Annals of Oncology Advance Access originally published online on April 2, 2008
Annals of Oncology 2008 19(8):1477-1484; doi:10.1093/annonc/mdn147
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hematologic malignancies |
Clinical heterogeneity of extranodal NK/T-cell lymphoma, nasal type: a national survey of the Korean Cancer Study Group
1 Department of Internal Medicine, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine
2 Department of Pathology, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine
3 Department of Internal Medicine, Korea Cancer Center Hospital, Seoul
4 Department of Internal Medicine, Busan National University College of Medicine, Busan
5 Department of Internal Medicine, College of Medicine, Catholic University, Seoul
6 Department of Internal Medicine, Dong-A University Medical Center, Busan
7 Department of Internal Medicine, Kyung Hee University College of Medicine, Seoul
8 Department of Internal Medicine, Inha University College of Medicine, Incheon
9 Department of Internal Medicine, Chungnam National University College of Medicine, Daejon
10 Department of Internal Medicine, Korea University College of Medicine, Seoul
11 Department of Internal Medicine, Kyungbook National University College of Medicine, Daegu
12 Department of Internal Medicine, Hallym University College of Medicine, Seoul
13 Department of Internal Medicine, Fatima Hospital, Daegu
14 Department of Internal Medicine, Asan Medical Center, Ulsan University College of Medicine, Seoul
15 Department of Internal Medicine, Chonbuk National University College of Medicine, Chonju
16 Department of Internal Medicine, Gyeongsang National University Hospital, Jinju
17 Department of Internal Medicine, Inje University Paik Hospital, Seoul, Korea
* Correspondence to: Dr D. S. Heo, Department of Internal Medicine, Seoul National University Hospital, 28 Yongon-dong, Chongno-gu, Seoul, 110-744, Korea. Tel: +82-2-2072-2857; Fax: +82-2-742-6689; E-mail: heo1013{at}snu.ac.kr
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Background: This national survey was undertaken to propose the classification of extranodal natural killer (NK)/T-cell lymphoma (NTCL) subtypes and to clarify a clinical heterogeneity.
Patients and methods: Two hundred and eighty patients newly diagnosed as NTCL were enrolled from 22 Korean medical centers. Two subsets were compared: one involving the upper aerodigestive tract (UAT) and another involving the non-upper aerodigestive tract (NUAT) region, which comprises the skin, gastrointestinal tract, and liver or soft tissues. Clinical prognostic factors, survival outcomes, and independent predictors for survival were compared between each subset.
Results: NUAT-NTCL (59 patients) had significantly higher proportions of disseminated disease, aggressive biologic features, and unfavorable host reactions compared with UAT-NTCL (221 patients). NUAT-NTCL had shortened 5-year overall survival (OS) (22% versus 41%, P = 0.001). Ann Arbor staging, the International Prognostic Index, and the NTCL prognostic index failed to predict the OS of NUAT-NTCL, but did predict the OS in UAT-NTCL. Independent predictors for OS by multivariate analyses differed between each subset. In the NUAT subset, extranodal sites and regional nodes predicted the OS, while Ann Arbor staging, age, performance status, and lactate dehydrogenase level predicted the OS in the UAT subset.
Conclusion: NUAT-NTCL may represent a distinctive disease entity in terms of clinical factors, independent predictors, and survival outcomes.
Key words: clinical heterogeneity, NK/T-cell lymphoma, prognostic factor
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introduction |
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The extranodal natural killer (NK)/T-cell lymphoma (NTCL) is a distinct clinicopathologic disease, rare in Western populations but common among Asians, Mexicans, and South Americans of American Indian descent [1, 2]. It is also common in Korea, with a marked preponderance of the NK cell phenotype, comprising up to 10.5% of all non-Hodgkin's lymphomas (NHLs) [3]. NTCL typically presents in the nasal cavity or nasopharynx, in which most of its cases are localized tumors of the upper aerodigestive tract (UAT) at presentation [1, 2]. Local tumor invasiveness is the principal factor for reducing survival [4]. In addition, tumors that present outside the UAT, but share identical histologic features with the UAT disease, have also been categorized into the NTCL [1]. However, in patients who present with tumors outside the UAT, there is clinical heterogeneity characterized as poor clinical outcome [5].
Although nasal and nasal-type NTCLs refer to cases presenting in the nasal region and outside the nasal cavity, respectively [1, 2], the definition of subtypes has been intermingled in several studies [4, 6–8]. The term UAT, which entails the nasal cavity or nasopharynx, oral cavity, oropharynx, and hypopharynx, has been preferred because disease restricted to the UAT outside the nasal cavity showed a comparable overall survival (OS) to the tumor of nasal cavity or nasopharynx [8, 9]. Furthermore, tumor occurring beyond the UAT has variable presentations depending on the major site of involvement [2] and typically takes a highly aggressive course, unlike the UAT tumor [5, 8].
Due to the highly aggressive features of tumors, every endeavor has been made to investigate factors associated with poor outcome, including Ann Arbor staging [10–13], local extension [4, 13], performance status (PS) [4, 8, 14], B symptoms [4, 10, 12, 14], lactate dehydrogenase (LDH) level [4, 8, 15], age [4, 9], number of extranodal sites [4], Epstein–Barr virus (EBV) status [16–18], the International Prognostic Index (IPI) score [4, 5, 13, 19], and the NK/T-cell lymphoma Prognostic Index (NKPI) score. Although the IPI has systematically predicted survivals for aggressive NHL [21], it failed to properly predict survival outcome in a few studies of early-stage NTCL [14, 22]. Moreover, the NKPI was not a significant predictor of survival for nasal-type NTCL [23]. Accordingly, controversial definitions of subtypes and diverse prognostic factors urged us to undertake this study, in which we propose to classify subtypes on the basis of clinical prognostic factors. In this study, we also clarify clinical heterogeneity in patients with NTCL.
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patients and treatments
We screened all 361 patients who had been newly diagnosed as NTCL and referred, treated, and observed in 22 participating centers between 1991 and 2003. Case reports were obtained from each center on each patient. Each case report contained the following information: age, sex, involved sites, bulky disease, Eastern Cooperative Oncology Group (ECOG) PS, LDH level, Ann Arbor stage, number of extranodal sites, date of diagnosis, histologic features with immunophenotyping (cytoplasmic CD3 [CD3
], CD45RO, CD56, and CD20), EBV RNA in situ hybridization (ISH), bone marrow involvement, presence of hemophagocytosis, treatment modalities, date of initial treatment, response to therapy, date of assessment of response, date of relapse/progression, date of last follow-up, and survival status.
A staging work-up was performed on the basis of physical or otolaryngologic examination, chest radiograph, computed tomography (CT) or magnetic resonance imaging of the head and neck, CT of the abdomen and pelvis, and bone marrow examination. Gastrointestinal (GI) tract endoscopy was performed only in patients who complained of GI symptoms or who had abnormal findings on CT of the abdomen. Eighty-one cases were excluded in the analysis for the following reasons: 66 patients had insufficient immunophenotyping data, four patients had CD3–CD56–, 7 patients were lost to follow-up, 2 patients were diagnosed as benign EBV-associated lymphoproliferative lesion, and 2 patients had blastic NK cell lymphoma and aggressive NK cell leukemia, respectively.
A total of 280 patients with typical histologic findings, CD3+ and/or CD56+, and negative B-cell markers were included in a retrospective study. Some had been included in previous studies [4, 20]. This study was approved by the Institutional Review Board at Seoul National University Hospital (R-0603-244-172). Pre-treatment consent was provided by each center according to the Declaration of Helsinki. Initial treatment modalities and chemotherapy regimens are specified in Table 1. The mean radiation dose was 47.6 ± 0.7 Gy (range 25.2–64.8 Gy). Selection of treatment modality was at the discretion of the treating physicians. Response to treatment was assessed according to the response criteria for NHLs [24].
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anatomical definition of tumor
NTCL subsets were classified as UAT-NTCL and non-upper aerodigestive tract (NUAT)-NTCL, on the basis of the anatomic distribution of the tumor at presentation. UAT-NTCL was defined as a primary tumor involving the nasal UAT (nasal cavity or nasopharynx) or the extranasal UAT (oral cavity, oropharynx, or hypopharynx), irrespective of dissemination to other sites. NUAT-NTCL corresponded to a primary tumor outside the UAT in places such as the skin, GI tract, bone marrow, lung, extremities, orbit, adrenal gland, testis, or central nervous system. Primary tumor localization was determined on the basis of the panendoscopy of UAT and staging work-up procedures.
Regional lymphadenopathy was considered positive if involved sites were found in surrounding lymph nodes, excluding metastatic nodes. Contiguous disease extending to adjacent structures or single extranodal disease was staged as IE. Lymph nodes 
1.0 cm were considered to be abnormal. Tumor anatomic factors (Ann Arbor stage, number of extranodal sites, and regional lymphadenopathy), tumor biologic factors (LDH level and presence of hemophagocytosis), and host-related factors (age, ECOG PS, and presence of B symptom) were compared between each subset.
histology, immunophenotyping, and detection of EBV
All pathologic specimens were reviewed and reclassified on the basis of strict morphologic criteria in adjunction with immunophenotyping analyses [1] by specialized hematopathologists of each participating center. In cases where insufficient immunophenotyping or EBV RNA data were provided, unstained slides were submitted to the study center. Then, immunophenotyping procedures were performed on paraffin sections of the tissue using a routine avidin–biotin–peroxidase complex method with the following antibodies: CD3 (Dako, Copenhagen, Denmark) and CD56 (Monosan, Uden, The Netherlands; DiNonA, Seoul, Korea). EBV-encoded RNA-ISH was performed using an ISH detection kit. All pathologic specimens were interpreted by the same panel of pathologists (represented by YKJ and CWK) blinded to clinical outcomes. Histologic findings showed angiocentricity (89% of patients), necrosis (93%), and pleomorphic infiltration (82%). Ninety (80%) of 113 UAT-NTCL patients and 17 (50%) of 34 NUAT-NTCL patients harbored EBV RNA (all available tissue samples were tested).
statistical analysis
The difference in clinical factors between the subsets was evaluated by the Pearson's 
2 test or Fisher's exact test, as appropriate. OS was measured from the date of diagnosis to the date of death or the last follow-up visit. Disease-free survival (DFS) was calculated from the date of complete remission (CR)/complete remission unconfirmed (CRu) to the first evidence of relapse. Progression-free survival (PFS) was measured from the date of initial treatment to the date of disease progression, death, or the last follow-up visit. Survival curves were derived by the Kaplan and Meier method [25]. Univariate analysis of OS was performed using the log-rank test. Factors independently associated with OS were identified by multivariate analysis using the Cox proportional hazards regression model [26]. Two-sided P values <0.05 were considered significant. All statistical analyses were performed using SPSS version 12.0 (SPSS Inc., Chicago, IL).
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clinical features and treatment outcomes
The clinical characteristics of 280 patients are shown in Table 2. The median age was 46 years with a male:female ratio of 1.9:1. Treatment outcomes were compared between the subsets in patients who received therapy and were evaluable for response, as shown in Table 3. The patient database was subdivided into groups on the basis of the location and spread of the disease. Patients with localized UAT-NTCL showed more favorable outcomes compared with patients who had localized NUAT-NTCL (CR/CRu 60% versus 32%, P = 0.011; 2-year OS 60% versus 32%, P = 0.020; and 2-year PFS 45% versus 14%, P = 0.004). This trend of a more favorable outcome associated with the UAT-NTCL patient group was seen in both stage IE and stage IIE groups (data not shown). Treatment modalities did not affect survivals both in stage IIE UAT-NTCL and in stage IE/IIE NUAT-NTCL (Ps > 0.050), whereas radiotherapy-based treatment improved median OS (90.3 versus 19.3 months; P = 0.022) and median PFS (66.0 versus 8.8 months; P = 0.001) in patients with stage IE UAT-NTCL. Extension to adjacent structures showed poor outcomes in stage IE UAT-NTCL patients treated with radiation-based treatment. In patients with disseminated disease, treatment outcomes did not differ significantly between UAT- and NUAT-NTCL groups.
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clinical heterogeneity of NTCL subsets
Comparison of clinical prognostic factors between patient subsets is summarized in Table 4. Within the UAT-NTCL group, there were no differences in clinical prognostic factors between nasal and extranasal UAT-NTCLs, except Ann Arbor stage (P = 0.024) and regional lymphadenopathy (P = 0.002). Extranasal UAT-NTCL and nasal UAT-NTCL evinced comparable survival rates (5-year OS 41% versus 41%, P = 0.543; 5-year PFS 38% versus 33%, P = 0.503; and 5-year DFS 57% versus 55%, P = 0.697), irrespective of Ann Arbor staging.
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When all patients with NTCL were combined into a single cohort and analyzed, patients with NUAT-NTCL showed higher proportions of advanced stage (P < 0.001), two or more extranodal sites (P < 0.001), positive regional lymphadenopathy (P = 0.020), elevated LDH level (P < 0.001), presence of B symptoms (P = 0.007), and poor ECOG PS (P < 0.001), compared with patients with UAT-NTCL (Table 4). As a result, survival rates of the NUAT-NTCL were lower to those of the UAT-NTCL (5-year OS 22% versus 41%, P = 0.001 [Figure 1A]; 5-year PFS 13% versus 34%, P < 0.001 [Figure 1B]; and 5-year DFS 33% versus 55%, P = 0.072). This clinical heterogeneity was consistent regardless of EBV status.
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The predilection sites of NUAT-NTCL group were skin (22 of 59 patients; 37%), liver or spleen (18; 31%), GI tract (14 [seven colon, five small bowel, and two duodenum]; 24%), bone marrow (13 of 58 patients; 22%), lung (8; 14%), extremities (5; 8%), and testis (3; 5%). Comparing stage IIIE/IV NUAT- and UAT-NTCL groups, there were no statistically significant differences in clinical prognostic factors and survival outcomes (Ps > 0.050) or in the pattern of dissemination, except for skin invasion (54% versus 26%, P = 0.019). Despite the distinctive clinical factors except for LDH level (P = 0.076), hemophagocytosis (P = 0.563), and B symptoms (P = 0.139), no statistical differences were observed in survival outcomes between widely accepted subtypes [2] (nasal NTCL versus nasal-type NTCL) (5-year OS 41% versus 30%, P = 0.103; 5-year PFS 33% versus 23%, P = 0.062; and 5-year DFS 55% versus 47%, P = 0.491).
survival analysis
After a median follow-up of 88 months (range 28–191 months), the 5-year OS, PFS, and DFS in 280 patients were 37%, 29%, and 52%, respectively.
While Ann Arbor stage IIIE/IV did adversely affect the OS in patients with UAT-NTCL (5-year OS 9% versus 47%, P < 0.001; Figure 2A), it did not significantly shorten the OS in those of NUAT-NTCL (2-year OS 26% versus 33%, P = 0.159; Figure 2B). The IPI score was able to identify four risk groups with separate median OS in both UAT-NTCL and NUAT-NTCL subsets (P < 0.001). Nonetheless, the IPI score did not discriminate between high-intermediate and high-risk groups in the UAT disease (2-year OS 9% versus 17%, P = 0.361; Figure 2C) or between low-intermediate and high-intermediate risk groups in the NUAT disease (2-year OS 25% versus 36%, P = 0.520; Figure 2D). Similarly, the NKPI could separate the patients into four risk groups with different survival outcomes in UAT-NTCL (Figure 2E), but it could not discriminate among risk groups ranging from two to four in NUAT-NTCL patients (2-year OSs 33%, 24%, and 21%, respectively; P = 0.455 [Figure 2F]).
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prediction of survival
In the case of a comparatively homogeneous subset, UAT-NTCL, the clinical factors associated with reduced OS in univariate analysis were the Ann Arbor stage IIIE/IV, ECOG PS two or more, presence of two or more extranodal sites, presence of hemophagocytosis, bone marrow involvement, elevated LDH level, presence of B symptoms, age older than 60 years, and regional lymphadenopathy (Table 5).
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Multivariate analysis indicated that independently significant factors for poor survival were Ann Arbor stage IIIE/IV (relative risk [RR] = 2.5, 95% confidence interval [CI] 1.5–4.2; P < 0.001), age older than 60 years (RR = 1.9, 95% CI 1.3–2.9; P = 0.001), ECOG PS two or more (RR = 2.0, 95% CI 1.2–3.1; P = 0.005), and elevated LDH level (RR = 1.6, 95% CI 1.1–2.3; P = 0.022).
Unlike UAT-NTCL, factors adversely affecting the OS of NUAT-NTCL by univariate analysis were as follows: two or more extranodal sites, ECOG PS two or more, elevated LDH level, presence of hemophagocytosis, and regional lymphadenopathy (Table 5).
Independent predictors for reduced OS by multivariate analysis were two or more extranodal sites (RR = 2.9, 95% CI 1.6–5.2; P = 0.001) and regional lymphadenopathy (RR = 2.0, 95% CI 1.1–3.6; P = 0.021).
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discussion |
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NUAT-NTCL may represent a unique subset of NTCL patients in terms of tumor anatomic factors, tumor biologic factors, and host-related factors. Previously, it was held that there were no differences in clinical factors or in survival between nasal and extranasal UAT-NTCL. We have, however, identified several independent survival predictors for NUAT-NTCL patients. Moreover, we have identified independent survival predictors for UAT-NTCL. Ann Arbor staging, the IPI score, and the NKPI were unable to dissect prognostic subgroups in NUAT disease, while they predicted OS in UAT disease. NUAT- and UAT-NTCL have different survival outcomes and clinical signs, whereas nasal and nasal-type NTCL have comparable outcomes.
NTCL that displayed a heterogeneous property involved the NUAT alone, or the UAT with/or without dissemination to similar sites to the NUAT [1–3, 11]. NUAT-NTCL disease was characterized to have a rapidly progressive course with a chemorefractory feature, compared with the UAT disease [2, 6, 8, 16, 27, 28]. A previous study [8] suggested a new classification system taking into consideration the indeterminate boundary for nasal and extranasal UAT-NTCLs. This new classification system determined that there were no differences in clinical factors between nasal and extranasal UAT lymphomas. However, due to intrinsic problems of analysis with a small sample number (10 patients) classified as having extranasal UAT-NTCL and the lack of prognostic variables for dividing the subgroups, it was not possible to draw a definite conclusion on the subtypes of NTCL [8].
Here, we compared two subsets of NTCL according to detailed prognostic variables stratified by tumor anatomic factors, tumor biologic factors, and host-related factors. Clinically, NUAT-NTCL patients had higher incidences of advanced stage disease, two or more extranodal sites, regional node involvement, elevated LDH level, hemophagocytosis, B symptoms, and poor ECOG PS than those with UAT-NTCL. These factors reduced survival duration in NUAT-NTCL patients. Unlike previous study [23], the survival outcomes of nasal-type NTCL were not different from those of nasal NTCL.
There were no significant differences in prognostic factors and survival rates, except for Ann Arbor staging and regional nodes, between nasal and extranasal UAT-NTCLs. UAT-NTCL therefore may be regarded as rather a clinically homogeneous subset. The lack of differences in clinical factors, treatment outcomes, and survivals between stage IIIE/IV UAT- and NUAT-NTCLs, however, implies that advanced NUAT disease may have an inseparable relation to disseminated UAT-NTCL without primary nasal lesions, possibly under the control of tumor immunosurveillance.
Our study demonstrates that independent factors having multivariate association with OS are widely distinctive between the subsets. In the NUAT-NTCL group, regional lymphadenopathy and number of extranodal sites and in the UAT-NTCL group, age, ECOG PS, Ann Arbor staging, and LDH level serve as independent predictors of survival. There were differences between survival predictors of the NKPI [20], i.e. B symptoms, Ann Arbor staging, LDH, and regional lymphadenopathy, and ours. Furthermore, significant factors for survival by univariate analysis varied considerably according to the subsets. Consequently, while the NKPI predicted the OS of UAT-NTCL, it was not predictive of NUAT-NTCL survival in our analysis. Similarly, the NKPI as well as other prognostic indices including T-cell IPI and IPI was not significant for nasal-type cases from the International T-Cell Lymphoma Project [23], corroborating that heterogeneous samples can mislead a log-rank test and Cox regression model [29].
Local tumor invasiveness provides the highest RR for reduced survival in patients with stage IE/IIE UAT-NTCL [4]. However, it is not appropriate to exploit local invasiveness as a prognostic variable for stage IIIE/IV UAT-NTCL, or NUAT-NTCL, because bony invasion, perforation, or invasion of the skin in UAT-NTCL cannot be substituted for other conditions. Additionally, advanced stages usually confer poorer outcomes [2, 6, 27].
Previous studies have shown that high IPI scores correlate with adverse survival outcomes [4, 13, 19]. Although IPI score did not discriminate between risk subgroups in both subsets, four IPI factors were independent predictors for survival in UAT-NTCL in this study.
To date, most studies have found Ann Arbor stage to be an independently significant prognostic factor for survival [10–13]. Our study showed that Ann Arbor stage was a survival predictor in UAT-NTCL but not in NUAT-NTCL. Additionally, Ann Arbor staging failed to predict survival outcome in stage IE/IIE UAT-NTCL (data not shown), consistent with a previous study [4]. Particularly, stage IE UAT-NTCL patients having single extranodal lesion benefited from radiation-based treatment. Given that extensive disease showed poor outcome, an additional therapy after radiation is necessary in stage IE UAT-NTCL extended to adjacent structures.
EBV has been detected virtually in all NTCL cases [1, 2]; however, the frequency of EBV positivity seemed to be lower in our cases, due to the limited number of EBV RNA tests and the inclusion of CD3+CD56–EBV– cases.
In conclusion, our study demonstrates that NTCL involving sites other than the UAT may represent a separate disease entity in terms of clinical factors, survival outcomes, and independent predictors for OS. Moreover, in localized disease, NUAT-NTCL showed lower probability of attaining CR/CRu, higher relapse rate with frequent systemic failure, and poor survivals as compared with UAT-NTCL. Disseminated disease revealed a grave prognosis regardless of NTCL subsets. Additionally, Ann Arbor staging, IPI score, and NKPI did not predict the OS of NUAT-NTCL, but did predict the OS of UAT disease. Nevertheless, caution is warranted in interpreting these results because of possible occult involvement of the nasal area in NUAT-NTCL and possible cases of peripheral T-cell lymphoma due to indeterminate cytotoxic molecules or EBV status. Furthermore, unbalanced treatment modalities between the subset and small number of NUAT-NTCL patients limit the interpretation of treatment outcome and clinical heterogeneity. Future efforts should be directed to develop a prognostic model of each subset in patients treated with homogeneous regimen in collaboration with international multicenters.
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Korean Cancer Association; the Korea Health 21 R&D Project (A050564); Innovative Research Institute for Cell Therapy (A0622660), Republic of Korea.
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Presented in part at the 9th International Conference on Malignant Lymphoma, Lugano, Switzerland, 9–11 June 2005. The following clinicians from the Korean Cancer Study Group were involved in this study: Myung-Ju Ahn, Seock-Ah Im, Yoo Hwan Park, Hyo Jung Kim, Jae Hoon Lee, and Kyung Hee Lee.
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These authors contributed equally to this work. 
Received for publication October 27, 2007. Revision received January 7, 2008. Revision received March 2, 2008. Accepted for publication March 4, 2008.
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