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The Oncologist, Vol. 12, No. 2, 221-230, February 2007; doi:10.1634/theoncologist.12-2-221
© 2007 AlphaMed Press

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Symptom Management and Supportive Care

Fatigue Experiences in Hepatocellular Carcinoma Patients During Six Weeks of Stereotactic Radiotherapy

Yeur-Hur Laia, Shiow-Ching Shuna, Ya-Li Hsiaob, Jeng-Fong Chiouc, Lin-Lin Weid, Jo-Ting Tsaie, Chung-Yu Kaof

a School of Nursing, College of Medicine, National Taiwan University, Taipei, Taiwan b Department of Nursing, Fooyin University, Kaohsiung, Taiwan c Department of Radiation Oncology, Taipei Medical University Hospital, Taipei, Taiwan d College of Nursing, Cardinal Tien College of Nursing, Taipei, Taiwan e Department of Radiation Oncology, Wanfang Hospital, Taipei, Taiwan f Department of Radiation Oncology, Min-Sheng General Hospital Chin-Kuo Campus, Taoyuan, Taiwan

Key Words. Fatigue • Liver cancer • Radiation therapy • Pattern • Symptom distress • Depression

Correspondence: Yeur-Hur Lai, R.N., Ph.D., No. 1, Jen-Ai Rd. Sec. 1, Taipei 100, Taiwan, Republic of China. Telephone: 886-2-23123456 ext. 8429; Fax: 886-2-3393-1027; e-mail: yhlai{at}ha.mc.ntu.edu.tw

Received August 9, 2006; accepted for publication December 1, 2006.


   ABSTRACT
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 Conclusion
 Disclosure of Potential...
 References
 
Purpose. To compare fatigue experiences and related factors during the first 6 weeks of stereotactic radiotherapy (SRT) for liver cancer patients with and without fatigue before SRT.

Patients and Methods. Subjects (n = 91) were liver cancer patients receiving SRT at two teaching hospitals in northern Taiwan. Data were collected at seven times: the week before SRT (T0) and the end of each of the first 6 weeks of SRT (T1, T2, T3, T4, T5, and T6). Study variables were fatigue intensity, fatigue interference (with patients’ daily life), functional status, symptom distress, sleep disturbance, depressive status, radiation dose, stage of cancer, and selected laboratory data.

Results. Subjects were divided at T0 into two groups by fatigue level: those without (group 1, n = 32) and with (group 2, n = 59) pretreatment fatigue distress. Patients in group 2 had higher levels of fatigue intensity and interference than did patients in group 1. Both groups had similar patterns of fatigue interference, peaking at T5. However, patterns of average fatigue intensity differed slightly. In group 2, fatigue intensity remained constant until T3 and then increased to a peak at T5. In group 1, fatigue intensity increased to a peak between T4 and T5. Generalized estimating equation analysis showed significant differences between groups in fatigue intensity and interference across 6 weeks. Examination of factors related to fatigue after SRT indicated that sleep disturbance significantly predicted both fatigue intensity and interference in group 1, but depressive status, overall symptom distress, and education level predicted fatigue intensity and interference for group 2.

Conclusion. Liver cancer patients with or without fatigue before treatment had different fatigue experiences across 6 weeks of radiation therapy. Fatigue experiences of liver cancer patients receiving SRT can be better understood through future studies exploring patients’ long-term fatigue changes and responses to fatigue-management interventions.


   INTRODUCTION
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 Conclusion
 Disclosure of Potential...
 References
 
Hepatocellular carcinoma (HCC), also known as primary liver cancer, is the fourth leading cause of cancer death worldwide [1]. With increases in hepatitis C virus infection, upward trends in HCC incidence and mortality have been reported in North America and Europe, where HCC was once considered rare [2, 3]. In Taiwan, which has been a high-risk area for HCC, its incidence and mortality in 2002 were ranked first among males; among females, HCC incidence was ranked fourth, and its mortality was ranked second [4].

Radiation therapy has traditionally played a minor role in treating patients with unresectable liver cancer because the liver’s radiation tolerance dose is limited to 30 Gy [5, 6]. Recently, stereotactic radiotherapy (SRT), a three-dimensional computed tomography-based treatment, has allowed irradiation of a portion of the liver at relatively higher doses [5–8]. With this advanced technique, radiotherapy has become safer, and survival times have been expanded [9, 10]. However, liver cancer patients receiving SRT have reported several treatment-related symptoms such as fatigue, vomiting, nausea, anorexia, pruritus, and hepatic pain [11].

Fatigue, a common adverse effect of radiation treatment [12], is reported by more than 75% of patients receiving radiotherapy [13]. It is one of the most common unrelieved symptoms of cancer, influencing all dimensions of quality of life [14, 15]. The profound impact of the distressing and debilitating experience of radiotherapy-related fatigue has motivated researchers to investigate its related factors (e.g., psychological and physical distress, functional status, and demographic factors) [16 –22] and patterns [13, 23–27]; however, most of these studies have targeted patients with breast or prostate cancer. Because patterns of radiotherapy-related fatigue might vary with cancer diagnosis and courses of radiation [12, 13], further examination of the fatigue experience in liver cancer patients undergoing SRT is necessary to help clinicians better understand the needs of these patients and, thus, to provide them with better care. However, to our knowledge, very few studies have examined issues related to liver cancer patients receiving SRT [9, 11], and even fewer have examined patients’ fatigue experiences. Only our preliminary study explored patterns of fatigue intensity and the relationship between fatigue and blood biochemistry values [28]; however, that study was limited by its design and small sample. Furthermore, pretreatment fatigue levels have been hypothesized to influence the development of fatigue patterns during radiotherapy [16, 18, 23, 27], but no studies have examined the effect of baseline fatigue levels on fatigue experiences (fatigue intensity and fatigue interference) that develop during radiotherapy in HCC patients.

To fill these gaps in knowledge, this study was designed to identify and compare (a) changes in fatigue intensity and fatigue interference (with patients’ daily life) across the first 6 weeks of treatment in liver cancer patients with and without fatigue before SRT and (b) predictive factors for fatigue intensity and fatigue interference in these two groups of patients.


   PATIENTS AND METHODS
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 Conclusion
 Disclosure of Potential...
 References
 
Sample
A prospective longitudinal design was used to examine changes in fatigue among liver cancer patients during the first 6 weeks of SRT. Participants were recruited from two radiation oncology outpatient centers in Taipei from April 2002 to October 2005. Eligible subjects were adult (≥ 18 years old) liver cancer patients who (a) knew their cancer diagnosis, (b) could communicate verbally, and (c) signed a consent form after receiving a detailed explanation of the study purposes and procedures. Of 100 patients recruited, 91 agreed to participate.

Procedures
Institutional review board approval was obtained before conducting the study. Informed consent was obtained before patients were assessed. Data were collected at seven times: 1 week before SRT (pretreatment, T0) and the end of each week during the first 6 weeks of SRT (T1, T2, T3, T4, T5, and T6). Demographic information was assessed at T0. Fatigue and functional status were assessed every week; symptom distress, sleep disturbance, and depressive status were measured at T0, T3, and T6. Blood hematologic data (hemoglobin and white blood cell [WBC] counts) were collected every week, and liver function data (aspartate aminotransferase [AST], alanine aminotransferase [ALT], and albumin) were collected at T0, T3, and T6.

Measures
The study variables were fatigue (intensity and interference), symptom distress, sleep disturbance, depressive status, performance status, and selected demographic and clinical characteristics. Instruments consisted of the Chinese versions of the Fatigue Symptom Inventory (FSI) [29, 30], the modified Symptom Distress Scale (SDS-m) [31], the Pittsburgh Sleep Quality Index (PSQI) [32], the short form of the Profiles of Mood States-Depression subscale (POMS-D) [33], and Eastern Cooperative Oncology Group performance status (ECOG-PS) [34]. All these scales have been translated into Chinese using back-translation and have been used in Taiwan [30, 35, 36]. A well-trained research assistant assessed patients’ functional status using the ECOG-PS. The research assistant also read each item of the FSI, SDS-m, PSQI, and POMS-D to subjects and recorded their responses.

Fatigue
Fatigue interference and intensity were assessed by the FSI, a 14-item self-report scale designed to assess fatigue intensity (four items: least fatigue, worst fatigue, fatigue on average, and present fatigue), daily fatigue pattern (one item), duration of fatigue (two items), and perceived interference of fatigue with daily life (seven items). Fatigue interference was assessed by summing seven items on the interference subscale. Responses to these items are self-rated on an 11-point Likert-type scale (0 = no fatigue at all/no interference; 10 = extreme fatigue/extreme interference). The higher the score, the greater the levels of fatigue intensity and fatigue interference. Fatigue intensity on average was used to measure fatigue intensity over the past 7 days. Psychometric testing of the FSI in cancer patients and healthy subjects showed good validity and reliability [29, 30]. Cronbach’s {alpha} for reliability of the fatigue interference subscale in this study ranged from .92 to .96 across seven assessments.

Symptom Distress
Level of symptom distress was assessed by the SDS-m. The SDS [37] is a 23-item checklist of symptoms rated on a 5-point Likert scale (1 = no symptom at all; 5 = severe and intolerable). The higher the score, the greater the level of symptom distress. This scale was modified by Lai [31] and tested in Taiwan [27]. Cronbach’s {alpha} for reliability of the SDS-m in this study ranged from .78 to .82 across three assessments.

Sleep Disturbance
Sleep disturbance was assessed by the PSQI [32], a self-rated questionnaire that assesses seven components of sleep quality: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbance, use of sleeping medication, and daytime dysfunction. The higher the score, the more severe the level of sleep disturbance. Cronbach’s {alpha} for reliability in this study ranged from .73 to .80.

Depressive Status
Depressive status was assessed by the depression subscale of the POMS-D [33]. Responses to the eight-item POMS-D are rated on a five-point Likert scale (0 = strongly disagree; 4 = strongly agree). The higher the score, the greater the level of depression. Cronbach’s {alpha} for the POMS-D in this study ranged from .96 to .98 across three data collection times.

Performance Status
Performance status was measured by ECOG-PS, a scale widely used to assess cancer patients’ functional status [34, 38]. Assessments range from 0 (fully active) to 5 (death), based on the patient’s self-care ability and on the proportion of waking hours spent in bed [39] .

Demographic and Treatment-Related Information
A researcher-designed form was used to collect basic demographic data (age, gender, religion, marital status, employment status, and education level), treatment characteristics (radiation dose and number of treatments), and selected laboratory data (hemoglobin and white blood cell count and AST, ALT, and albumin levels).

Statistical Methods
To test the hypothesis that pretreatment fatigue influences patterns of fatigue in patients receiving SRT, we divided patients into two groups based on their pretreatment fatigue, as measured by the fatigue item in the SDS-m. Patients who answered "no distress at all from fatigue" on the SDS-m were grouped as "without pretreatment fatigue." Patients who answered anything else on the SDS-m (from a little distress to extreme distress due to fatigue) were grouped as "with pretreatment fatigue." Differences in demographic, disease-, and treatment-related characteristics between patients in the two groups were examined by independent samples t test and {chi}2 test.

To determine whether fatigue experiences (intensity and interference) were different across time in patients with and without pretreatment fatigue (aim 1), the generalized estimating equation (GEE) [40, 41] was applied to examine any group effect by controlling the time effect. The GEE has commonly been used to analyze longitudinal data and does not require a normal distribution for data [42]. Fatigue experiences, including average fatigue intensity and fatigue interference, were analyzed separately. To determine whether fatigue intensity and interference changed over time, their weekly levels during the first 6 weeks of SRT were compared with baseline levels and analyzed with the GEE. Factors related to changes in fatigue intensity and interference across these 6 weeks were also examined with the GEE.

To identify factors (independent variables) that predict patterns of fatigue intensity and fatigue interference (dependent variables) in patients with or without pretreatment fatigue (aim 2), we conducted a two-level GEE analysis. In the first step, 15 independent variables were categorized by their characteristics into three groups: (a) seven disease- and treatment-related factors (i.e., radiation therapy dose, stage of cancer, hemoglobin and WBC and AST, ALT, and albumin levels); (b) four demographic characteristics (i.e., age, gender, marital status, and education level); and (c) four physical and psychological factors (i.e., functional status, sleep disturbance, depressive status, and overall symptom distress). Because fatigue intensity and interference were dependent variables and symptom distress was an independent variable, the fatigue item in the SDS-m was not summed into the overall symptom-distress score.

In the first level of GEE analysis, variables in each of the three groups were entered separately by group as independent variables to predict the patterns of fatigue intensity and interference. Only those independent variables that reached statistical significance were selected and entered into the second level of GEE analysis. The first-level GEE analysis showed nine significant predictive factors: radiation therapy dose, hemoglobin, and albumin (disease- and treatment-related factors); gender and education level (demographic factors); and functional status, sleep disturbance, depressive status, and overall symptom distress (physical and psychological factors). These nine factors (independent variables) were entered into the final GEE model and analyzed separately as fatigue intensity and fatigue interference models by group (with and without pretreatment fatigue).


   RESULTS
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 Conclusion
 Disclosure of Potential...
 References
 
Patient Characteristics
Of 100 patients who agreed to participate, 9 (9%) did not complete the study because they withdrew from radiation therapy, which left 91 patients (91%) for whom complete data were collected. Those who withdrew did not differ significantly from participants in demographic and treatment-related characteristics. The 91 subjects who completed the study had a mean age of 62.4 years (SD = 12.0 years). Most were married (88%) and unemployed (77%; Table 1Go). They received a mean total dose of 4,645 cGy (SD = 853 cGy), with an irradiated volume of 204.27 cm3 (SD = 308.30 cm3). Most subjects were assessed at baseline (before SRT) as fully active (60%) and experiencing fatigue (65%). Their baseline levels of hemoglobin, AST, ALT, and serum albumin were 12.38 g/dl (SD = 1.96 g/dl), 70.08 U/l (SD = 54.18 U/l), 59.07 U/l (SD = 43.87 U/l), and 3.73 g/dl (SD = 0.50 g/dl), respectively. No differences were found in demographic background and treatment-related factors between patients with and without pretreatment fatigue. However, GEE analysis indicated that these two groups differed significantly in their response to SRT: average fatigue intensity (ß = 9.22, p =.0001) and fatigue interference (ß = 1.03, p =.014) were both different from baseline. Details of these patterns and predictors for the two groups follow.


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  		Table 1. Demographic information for patients

 
Changes in Fatigue Intensity and Interference Across the First 6 Weeks of SRT
Patterns of fatigue intensity differed slightly between the two groups: group 1 (no pretreatment fatigue) and group 2 (with pretreatment fatigue; Fig. 1Go). For patients in group 1, fatigue intensity increased steadily from very mild before SRT (T0, Mean [M] = 0.48) to a significantly higher level at week 2 (T2, M = 1.52, p = .0007; Table 2Go). Fatigue intensity continued increasing to a peak at T4 (M = 2.59) and dropped slightly at T5 and T6 but was still higher than at T0. For patients in group 2, fatigue intensity remained constant at the pretreatment level (T0, M = 2.97) and reached a significantly higher level (M = 4.02, p < .001) at T5. After reaching a peak at T5, fatigue intensity dropped at week 6 to a level not significantly different from that at T0 (M = 3.29, p =.305; Fig. 1Go; Table 2Go).


Figure 1
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  		Figure 1. Changes in average fatigue intensity by subgroup. The data are shown as mean ± 1.96 SEM (error bars). Abbreviation: SRT, stereotactic radiotherapy.

 

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  		Table 2. Generalized estimating equation analysis of changes in fatigue intensity and interference for group 1 (n = 32) and group 2 (n = 59)

 
On the other hand, patterns of fatigue interference were similar between the two groups (Fig. 2Go), although their levels were different. For patients in group 1, fatigue interference increased steadily from very mild at T0 (M = 0.27) to a significantly higher level at T3 (M = 0.98, p = .012; Table 2Go) and peaked at T5 (M = 1.61, p < .001) before dropping slightly at T6. For patients in group 2, fatigue interference changed little from T0 (M = 1.70) to T1 and T2 (M = 1.73 and 1.88, respectively) but increased steadily thereafter, reaching a significantly higher level (M = 2.60, p < .001) at T4. Fatigue interference peaked at T5 (M = 3.24) and dropped slightly at T6 (Fig. 2Go; Table 2Go). Fatigue interference at T6 was significantly higher in both groups than at baseline (T0).


Figure 2
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  		Figure 2. Changes in fatigue interference by subgroup. The data are shown as mean ± 1.96 SEM (error bars). Abbreviation: SRT, stereotactic radiotherapy.

 
Factors Related to Changes in Fatigue Across the First 6 Weeks of SRT
To identify the factors related to changes in fatigue intensity and interference in each group (with and without pretreatment fatigue), GEE analysis was used to examine the relationships between fatigue and demographic variables (gender and education), treatment-related variables (radiation dose, hemoglobin, and albumin), physical status, sleep disturbance, symptom distress, and depressive status (Table 3Go). For subjects in group 1 (without fatigue before SRT), the only factor significantly related to changes in fatigue intensity was sleep disturbance (ß = .15, p = .004), whereas for group 2 (with fatigue before SRT), the only significantly related factors were education (ß = .10, p = .002), depressive status (ß =.06, p = .008), and symptom distress (ß = 1.63, p = .027). In other words, for patients without fatigue before SRT, fatigue intensity was affected by sleep disturbance; the worse their sleep quality, the more severe their fatigue intensity. However, for patients with fatigue before SRT, fatigue intensity was affected by education level, depressive status, and symptom distress. The higher their level of education, the worse their depressive status, and the greater their symptom distress, the more severe their fatigue intensity.


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  		Table 3. Fatigue intensity and interference predicted by generalized estimating equation for groups with and without pretreatment fatigue

 
With respect to changes in fatigue interference, the significantly related factors for group 1 were sleep disturbance (ß =.12, p = .002) and depressive status (ß =.07, p = .003), whereas for group 2, the significantly related factors were education (ß =.12, p = .001), depressive status (ß =.08, p = .000), and symptom distress (ß = 1.95, p = .003). For the two groups, disease- and treatment-related factors (i.e., stage of cancer, radiation dose, and hemoglobin and albumin levels) were not significantly associated with patients’ fatigue experience during the first 6 weeks of SRT (Table 3Go).


   DISCUSSION
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
Conclusion
 Disclosure of Potential...
 References
 
This prospective longitudinal study examined and compared patterns of fatigue intensity and interference and their related factors during the first 6 weeks of SRT in two groups of liver cancer patients: those with and without fatigue distress before treatment. Several important findings are discussed in the following paragraphs.

Overall, liver cancer patients in this study perceived a mild to moderate level of fatigue intensity and a mild level of fatigue interference during the first 6 weeks of SRT. These results are similar to those from our previous preliminary study of liver cancer patients’ fatigue experiences [28]. Our current finding of a plateau in fatigue-intensity levels for liver cancer patients at the 4th and 5th weeks of radiation therapy is also consistent with results of previous studies on patients with breast and prostate cancers [19, 23, 25, 26].

Most importantly, our findings strongly support the hypothesis that the existence of pretreatment fatigue distress can lead to different fatigue changes for patients undergoing radiation therapy [18, 19]. Patients in the group without pretreatment fatigue experienced a linear increase from mild fatigue at baseline to a plateau between weeks 4 and 5. Overall, however, their fatigue intensity remained mild. On the other hand, although patients with pretreatment fatigue distress continued to experience the same mild level of fatigue during the first 3 weeks of SRT, fatigue intensity increased to a moderate level during the 4th and 5th weeks. In addition, patients with pretreatment fatigue had relatively higher levels of both average fatigue intensity and interference than did patients without fatigue before SRT treatment.

Therefore, these results suggest that clinicians should assess the pretreatment fatigue distress of liver cancer patients to distinguish between the two types of fatigue changes patients might experience during treatment. Although fatigue intensity did not change significantly for patients with pretreatment fatigue distress during the first 3 weeks of SRT, clinicians could expect higher levels of fatigue intensity over the next 3 weeks. Thus, it is important to maintain or even decrease the level of fatigue in this group of patients. Factors related to changes in fatigue intensity should also be assessed.

Our study results indicate that factors related to changes in fatigue intensity were also largely different between the two groups of patients, further supporting our hypothesis about the influence of pretreatment fatigue distress on fatigue experiences during radiation therapy. For the group with pretreatment fatigue, the three factors related to fatigue intensity during SRT were depressive status, symptom distress, and education level. For patients without pretreatment fatigue distress, the only factor related to fatigue intensity was sleep disturbance. These differences might best be explained from the perspectives of acute and chronic fatigue.

The radiation therapy-related fatigue of patients without pretreatment fatigue distress could be viewed as an acute fatigue experience because their fatigue could be ameliorated after a night of good-quality sleep. However, patients who have had fatigue for a considerable time (chronic fatigue) would not significantly benefit from one night of good sleep. Therefore, patients without fatigue distress before SRT might be more likely to develop fatigue during radiotherapy if they have difficulty sleeping. The same reasoning might explain why sleep disturbance was also a factor related to fatigue interference in the same group of patients.

Symptom distress has been recognized as an important predictor for the level of radiotherapy-related fatigue in breast cancer patients [18, 19] and the level of fatigue in liver cancer patients receiving transcatheter arterial chemoembolization [27, 43]. However, symptom distress was not significantly related in the present study to fatigue intensity and interference in patients without pretreatment fatigue. In contrast, symptom distress was significantly related to fatigue intensity and interference in patients with pretreatment fatigue. The difference between these two groups may be explained by their different levels of symptom distress. The patients with no pretreatment fatigue had low levels of symptom distress, resulting in no effect on their fatigue intensity and interference, whereas the higher levels of symptom distress in patients with pretreatment fatigue affected both fatigue intensity and interference. This difference raises the clinical question as to what level of symptom distress might add to changes in fatigue intensity during radiotherapy. Another question that requires further examination is what symptoms might be more specific to patients’ fatigue.

Depressive status was significantly related to fatigue interference in both groups but to fatigue intensity only in patients with pretreatment fatigue distress. These results are similar to those of previous studies [18, 19] and support the critical role of depression in treatment-related fatigue.

The only demographic factor related to changes in fatigue intensity and interference was education. We found that the higher the level of education in patients, the more SRT-related fatigue they perceived; however, this result contradicts previous reports [27, 43]. Furthermore, education level was not identified as related to the fatigue experience of patients without pretreatment fatigue. This issue should be further examined in a future study.

None of the disease- and treatment-related factors we examined (stage of cancer, radiation dose, and hemoglobin and albumin levels) were significantly associated with patients’ fatigue experience during the first 6 weeks of SRT. One possible explanation for the lack of association with radiation dose is that it was gradually increased over the 6 weeks, thus increasing the cumulative dose, which is more likely to influence fatigue than is the dose itself. Furthermore, the effect of radiation dose on fatigue levels might have been delayed, so that fatigue might occur after treatment. Like radiation dose, hemoglobin levels did not contribute to changes in fatigue, likely because our sample of patients had relatively acceptable and stable hemoglobin levels during treatment (range = 12.40 ± 1.97 g/dl to 11.96 ± 1.85 g/dl). Serum albumin was also not significantly associated with fatigue experience. This result could be due to the lack of variability in serum albumin levels during the 6 weeks.

Despite the importance of our findings, the study had a few limitations. First, although we followed patients’ fatigue experience for 7 weeks, long-term changes after treatment (e.g., 6 months to 1 year or longer) and possible differences in fatigue experiences between groups were not well defined and need to be further explored. Therefore, these results cannot be generalized to patient fatigue levels after radiation. Second, because the patients in this study perceived mild to moderate levels of fatigue, their fatigue-related factors might be different from those of patients with severe levels of fatigue. This issue should be validated in future studies.


   CONCLUSION
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Conclusion
Disclosure of Potential...
 References
 
In summary, our results support the hypothesis that pretreatment fatigue distress influences changes in the pattern of fatigue intensity among liver cancer patients during the first 6 weeks of SRT. Predictors for fatigue experiences were also different between groups with or without pretreatment fatigue. Therefore, patients’ pretreatment fatigue status should be integrated into the clinical monitoring of fatigue. To improve understanding of long-term fatigue changes during and after SRT, future studies should expand the period of assessment. Developing and testing interventions that target the factors we have identified as related to different fatigue experiences may improve clinical management of radiotherapy-related fatigue.


   DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Conclusion
 Disclosure of Potential...
References
 
The authors indicate no potential conflicts of interest.


   ACKNOWLEDGMENT
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Conclusion
 Disclosure of Potential...
 References
 
This study was partially supported by a grant from the National Science Council in Taiwan. We thank the patients who participated in this study and Claire Baldwin for help in editing the English.


   REFERENCES
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Conclusion
 Disclosure of Potential...
 References
 

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