This Article Abstract Full Text (PDF) All Versions of this Article: 1078-0432.CCR-07-1032v1 1078-0432.CCR-07-1032v2 14/2/428    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Liao, W.-C. Articles by Wu, M.-S. Search for Related Content PubMed PubMed Citation Articles by Liao, W.-C. Articles by Wu, M.-S.

Serum Interleukin-6 Level but not Genotype Predicts Survival after Resection in Stages II and III Gastric Carcinoma

Authors' Affiliations: ¹ Department of Internal Medicine and ² Department of Surgery, National Taiwan University Hospital, National Taiwan University College of Medicine; ³ Graduate Institute of Clinical Medicine, College of Medicine and ⁴ Center of Biostatistics Consultation and ⁵ Biostatistics Laboratory, College of Public Health, National Taiwan University, Taipei, Taiwan; ⁶ Division of Gastroenterology, Taichung Veterans General Hospital; and ⁷ College of Public Health, China Medical University, Taichung, Taiwan

Requests for reprints: Ming-Shiang Wu, Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, 7 Chung-Shan South Road, Taipei 10017, Taiwan. Phone: 886-2-23562246; Fax: 886-2-23947899; E-mail: mingshiang{at}ntu.edu.tw.

	Abstract

Top Abstract Materials and Methods Results Discussion References

 
Purpose: It has been suggested that interleukin-6 (IL-6) is a prognostic indicator for survival in patients with gastric carcinoma, but this has not been proved using survival analysis. In Asians, the –634G allele is associated with increased IL-6 production. The objective of this study was to evaluate the association between serum IL-6 levels, –634G/C polymorphism, and overall survival after resection for gastric carcinoma.

Experimental Design: A total of 155 consecutive patients with gastric carcinoma were evaluated. Serum IL-6 levels were analyzed using an enzyme-linked immunoabsorbent assay. Genotype was determined by PCR and restriction fragment length polymorphism. Serum levels and survival were correlated with genotype and clinicopathologic factors.

Results: Age and stage, but not –634G/C genotype, were associated with serum IL-6 levels. The median survival for patients with stage II or stage III gastric carcinoma was 1,418 days in patients with low (13 pg/mL) versus 618 days in patients with high (>13 pg/mL) serum IL-6 levels (P = 0.038). Results of a multivariate analysis showed that serum IL-6 level of >13 pg/mL was a significant predictor of poor survival (hazard ratio, 1.77; 95% confidence interval, 1.07-2.92; P = 0.026).

Conclusions: Serum IL-6 level of >13 pg/mL correlates with tumor progression and is an independent predictor of poor survival after resection. In patients with stage II and III gastric carcinoma, serum IL-6 level is more effective than stage as a prognostic indicator. By measuring IL-6, these patients can be divided into two groups with significant differences in survival. The –634G/C polymorphism is not associated with serum IL-6 level or survival.

Circulating levels of IL-6 are mainly regulated at the level of expression (9). Several polymorphisms in the IL-6 gene have been reported, some of which have been suggested to regulate its expression (10–13). The –174G/C single-nucleotide polymorphism (SNP) in the promoter region is the best studied. The G allele is associated with an increased inflammatory response in vivo and the occurrence/prognosis of various diseases, including cancer, Alzheimer's disease, atherosclerosis, cardiovascular disease, non–insulin-dependent diabetes mellitus, osteoporosis, and systemic onset juvenile chronic arthritis (10, 11, 14–20). In Asian populations, however, this SNP is very rare (21–23) and a more common and important SNP at position –634 (C>G) in the promoter region has been reported (22). The –634G allele has been associated with increased production and secretion of IL-6 by peripheral blood mononuclear cells in vitro (12). It has also been reported as a risk factor for progression of diabetic nephropathy and for lung cancer in conjunction with asthma/atopy (12, 24).

Although the –634G allele has been associated with increased production of IL-6 in vitro, its effect in healthy subjects and patients with gastric adenocarcinoma has not been studied. We hypothesize that in patients with gastric adenocarcinoma, the –634G allele is associated with higher serum levels of IL-6 and shorter survival compared with –634C allele. The objectives of this study were (a) to compare serum IL-6 levels between –634G and –634C alleles in healthy subjects and in patients with gastric adenocarcinoma and (b) to analyze the potential associations between serum IL-6 level, –634G/C polymorphism, and overall survival after surgical resection.

	Materials and Methods

Top Abstract Materials and Methods Results Discussion References

 
Patients and preparation of samples. This was a retrospective cohort study conducted at National Taiwan University Hospital. The study protocol was approved by the institutional review board, and informed consent was obtained from all subjects.

Between 1999 and 2002, a total of 194 patients with histologically confirmed gastric adenocarcinoma were diagnosed by the investigators. Patients who consented to blood collection and underwent surgical resection at National Taiwan University Hospital were considered eligible. A total of 155 consecutive eligible patients were evaluated, and their serum IL-6 level was correlated with genotype and pathologic stage. In the evaluation of the association between survival and serum IL-6 level and genotype, data for eight patients who underwent palliative resection were excluded. The surgical procedures included resection of the tumor and at least D1 lymphadenectomy. Chemotherapy or radiotherapy was given as an adjuvant or for recurrence at the discretion of the physicians. Histopathology was evaluated by independent pathologists who were blinded to the clinical details of the patients. Tumor node metastasis (TNM) stage was defined according to the sixth edition of American Joint Committee on Cancer staging system (25). Patient outcome data were obtained from review of medical records and the Cancer Registry, Office of Medical Records at National Taiwan University Hospital. Two hundred and eleven healthy subjects who received a routine health check up during the same period and who consented to blood sampling were recruited as controls. Venous blood samples were collected from all subjects and controls. Serum was separated by centrifuge and stored at –80°C until use. Buffy coat was prepared by centrifugation of whole blood collected in tubes containing heparin and was stored at –80°C until use. Samples were coded for blind analysis.

IL-6–634 G/C and –174 G/C genotyping. Genotyping was done for all gastric cancer and control subjects. Genomic DNA was extracted from buffy coat using a genomic DNA purification kit (Puregene DNA Purification System, Gentra Systems) according to the manufacturer's instructions. DNA was stored at –30°C until analysis. The IL-6–174G/C polymorphism was determined by PCR followed by RFLP analysis (10). The 299-bp PCR product was amplified using forward primer 5'-TTGTCAAGACATGCCAAAGTGCT-3' and reverse primer 5'-GCCTCAGACATCTCCAGTCC-3' with Taq polymerase (Promega) in the presence of 1.5 mmol/L Mg²⁺. Cycling variables were denaturation at 95°C (30 s), annealing at 65°C (30 s), and extension at 72°C (45 s) for 35 cycles with final extension at 72°C for 10 min. Digestion was done with NlaIII (New England Biolabs) at 37°C for 3 h. The PCR product is cleaved into three fragments of 227, 59, and 13 bp in the presence of the G allele. The PCR product is cleaved into four fragments of 118, 109, 59, and 13 bp in the presence of the C allele. The IL-6 –634G/C polymorphism was determined by PCR followed by RFLP analysis (26). The 180-bp PCR product was amplified using forward primer 5'-GAGACGCCTTGAAGTAACTG-3' and reverse primer 5'-AACCAAAGATGTTCTGAACTGA-3' with Taq polymerase (Promega) in the presence of 1.5 mmol/L Mg²⁺. Cycling variables were denaturation at 95°C (45 s), annealing at 60°C (45 s), and extension at 72°C (60 s) for 35 cycles with final extension at 72°C for 10 min. Digestion was done with BsrBI (New England Biolabs) at 37°C for 3 h. The C allele has no BsrBI cleavage site, whereas the PCR product is cleaved into two fragments of 120 bp and 60 bp in the presence of the G allele.

Enzyme-linked immunoabsorbent assay for IL-6. Serum IL-6 level was measured in all gastric adenocarcinoma patients and 63 control subjects selected by –634 C/G status (31 CC, 23 GC, and 9 GG subjects). Serum IL-6 levels were analyzed with a highly sensitive ELISA using a sandwich technique (Quantikine human IL-6 immunoassay, R&D Systems).

Statistical analysis. Quantitative data were summarized as mean ± SD. Categorical variables were reported as percentages. The Fisher exact test was used to compare proportions. Student's t test was used to compare continuous variables. The associations between genotype and serum IL-6 level with adjustment for clinical variables, including sex, age, and TNM stage, were evaluated using multiple linear regression. Overall survival was calculated from the date of surgery, and only deaths due to gastric cancer were considered. Data for patients who were alive at last follow-up or had died due to other causes were censored at the date of last follow-up or death. As there was no clinically defined cutoff point for serum IL-6 level, the median was used to divide the patients into two groups (low versus high serum IL-6 level). The survival curves were graphed using the Kaplan-Meier method. The log-rank test was used to compare the equality of curves. The Cox proportional hazard regression model was used to evaluate the effects of genotype of IL-6 gene and serum IL-6 level when clinical prognostic factors were adjusted. Prognostic factors for univariate analysis included age, sex, depth of invasion (T), lymph node invasion (N), distant metastasis (M), tumor size, genotype of IL-6 gene, and categories of serum IL-6 level. Statistical software was used (SAS 9.1, SAS Institute) for analysis. All tests were two-tailed, and differences were considered statistically significant if the P value was <0.05. The Reporting Recommendations for Tumor Marker Prognostic Studies criteria were used for reporting the results (27).

Power of the study. The primary objective of this study was to evaluate serum IL-6 as a prognostic indicator of gastric cancer mortality. Assuming an value of 0.05 and a baseline 5-year survival rate of 25% (28, 29), 73 patients in each group would provide 79% to 98% power to detect a clinically relevant difference in the survival curves corresponding to hazard ratios between 1.81 and 2.71. The power estimation was done with statistical software (nQuery Advisor 4.0).

	Results

Top Abstract Materials and Methods Results Discussion References

 
Genotype distributions in controls and gastric cancer patients. The genotype distribution of –634 G/C was not significantly different between gastric carcinoma patients and controls (P = 0.469; Table 1 ). No significant deviations from Hardy-Weinberg equilibrium were noted in gastric cancer patients and controls (P = 0.670 and P = 0.657, respectively). All controls and patients had GG at the –174 position.

View larger version (10K): [in this window] [in a new window] [Download PPT slide]   Fig. 1. Kaplan-Meier estimates of overall survival after surgical resection. Top, patients of all TNM stages by serum IL-6 level (A) and by –634G/C IL-6 promoter polymorphism (B). Bottom, patients with stages II, IIIa, and IIIb diseases by TNM stage (A) and by serum IL-6 level (B).

	Discussion

Top Abstract Materials and Methods Results Discussion References

 
To our knowledge, this is the first study that confirms the prognostic value of serum IL-6 level in gastric carcinoma with survival of patients as the outcome measure. The effect of the IL-6 gene SNP –634 C/G on serum IL-6 level and survival in gastric adenocarcinoma has also not been studied before.

Correa's hypothesis of gastric cancer progression suggests inflammation as the key driving force in tumor development (30), and IL-6 as a proinflammatory cytokine has been implicated in tumor growth (4). Expression of IL-6 and the IL-6 receptor has been noted in gastric cancer cell lines, and IL-6 may act as a paracrine growth factor (4, 5). IL-6 induces gastric cancer cell invasion via activation of the c-Src/RhoA/ROCK signaling pathway (31), and our previous studies also indicated that IL-6 may play a role in the angiogenesis of gastric carcinoma via modulation of vascular endothelial growth factor (32). Collectively, these studies are consistent with our results and suggest that IL-6 is crucial in tumor development and progression and may be a potential target for future research in the treatment of gastric carcinoma.

The median IL-6 level (13 pg/mL) was used as the cutoff level for the primary Cox regression analysis. Other cutoff values were also analyzed (25th and 75th percentile and starting from 5 pg/mL with an incremental increase of 5 pg/mL) for their sensitivity in predicting death due to gastric cancer. The results showed that in both univariate and multivariate analyses, the median was the most effective cutoff with the highest hazard ratio. For example, the hazard ratios of death of the high versus low IL-6 group in univariate analysis using the 25th and 75th percentile (4.7 and 38.5 pg/mL) as the cutoff were 1.85 (95% CI, 1.03-3.33; P = 0.039) and 2.08 (95% CI, 1.27-3.43; P = 0.004), respectively. Therefore, post-hoc analysis of the data also supported the median as the most effective cutoff value of serum IL-6 level in predicting survival after resection for gastric cancer.

The most important finding of this study was that serum IL-6 level was more effective than TNM stage in predicting long versus short overall survival after resection for stage II and stage III diseases. In Taiwan and Western countries, gastric carcinoma is usually diagnosed at an advanced stage, after the tumor has penetrated submucosa and invaded the muscle layer (33–35). The 5-year survival rate after surgery is only 20% to 30% once the tumor has penetrated the submucosa (29). Controversies remain as to whether perioperative or neoadjuvant chemotherapy improves survival. Although a survival benefit compared with surgery alone has been observed with perioperative epirubicin, cisplatin, and fluorouracil (33), neoadjuvant fluorouracil, doxorubicin, and methotrexate have been shown to be associated with a shorter median survival, although not significantly (34). In those studies, as in the current study, 50% of patients were diagnosed at stage II or stage III. Our results revealed that these patients can be divided into low versus high serum IL-6 groups with significant differences in survival. We propose that whereas chemotherapy may improve survival in patients with high serum IL-6 level, its benefit in patients with low serum IL-6 level may be marginal and offset by adverse effects. Therefore, the conflicting results in previous studies might be partly attributed to heterogeneity in IL-6 status and survival of patients in different studies. Our results indicated that serum IL-6 level was more effective than TNM stage in predicting patients with shorter survival after resection for stage II and stage III disease and could be used to identify patients who would benefit from perioperative or neoadjuvant chemotherapy. Additional studies are necessary to address this point.

It is worth noting that whereas survival differences in stages II, IIIa, and IIIb patients after gastrectomy have been reported by the National Cancer Data Base report of 50,169 gastric carcinoma cases diagnosed from 1985 to 1996 (28), there was no significant difference in survival among these stages in our patients. In addition to differences in sample size, an important explanation for the different results in this study is the adequacy of lymphadenectomy. As noted in the National Cancer Data Base report, surgical undertreatment was a problem in their series, as only 18% of patients had 15 or more lymph nodes analyzed, with inadequate (D0) lymphadenectomy and a high likelihood of residual regional lymph node disease and inadequate staging (28). In comparison, our patients underwent at least D1 dissection and more than half underwent D2 dissection and had more lymph nodes analyzed (Table 4). Data from the Surveillance, Epidemiology, and End Results cancer registries also document that lymphadenectomy is frequently inadequate and that adequate lymphadenectomy is associated with an improvement in survival (36–40). If D1 resection was mandated for all patients in the National Cancer Data Base series, the differences in survival among stages II, IIIa, and IIIb might become less significant because of improved survival due to more complete surgical treatment and the effect of stage migration. The longer median survivals in our patients compared with the National Cancer Data Base series in stage II (1,431 days versus <3 years), stage IIIA (1,156 days versus <2 years), and stage IIIb (836 days versus 1 year) also support this explanation.

Although serum IL-6 level has also been reported to correlate with stage (5–7), it was not an independent predictor of survival in the only other study that evaluated patient survival (5). Possible explanations for the discrepant results include differences in the relative importance of various prognostic factors across stages and differences in the proportion of stages in the study populations. Our results indicated that serum IL-6 level was more effective than stage in predicting survival in stages II and III patients, although no differences in survival were noted in patients with high or low serum IL-6 level in stages 0, I, and IV. Stages 0/I and IV represent the two extremes of the disease. Serum IL-6 level might be less important than stage in predicting survival in these patients, because the prognosis after resection is usually good in stages 0 and I and the risk of recurrence is high in stage IV after surgery (41–43). As in the previous study, more patients were diagnosed as stage I or stage IV (61% versus 44% in this study); thus, the study may not have been adequately powered to identify serum IL-6 level as an independent predictor of survival. Another possible explanation is the improvement in treatment and care that occurred during the time between the two studies, which made serum IL-6 level more important as a prognostic factor in our study.

Tumor size of 8 cm has also been reported as an independent predictor of shorter survival after controlling for TNM status (44). In our study, tumor size of 8 cm was significant in univariate analysis, but it was not significant after controlling for TNM status and serum IL-6 level. One explanation is that the effect of tumor size might be mostly attributed to TNM status and serum IL-6 level. It is also possible that because only 25 subjects (17%) of patients in our study had a tumor of 8 cm, it may not have been adequately powered to identify tumor size as an independent predictor of survival.

Polymorphisms in the promoter of IL-6 gene have been shown to affect transcription and expression (10, 13). Fishman et al. have shown that the IL-6 –174G allele is associated with increased expression and high levels of IL-6 (10). Terry and colleagues have reported that other promoter polymorphisms of IL-6 might also influence IL-6 expression (13). It is noteworthy that ethnic variations of SNPs and cytokine expression exist. In the Asian populations, the –634 G allele has been found to increase production/secretion of IL-6 in vitro and is associated with diabetic nephropathy and lung cancer (12, 24). One of the objectives of the present study was to investigate the potential influence of the –634 G allele on serum IL-6 level and survival. Our results showed no differences in serum level and survival between patients with and without the –634 G allele and suggested that the effect of this SNP on IL-6 expression was limited. In our subjects, we also assessed the most well-studied SNP –174 G/C and detected no polymorphism at this position, which was consistent with prior studies (21–23). Additional studies are needed to identify functional polymorphisms of IL-6 in Asian populations.

In this study, treatment for gastric cancer was comparable between patients with low and high serum IL-6 levels (Table 4). Only 7 (4.8%) of the patients underwent adjuvant chemotherapy. Whereas the Southwest Oncology Group study (SWOG-9008) which was published at the late phase of our enrollment period showed a survival benefit for adjuvant chemoradiotherapy and concluded that it should be considered for patients at high risk for recurrence after resection (45), adjuvant chemotherapy did not confer survival benefit in other studies (46, 47). In the SWOG-9008 trial, 54% of patients underwent inadequate lymphadenectomy (D0 resection), and further analysis by the same authors showed that surgical undertreatment in this trial undermined survival (37). Therefore, the value of adjuvant chemotherapy or chemoradiotherapy in patients undergoing adequate lymphadenectomy as in our patients may require further study.

A limitation in this study was that the time to recurrence could not be determined with appropriate precision in some cases; thus, the relationship between various factors and disease-free survival could not be analyzed. Another limitation was that serum samples after surgical resection were not available, so the usefulness of serum IL-6 level for detecting recurrence after resection could not be evaluated. Whereas it may be inferred that serum IL-6 level may also be associated with recurrence and disease-free survival, additional studies are needed to address this point. Further study to investigate and validate the usefulness of serum IL-6 level in predicting prognosis and guiding treatment strategy will be conducted in a prospective cohort of gastric carcinoma patients.

In summary, the results of this study indicate that a serum IL-6 level of >13 pg/mL correlates positively with tumor progression and is an independent predictor of poor survival after resection. In stages II and III diseases, it is more effective than TNM stage as a prognostic factor. The –634G/C polymorphism is not associated with serum IL-6 level or survival in gastric carcinoma. As >50% of patients who undergo surgery are diagnosed at these stages in Taiwan and Western countries, serum IL-6 level is an important predictor of survival and may influence treatment strategy and subsequent patient outcome. Additional studies are needed to investigate the optimal treatment strategies, taking into account serum IL-6 levels.

	Footnotes

 
Grant support: National Science Council grant NSC 95-2321-B002-004.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 1/ 5/07; revised 9/12/07; accepted 10/17/07.

	References

Top Abstract Materials and Methods Results Discussion References

 

1. Bataille R, Jourdan M, Zhang XG, Klein B. Serum levels of interleukin 6, a potent myeloma cell growth factor, as a reflect of disease severity in plasma cell dyscrasias. J Clin Invest 1989;84:2008–11.[Medline]
2. Blay JY, Negrier S, Combaret V, et al. Serum level of interleukin 6 as a prognosis factor in metastatic renal cell carcinoma. Cancer Res 1992;52:3317–22.[Abstract/Free Full Text]
3. Nakashima J, Tachibana M, Horiguchi Y, et al. Serum interleukin 6 as a prognostic factor in patients with prostate cancer. Clin Cancer Res 2000;6:2702–6.[Abstract/Free Full Text]
4. Matsuo K, Oka M, Murase K, et al. Expression of interleukin 6 and its receptor in human gastric and colorectal cancers. J Int Med Res 2003;31:69–75.[Medline]
5. Wu CW, Wang SR, Chao MF, et al. Serum interleukin-6 levels reflect disease status of gastric cancer. Am J Gastroenterol 1996;91:1417–22.[Medline]
6. Tang LP, Cho CH, Hui WM, et al. An inverse correlation between interleukin-6 and select gene promoter methylation in patients with gastric cancer. Digestion 2006;74:85–90.[CrossRef][Medline]
7. Thong-Ngam D, Tangkijvanich P, Lerknimitr R, Mahachai V, Theamboonlers A, Poovorawan Y. Diagnostic role of serum interleukin-18 in gastric cancer patients. World J Gastroenterol 2006;12:4473–7.[Medline]
8. Yamaoka Y, Kodama T, Kita M, Imanishi J, Kashima K, Graham DY. Relation between cytokines and Helicobacter pylori in gastric cancer. Helicobacter 2001;6:116–24.[CrossRef][Medline]
9. Castell JV, Geiger T, Gross V, et al. Plasma clearance, organ distribution and target cells of interleukin-6/hepatocyte-stimulating factor in the rat. Eur J Biochem 1988;177:357–61.[Medline]
10. Fishman D, Faulds G, Jeffery R, et al. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest 1998;102:1369–76.[Medline]
11. Bennermo M, Held C, Stemme S, et al. Genetic predisposition of the interleukin-6 response to inflammation: implications for a variety of major diseases? Clin Chem 2004;50:2136–40.[Abstract/Free Full Text]
12. Kitamura A, Hasegawa G, Obayashi H, et al. Interleukin-6 polymorphism (-634C/G) in the promotor region and the progression of diabetic nephropathy in type 2 diabetes. Diabet Med 2002;19:1000–5.[CrossRef][Medline]
13. Terry CF, Loukaci V, Green FR. Cooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulation. J Biol Chem 2000;275:18138–44.[Abstract/Free Full Text]
14. Rundek T, Elkind MS, Pittman J, et al. Carotid intima-media thickness is associated with allelic variants of stromelysin-1, interleukin-6, and hepatic lipase genes: the Northern Manhattan Prospective Cohort Study. Stroke 2002;33:1420–3.[Abstract/Free Full Text]
15. Vozarova B, Fernandez-Real JM, Knowler WC, et al. The interleukin-6 (-174) G/C promoter polymorphism is associated with type-2 diabetes mellitus in native Americans and Caucasians. Hum Genet 2003;112:409–13.[Medline]
16. Humphries SE, Luong LA, Ogg MS, Hawe E, Miller GJ. The interleukin-6 -174 G/C promoter polymorphism is associated with risk of coronary heart disease and systolic blood pressure in healthy men. Eur Heart J 2001;22:2243–52.[Abstract/Free Full Text]
17. Licastro F, Grimaldi LM, Bonafe M, et al. Interleukin-6 gene alleles affect the risk of Alzheimer's disease and levels of the cytokine in blood and brain. Neurobiol Aging 2003;24:921–6.[CrossRef][Medline]
18. Chung HW, Seo JS, Hur SE, et al. Association of interleukin-6 promoter variant with bone mineral density in pre-menopausal women. J Hum Genet 2003;48:243–8.[CrossRef][Medline]
19. Cozen W, Gill PS, Ingles SA, et al. IL-6 levels and genotype are associated with risk of young adult Hodgkin lymphoma. Blood 2004;103:3216–21.[Abstract/Free Full Text]
20. DeMichele A, Martin AM, Mick R, et al. Interleukin-6 -174G->C polymorphism is associated with improved outcome in high-risk breast cancer. Cancer Res 2003;63:8051–6.[Abstract/Free Full Text]
21. Lim CS, Zheng S, Kim YS, et al. The -174 G to C polymorphism of interleukin-6 gene is very rare in Koreans. Cytokine 2002;19:52–4.[CrossRef][Medline]
22. Nakajima T, Ota N, Yoshida H, Watanabe S, Suzuki T, Emi M. Allelic variants in the interleukin-6 gene and essential hypertension in Japanese women. Genes Immun 1999;1:115–9.[CrossRef][Medline]
23. Zhai R, Liu G, Yang C, Huang C, Wu C, Christiani DC. The G to C polymorphism at -174 of the interleukin-6 gene is rare in a Southern Chinese population. Pharmacogenetics 2001;11:699–701.[CrossRef][Medline]
24. Seow A, Ng DP, Choo S, et al. Joint effect of asthma/atopy and an IL-6 gene polymorphism on lung cancer risk among lifetime non-smoking Chinese women. Carcinogenesis 2006;27:1240–4.[Abstract/Free Full Text]
25. Gastric cancer. In: Greene FL, Page DL, Fleming ID, et al., editors. AJCC Cancer Staging Manual. 6th ed. New York: Springer-Verlag; 2002. p. 99–106.
26. Nishimura M, Matsuoka M, Maeda M, et al. Association between interleukin-6 gene polymorphism and human T-cell leukemia virus type I associated myelopathy. Hum Immunol 2002;63:696–700.[CrossRef][Medline]
27. McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM. Reporting recommendations for tumor marker prognostic studies. J Clin Oncol 2005;23:9067–72.[Free Full Text]
28. Hundahl SA, Phillips JL, Menck HR. The National Cancer Data Base Report on poor survival of U.S. gastric carcinoma patients treated with gastrectomy: Fifth Edition American Joint Committee on Cancer staging, proximal disease, and the "different disease" hypothesis. Cancer 2000;88:921–32.[CrossRef][Medline]
29. Siewert JR, Bottcher K, Roder JD, Busch R, Hermanek P, Meyer HJ. Prognostic relevance of systematic lymph node dissection in gastric carcinoma. German Gastric Carcinoma Study Group. Br J Surg 1993;80:1015–8.[Medline]
30. Correa P. The biological model of gastric carcinogenesis. IARC Sci Publ 2004;157:301–10.[Medline]
31. Lin MT, Lin BR, Chang CC, et al. IL-6 induces AGS gastric cancer cell invasion via activation of the c-Src/RhoA/ROCK signaling pathway. Int J Cancer 2007;120:2600–8.[CrossRef][Medline]
32. Huang SP, Wu MS, Wang HP, Yang CS, Kuo ML, Lin JT. Correlation between serum levels of interleukin-6 and vascular endothelial growth factor in gastric carcinoma. J Gastroenterol Hepatol 2002;17:1165–9.[CrossRef][Medline]
33. Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006;355:11–20.[Abstract/Free Full Text]
34. Hartgrink HH, van de Velde CJ, Putter H, et al. Neo-adjuvant chemotherapy for operable gastric cancer: long term results of the Dutch randomised FAMTX trial. Eur J Surg Oncol 2004;30:643–9.[CrossRef][Medline]
35. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2006. CA Cancer J Clin 2006;56:106–30.[Abstract/Free Full Text]
36. Coburn NG, Swallow CJ, Kiss A, Law C. Significant regional variation in adequacy of lymph node assessment and survival in gastric cancer. Cancer 2006;107:2143–51.[CrossRef][Medline]
37. Hundahl SA, Macdonald JS, Benedetti J, Fitzsimmons T. Surgical treatment variation in a prospective, randomized trial of chemoradiotherapy in gastric cancer: the effect of undertreatment. Ann Surg Oncol 2002;9:278–86.[Abstract/Free Full Text]
38. Le A, Berger D, Lau M, El-Serag HB. Secular Trends in the use, quality, and outcomes of gastrectomy for noncardia gastric cancer in the United States. Ann Surg Oncol 2007;14:2519–27.[Abstract/Free Full Text]
39. Schwarz RE, Smith DD. Clinical impact of lymphadenectomy extent in resectable gastric cancer of advanced stage. Ann Surg Oncol 2007;4:317–28.
40. Smith DD, Schwarz RR, Schwarz RE. Impact of total lymph node count on staging and survival after gastrectomy for gastric cancer: data from a large US-population database. J Clin Oncol 2005;23:7114–24.[Abstract/Free Full Text]
41. Rohatgi PR, Yao JC, Hess K, et al. Outcome of gastric cancer patients after successful gastrectomy: influence of the type of recurrence and histology on survival. Cancer 2006;107:2576–80.[CrossRef][Medline]
42. Sue-Ling HM, Johnston D, Martin IG, et al. Gastric cancer: a curable disease in Britain. BMJ 1993;307:591–6.[Abstract/Free Full Text]
43. Kitano S, Shiraishi N, Uyama I, Sugihara K, Tanigawa N. A multicenter study on oncologic outcome of laparoscopic gastrectomy for early cancer in Japan. Ann Surg 2007;245:68–72.[CrossRef][Medline]
44. Saito H, Osaki T, Murakami D, et al. Macroscopic tumor size as a simple prognostic indicator in patients with gastric cancer. Am J Surg 2006;192:296–300.[CrossRef][Medline]
45. Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 2001;345:725–30.[Abstract/Free Full Text]
46. Hermans J, Bonenkamp JJ, Boon MC, et al. Adjuvant therapy after curative resection for gastric cancer: meta-analysis of randomized trials. J Clin Oncol 1993;11:1441–7.[Abstract/Free Full Text]
47. Macdonald JS, Fleming TR, Peterson RF, et al. Adjuvant chemotherapy with 5-FU, adriamycin, and mitomycin-C (FAM) versus surgery alone for patients with locally advanced gastric adenocarcinoma: a Southwest Oncology Group study. Ann Surg Oncol 1995;2:488–94.[Abstract]

This Article Abstract Full Text (PDF) All Versions of this Article: 1078-0432.CCR-07-1032v1 1078-0432.CCR-07-1032v2 14/2/428    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Liao, W.-C. Articles by Wu, M.-S. Search for Related Content PubMed PubMed Citation Articles by Liao, W.-C. Articles by Wu, M.-S.