estrogen levels than noncarriers, while women with the 8-repeat allele have higher estrogen levels than noncarriers.

Given the critical role of CYP19 in estrogen synthesis, the potential influence of genetic polymorphisms at CYP19 on breast cancer patient survival, and hence management, deserves further study. In the present study of 482 Taiwanese patients with stage I–II and operable stage III breast cancers, with information on conventional prognostic factors available for >85%, we examined the TTTAn repeat polymorphism of CYP19 and explored its clinical significance.


   METHODS
Top
 Learning Objectives
 Abstract
 Introduction
 Methods
Results
 Discussion
 Author Contributions
 Acknowledgments
 References
 
Study Cohort and Sources of Information
Eligible women were newly diagnosed patients with stage I, II, or operable stage III [16] breast cancer diagnosed at the National Taiwan University Hospital between January 1, 1992 and December 31, 2000. Most had been invited to take part in our previous molecular epidemiological studies [17–20], aimed at defining the contribution of genotypic polymorphisms of carcinogen- and estrogen– metabolizing genes as susceptibility factors for breast cancer development in Taiwan. Genomic DNA and detailed demographic information were obtained from the patients with their consent. Pathologic and clinical information regarding treatment, including the type of surgery, receipt or nonreceipt of adjuvant systemic therapy, the type and dose of adjuvant systemic therapy, and follow-up information, including recurrence and distant metastasis, was obtained from the pathology reports or clinical records. If the last menstruation of a woman had taken place within 1 year, she was considered as premenopausal, and postmenopausal otherwise. Women who had undergone hysterectomy but without bilateral oophorectomy were considered as premenopausal if they were <52 years of age and as postmenopausal if older. Data on the histological grade and hormone receptor (HR) status of the primary tumors, if available, were reviewed by one pathologist, Dr. Lien. The patients were considered HR positive if the percentage of ER- or progesterone receptor (PgR)-positive epithelial cells was ≥10%.

Recently, we demonstrated that breast cancer patients receiving standard adjuvant chemotherapy have greater disease-free survival (DFS) and overall survival (OS) rates than those receiving nonstandard adjuvant chemotherapy [21]. In that study, the definition of standard adjuvant treatment was based on whether the indication and regimen and dose of adjuvant chemotherapy were the same as those in the literature or those recommended by the National Comprehensive Cancer Network guidelines, National Institutes of Health consensus, and St. Gallen's consensus [22–24]. Patients receiving nonstandard adjuvant chemotherapy were defined as those who did not receive standard or high-dose chemotherapy, or who received incomplete courses of chemotherapy, or who received <85% of the calculated optimal dose of standard-dose chemotherapy or single-agent chemotherapy [21]. Adjuvant hormone therapy for at least 5 years was given to all ER- and/or PgR-positive patients and most of the ER-/PgR-negative patients. It is also our policy to administer radiotherapy as an adjuvant strategy for post–breast conserving surgery patients or postmastectomy patients with risk factors, including four or more involved nodes, a locally advanced primary tumor, and a positive margin. Of these patients receiving postoperative radiotherapy, all patients received the optimal dose of radiation (with a biologically equivalent dose of 50–60 Gy in 2-Gy fractions) [25].

The patients were regularly followed up in our clinic after surgery and adjuvant therapy. If patients were lost to follow-up, information on disease status and survival was obtained from the patients' charts, hospital cancer registry records, and the National Death Registry.

Aromatase Genotyping
A sample of peripheral blood collected in acetate-citrate dextrose was obtained from each breast cancer patient and the buffy coat was prepared immediately and stored at –80°C until extraction of genomic DNA. Genomic DNA was obtained by conventional proteinase K extraction and stored at –80°C. The CYP19 genotyping analysis was performed as follows: the polymerase chain reaction (PCR) fragment was made using the primers 5'-GTCTATGAATATGCCTTTTT-3' and 5'-GTTTGACTCCGTGTGTTTGA-3' [13, 26–28]. The forward primer was 5'-labeled with a fluorescent dye (FAM, 5-carboxy-fluorescein) for automatic analysis. The PCR reaction was performed in a final volume of 50 µl containing 40 ng of genomic DNA, 1.0 units of Taq polymerase, 1.5 mM MgCl2, 200 µM of each deoxynucleotide triphosphate, 0.3 µM of each primer, and 5 µl of 10x PCR buffer (500 mM KCl and 200 mM Tris-HCl) and water to a total volume of 50 µl. The thermal cycling conditions were an initial denaturation step at 94°C for 4 minutes, followed by 35 cycles of denaturation at 94°C for 40 seconds, annealing at 55°C for 30 seconds, extension at 72°C for 60 seconds, and a final extension at 72°C for 10 minutes. Two microliters of 10x diluted PCR products were mixed in a running mixture consisting of 8 µl formamide and 0.5 µl ET400-R (Rox) fluorescent size standard (Amersham Biosciences, Piscataway, NJ), subsequently denatured, and subjected to electrophoresis in the ABI PRISM 310 (PE Applied Biosystems, Foster City, CA). Allelic bands were analyzed using ABI PRISM Genescan software. Homozygote alleles detected by Genescan software were sequenced to confirm the repeat length of the CYP19 polymorphism.

Statistical Analysis
The follow-up data available as of February 28, 2005 were analyzed. DFS was measured from the date of the original surgery for breast cancer to the date of locoregional or distant recurrence or death from any cause. OS was calculated from the first day of surgery to the day of death from any cause or the last follow-up date. Survival was calculated using the product limit method of Kaplan and Meier. Differences in survival were compared between groups using the log-rank test. The {chi}2 test and Fisher's exact test were used to compare differences in clinicopathologic parameters. The variables and categories used for the univariate analyses and Cox regression analyses were tumor-related variables, dose of adjuvant chemotherapy, and genetic polymorphism of CYP19. All statistical analyses were performed using SAS 9.0 (SAS Institute, Cary, NC).


   RESULTS
Top
 Learning Objectives
 Abstract
 Introduction
 Methods
 Results
Discussion
 Author Contributions
 Acknowledgments
 References
 
Clinicopathologic Features and Genetic Polymorphism of CYP19
The median age was 47 years (range, 29–75 years); 291 were premenopausal and 191 were postmenopausal. The median follow-up time was 78 months (range, 36–176 months). Detailed information for the clinical outcome, tumor characteristics, and treatments of the 482 patients was shown in our recent study [21]. Briefly, all ER- and/or PgR-positive patients (360 patients) and 76 (80%) of the 95 ER-/PgR-negative patients received tamoxifen. None of the patients received aromatase inhibitors as adjuvant hormonal therapy. One hundred and seventy-seven (37%) received no chemotherapy, 80 (16%) received suboptimal treatment, and 225 (47%) received standard treatment.

The breast cancer patients were divided into two groups, with the long allele or without the long allele of the CYP19 polymorphism, using the 7-repeat TTTA repeat polymorphism as the cutoff [13, 26, 28]. The most frequent CYP19 TTTAn/CYP19 TTTAn genotype was 7/11 (183 patients), followed by 7/7 (157 patients), 11/11 (72 patients), 7/12 (30 patients), 11/12 (28 patients), 10/11 (six patients), 10/12 (two patients), 10/ 13 (one patient), 12/12 (two patients), and 6/7 (one patient).

There were 324 patients with the long allele of the CYP19 polymorphism and 158 patients without the long allele. There were no significant differences in clinicopathologic features or systemic adjuvant treatment between patients in these two groups (Table 1).


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  		Table 1. Pertinent clinicopathologic features of breast cancer patients without the long or with the long allele of the CYP19 polymorphism

 
CYP19 Polymorphisms and Prognosis
The long allele was significantly associated with higher 8-year DFS and OS rates in all patients (Table 2). The prognostic effect of allele length was seen in premenopausal patients (with the long allele versus without the long allele: 8-year DFS rate, 75% versus 60%; p = .021; Fig. 1A; 8-year OS rate, 84% versus 67%; p = .001; Fig. 1B), but not in postmenopausal patients (with the long allele versus without the long allele: 8-year DFS rate, 75% versus 62%; p = .371; 8-year OS rate, 77% versus 66%; p = .687). In addition, in patients with an ER-positive and/or PgR-positive tumor, the long allele was associated with a significantly higher 8-year DFS rate (p = .040) and OS rate (p = .003) in premenopausal patients, but not in postmenopausal patients (Table 2). In ER-/PgR-negative patients, there was no significant difference in DFS and OS between patients with the long allele and those without the long allele (Table 2).


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  		Table 2. DFS and OS in early breast cancer patients as a function of the CYP19 polymorphism

 


Figure 1
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  		Figure 1. Overall treatment results of premenopausal patients as a function of the CYP19 polymorphism. (A): Disease-free survival. (B): Overall survival.

Abbreviation: CI, confidence interval.

 
Further multivariate analyses in premenopausal patients identified positive lymph nodes, tumor size >5 cm, a histological grade of III, negative ER and PR status, suboptimal chemotherapy, and being without the long allele of the CYP19 polymorphism as independent prognostic factors for OS (Table 3). In contrast, lymph node positivity was an independent prognostic factor for both DFS and OS in postmenopausal patients (Table 3), while suboptimal chemotherapy and ER- and PgR-negative status were independent prognostic factors for OS (Table 3). Given that the clinical outcome may differ between stage I–II and operable stage III premenopausal patients, we tried to elucidate whether the CYP19 polymorphism affected the DFS and OS in these two different groups of patients. We found that not having the long allele of the CYP19 polymorphism was an independent prognostic factor for both DFS and OS in stage I–II patients with and/or without lymph node metastasis and operable stage III premenopausal breast cancer patients (Table 4).


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  		Table 3. Multivariate analysis of prognostic factors and DFS and OS for the patients

 


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  		Table 4. Multivariate analysis of prognostic factors (the CYP19 polymorphism) and DFS and OS for the patients

 
Treatment Variation and Prognosis of the Two Subgroups (With and Without the Long Allele of the CYP19 Polymorphism)
In premenopausal women with HR-positive cancers and the long allele, there was no significant difference in DFS and OS (a) between low-risk and high-risk node-negative patients who did not receive adjuvant chemotherapy, (b) between those node-negative patients who received standard chemotherapy and those who received suboptimal chemotherapy, (c) among all node-negative patients, and (d) between those node-positive patients receiving standard chemotherapy and those receiving suboptimal chemotherapy (Table 5). In premenopausal women with HR-positive cancers and without the long allele, we found that, compared with suboptimal adjuvant chemotherapy, standard chemotherapy resulted in a significantly greater DFS (p = .028) and OS (p = .034) rate (Table 5).


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  		Table 5. DFS and OS of ER+ and/or PgR+ premenopausal patients with or without the long allele of the CYP19 polymorphism as a function of adjuvant chemotherapy treatment

 

   DISCUSSION
Top
 Learning Objectives
 Abstract
 Introduction
 Methods
 Results
 Discussion
Author Contributions
 Acknowledgments
 References
 
In the present study, we demonstrated that, in HR-positive breast cancer patients, premenopausal women with the long allele of the CYP19 polymorphism had a significantly higher DFS and OS rate than those without the long allele, but this prognostic effect of the CYP19 polymorphism was not seen in postmenopausal patients. This difference was further demonstrated by multivariate analysis. In HR-negative cancers, no significant difference in DFS or OS was seen between patients with the long allele and those without the long allele. Standard adjuvant chemotherapy did not result in a higher survival rate than suboptimal chemotherapy in premenopausal patients with the long allele, irrespective of lymph node status, but it did in premenopausal patients without the long allele.

Several genotypic polymorphisms of CYP19 have been reported, and the reasons that we focused on this length of polymorphism in the present study are: (a) This length of polymorphism of CYP19 was reported to be associated with the prognosis of breast cancer in a British population-based study [15]; in order to compare our findings with other ethnic groups, we decided to genotype the same polymorphism. (b) Compared with single-nucleotide polymorphisms (SNPs), this length of polymorphism is more informative because it is more polymorphic. (c) The TTTAn tetranucleotide repeat polymorphism has been suggested to be associated with the expression of CYP19, and we considered that quantitative changes (versus qualitative changes) in this gene were more clinically relevant to the issue we address in the present study. (d) On the basis of previous studies, the polymorphisms in CYP19 are in linkage disequilibrium [13, 14]. Thus, if there are other undefined causal alleles determining breast cancer prognosis, it is reasonable to expect that this length of polymorphism genotyped can probably capture and reflect these polymorphisms.

Given the critical role of aromatase in estrogen synthesis, the explanation of our findings may include the difference in estrogen levels between women carrying the long allele and women without the long allele. A study in postmenopausal women demonstrated that women with a different repeat number allele of the TTTA repeat polymorphism have different estrogen levels [13]. Although the TTTA repeat polymorphism, which is located in an intron, is unlikely to directly affect the function of CYP19, one study reported linkage between a higher number of TTTA repeats and a C–T substitution in exon 10 of CYP19, which was associated with greater aromatase activity [11]. These results suggest that the long allele of the CYP19 TTTA repeat polymorphism may result in greater aromatase activity, and thus increase estrogen production. In addition, a higher repeat number of the TTTA repeat polymorphism was found to be associated with longer survival in breast cancer patients [15], which further supports the use of this polymorphism to predict survival in breast cancer. Because the study by Haiman et al. [13] revealed that women with the 7-repeat allele of the TTTA polymorphism have lower estrogen levels than noncarriers, while women with the 8-repeat allele of the TTTA polymorphism have higher estrogen levels than noncarriers, we chose the 7-repeat number as the cutoff point. The same cutoff point was used in the recent studies of prostate cancer risk and the prognosis of metastatic prostate cancer [26, 28].

Our finding that the prognostic effect of the TTTA repeat polymorphism of CYP19 was only observed in premenopausal women is intriguing. On the basis of the association between the repeat number of the TTTA polymorphism of CYP19 and the estrogen level, mentioned above, we speculate that premenopausal women carrying a longer allele may have a higher level of circulating estrogen, and, most importantly, the difference in estrogen levels among women with different alleles may be more obvious in premenopausal patients than in postmenopausal patients. Antihormone treatment, such as tamoxifen and ovarian ablation, might cause a greater change in estrogen levels in premenopausal patients with the long allele than in those without the long allele, and thus might be more effective in patients with the long allele. However, the difference in estrogen levels is not so great between postmenopausal patients with the long allele and those without the long allele, so the repeat length of the TTTA polymorphism in CYP19 does not impose a survival difference between patients with the long allele and those without the long allele after tamoxifen treatment. Studies of menopausal symptoms and breast cancer survival after tamoxifen treatment have provided support for the benefit of a greater change in hormonal levels on survival, because those with a worse survival experience a lower incidence of hot flushes [29, 30].

Our results are consistent with those reported in a recent study conducted in a Chinese population in Shanghai, in which CYP19 polymorphism was associated with survival in premenopausal breast cancer patients [31]. In that study, a haplotype approach based on 19 tagging SNPs was used to evaluate the contribution of CYP19 and showed that each of the five SNPs in haplotype block 2 of the CYP19 gene was associated with DFS and that the nonsynonymous SNP in haplotype block 4 was associated with DFS and OS [31]. These associations were only observed in premenopausal women.

The explanation that the survival benefit may be a result of a large difference in estrogen levels seems consistent with another finding in this study that, in these tamoxifen-treated patients, standard adjuvant chemotherapy did not result in longer survival than with suboptimal chemotherapy in patients with the long allele of the CYP19 polymorphism, but it did in those without the long allele, and is also consistent with emerging data that hormone-responsive tumors may be more resistant to chemotherapy, especially in premenopausal patients [32–36]. These data have sparked an unresolved debate about the benefits of chemotherapy in HR-positive breast cancers. In addition, the major mechanism of action of adjuvant chemotherapy in premenopausal breast cancers has been suggested to be an endocrine effect through ovarian suppression, as reflected by amenorrhea [37, 38].

Because all the patients in this study received tamoxifen for hormonal therapy, individual variation in the metabolism of tamoxifen may affect their survival. 4-hydroxy tamoxifen and 4-hydroxy-N-desmethyl tamoxifen, or endoxifen, are two important metabolites of tamoxifen [39]. Both have greater affinity for the ER and greater potency in suppressing estrogen-dependent cell proliferation than tamoxifen. Via cytochrome P450 2D6 (CYP2D6), tamoxifen is metabolized to endoxifen. A recent study in postmenopausal women treated with adjuvant tamoxifen alone demonstrated that patients with homozygous inactive alleles of CYP2D6 had a lower DFS rate and did not experience moderate or severe hot flushes, compared with patients who were homozygous or heterozygous for the wild-type allele [29]. Sulfotransferase 1A1 (SULT1A1) catalyzes the sulfation of 4-hydroxy tamoxifen [40]. A genetic polymorphism in exon 7 of SULT1A1 results in lower activity of SULT1A1. A study of 337 tamoxifen-treated patients (141 of them <50 years of age and 196 ≥50 years of age) reported that the risk for breast cancer death among patients who had homozygous low-activity alleles of SULT1A1 was three times that of patients who were heterozygous or homozygous for the common allele [41]. Via affecting the efficacy of hormonal therapy of different mechanisms, targeting the ER or lowering the estrogen level, genotypic variations in CYP19, CYP2D6, and SULT1A1 should have different effects on the prognosis of breast cancer. Further studies with larger sample sizes should incorporate these genes together in order to understand the combined effect of these polymorphisms in tamoxifen-treated patients. In addition, whether the allele length of polymorphisms of CYP19 will have a similar survival impact on postmenopausal patients receiving aromatase inhibitors and on premenopausal women undergoing ovarian ablation, both of which cause a change in the estrogen level, needs to be studied.

In summary, this study demonstrates that the TTTA repeat polymorphism of CYP19 is associated with prognosis in premenopausal breast cancer patients and that the use of adjuvant chemotherapy does not affect the prognosis of premenopausal patients with the long allele of the CYP19 polymorphism, but leads to a greater survival rate in those without the long allele. This raises the question of whether we need to revisit the routine use of adjuvant chemotherapy in high-risk premenopausal patients. Further validation in a randomized study with a large sample size is needed to determine whether adjuvant chemotherapy can be waived in hormone-responsive premenopausal patients with the long allele of the CYP19 polymorphism.


   AUTHOR CONTRIBUTIONS
Top
 Learning Objectives
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Author Contributions
Acknowledgments
 References
 
Conception/design: Chiun-Sheng Huang, Sung-Hsin Kuo, Huang-Chun Lien

Provision of study materials or patients: Chiun-Sheng Huang, Ching-Hung Lin, Yen-Sen Lu, King-Jeng Chang

Collection/assembly of data: Chiun-Sheng Huang, Sung-Hsin Kuo, Huang-Chun Lien, Shi-Yi Yang, San-Lin You, Chen-Yang Shen

Data analysis and interpretation: Chiun-Sheng Huang, Sung-Hsin Kuo, Shi-Yi Yang, San-Lin You, Chen-Yang Shen, Ching-Hung Lin, Yen-Sen Lu, King-Jeng Chang

Manuscript writing: Chiun-Sheng Huang, Sung-Hsin Kuo, Shi-Yi Yang, Chen-Yang Shen, Ching-Hung Lin, Yen-Sen Lu

Final approval of manuscript: Chiun-Sheng Huang, Sung-Hsin Kuo

Pathology review: Sung-Hsin Kuo


   ACKNOWLEDGMENTS
Top
 Learning Objectives
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Author Contributions
 Acknowledgments
References
 
This study was supported by research grant NSC94-2314-B-002-100 from the National Science Council, Taiwan, and NTUH 95-S418 from the National Taiwan University Hospital, Taiwan.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Author Contributions
 Acknowledgments
 References
 

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