Lung cancer is the leading cause of cancer death in the

Arterial Invasion Predicts Early Mortality in Stage I Non Small Cell Lung Cancer Taine T. V. Pechet, MD, Shamus R. Carr, MD, Joshua E. Collins, BS, Herbert E. Cohn, MD, and John L. Farber, MD Division of Thoracic Surgery and Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania Background. A retrospective study was performed to evaluate the association between arterial invasion and survival in patients with stage I non small cell lung cancer. Methods. One hundred patients were identified who had undergone complete anatomic resection as definitive treatment for stage I non small cell lung cancer. The tumors were reviewed for the presence or absence of arterial invasion. Five-year survival data were obtained for all patients. Results. The 100 patients had an overall 5-year survival of 61%. There were 64 stage IA patients with a 62% 5-year survival and 36 stage IB patients with a 58% 5-year survival. The 39 patients identified with arterial invasion had a 38% 5-year survival compared with a 73% 5-year survival in the 61 patients without arterial invasion (p < 0.001), with an unadjusted hazard ratio of 3.5 (p < 0.001). Multivariate analysis by stage IA versus IB and by size greater or less than 2 cm demonstrated hazard ratios of 3.5 and 4.0, respectively (p < 0.001). This difference was independent of demographic characteristics, tumor type, or grade. Subgroup analysis revealed a hazard ratio of 5.8 in patients with stage IA non small cell lung cancer (p < 0.001) and 19.8 in patients with tumors < 2cm(p 0.006). Conclusions. Arterial invasion is present in a substantial percentage of patients with stage I non small cell lung cancer and is adversely associated with survival. (Ann Thorac Surg 2004;78:1748 54) 2004 by The Society of Thoracic Surgeons Lung cancer is the leading cause of cancer death in the Western hemisphere [1]. Regardless of recent treatment advances, survival for all patients remains near 15% [2]. Revised pathologic staging on the basis of tumor size less than or equal to 3 cm (stage IA) or greater than 3 cm (stage IB) with no local invasion or nodal metastasis identifies patients with a favorable prognosis. Anatomic resection is the current treatment recommendation for stage I non small cell lung cancer (NSCLC) patients with no clinical evidence of distant metastatic disease and pathologically negative mediastinal lymph nodes. Whereas induction therapy is not routinely used in early stage NSCLC, recent data suggest that adjuvant chemotherapy may improve survival among patients with completely resected NSCLC [3]. The 5-year survival for stages IA and IB, however, remains only 67% and 57%, respectively [4]. Several studies have attempted to define factors that contribute to this poor survival [5 14]. Blood vessel invasion has been evaluated as a prognostic factor with varying results [6 13, 15 20]. The present study examined the association between arterial invasion and survival in 100 patients with stage I NSCLC treated with definitive anatomic resection. Accepted for publication April 20, 2004. Address reprint requests to Dr Pechet, Presbyterian-University of Pennsylvania Medical Center, 266 Wright-Saunders Bldg, 39th and Market Sts, Philadelphia, PA 19104; e-mail: taine.pechet@uphs.upenn.edu. Material and Methods We conducted a retrospective chart review of all 227 patients with NSCLC identified in a tumor registry database at an academic medical center who underwent resection between 1996 and 1998. There were 140 patients with stage I cancers, 40 of whom were excluded. Of the remaining 100, none had pleural invasion. Patients who did not undergo anatomic resection (n 8), who had undergone previous lung resection (n 5), or with synchronous or metachronous lesions at presentation (n 4) were excluded. Any patient who received induction or adjuvant chemotherapy or radiation therapy (n 2) was excluded. Seven patients were excluded because of incomplete mediastinal nodal assessment, 1 because pathologic review revealed an adenocarcinoma of metastatic origin, and 13 because of insufficient pathologic material (a minimum of two slides of the original tumor were not available for review). Patients with recurrences were treated with varying protocols of chemotherapy or radiation therapy. All patients underwent pathologic evaluation of their mediastinal lymph nodes (11 sequential mediastinoscopy and thoracotomy, 79 complete intrathoracic nodal dissection [levels 2 to 4, 7 to 9, and 5 to 6 when appropriate], 10 intrathoracic mediastinal nodal sampling). A single surgeon (H.E.C.) performed the 79 mediastinal nodal dissections and the 11 sequential mediastinoscopies. The latter was performed on the basis of preoperative concerns on a case by case basis. These selection criteria yielded 100 patients for analysis. Outpatient and inpatient charts were reviewed for inclusion 2004 by The Society of Thoracic Surgeons 0003-4975/04/$30.00 Published by Elsevier Inc doi:10.1016/j.athoracsur.2004.04.061

Ann Thorac Surg PECHET ET AL 2004;78:1748 54 ARTERIAL INVASION AND SURVIVAL IN NSCLC 1749 and exclusion criteria, demographic information, staging, and follow-up data, with mortality confirmed using the social security death index through August 2003. Cardiovascular disease was defined as a history of myocardial infarction, coronary artery disease, or hypertension. Pathology slides prepared at the time of surgical resection were reviewed by the single pathologist (J.L.F.) with at least one additional author (S.R.C. or T.T.V.P.). Arterial invasion was defined as the presence of tumor within the lumen of a muscular vessel with a clearly defined internal or external elastic lamina. A positive score required the documentation of arterial invasion in at least two anatomically distinct vessels. In all cases included for review, a minimum of two slides of the original tumor were examined; cases with only a single available slide of the original tumor were excluded. This more stringent requirement for at least two slides with two separate sites of invasion to be considered a positive was chosen to ensure proper classification of all cases. Statistical analyses were performed using SPSS 11.0 (SPSS, Inc, Chicago, IL) and Stata 7.0 (StataCorp, College Station, TX). The groups with and without arterial invasion were compared with the nonparametric Wilcoxon s test for continuous variables and Fisher s exact test for categorical variables. Survival analyses were carried out by means of the Kaplan-Meier approach (log-rank test) and Cox proportional hazards regression. In the multivariable modeling, vascular invasion along with tumor type, stage (or size), and grade were forced into the model irrespective of their statistical significance. Tumor grade was coded with three levels (0 well, 1 moderate, 2 poor) and was used as a continuous variable. The hazard ratio (HR) for this variable corresponds to a comparison of two adjacent grades. For the remaining variables, a stepwise backward elimination algorithm was used, with variables retained if they were significant at the 0.10 level. For 15 patients, the forced expiratory volume in 1 second as a percentage was missing; therefore, this variable was not used during the main modeling analyses, but was only considered for inclusion at the end. This study was reviewed and approved by the institutional review board at Thomas Jefferson University on February 13, 2003. Table 1. Patient Characteristics a Variable Arterial Invasion No (n 61) Yes (n 39) p Value Age, mean (SD) 67.5 (8.4) 67.6 (8.2) 0.927 Sex, n (%) 0.015 Female 36 (59) 13 (33) Male 25 (41) 26 (67) Race, n (%) 0.530 White 55 (90) 33 (85) Nonwhite b 6 (10) 6 (15) Cardiovascular disease, n (%) 34 (56) 22 (56) 1.000 Diabetes, n (%) 9 (15) 9 (23) 0.301 Creatinine (mg/dl), mean 1.01 (0.35) 0.96 (0.25) 0.792 (SD) FEV 1 %, mean (SD) 0.75 (0.19) 0.77 (0.16) 0.844 Bone scan, n (%) 32 (53) 22 (56) 0.838 Brain scan, n (%) 28 (47) 24 (62) 0.157 Smoking (pack-years), mean 50.0 (24.9) 53.2 (24.8) 0.627 (SD) Operation, n (%) 0.429 Segmentectomy 0 (0) 2 (5) Lobectomy 57 (93) 35 (90) Bilobectomy 3 (5) 1 (3) Pneumonectomy 1 (2) 1 (3) Tumor type, n (%) 0.537 Adenocarcinoma 26 (43) 14 (36) Squamous cell c 35 (57) 25 (64) Tumor stage, n (%) 0.286 IA 42 (69) 22 (56) IB 19 (31) 17 (44) Tumor size (cm), mean (SD) 2.9 (1.5) 3.7 (2.2) 0.084 Tumor size, n (%) 0.277 2 cm 23 (38) 10 (26) 2 cm 38 (62) 29 (74) Tumor grade, n (%) 0.056 Well differentiated 14 (23) 6 (15) Moderately differentiated 23 (38) 8 (21) Poorly differentiated 24 (39) 25 (64) a Age range, 44 to 84 years; creatinine range, 0.5 to 2.6 mg/dl; FEV 1 % range, 0.31 to 1.18 (based on 85 subjects; FEV 1 % was not available for 15 subjects); smoking, 3 nonsmokers (0 pack-years) plus 97 smokers (8 to 110 pack-years); b Includes 1 Asian (in the no vascular invasion group); c Includes 3 spindle tumors (all in the vascular invasion group). FEV 1 % forced expiratory volume in 1 second as a percentage; SD standard deviation. Results Demographics and Tumor Characteristics Table 1 summarizes the patient population for the groups with and without arterial invasion. Arterial invasion was identified in 39 patients, whereas 61 did not have arterial invasion. All patients included in this study were confirmed to have stage I NSCLC by mediastinoscopy or intraoperative lymph node sampling or dissection. Metastatic disease was excluded by clinical or radiographic evaluation, with one half of the patients undergoing brain or bone imaging. All patients underwent complete anatomic resection. There was no significant difference in the proportion of patients who underwent segmentectomy, lobectomy, bilobectomy, or pneumonectomy. The two groups did not differ with respect to age, race, presence of cardiovascular disease, diabetes, renal function, smoking history, or preoperative lung function. The distribution of tumor type was also similar between the patients with or without arterial invasion. The arterial invasion group included relatively more men. Tumors with arterial invasion tended to be larger and more poorly differentiated. There was no significant difference between the proportion of stage IA and stage IB cancers, or the proportion of patients with tumors greater or less than 2 cm. Stage (IA and IB) and the alternative definition

1750 PECHET ET AL Ann Thorac Surg ARTERIAL INVASION AND SURVIVAL IN NSCLC 2004;78:1748 54 Table 2. Unadjusted Mortality Results (n 100) a Variable HR (95% CI) p Value Arterial invasion (yes vs no) 3.50 (1.87 6.54) 0.001 Tumor type (squamous cell 0.98 (0.80 1.20) 0.867 vs adenocarcinoma) Tumor stage (IB vs IA) 1.03 (0.55 1.93) 0.936 Tumor size ( 2 cmvs 1.76 (0.87 3.59) 0.118 2 cm) Tumor grade 0.96 (0.65 1.42) 0.838 Age (increment of 10 y) 1.18 (0.81 1.72) 0.400 Sex (male vs female) 2.05 (1.09 3.86) 0.026 Race (nonwhite vs white) 1.05 (0.41 2.66) 0.925 Coronary artery disease 1.37 (0.74 2.56) 0.318 (yes vs no) DM (yes vs no) 1.37 (0.82 3.43) 0.153 Creatinine (increment of 0.75 (0.27 2.10) 0.587 1 mg/dl) FEV 1 % (increment of 0.1) 0.79 (0.66 0.96) 0.016 Bone scan (yes vs no) 1.04 (0.56 1.92) 0.900 Brain scan (yes vs no) 0.92 (0.50 1.68) 0.776 Smoking (increment of 10 pack-years) 1.09 (0.97 1.22) 0.168 a Except for FEV 1 %(n 85; information not available for 15 patients) and brain scan (n 99; brain scan information not available for 1 patient). DM diabetes mellitus; FEV 1 % forced expiratory volume in 1 second as percentage; HR hazard ratio; 95% CI 95% confidence interval. based on size ( 2cmor 2 cm) overlapped substantially. By definition, all stage IB tumors were larger than 2 cm (n 36) as none demonstrated pleural invasion. By contrast, stage IA tumors were equally divided between those 2 cm or less and those more than 2 cm (n 33 and 31, respectively). Complete data, as they relate to recurrence, were available for 64 patients, with a median follow-up of 62 months. From those patients, 16 had arterial invasion and 48 did not. In the group with arterial invasion the median follow-up was 29 months, with 12 (75%) having either distant or local recurrence. In those who had recurrence and arterial invasion, only 2 were alive at 5 years. The remaining 4 patients with arterial invasion who did not have a recurrence were alive at 5 years. For those without arterial invasion, the median follow-up was 69 months, with 9 (19%) having a recurrence. Only 3 patients without arterial invasion who had a recurrence were alive at 5 years, whereas all patients without arterial invasion and recurrence were alive at 5 years. Survival The 100 patients had an overall 5-year survival of 61%. There were 64 stage IA patients with a 62% 5-year survival and 36 stage IB patients with a 58% 5-year survival. Thirty-three patients had tumors less than or equal to 2 cm in size with a 5-year survival of 73%, whereas 67 patients had tumors greater than 2 cm and a 5-year survival of 50%. Table 2 shows the univariate analysis results from Cox proportional hazards regressions. The 5-year survival for all patients showed no correlation with tumor type or grade. The unadjusted estimated HR for arterial invasion was 3.5 (p 0.001). There were 16 deaths in the group without arterial invasion and 26 deaths in those with arterial invasion. The unadjusted mortality rates were 5.1 deaths per 100 person-years and 19.3 deaths per 100 person-years in the two groups, respectively. The Kaplan-Meier survival graph (Fig 1) shows substantially better survival in those without arterial invasion (p 0.001). Patients without arterial invasion had a 73% 5-year survival. By contrast, only 38% of patients with arterial invasion survived 5 years (p 0.001). Median survival was 35 months with arterial invasion. Importantly, the median survival of patients without arterial invasion was not reached at 5 years. The stage I population was further analyzed on the basis of size, using the standard 3-cm criterion for stage IA or IB [4] or a recently proposed 2-cm definition [14, 21]. Table 3 shows two sets of multivariate analysis results from a Cox proportional hazards model (variables included in the model simultaneously). One model corresponds to dividing the patients into those with tumors less than or equal to 3 cm (stage IA) and those greater than 3 cm (stage IB). The second model uses 2 cm as the discriminator. With either model, arterial invasion remained highly significant, with an associated threefold to fourfold increase in mortality. There was virtually no difference in mortality between squamous cell carcinomas and adenocarcinomas. Tumor grade was also not significant. Tumor stage (IA versus IB) showed a small and nonsignificant association with mortality. By contrast, the alternative definition based on tumor size ( 2 cm versus 2 cm) showed a statistically significant (more than twofold) difference in mortality between Fig 1. The Kaplan-Meier survival graph of all 100 patients with stage I non small cell lung cancer. Dotted line overall; solid line no arterial invasion; dashed line arterial invasion.

Ann Thorac Surg PECHET ET AL 2004;78:1748 54 ARTERIAL INVASION AND SURVIVAL IN NSCLC 1751 Table 3. Adjusted Mortality Results (n 85) Variable Using 3-cm Size Using 2-cm Size HR (95% CI) p Value HR (95% CI) p Value Arterial invasion (yes vs no) 3.54 (1.74 7.20) 0.001 4.03 (1.90 8.52) 0.001 Tumor type (squamous cell 1.02 (0.80 1.28) 0.897 0.94 (0.74 1.19) 0.592 vs adenocarcinoma) Tumor stage (IB vs IA) 1.34 (0.64 2.84) 0.437 Tumor size ( 2 cmvs 2 cm) 2.59 (1.04 6.45) 0.041 Tumor grade 0.78 (0.47 1.14) 0.168 0.70 (0.43 1.05) 0.078 Brain scan (yes vs no) NS 0.47 (0.22 1.01) 0.054 FEV 1 % (increment of 0.1) 0.78 (0.64 0.96) 0.020 0.84 (0.70 1.01) 0.063 FEV 1 % forced expiratory volume in 1 second as a percentage; HR hazard ratio; 95% CI 95% confidence interval; NS not significant (p 0.10; variable omitted from final model); small and large tumors. Although significant in the univariate model (Table 2), sex was no longer significant in the multivariate analyses (Table 3). The univariate sex effect (men having higher mortality than women) was mostly a result of the confounding effect of arterial invasion. Arterial invasion was almost twice as common among men as among women (51% versus 27%), and when this difference was adjusted for, the sex effect disappeared. There were 64 patients with stage IA NSCLC and their 5-year survival was 62%. With arterial invasion the 5-year survival was 28% versus 81% without arterial invasion (p 0.001; Fig 2A). This resulted in a 5.8-fold higher risk of dying with arterial invasion than without arterial invasion in the multivariate analysis (p 0.001). The median survival for stage IA patients with arterial invasion was 35 months, and again the median survival was not reached in those patients without arterial invasion. Patients with stage IB cancer had a 5-year survival of 58%. The 5-year survival with (53%) and without (63%) arterial invasion did not reach statistical significance (Fig 2B). This resulted in a 1.7-fold risk of dying with arterial Fig 2. The Kaplan-Meier survival graph of patients with stage IA (A), stage IB (B), with tumors less than or equal to 2 cm (C), or tumors grater than 2 cm (D). Solid lines no arterial invasion; dashed lines arterial invasion.

1752 PECHET ET AL Ann Thorac Surg ARTERIAL INVASION AND SURVIVAL IN NSCLC 2004;78:1748 54 invasion as compared with those without arterial invasion in the multivariate analysis (p 0.359). Patients with tumors less than or equal to 2 cm in size and without arterial invasion had a 5-year survival of 92% versus 31% in patients with arterial invasion (p 0.001; Fig 2C). This resulted in a 19.8-fold higher risk of dying with arterial invasion than without arterial invasion in the multivariate analysis (p 0.006). Median survival was 35 months and was not reached in patients without arterial invasion. A similar difference in survival was noted in patients with tumors greater then 2 cm. Patients without arterial invasion had a 5-year survival of 66% versus 41% in patients with arterial invasion (p 0.02; Fig 2D). This resulted in a 2.9-fold higher risk of dying with arterial invasion than without arterial invasion in the multivariate analysis (p 0.012). Median survival was 32 months with arterial invasion and was not reached at 5 years for patients without arterial invasion. Finally, the hypothesis was tested that arterial invasion has a stronger association with survival in patients with smaller tumors. This was evaluated by adding an interaction term between vascular invasion and tumor stage (or size) to the models shown in Table 3. Although not proven, the hypothesis was qualitatively supported. In the multivariate model with tumor stage, the vascular invasion effect appeared greater among stage IA than among stage IB tumors, with an estimated HR of 5.82 and 1.71, respectively. An even stronger result emerged in the model with tumor size, in which the HR for arterial invasion was 19.8 among tumors 2 cm and 2.85 among tumors more than 2 cm. The interaction, however, did not reach statistical significance in either case (p values for interaction of 0.114 for arterial invasion and stage, and 0.092 for arterial invasion and size), a fact that reflects the limited power for detecting interactions with the small sample size of this study. Comment The data presented show that arterial invasion is strongly associated with 5-year survival in patients with stage I NSCLC. This conclusion was shown by both univariate (Table 2) and multivariate (Table 3) analyses. It deserves emphasis that the observed HR of 3.5 to 4 represents a substantially increased risk of dying in patients with arterial invasion. The effect of arterial invasion was independent of all demographic factors and independent of tumor type, stage (IA or IB), and grade (Table 3). Tumor size greater than 2 cm and poor preoperative lung function were independently associated with early mortality. Although not a feature of our initial objective, we chose to explore whether tumor size and arterial invasion are related. The data suggest that in smaller tumors, arterial invasion has a greater effect on survival. The study population was subdivided on the basis of tumor size by two criteria. First, patients were divided into those with tumors greater or less than 3 cm, a demarcation that reflects the current staging system [4]. Alternatively, a 2-cm demarcation was used to subdivide the patients in accordance with recent data suggesting that smaller size is a more sensitive prognostic indicator [14, 21]. In all subgroups, arterial invasion was highly associated with survival (Fig 2). Arterial invasion in stage IA patients was associated with a 53% difference in survival and a 5.8-fold increased risk of dying. Similarly, in patients with stage I tumors less than or equal to 2 cm, arterial invasion predicted a 61% difference in survival and a 19.8-fold increased risk of dying. In patients with tumors greater than 2 cm, arterial invasion predicted a 25% difference in survival (HR 2.85). Overall survival was chosen as the endpoint of this study rather than disease-free survival. This is a potential limitation, and it would be of interest to determine the association between arterial invasion and the incidence of local or distant recurrence. We were not able to evaluate such an association because of incomplete follow-up data on a third of the patients. Also, despite the fact that a single surgeon performed a majority of the operations with complete mediastinal lymph node dissection, a reliable count of the number of lymph nodes originally sampled at each station was also not available. Although not unique to this study, this may contribute to diminished staging accuracy. It would also be of interest to know whether patients with arterial invasion have a higher incidence of nodal metastasis. That is, does arterial invasion indicate more aggressive tumor behavior in general? An important feature of this study is the identification of a prognostic factor readily identifiable on routine pathologic examination. The focus on arterial invasion as a variable eliminates ambiguity resulting from attention to lymphatic or venous invasion. Lymphatics are notoriously difficult to identify with certainty owing to fixation artifacts. The definitive identification of venous channels on routine hematoxylin and eosin stains can be similarly ambiguous in the absence of histochemical delineation of elastic lamellae. By contrast, arteries are readily identified, and the presence of tumor invasion can be accurately assessed. The mechanism whereby arterial invasion dramatically affects survival, however, is not apparent. It can be speculated that arterial invasion is a marker of a more aggressive neoplasm, a feature that relates to survival. Prior studies have examined the relationship between vascular invasion and survival with widely differing conclusions [6, 7, 13, 17, 19, 20]. Several groups have also concluded that vascular invasion portends an adverse prognosis. Many of these studies [9 13, 18, 22], however, are subject to the difficulty inherent in unequivocally identifying venous and lymphatic channels in fixed tissue. Ogawa and colleagues [13] evaluated the effect of blood vessel invasion on survival in stage I NSCLC patients. A significant effect was found with univariate and multivariate analysis. It was not specified, however, whether nonanatomic resections were included in the study population. In addition, both arterial and venous invasion were classed together, and the proportion of the two was not stated. Another Japanese group also reported on prognostic factors in early NSCLC [11, 12]. Arterial invasion was found to predict an adverse sur-

Ann Thorac Surg PECHET ET AL 2004;78:1748 54 ARTERIAL INVASION AND SURVIVAL IN NSCLC 1753 vival in the univariate but not the multivariate analysis. Other studies included advanced stage cancers in their analyses [8, 15, 16, 23]. Macchiarini and associates [9] showed that blood vessel invasion was an independent predictor of survival in patients with stage I NSCLC treated with wedge resection alone. In a subsequent analysis [10], nearly 25% of patients also had nonanatomic resections. Inasmuch as anatomic resection is the current optimal treatment strategy, it is difficult to interpret the relevance of the Pisa group s data. In conclusion, arterial invasion defines a patient population with stage I NSCLC associated with reduced 5-year survival. Clearly, such patients might benefit from additional therapeutic interventions. A prospective trial evaluating the impact of adjuvant chemotherapy on survival in patients with identified arterial invasion is indicated. In light of the recent International Adjuvant Lung Cancer Trial study [3], our data may define a cohort of patients with early stage tumors that would demonstrate increased benefit with adjuvant therapy. Because the effect of arterial invasion is substantial, a targeted trial may be able to expeditiously demonstrate improved survival. Furthermore, the identification of arterial invasion as an adverse prognostic indicator provides a target population with which to correlate genetic and proteonomic analyses. Such an approach may provide information related to the genetic basis of the biologic differences in tumor behavior. References 1. Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ. Cancer statistics, 2003. CA: Cancer J Clin 2003;53:5 26. 2. Merrill RM, Henson DE, Barnes M. Conditional survival among patients with carcinoma of the lung [Comment]. Chest 1999;116:697 703. 3. Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J. 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Ichinose Y, Yano T, Yokoyama H, Inoue T, Asoh H, Katsuda Y. The correlation between tumor size and lymphatic vessel invasion in resected peripheral stage I non-small-cell lung cancer. A potential risk of limited resection. J Thorac Cardiovasc Surg 1994;108:684 6. 23. Yang X, Yan H, Liu H, Xie Y, Hu M, Soimakallio S. Vascular manifestations of small solitary pulmonary masses. Angiographic-pathologic correlations and clinical significance. Invest Radiol 1996;31:275 9. INVITED COMMENTARY The report by Pechet and colleagues reviews the potentially important prognostic indicator of arterial invasion in patients with stage I non small cell lung cancer. The study has retrospectively reviewed all patients with stage I cancer operated on within a three-year period. A subset of relatively homogeneous patients (n 100) who had 2004 by The Society of Thoracic Surgeons 0003-4975/04/$30.00 Published by Elsevier Inc doi:10.1016/j.athoracsur.2004.05.041