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10.1245/ASO.2006.05.018
Annals of Surgical Oncology 13:1010-1018 (2006)
© 2006 Society of Surgical Oncology
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Original Article

High Serum Concentrations of Sialyl Lewisx Predict Multilevel N2 Disease in Non–Small-Cell Lung Cancer

Shinjiro Mizuguchi, MD1,2, Kiyotoshi Inoue, MD1, Takashi Iwata, MD1, Tatsuya Nishida, MD1, Nobuhiro Izumi, MD1, Takuma Tsukioka, MD1,2, Noritoshi Nishiyama, MD1, Takahiro Uenishi, MD3 and Shigefumi Suehiro, MD2

1 Department of Thoracic Surgery, Osaka City University Medical School, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
2 Department of Cardiovascular Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
3 Department of Hepato-Biliary-Pancreatic Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan

Correspondence: Address correspondence and reprint requests to: Shinjiro Mizuguchi, MD, Department of Thoracic Surgery, Osaka City University, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan; E-mail: m1293795{at}misc.med.osaka-cu.ac.jp.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: The purpose of this study was to analyze the clinical significance of serum Sialyl Lewisx (SLX) concentrations as a predictor of N2 disease in patients with non–small-cell lung cancer.

Methods: The study included 272 patients with non–small-cell lung cancer who underwent pulmonary resection in our institution between January 1998 and December 2003. Of 272 patients, the serum concentrations of SLX were measured by using a commercially available radioimmunoassay kit.

Results: The 5-year survival rates of patients with concentrations of SLX > 38 U/mL and those with lower concentrations were 32% and 69%, respectively (P < .0001). The median serum concentration of SLX in patients with multilevel N2 or N3, single-level N2, and N0/1 disease were 44, 30, and 27 U/mL, respectively. The concentrations of serum SLX in patients with multilevel N2 disease were significantly higher than those in patients with single-level N2 or those with N0/1 disease (Mann-Whitney U-test; P < .0001). Although the sensitivity of SLX for identifying patients with non–small-cell lung cancer was only 24% in all patients, the sensitivity of SLX increased as the N-factor increased; the sensitivity of N0/1 disease was 15%, that of single-level N2 disease was 22%, and that of multilevel N2 or N3 disease was 71%.

Conclusions: High serum concentrations of SLX predicted multilevel N2 disease and the associated poor outcome. Although the sensitivity of serum SLX is not acceptable for use as a screening tumor marker, we suggest that the serum concentration of SLX is useful as a staging marker to determine the strategy of treatment.

Key Words: Sialyl Lewisx • Lung cancer • Mediastinal lymph node • N2 • Multilevel


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The histological N factor of non–small-cell lung cancer (NSCLC) is one of the strongest predictors of survival1–7; the 5-year survival rate of patients with N0 disease is 56% to 85%. Despite improvements in pulmonary surgery, chemotherapy, and radiotherapy, the postoperative outcome of patients with N2 disease is extremely poor, with a survival rate at 5 years of only 14% to 35%. Recently, several authors have reported that the number of metastatic N2 stations is a prognostic factor in patients with NSCLC. Specifically, the 5-year survival rates in patients with single-level N2 and multilevel N2 disease are approximately 42% to 54% and 11% to 17%, respectively.6–9 In previous reports, neoadjuvant therapy has been shown to improve the postoperative outcome of patients with N2 disease.5,10–12 Therefore, it is important to correctly diagnose clinical N2 disease. Despite careful preoperative staging, including imaging studies, mediastinoscopy, or both, metastases to the mediastinal lymph nodes were detected histologically in approximately 25% of patients with a preoperative diagnosis of N2-negative NSCLC.13,14

Recently, cytokeratin 19 fragment (CYFRA 21-1) was found to be significantly more sensitive than established markers such as carcinoembryonic antigen (CEA) and squamous cell carcinoma–related antigen (SCC) in evaluating NSCLC. High serum concentrations of CYFRA 21-1 are mainly related to the tumor burden (T factor)15–18 and indicate a poor prognosis.15–19 Although some reports have shown that high concentrations of CEA20,21 and CYFRA 21-122 in the serum predict the presence of N2 disease, there are no tumor markers that identify an increased risk of multilevel N2 metastases. Conversely, adhesion molecules, such as carbohydrate antigens, including Sialyl Lewisx (SLX), have been used as tumor markers of carcinomas from many organs, including lung cancer. E selectin is an adhesion molecule expressed on cytokine-activated endothelial cells and is released into the bloodstream as soluble E selectin. It has been reported that endothelial leukocyte adhesion molecule 1 mediates the migration of neutrophils and monocytes to inflammatory foci.23 It has also been reported that carbohydrate antigens are ligands for selectin, an adhesion molecule expressed on vascular endothelial cells,24–27 which play important roles in local tumor invasiveness and metastasis.28,29 In gastric cancer and colon cancer, it has been reported that high serum concentrations of SLX are related to lymph node metastasis and distant metastasis.30–36 Several authors have determined that increased expression of SLX or other carbohydrate antigens in malignant tissue, according to immunohistochemical analysis, has been shown to correlate with tumor progression and poor outcome in patients with NSCLC.37,38

The purpose of this study was to determine the significance of the serum SLX concentration as an indicator of N2 disease in patients with NSCLC. In determining the predictors of N2 disease in patients with NSCLC, we compared SLX with three widely used tumor markers—CEA, SCC, and CY-FRA 21-1—in a large number of patients with NSCLC.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
From January 1998 to December 2003, 349 patients with NSCLC underwent pulmonary resections in our institution. The subjects in this study were 272 patients with NSCLC who underwent pulmonary resection with mediastinal lymph node dissection. The 272 patients had four tumor markers measured: SLX, CEA, CYFRA 21-1, and SCC. It is reported that there can be false-positive results with SLX in lung disease. In previous studies, high serum SLX concentrations were detected in patients with benign diseases such as diffuse panbronchiolitis or interstitial pneumonia,39,40 thus resulting in a sensitivity of 20% for SLX.40 Our study excluded patients with any other cancers and those who underwent neoadjuvant therapy, to avoid the risk of radiation pneumonitis and interstitial pneumonia. The 272 patients included 181 men and 91 women, with a median age of 69 years (range, 32–92 years). One operative death occurred. Histological classification was performed according to the World Health Organization histological typing of lung tumors.41 One hundred sixty-four patients had adenocarcinoma, 99 had squamous cell carcinoma, 5 had large-cell carcinoma, and 4 had adenosquamous carcinoma. Postoperative staging of the patients was based on the international tumor-node-metastasis classification for lung cancer.1 In histological staging, 80 patients were in stage I, 45 were in stage II, 73 were in stage III, and 14 were in stage IV. Mediastinal lymph node dissection in this study indicates a radical en-bloc mediastinal lymphadenectomy according to previous descriptions.42,43 Informed consent was obtained from all patients.

Methods
Of 272 patients, the serum concentrations of SLX, CEA, SCC, and CYFRA 21-1 in the peripheral blood were measured retrospectively between January 1998 and December 2003. Serum samples were collected just before surgery and were stored at –80°C until the time of analysis. We measured SLX once every month by using a commercially available radioimmunoassay kit (Fh-6 Otsuka; Otsuka Assay Laboratory, Tokushima, Japan). For comparison, chemiluminescent immunoassays or immunoradiometric assays were used to measure conventional tumor markers (CEA, CYFRA 21-1, and SCC). According to the manufacturers’ instructions, the diagnostic cutoff values were 38 U/mL for SLX, 6.5 ng/mL for CEA, 1.5 ng/mL for SCC, and 2.0 ng/mL for CYFRA 21-1.

For correlations between SLX and other tumor markers, Pearson’s correlation coefficient was used, with –.4 to .4 considered as having no correlation. Data are reported as medians with 25th and 75th percentiles for marker concentrations. The Kaplan-Meier method and the log-rank test were used for survival analysis, but not for operative mortality. Multivariate analysis was performed by using a Cox regression model with forward stepwise selection. Multivariate risk ratios with 95% confidence intervals were computed. Kruskal-Wallis one-way analysis of variance was performed initially for multiple-comparison tests. When this analysis was significant, pairs of groups were compared by using the Mann-Whitney U-test. Statistical analysis was performed with the StatView 5.0J software package (SAS Institute, Cary, NC).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Sensitivities of the Tumor Markers in All Patients
In 272 patients with NSCLC, the medians and interquartile ranges of serum SLX, CEA, SCC, and CYFRA 21-1 concentrations were 28.5 U/mL (23.3–36.7 U/mL), 6.1 ng/mL (3.5–11.1 ng/mL), .9 ng/mL (.5–1.7 ng/mL), and 2.3 ng/mL (1.3–4.4 ng/mL), respectively. In this study, the most sensitive marker in all of the patients was CYFRA 21-1 (55%); the sensitivity of CEA was 47%, that of SCC was 28%, and that of SLX was 24%. In 40 patients with a serum concentration of SLX greater than the recommended cutoff value, postoperative serum concentrations of SLX were measured. Of the 40 patients, the median and interquartile ranges of serum SLX concentrations before and after surgery were 47.1 U/mL (42.5–61.3 U/mL) and 33.8 U/mL (30.2–44.7 U/mL), respectively. The postoperative serum concentration of SLX decreased in 36 patients (90%) and decreased to a normal level in 24 (60%).

Clinicopathologic Variables and Postoperative Outcome of Patients Based on the Serum Concentration of SLX
There was no significant difference in the serum concentration of SLX according to age, sex, tumor size, or the histological characteristics of the resected tumor (Table 1Go). The serum concentrations of SLX tended to increase as the T factor increased (P = .086). The serum concentrations of SLX significantly increased with increases in the N factor (P < .0001) and postoperative staging (P < .0001).


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  		TABLE 1. Clinicopathologic variables and serum SLX concentrations of 272 patients with NSCLC
 
Figure 1Go shows the survival rates for patients with resected NSCLC based on the concentration of SLX in serum, but not the rates for operative mortality. The mean follow-up period for the entire study population was 743 days (range, 32–2543 days). The patients were divided into two groups based on the serum SLX concentration: a high-concentration group (n = 65) with a serum concentration greater than the recommended cutoff value and a low concentration group (n = 206) with a concentration less than the cutoff value. The 1-, 3-, and 5-year survival rates in patients in the high- and the low-concentration SLX groups were 74%, 41%, and 32% and 94%, 76%, and 67%, respectively. The outcome of patients in the high-concentration group was significantly poorer than that in the low-concentration group (P < .0001). For the other tumor markers, the 1-, 3-, and 5-year survival rates in patients in the high- and low-concentration groups for CYFRA 21-1 were 82%, 60%, and 49% and 98%, 76%, and 70%, respectively, and there was a significant difference between groups (P = .007). There were no significant differences in the survival rates of patients according to the serum concentrations of CEA and SCC (P = .178 and P = .214, respectively).


Figure 1
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  		FIG. 1. Survival rates of patients with resected non–small-cell lung cancer according to the concentration of Sialyl Lewisx (SLX) in the serum. The 5-year survival of patients with concentrations greater than the cutoff value (38 U/mL) for SLX was significantly lower than that in patients with concentrations less than the cutoff value.

 
Tumor Marker Distribution, Stage, and T Factor in Patients With NSCLC
The medians and interquartile ranges of serum SLX concentrations were 26.2 U/mL (21.8–32.6 U/mL), 29.4 U/mL (24.1–36.0 U/mL), and 35.5 U/mL (25.6–44.0 U/mL) for stages I, II, and III/IV, respectively (Table 1Go; Fig. 2Go). An overall tendency toward an increase in serum concentration was observed from stages I to III/IV, and a significant difference was noted (Kruskal-Wallis test; P < .0001). Serum CEA and CYFRA 21-1 concentrations were also significantly different among these groups (Kruskal-Wallis test; P = .032 and P = .0029, respectively). The medians and interquartile ranges of serum concentrations were 5.0 ng/mL (3.3–9.6 ng/mL), 6.3 ng/mL (3.7–10.0 ng/mL), and 8.0 ng/mL (4.0–15.6 ng/mL) for CEA for stages I, II, and III/IV, respectively, and 1.9 ng/mL (1.1–3.3 ng/mL), 2.9 ng/mL (1.6–8.2 ng/mL), and 2.6 ng/mL (1.4–5.0 ng/mL) for CYFRA 21-1 for stages I, II, and III/IV, respectively. No significant difference for serum SCC concentration was evident between tumor stages (Kruskal-Wallis test; P = .122). There was a trend toward higher concentrations of SLX as the T factor increased. Medians and interquartile ranges of serum SLX concentrations were 27.4 U/mL (22.0–33.2 U/mL), 29.5 U/mL (23.9–39.9 U/mL), and 29.4 U/mL (21.8–46.0 U/mL) for T1, T2, and T3/4, respectively, and no significant difference was noted (Kruskal-Wallis test; P = .086). In contrast, an overall tendency toward an increase in the serum concentrations of the other tumor markers (i.e., CEA, CYFRA 21-1, and SCC) was observed from T1 to T3/4 (Kruskal-Wallis test; P = .019, P < .0001, and P = .0001, respectively).


Figure 2
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  		FIG. 2. Distribution of individual serum Sialyl Lewisx (SLX) concentrations in patients with stage I, stage II, and stage III/IV disease. Data are presented as upper and lower quartile range (box), median value (horizontal line), and middle 90% distribution (whisker line).

 
Postoperative Outcome According to Lymph Node Metastasis
The patients were divided into three groups according to lymph node metastasis. The 1-, 3-, and 5-year survival rates in patients with N0/1 disease (n = 207) were 94%, 77%, and 66%, respectively. Those in patients with single-level N2 disease (n = 23) and multilevel N2 or N3 disease (n = 41) were 82%, 60%, and 54% and 68%, 28%, and 19%, respectively (Fig. 3Go). Patients with multilevel N2 or N3 disease had significantly lower survival rates than those with single-level N2 disease (P = .033).


Figure 3
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  		FIG. 3. Overall survival of patients with resected non–small-cell lung cancer according to the N factor. The 5-year survival rates of patients with multilevel N2 or N3 disease were significantly lower than those in patients with single-level N2 disease.

 
Sensitivity and Distribution of SLX and Other Tumor Markers in Relation to the N Factor
The sensitivity of serum SLX, CEA, SCC, and CYFRA 21-1 in N0/1 disease was 15%, 44%, 26%, and 52%, respectively (Table 2Go). In contrast, the sensitivity of serum SLX, CEA, SCC, and CYFRA 21-1 in N2 or N3 disease was 53%, 58%, 33%, and 63%, respectively. The concentrations of serum SLX, CEA, and CYFRA 21-1 in patients with N2 or N3 disease were significantly higher than in those with N0/1 disease. The medians and interquartile ranges of serum SLX, CEA, SCC, and CYFRA 21-1 concentrations in patients with N0/1 disease were 27 U/mL (22–34 U/mL), 5.8 ng/mL (3.4–10 ng/mL), .9 ng/mL (.5–1.6 ng/mL), and 2.1 ng/mL (1.3-3.8 ng/mL), respectively. For those with in N2 or N3 disease, the values were 37 U/mL (29–48 U/mL), 8.1 ng/mL (4.2–17 ng/mL), 1.2 ng/mL (.6–2.4 ng/mL), and 3.2 ng/mL (1.7–6.2 ng/mL), respectively. The concentrations of serum SLX, CEA, and CYFRA 21-1 for patients with N2 or N3 disease were significantly higher than those in patients with N0/1 disease (Mann-Whitney U-test; P < .0001, P = .034, and P = .008, respectively). The distributions of serum SLX concentrations for multilevel N2 or N3 (44 U/mL; interquartile range, 36–52 U/mL), single-level N2 (30 U/mL; 24–37 U/mL), and N0/1 (27 U/mL; 22–34 U/mL) disease are shown in Fig. 4Go. The concentrations of SLX were significantly higher in patients with multilevel N2 disease than in those with single-level N2 disease (Mann-Whitney U-test; P < .0001) or N0/1 disease (P < .0001), whereas the serum concentrations of the other tumor markers (CEA, SCC, and CYFRA 21-1) were not significantly different between single-level N2 disease and multilevel N2 or N3 disease (Mann-Whitney U-test; P = .450, P = .823, and P = .367, respectively). The sensitivity of SLX increased as the N factor progressed; the sensitivity of SLX in N0/1 disease was 15%, that in single-level N2 disease was 22%, and that in multilevel N2 or N3 disease was 71%. No correlations between the individual tumor markers were found (coefficient of correlation: SLX vs. CEA, .316; SLX vs. SCC, –.036; and SLX vs. CYFRA, .084). Therefore, combination assays using SLX and other tumor markers were performed (Table 3Go). Sensitivities > 80% were obtained when other tumor markers were combined with SLX in multilevel N2 or N3 disease, although specificities reduced to approximately 20%.


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  		TABLE 2. Relationship between N factor and sensitivities of tumor markers in patients with NSCLC
 

Figure 4
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  		FIG. 4. Distribution of individual serum Sialyl Lewisx (SLX) concentrations in patients with multilevel N2 or N3, single-level N2, and N0/1 disease. Data are presented as upper and lower quartile range (box), median value (horizontal line), and middle 90% distribution (whisker line).

 

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  		TABLE 3. Positive rates performed by combination assay with SLX and other tumor markers
 
Multivariate Analysis With Tumor Markers and Clinical Functions
A log-rank test revealed that clinical T factor (P < .001), clinical N factor (P = .014), SLX (P < .001), and CYFRA 21-1 (P < .001) were associated with a significantly higher survival rate. By multivariate analysis, clinical T factor, clinical N factor, and SLX (risk ratio, 3.30; P < .001) were independent factors associated with survival (Table 4Go).


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  		TABLE 4. Patient characteristics in NSCLC (271 patients): multivariate analysis with respect outcome
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The improvements of imaging studies such as helical computed tomography and positron emission tomography make possible the early detection of NSCLC. The preoperative staging of NSCLC is also improved by these imaging studies. However, tumor markers are also useful in screening and predicting the stage before surgery. Recently, CYFRA 21-1 was found to be significantly more sensitive than established tumor markers (CEA and SCC) in predicting outcome. In this study, the serum concentration of CYFRA 21-1 had the highest sensitivity (55%) in all of the NSCLC patients, which has been previously reported (49%–65%).17–19,22 It is believed that high concentrations of CYFRA 21-1 in serum are mainly related to tumor burden and are associated with poor outcome.15–19 High concentrations of CYFRA 21-1 were also related to poor outcome in this study (P = .007).

In contrast, the sensitivity of SLX, an adhesion molecule like carbohydrate antigen, was only 24% in all patients with NSCLC in this study and was 32% in a previous study44; therefore, it is not acceptable as a screening tumor marker. SLX has been used as a tumor marker of carcinomas from many organs,45 including lung cancer. High serum concentrations of SLX are associated with tumor stage, lymph node metastasis, depth of invasion, liver metastasis, peritoneal dissemination, and distant metastasis in gastric cancer30,31 and are also associated with tumor stage, liver metastasis, and early recurrence in colon cancer.33–36 Several authors have demonstrated that the high concentration of SLX in serum in advanced stages of cancer46 or increased immunohistochemical expression of SLX in the tumor tissue37,38 is associated with poor outcome. In this study, the 5-year survival rates of patients with high and low SLX concentrations were 32% and 67%, respectively (P < .0001). However, the real effect of a high SLX concentration in patients with NSCLC remains controversial because there have been few reports of its prognostic importance.

There was an overall trend toward an increase in the serum concentration of SLX from stages I to III/IV (Kruskal-Wallis test; P < .0001). High concentrations of SLX in the serum predicted advanced stages of cancer in this study, and this was also noted in a previous study.46 High concentrations of CEA and CYFRA 21-1 were significantly related to the T factor in this study. It is reasonable to conclude that high concentrations of serum CEA and CYFRA 21-1 have a poor prognosis related to the T factor in this study, because both tumor markers reflect tumor burden.15–19 In contrast, the serum concentration of SLX was not related to the T factor (Kruskal-Wallis test; P = .086).

Postoperative survival of patients with multilevel N2 NSCLC is poor, because approximately 50% of patients with multilevel N2 NSCLC have local recurrences.6 Our study also demonstrated a similar tendency in postoperative outcome: the 5-year survival rates in patients with single-level N2 disease and multilevel N2 or N3 disease were 54% and 19%, respectively (P = .033). Many investigators have reported that several adhesion molecules, degradative enzymes of the extracellular matrix,47 and growth factors with angiogenic activity48 are associated with metastasis, including lymph node metastasis. Several authors have demonstrated that the coexpression of vascular endothelial growth factor, platelet-derived growth factor, and basic fibroblast growth factor is significantly associated with lymph node involvement.49,50 Expression of CD44 is also associated with lymph node metastasis.51,52 Several studies have shown that the levels of matrix metalloproteinases are associated with the lysis of basement membranes and with lymph node metastasis in lung cancer.53–55 According to the relationships of tumor markers and lymph node metastasis, several studies have shown that high concentrations of CEA20,21 and CYFRA 21-122 in the serum predict N2 disease, and our study demonstrated the same result. Serum concentrations of CEA and CYFRA 21-1 were significantly higher in patients with N2 disease than in those with N0/1 disease. Although the relationship between lymph node metastasis in NSCLC and serum concentrations of SLX has not been mentioned in previous articles, the serum SLX concentrations in patients with N0/1, single-level N2, and multilevel N2 or N3 disease were 27, 30, and 44 U/mL, respectively. The proportion of patients with high concentrations of SLX increased as the N factor progressed in this study (Kruskal-Wallis test; P < .0001). Significantly higher concentrations of SLX were also noted in patients with multilevel N2 disease compared with single-level N2 disease or N0/1 disease. Furthermore, because other tumor markers did not correlate with multilevel N2 and with single-level N2 disease in this study, only the high concentration of SLX predicted the risk of multilevel N2 disease. It is reasonable to assume that the high concentration of serum SLX, which is an adhesion molecule, predicts a poor outcome associated with lymph node metastasis or distant metastases.

In conclusion, a high concentration of serum SLX was an independent prognostic factor. Although the sensitivity of SLX for NSCLC is only 24%, the sensitivity of SLX for predicting multilevel N2 or N3 disease is extremely high (71%). Therefore, the concentration of SLX in serum can predict the risk of multilevel N2 disease and the related poor outcome. Because the sensitivity of serum SLX is not acceptable for its use as a screening tumor marker, prospective studies should be performed to evaluate the real effect of serum SLX as a marker for NSCLC.

Received for publication June 9, 2005. Accepted for publication February 7, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest 1997; 111:1710–7.[Medline]
  2. Vansteenkiste JF, De Leyn PR, Deneffe GJ, et al. Survival and prognostic factors in resected N2 non-small cell lung cancer: a study of 140 cases. Leuven Lung Cancer Group. Ann Thorac Surg 1997; 63:1441–50.[Abstract/Free Full Text]
  3. Okada M, Tsubota N, Yoshimura M, Miyamoto Y, Matsuoka H. Prognosis of completely resected pN2 non-small cell lung carcinomas: what is the significant node that affects survival? J Thorac Cardiovasc Surg 1999; 118:270–5.[Abstract/Free Full Text]
  4. Riquet M, Manac’h D, Le Pimpec-Barthes F, Dujon A, Chehab A. Prognostic significance of surgical-pathologic N1 disease in non-small cell carcinoma of the lung. Ann Thorac Surg 1999; 67:1572–6.[Abstract/Free Full Text]
  5. Robinson LA, Wagner H Jr, Ruckdeschel JC. Treatment of stage IIIA non-small cell lung cancer. Chest 2003; 123:202–20.[Medline]
  6. Ichinose Y, Kato H, Koike T, et al. Overall survival and local recurrence of 406 completely resected stage IIIa-N2 non-small cell lung cancer patients: questionnaire survey of the Japan Clinical Oncology Group to plan for clinical trials. Lung Cancer 2001; 34:29–36.[CrossRef][Medline]
  7. Tanaka F, Yanagihara K, Otake Y, et al. Prognostic factors in resected pathologic (p-) stage IIIA-N2, non-small-cell lung cancer. Ann Surg Oncol 2004; 11:612–8.[Abstract/Free Full Text]
  8. Sawabata N, Keller SM, Matsumura A, et al. The impact of residual multilevel N2 disease after induction therapy for non-small cell lung cancer. Lung Cancer 2003; 42:69–77.[CrossRef][Medline]
  9. Ueda K, Kaneda Y, Sakano H, et al. Independent predictive value of the overall number of metastatic N1 and N2 stations in lung cancer. Jpn J Thorac Cardiovasc Surg 2003; 51:297–301.[Medline]
  10. De Leyn P, Vansteenkiste J, Deneffe G, Van Raemdonck D, Coosemans W, Lerut T. Result of induction chemotherapy followed by surgery in patients with stage IIIA N2 NSCLC: importance of pre-treatment mediastinoscopy. Eur J Cardiothorac Surg 1999; 15:608–14.[Abstract/Free Full Text]
  11. Friedel G, Hruska D, Budach W, et al. Neoadjuvant chemoradiotherapy of stage III non-small-cell lung cancer. Lung Cancer 2000; 30:175–85.[CrossRef][Medline]
  12. Trodella L, Granone P, Valente S, et al. Neoadjuvant concurrent radiochemotherapy in locally advanced (IIIA-IIIB) non-small-cell lung cancer: long-term results according to downstaging. Ann Oncol 2004; 15:389–98.[Abstract/Free Full Text]
  13. Fernando HC, Goldstraw P. The accuracy of clinical evaluative intrathoracic staging in lung cancer as assessed by post-surgical pathologic staging. Cancer 1990; 65:2503–6.[CrossRef][Medline]
  14. Goldstraw P, Mannam GC, Kaplan DK, Michail P. Surgical management of non-small-cell lung cancer with ipsilateral mediastinal node metastasis (N2 disease). J Thorac Cardiovasc Surg 1994; 107:19–27.[Abstract/Free Full Text]
  15. Moro D, Villemain D, Vuillez JP, Delord CA, Brambilla C. CEA, CYFRA21-1 and SCC in non-small cell lung cancer. Lung Cancer 1995; 13:169–76.[CrossRef][Medline]
  16. Pujol JL, Molinier O, Ebert W, et al. CYFRA 21-1 is a prognostic determinant in non-small-cell lung cancer: results of a meta-analysis in 2063 patients. Br J Cancer 2004; 90:2097–105.[Medline]
  17. Stieber P, Hasholzner U, Bodenmuller H, et al. CYFRA 21-1. A new marker in lung cancer. Cancer 1993; 72:707–13.[CrossRef][Medline]
  18. Sugama Y, Kitamura S, Kawai T, et al. Clinical usefulness of CYFRA assay in diagnosing lung cancer: measurement of serum cytokeratin fragment. Jpn J Cancer Res 1994; 85:1178–84.[CrossRef][Medline]
  19. Brechot JM, Chevret S, Nataf J, et al. Diagnostic and prognostic value of Cyfra 21-1 compared with other tumour markers in patients with non-small cell lung cancer: a prospective study of 116 patients. Eur J Cancer 1997; 33:385–91.[Medline]
  20. Takamochi K, Nagai K, Suzuki K, Yoshida J, Ohde Y, Nishiwaki Y. Clinical predictors of N2 disease in non-small cell lung cancer. Chest 2000; 117:1577–82.[Medline]
  21. Ando S, Kimura H, Iwai N, Kakizawa K, Shima M, Ando M. The significance of tumour markers as an indication for mediastinoscopy in non-small cell lung cancer. Respirology 2003; 8:163–7.[CrossRef][Medline]
  22. Takada M, Masuda N, Matsuura E, et al. Measurement of cytokeratin 19 fragments as a marker of lung cancer by CY-FRA 21-1 enzyme immunoassay. Br J Cancer 1995; 71:160–5.[Medline]
  23. Bevilacqua MP, Pober JS, Mendrick DL, Cotran RS, Gimbrone MA Jr. Identification of an inducible endothelial-leukocyte adhesion molecule. Proc Natl Acad Sci USA 1987; 84:9238–42.[Abstract/Free Full Text]
  24. Lowe JB, Stoolman LM, Nair RP, Larsen RD, Berhend TL, Marks RM. ELAM-1–dependent cell adhesion to vascular endothelium determined by a transfected human fucosyl-transferase cDNA. Cell 1990; 63:475–84.[CrossRef][Medline]
  25. Phillips ML, Nudelman E, Gaeta FC, et al. ELAM-1 mediates cell adhesion by recognition of a carbohydrate ligand, sialyl-Lex. Science 1990; 250:1130–2.[Abstract/Free Full Text]
  26. Walz G, Aruffo A, Kolanus W, Bevilacqua M, Seed B. Recognition by ELAM-1 of the sialyl-Lex determinant on myeloid and tumor cells. Science 1990; 250:1132–5.[Abstract/Free Full Text]
  27. Takada A, Ohmori K, Takahashi N, et al. Adhesion of human cancer cells to vascular endothelium mediated by a carbohydrate antigen, sialyl Lewis A. Biochem Biophys Res Commun 1991; 179:713–9.[CrossRef][Medline]
  28. Berg EL, Magnani J, Warnock RA, Robinson MK, Butcher EC. Comparison of L-selectin and E-selectin ligand specificities: the L-selectin can bind the E-selectin ligands sialyl Le(x) and sialyl Le(a). Biochem Biophys Res Commun 1992; 184:1048–55.[CrossRef][Medline]
  29. Bresalier RS, Ho SB, Schoeppner HL, et al. Enhanced sialylation of mucin-associated carbohydrate structures in human colon cancer metastasis. Gastroenterology 1996; 110:1354–67.[CrossRef][Medline]
  30. Imada T, Rino Y, Takahashi M, et al. Serum CA 19-9, SLX, STN and CEA levels of the peripheral and the draining venous blood in gastric cancer. Hepatogastroenterology 1999; 46:2086–90.[Medline]
  31. Nakagoe T, Sawai T, Tsuji T, et al. Predictive factors for preoperative serum levels of sialy Lewis(x), sialyl Lewis(a) and sialyl Tn antigens in gastric cancer patients. Anticancer Res 2002; 22:451–8.[Medline]
  32. Ikeda Y, Mori M, Kajiyama K, Haraguchi Y, Sasaki O, Sugimachi K. Immunohistochemical expression of sialyl Tn, sialyl Lewis a, sialyl Lewis a-b-, and sialyl Lewis x in primary tumor and metastatic lymph nodes in human gastric cancer. J Surg Oncol 1996; 62:171–6.[CrossRef][Medline]
  33. Nakagoe T, Kusano H, Hirota M, et al. Serological and immunohistochemical studies on sialylated carbohydrate antigens in colorectal carcinoma. Gastroenterol Jpn 1991; 26:303–11.[Medline]
  34. Nakagoe T, Fukushima K, Hirota M, et al. Immunohistochemical expression of sialyl Lex antigen in relation to survival of patients with colorectal carcinoma. Cancer 1993; 72:2323–30.[CrossRef][Medline]
  35. Tanaka K, Togo S, Nanko M, et al. Sialyl Lewis X expression in vascular permeating lesions as a factor for predicting colorectal cancer metastasis. Hepatogastroenterology 1999; 46:875–82.[Medline]
  36. Yamaguchi A, Goi T, Seki K, et al. Clinical significance of combined immunohistochemical detection of CD44v and sialyl LeX expression for colorectal cancer patients undergoing curative resection. Oncology 1998; 55:400–3.[CrossRef][Medline]
  37. Ogawa J, Tsurumi T, Yamada S, Koide S, Shohtsu A. Blood vessel invasion and expression of sialyl Lewisx and proliferating cell nuclear antigen in stage I non-small cell lung cancer. Relation to postoperative recurrence. Cancer 1994; 73:1177–83.[CrossRef][Medline]
  38. Tsumatori G, Ozeki Y, Takagi K, Ogata T, Tanaka S. Relation between the serum E-selectin level and the survival rate of patients with resected non-small cell lung cancers. Jpn J Cancer Res 1999; 90:301–7.[CrossRef][Medline]
  39. Mukae H, Hirota M, Kohno S, et al. Elevation of tumor-associated carbohydrate antigens in patients with diffuse panbronchiolitis. Am Rev Respir Dis 1993; 148:744–51.[Medline]
  40. Yokoyama A, Kohno N, Kondo K, et al. Comparative evaluation of sialylated carbohydrate antigens, KL-6, CA19-9 and SLX as serum markers for interstitial pneumonia. Respirology 1998; 3:199–202.[Medline]
  41. World Health Organization. Histological typing of lung and pleural tumours. In: Travis WD, Colby TV, Corrin B, Shimosato Y, Brambilla E, (eds). Collaboration with Pathologists in 14 Countries. 3rd ed. Geneva: World Heath Organization, 1999.
  42. Naruke T, Suemasu K, Ishikawa S. Surgical treatment for lung cancer with metastasis to mediastinal lymph nodes. J Thorac Cardiovasc Surg 1976; 71:279–85.[Abstract]
  43. Martini N, Flehinger BJ. The role of surgery in N2 lung cancer. Surg Clin North Am 1987; 67:1037–49.[Medline]
  44. Oyama T, Kawamoto T, Matsuno K, et al. A case-case study comparing the usefulness of serum trace elements (Cu, Zn and Se) and tumor markers (CEA, SCC and SLX) in non-small cell lung cancer patients. Anticancer Res 2003; 23:605–12.[Medline]
  45. Nishida K, Yamamoto H, Ohtsuki T, et al. Elevated tissue concentrations of sialyl Lex-i in cancerous tissues compared with those in noncancerous tissues of various organs. Cancer 1991; 68:111–7.[CrossRef][Medline]
  46. Kawai T, Suzuki M, Kase K, Ozeki Y. Expression of carbohydrate antigens in human pulmonary adenocarcinoma. Cancer 1993; 72:1581–7.[CrossRef][Medline]
  47. Stetler-Stevenson WG, Aznavoorian S, Liotta LA. Tumor cell interactions with the extracellular matrix during invasion and metastasis. Annu Rev Cell Biol 1993; 9:541–73.[CrossRef][Medline]
  48. Folkman J. Tumor angiogenesis. Adv Cancer Res 1985; 43:175–203.[Medline]
  49. Volm M, Koomagi R, Mattern J. PD-ECGF, bFGF, and VEGF expression in non-small cell lung carcinomas and their association with lymph node metastasis. Anticancer Res 1999; 19:651–5.[Medline]
  50. O’Byrne KJ, Koukourakis MI, Giatromanolaki A, et al. Vascular endothelial growth factor, platelet-derived endothelial cell growth factor and angiogenesis in non-small-cell lung cancer. Br J Cancer 2000; 82:1427–32.[Medline]
  51. Miyoshi T, Kondo K, Hino N, Uyama T, Monden Y. The expression of the CD44 variant exon 6 is associated with lymph node metastasis in non-small cell lung cancer. Clin Cancer Res 1997; 3:1289–97.[Abstract]
  52. Tran TA, Kallakury BV, Sheehan CE, Ross JS. Expression of CD44 standard form and variant isoforms in non-small cell lung carcinomas. Hum Pathol 1997; 28:809–14.[CrossRef][Medline]
  53. Tokuraku M, Sato H, Murakami S, Okada Y, Watanabe Y, Seiki M. Activation of the precursor of gelatinase A/72 kDa type IV collagenase/MMP-2 in lung carcinomas correlates with the expression of membrane-type matrix metalloproteinase (MT-MMP) and with lymph node metastasis. Int J Cancer 1995; 64:355–9.[Medline]
  54. Sasaki H, Yukiue H, Moiriyama S, et al. Clinical significance of matrix metalloproteinase-7 and Ets-1 gene expression in patients with lung cancer. J Surg Res 2001; 101: 242–7.[CrossRef][Medline]
  55. Tamura M, Oda M, Matsumoto I, et al. The combination assay with circulating vascular endothelial growth factor (VEGF)-C, matrix metalloproteinase-9, and VEGF for diagnosing lymph node metastasis in patients with non-small cell lung cancer. Ann Surg Oncol 2004; 11:928–33.[Abstract/Free Full Text]



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S. Mizuguchi, N. Nishiyama, T. Iwata, T. Nishida, N. Izumi, T. Tsukioka, K. Inoue, M. Kameyama, and S. Suehiro
Clinical Value of Serum Cytokeratin 19 Fragment and Sialyl-Lewis X in Non-Small Cell Lung Cancer
Ann. Thorac. Surg., January 1, 2007; 83(1): 216 - 221.
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