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Originally published as JCO Early Release 10.1200/JCO.2005.03.7960 on January 3 2006 © 2006 American Society of Clinical Oncology. Serum YKL-40 Predicts Relapse-Free and Overall Survival in Patients With American Joint Committee on Cancer Stage I and II MelanomaFrom the Departments of Oncology, Plastic Surgery, and Clinical Biochemistry, Aarhus University Hospital; Department of Rheumatology, Herlev University Hospital, Herlev; and the Department of Surgical Gastroenterology, Hvidovre University Hospital, Hvidovre, Denmark Address reprint requests to Henrik Schmidt, MD, Department of Oncology, Aarhus University Hospital, Norrebrogade 44, 8000 Aarhus C, Denmark; e-mail: hesch{at}as.aaa.dk
PURPOSE: To evaluate the novel tumor biomarker YKL-40 in serial serum samples from patients with American Joint Committee on Cancer (AJCC) stage I and II melanoma from the time of diagnosis and during routine follow-up. Macrophages, neutrophils, and cancer cells secrete YKL-40, and a high serum level has been associated with poor prognosis in patients with several cancer types. PATIENTS AND METHODS: Serum samples from 234 patients with stage I (n = 162) and II (n = 72) melanoma were analyzed for YKL-40 by enzyme-linked immunosorbent assay. Serial samples were obtained before definitive primary surgery and during follow-up. RESULTS: After a median follow-up period of 66 months (range, 1 to 97 months), 41 relapses (18%) and 39 deaths (17%) were observed. Serum YKL-40 treated as an updated continuous covariate were analyzed together with the covariates sex, age, primary tumor site, ulceration, thickness, Clark level and histologic subtype in a Cox proportional hazard model. Serum YKL-40 was an independent prognostic factor of relapse-free survival (hazard ratio [HR], 1.6; 95% CI, 1.1 to 2.5; P = .03) and overall survival (HR, 1.8; 95% CI, 1.2 to 2.6; P = .002) together with thickness and ulceration. The serum level of YKL-40 (dichotomized as normal or elevated) at the time of diagnosis was also an independent prognostic factor for overall survival (HR, 3.6, 95% CI, 1.7 to 7.7; P = .001). CONCLUSION: Serum YKL-40 may be an early biomarker of relapse and survival in patients with AJCC stage I and II melanoma. Serum YKL-40 may also be useful for patient stratification and follow-up in clinical trials. Our results need confirmation in an independent study.
The most important prognostic factors for relapse after resection of a primary melanoma are thickness, ulceration, and sentinel lymph node status,1 but there is currently no accurate method to identify patients who will develop recurrence. Interest in new prognostic biomarkers has arisen with the goal of early detection of relapse, as well as stratification of patients before enrollment onto adjuvant treatment studies. A number of serum biomarkers have been evaluated as potential prognostic factors in melanoma. The majority of these are proteins released from melanoma cells such as S100ß, melanoma inhibitory factor (MIA), and the tumor-associated antigen TA90. Of these, only TA90 is melanoma specific. TA90 has shown promise as a predictor of survival and relapse in patients with stage I to III melanoma.2 Serum S100ß has shown prognostic impact in patients with stages III to IV melanoma, but not in stages I to II.3,4 MIA is thought to promote melanoma progression,5 and several studies have shown MIA as a promising prognostic biomarker, but mainly in stage II-IV melanoma.6,7 YKL-40, a phylogenetically highly conserved heparin- and chitin-binding lectin, is a member of "mammalian chitinase-like proteins."8-11 It is also named human cartilage glycoprotein-39 (HC gp-39), 38-kDa heparin-binding glycoprotein (Gp38k), Chitinase-3-like-1 protein (CHI3L1), breast-regressing protein 39 Kd (brp-39), and chondrex. The gene for human YKL-4012,13 is localized on chromosome 1 and its crystal structure has been described previously.14,15 Microarray gene analyses have identified the YKL-40 gene as one of the most over-expressed genes in glioblastoma,16,17 papillary thyroid carcinoma,18 and extracellular myxoid chondrosarcoma.19 YKL-40 is secreted in vitro by some cancer cell lines,20-22 activated neutrophils,23 and macrophages,10,12,13 and in vivo by macrophages in tissues with inflammation24 and by tumor-associated macrophages.25 Several studies of patients with solid tumors have demonstrated that serum YKL-40 is elevated (compared with healthy subjects) in some patients with primary or metastatic carcinoma of the breast,26-28 colon/rectum,29,30 ovary,31-33 lung,34 prostate,35 kidney,36 and glioblastoma,17 and recently in stage IV melanoma.37 Interestingly, the studies showed that high serum YKL-40 was related to short recurrence-free interval and short overall survival, and that high serum YKL-40 was an independent prognostic factor of poor survival.26-37 In patients treated surgically for colorectal cancer, a high serum YKL-40 postoperatively increased the risk of recurrence or death within the following 6 months by 6.9- and 8.5-fold, respectively.30 The present study describes baseline and serial serum YKL-40 measurements in 234 consecutive patients with stage I to II melanoma according to the American Joint Committee on Cancer (AJCC). The prognostic impact on relapse-free and overall survival was evaluated.
Patients The study was conducted as a serial collection of serum samples from 234 consecutive patients with AJCC stage I to II melanoma from February 1997 to December 2002. The local ethics committee accepted the present project, and written informed consent was obtained from each patient. Serum samples were collected at baseline (before definitive primary surgery) and during the follow-up period until 2 years after inclusion of the last patient. A baseline serum sample was missing in nine patients (4%). Baseline staging procedures for all patients included a chest x-ray together with a full blood count, including liver enzymes. Sentinel node procedures were not performed during this study. Disease status was coded according to the AJCC guidelines 2001 version.38 It was not possible to measure tumor thickness in 12 cases, and these patients were coded as thick melanomas (stage II). Follow-up visits were performed every 3 months for the first 2 years and then every 6 months up to 5 years. At each visit, a clinical history, physical examination, and serum sample were obtained. Diagnostic imaging (ie, x-ray, ultrasonography, or computed tomography) were performed if clinically indicated.
Processing of Serum Samples and YKL-40 Analysis The normal range of serum YKL-40 was determined in 245 healthy patients (134 women and 111 men; median age, 49 years, range, 18-79 years). These patients received no medication, and had no signs or clinical symptoms of cancer, joint, liver, metabolic or endocrine disease.40 A normal reference range was calculated as described by Royston41 on the logarithmically (log-) transformed serum YKL-40 values of the healthy controls, adjusting for age, and the 95% percentile was chosen as the cut point.
Statistics
The simultaneous relationship of multiple prognostic factors for survival was assessed using the Cox proportional hazards model with backward reduction. Factors with P < .10 in the univariate analyses were included in the multivariate analysis to identify factors of independent significance. The assumption of proportional hazards was verified. The potential prognostic factors used for covariate selection were the following: sex (female v male), age (< median age v
Patient Characteristics This study was conducted on serial serum samples from 234 consecutive stage I to II melanoma patients. A total of 2,245 serum samples were collected before definitive surgery and during the follow-up period. The median number of samples collected from each patient was 10, with a range of one to 15 samples (one sample, 4%; two to seven samples, 14%; eight to 10 samples, 38%; 11 to 15 samples, 44%). The median follow-up interval between the first sample and the last follow-up or death was 66 months (range, 1 to 97 months). The median follow-up interval from the first to the last serum sample was 36 months (range, 1 to 66 months). The patients' characteristics are summarized in Table 1.
Associations Between Baseline Serum YKL-40 and Patient Characteristics The median serum concentration of YKL-40 at baseline in patients with stage II melanoma was significantly higher compared with stage I patients (median, 63 µg/L; range, 16 to 935 µg/L v median, 43 µg/L; range, 15 to 613 µg/L; P = .01), and healthy controls (median 63 µg/L, range, 16 to 935 µg/L v median, 43 µg/L; range, 20 to 184 µg/L; P = .046) after correction for age. There was no significant difference between serum YKL-40 levels in patients with stage I melanoma patients and healthy controls (P = .99) after correction for age. Serum YKL-40 was associated with sex (P < .0001) and age (P < .0001) and correlated with tumor thickness (r = 0.20; P = .003) but not with the other covariates such as primary tumor site, ulceration, Clark level, and histologic subtype. Twenty percent of the patients had all serum YKL-40 levels during the study period in the normal range, and 72% had less than 50% of the samples with an elevated serum YKL-40. In 4% of the patients, all serum YKL-40 levels were elevated during the study.
Associations of Serial Serum YKL-40 Levels With Relapse-Free and Overall Survival
A total of 39 patients (17%) died during follow-up: 27 (12%) patients as a result of melanoma after relapse, and 12 (5%) patients as a result of other causes. The median follow-up of patients alive at time of analysis with regard to survival was 83 months with a range of 57 to 109 months. Univariate analyses revealed the following covariates as significantly correlated to overall survival: serum YKL-40 (log-transformed and treated as an updated continuous variable), sex, age, ulceration, thickness, Clark level, and histologic subtype. In the multivariate model, the following variables were independent prognostic factors for overall survival: serum YKL-40 (HR, 1.8; 95% CI, 1.2 to 2.6; P = .002), thickness (HR, 3.0; 95% CI, 2.1 to 4.2; P < .0001) and ulceration (HR, 2.0; 95% CI, 1.0 to 4.1; P = .049; Table 3).
Association of Baseline Serum YKL-40 With Relapse-Free and Overall Survival We also examined baseline levels of serum YKL-40 (normal v elevated) in relation to relapse-free and overall survival. With regard to relapse-free survival, serum YKL-40 was not significant in the univariate analyses (P = .44), and therefore no multivariate analysis was performed. With regard to overall survival, serum YKL-40 was significant in the univariate analysis (P < .0001). Multivariate analysis demonstrated that baseline serum YKL-40 (HR, 3.6; 95% CI, 1.7 to 7.7; P = 0.001) was an independent prognostic factor for overall survival together with thickness (HR, 3.3; 95% CI, 2.5 to 4.9; P < .0001) and ulceration (HR, 2.0; 95% CI, 1.0 to 4.1; P = .046). Figure 1 illustrates overall survival stratified by baseline YKL-40.
We report here on the clinical relevance of the novel serum biomarker YKL-40 in 2,245 serial samples from 234 consecutive stage I and II melanoma patients with a median follow-up of 66 months. Thepresent study demonstrates that serum YKL-40 is an independent prognostic factor for relapse and death. We found that 13% of the patients before definitive surgery had elevated serum YKL-40 compared with healthy patients, and that these patients had the poorest prognosis. Multivariate Cox analysis including serum YKL-40 (log transformed and treated as an updated continuous covariate during the postoperative follow-up of the patients) and sex, age, primary tumor site, ulceration, thickness, Clark level, and histologic subtype demonstrated that serum YKL-40 was an independent prognostic factor for both relapse and death. When applying the predefined cut level (normal v elevated) to baseline samples, we observed that an elevated serum YKL-40 was an independent prognostic factor for overall survival but not for relapse-free survival, as was the case when we analyzed YKL-40 as a log-transformed covariate. This can imply that a more optimal cut level exists. The level we applied was derived from healthy controls as the upper 95% reference level, and was previously evaluated in stage IV melanoma patients.37 To investigate this issue, we have initiated an independent confirmatory study. We have recently reported that serum YKL-40 was elevated in 45% of patients with stage IV melanoma, and an elevated level of YKL-40 was correlated to visceral metastases and to poor performance status. Significant increments in serum YKL-40 were observed together with disease progression, and elevated serum YKL-40 was an independent prognostic factor for short survival in stage IV melanoma.37 Serum concentrations of YKL-40 was found to be independent of serum lactate dehydrogenase in patients with stage IV melanoma37 and small-cell lung cancer,34 of serum carcinoembryonic antigen in colorectal cancer patients,29,30 of serum CA-125 and CA15-3 in ovarian cancer patients31-33 of serum HER2 in metastatic breast cancer patients,26 and of serum PSA in patients with metastatic prostate cancer,35 indicating that serum YKL-40 reflects other aspects of tumor growth and metastasis than these tumor markers. The most extensively studied serum markers in melanoma are S100ß and MIA. Both have shown prognostic impact in stages III to IV melanoma,4,6,7,42 but an independent prognostic impact has not been shown in patients with stages I and II.3 Not all patients with cancer have elevated serum YKL-40 levels compared with healthy age-matched controls, suggesting that not all tumors secrete YKL-40 or that the protein is secreted at a low level. Cancer cells that secrete YKL-40 may have a different phenotype from cancer cells that do not express and secrete YKL-40. The protein may therefore reflect differences in the biology of various cancer cells. The biologic functions of YKL-40 in solid tumors are unknown. It has been suggested that YKL-40 may play a role in proliferation and differentiation of the malignant cells, protect the cells from undergoing apoptosis, stimulate angiogenesis, and have an effect on extracellular tissue remodeling, although in vivo proof of this is yet to be obtained. Cancer progression depends on the interplay between the cancer cells and their microenvironment, particularly cells in the surrounding extracellular matrix. The balance between synthesis and degradation of extracellular matrix components is a key modulator of cancer growth and metastasis.43 The stroma around the periphery of solid cancers have several similarities with granulation tissue such as that found in wound healing or inflammation.44-46 Recent studies have shown that tumor-associated macrophages and leukocytes play important roles in aiding tumor growth and metastasis because these cells produce growth and angiogenic factors, chemokines, metalloproteinases, and other extracellular matrix–degrading enzymes.47-49 In vitro, YKL-40 is expressed and secreted by activated neutrophils23 and macrophages,10,12,13 and in situ hybridization of biopsies from small-cell lung cancer has shown that YKL-40 mRNA expression was found in tumor-associated macrophages, not in the cancer cells,25 suggesting that YKL-40 play a role in the extracellular tissue remodeling processes surrounding the tumor cells. The source of the elevated serum YKL-40 levels in patient with stage I and II melanoma is unknown. To address this question, we have initiated immunohistochemical and in situ hybridization analyses of tumor biopsies from stage I to III melanoma patients. The migration of endothelial cells is stimulated by YKL-40 at a level comparable to that achieved by basic fibroblast growth factor, and YKL-40 modulates vascular endothelial cell morphology by promoting the formation of branching tubules.50,51 YKL-40 may therefore be a positive regulator of angiogenesis and may play a role in the growth of primary and metastatic tumors. Upregulated YKL-40 expression has been observed in a human glioblastoma cell line exposed to genotoxic and microenvironmental stress (eg, hypoxia, ionizing radiation).21 Furthermore, human astrocytes transfected with YKL-40 had increased resistance to radiation and increased invasion capacity in vitro.16 This suggests that YKL-40 plays a role in the malignant phenotype as a cellular survival factor. Recent immunohistochemical analyses of biopsies from glioblastoma demonstrated that YKL-40 is a differential diagnostic marker for histologic subtypes of high-grade gliomas,52 and that the expression in the glioblastoma cells was related to poor response to radiotherapy and an independent predictor of poor survival.53 In conclusion, our study identified serum YKL-40 as an independent new prognostic biomarker for relapse-free and overall survival in patients with stage I to II melanoma. Our study suggests that the serum concentration of YKL-40 in patients at the time of diagnosis may be useful for patient stratification in clinical trials. Serum YKL-40 may also be useful to monitor during follow-up after operation of stage I to II melanoma. Our results need confirmation in an independent study.
The authors indicated no potential conflicts of interest.
Angiogenic factors: A group of small proteins and cytokines that are involved in the growth of new bloodvessels. Apoptosis: Also called programmed cell death, it is a signaling pathway that leads to cellular suicide in an organized manner. Several factors and receptors are specific to the apoptotic pathway. The net result is that cells shrink, develop blebs on their surface, and their DNA undergoes fragmentation. Biomarker (biologic marker): A characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. Chemokines: Cytokines that are responsible for chemotactic responses, chemokines are heparin-binding proteins, which play a role in a variety of biologic processes, the most important onebeing leukocyte chemotaxis. Their classification as C, CC, CXC, and CX3C is based on the position of cysteine residues that formtwo disulfide bonds. Typically, chemokines mediate their effects through G protein–coupled seven-transmembrane domain receptors, which belong to four families based on their affinity for a given chemokine: CXCR1 to CXCR5, CCR1 to CCR9, XCR1, and CX3CR1. Microarray: A large set of cloned DNA molecules spotted onto a solid matrix for use in probing a biologic sample to determine gene expression, marker pattern or nucleotide sequence of DNA/RNA. Updated covariate: Also known as time-dependent covariate in contrast to a fixed covariate, which is measured at a single point in time. YKL-40: A member of the chitinase glycoprotein family, it has been reported to be involved in angiogenesis and matrix degradation. However, its exact function remains unknown.
The expert technical assistance of Tonni Loeve Hansen and Debbie Nadelmann, Herlev University Hospital is gratefully acknowledged. The authors also wish to thank Torben Steiniche, MD, for his help with reviewing the histopathologic samples.
Supported by grants awarded by the Danish Cancer Society, "Direktor Jens Aage Sorensen og Hustru Edith Ingeborg Sorensens Mindefond," "Aase og Ejner Danielsens Fond," and "Radiumstationens forskningsfond." Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Balch CM, Soong SJ, Gershenwald JE, et al: Prognostic factors analysis of 17,600 melanoma patients: Validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 19:3622-3634, 2001 2. Kelley MC, Gupta RK, Hsueh EC, et al: Tumor-associated antigen TA90 immune complex assay predicts recurrence and survival after surgical treatment of stage I-III melanoma. J Clin Oncol 19:1176-1182, 2001 3. Martenson ED, Hansson LO, Nilsson B, et al: Serum S-100b protein as a prognostic marker in malignant cutaneous melanoma. J Clin Oncol 19:824-831, 2001 4. Schmidt H, Sorensen BS, Nexo E, et al: S100 protein in peripheral blood may predict progressive disease during IL-2 based immunotherapy in patients with metastatic melanoma. Melanoma Res 14:211-215, 2004[Medline] 5. Poser I, Tatzel J, Kuphal S, et al: Functional role of MIA in melanocytes and early development of melanoma. Oncogene 23:6115-6124, 2004[CrossRef][Medline] 6. Bosserhoff AK, Kaufmann M, Kaluza B, et al: Melanoma-inhibiting activity, a novel serum marker for progression of malignant melanoma. Cancer Res 57:3149-3153, 1997 7. Deichmann M, Benner A, Bock M, et al: S100-Beta, melanoma-inhibiting activity, and lactate dehydrogenase discriminate progressive from nonprogressive American Joint Committee on Cancer stage IV melanoma. J Clin Oncol 17:1891-1896, 1999 8. Hakala BE, White C, Recklies AD: Human cartilage gp-39, a major secretory product of articular chondrocytes and synovial cells, is a mammalian member of a chitinase protein family. J Biol Chem 268:25803-25810, 1993 9. Johansen JS, Jensen HS, Price PA: A new biochemical marker for joint injury: Analysis of YKL-40 in serum and synovial fluid. Br J Rheumatol 32:949-955, 1993 10. Renkema GH, Boot RG, Au FL, et al: Chitotriosidase, a chitinase, and the 39-kDa human cartilage glycoprotein, a chitin-binding lectin, are homologues of family 18 glycosyl hydrolases secreted by human macrophages. Eur J Biochem 251:504-509, 1998[Medline] 11. Shackelton LM, Mann DM, Millis AJ: Identification of a 38-kDa heparin-binding glycoprotein (gp38k) in differentiating vascular smooth muscle cells as a member of a group of proteins associated with tissue remodeling. J Biol Chem 270:13076-13083, 1995 12. Rehli M, Krause SW, Andreesen R: Molecular characterization of the gene for human cartilage gp-39 (CHI3L1), a member of the chitinase protein family and marker for late stages of macrophage differentiation. Genomics 43:221-225, 1997[CrossRef][Medline] 13. Rehli M, Niller HH, Ammon C, et al: Transcriptional regulation of CHI3L1, a marker gene for late stages of macrophage differentiation. J Biol Chem 278:44058-44067, 2003 14. Fusetti F, Pijning T, Kalk KH, et al: Crystal structure and carbohydrate-binding properties of the human cartilage glycoprotein-39. J Biol Chem 278:37753-37760, 2003 15. Houston DR, Recklies AD, Krupa JC, et al: Structure and ligand-induced conformational change of the 39-kDa glycoprotein from human articular chondrocytes. J Biol Chem 278:30206-30212, 2003 16. Nigro JM, Misra A, Zhang L, et al: Integrated array-comparative genomic hybridization and expression array profiles identify clinically relevant molecular subtypes of glioblastoma. Cancer Res 65:1678-1686, 2005 17. Tanwar MK, Gilbert MR, Holland EC: Gene expression microarray analysis reveals YKL-40 to be a potential serum marker for malignant character in human glioma. Cancer Res 62:4364-4368, 2002 18. Huang Y, Prasad M, Lemon WJ, et al: Gene expression in papillary thyroid carcinoma reveals highly consistent profiles. Proc Natl Acad Sci U S A 98:15044-15049, 2001 19. Sjogren H, Meis-Kindblom JM, Orndal C, et al: Studies on the molecular pathogenesis of extraskeletal myxoid chondrosarcoma-cytogenetic, molecular genetic, and cDNA microarray analyses. Am J Pathol 162:781-792, 2003 20. Johansen JS, Williamson MK, Rice JS, et al: Identification of proteins secreted by human osteoblastic cells in culture. J Bone Miner Res 7:501-512, 1992[Medline] 21. Junker N, Johansen JS, Hansen LT, et al: Regulation of YKL-40 expression during genotoxic or microenvironmental stress in human glioblastoma cells. Cancer Sci 96:183-190, 2005[Medline] 22. Morrison BW, Leder P: Neu and ras initiate murine mammary tumors that share genetic markers generally absent in c-myc and int-2-initiated tumors. Oncogene 9:3417-3426, 1994[Medline] 23. Volck B, Price PA, Johansen JS, et al: YKL-40, a mammalian member of the chitinase family, is a matrix protein of specific granules in human neutrophils. Proc Assoc Am Physicians 110:351-360, 1998[Medline] 24. Volck B, Johansen JS, Stoltenberg M, et al: Studies on YKL-40 in knee joints of patients with rheumatoid arthritis and osteoarthritis: Involvement of YKL-40 in the joint pathology. Osteoarthritis Cartilage 9:203-214, 2001[CrossRef][Medline] 25. Junker N, Johansen JS, Andersen CB, et al: Expression of YKL-40 by peritumoral macrophages in human small cell lung cancer. Lung Cancer 48:223-231, 2005[CrossRef][Medline] 26. Jensen BV, Johansen JS, Price PA: High levels of serum HER-2/neu and YKL-40 independently reflect aggressiveness of metastatic breast cancer. Clin Cancer Res 9:4423-4434, 2003 27. Johansen JS, Cintin C, Jorgensen M, et al: Serum YKL-40: A new potential marker of prognosis and location of metastases of patients with recurrent breast cancer. Eur J Cancer 31A:1437-1442, 1995 28. Johansen JS, Christensen IJ, Riisbro R, et al: High serum YKL-40 levels in patients with primary breast cancer is related to short recurrence free survival. Breast Cancer Res Treat 80:15-21, 2003[CrossRef][Medline] 29. Cintin C, Johansen JS, Christensen IJ, et al: Serum YKL-40 and colorectal cancer. Br J Cancer 79:1494-1499, 1999[CrossRef][Medline] 30. Cintin C, Johansen JS, Christensen IJ, et al: High serum YKL-40 level after surgery for colorectal carcinoma is related to short survival. Cancer 95:267-274, 2002[CrossRef][Medline] 31. Dehn H, Hogdall EV, Johansen JS, et al: Plasma YKL-40, as a prognostic tumor marker in recurrent ovarian cancer. Acta Obstet Gynecol Scand 82:287-293, 2003[CrossRef][Medline] 32. Dupont J, Tanwar MK, Thaler HT, et al: Early detection and prognosis of ovarian cancer using serum YKL-40. J Clin Oncol 22:3330-3339, 2004 33. Hogdall EV, Johansen JS, Kjaer SK, et al: High plasma YKL-40 level in patients with ovarian cancer stage III is related to shorter survival. Oncol Rep 10:1535-1538, 2003[Medline] 34. Johansen JS, Drivsholm L, Price PA, et al: High serum YKL-40 level in patients with small cell lung cancer is related to early death. Lung Cancer 46:333-340, 2004[CrossRef][Medline] 35. Brasso, K, Christensen, IJ, and Johansen, JS: Prognostic value of PINP, bone alkaline phospatase, CTX-1 and YKL-40 in patients with metastatic prostate carcinoma. Prostate (in press) 36. Geertsen P, Johansen JS, von der Maase H, et al: High pretreatment serum level of YKL-40 is related to short survival in patients with advanced renal cell carcinoma treated with high-dose continous intravenous infusion of Interleukin-2. Proc Am Soc Clin Oncol 22:399, 2003 (abstr 1603) 37. Schmidt H, Johansen JS, Gehl J, et al: Elevated serum level of YKL-40 is an independent prognostic factor for poor survival in patients with metastatic melanoma. Cancer (in press) 38. Balch CM, Buzaid AC, Soong SJ, et al: Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 19:3635-3648, 2001 39. Harvey S, Weisman M, O'Dell J, et al: Chondrex: New marker of joint disease. Clin Chem 44:509-516, 1998 40. Johansen JS, Hvolris J, Hansen M, et al: Serum YKL-40 levels in healthy children and adults: Comparison with serum and synovial fluid levels of YKL-40 in patients with osteoarthritis or trauma of the knee joint. Br J Rheumatol 35:553-559, 1996 41. Royston P: Constructing time-specific reference ranges. Stat Med 10:675-690, 1991[Medline] 42. Hauschild A, Michaelsen J, Brenner W, et al: Prognostic significance of serum S100B detection compared with routine blood parameters in advanced metastatic melanoma patients. Melanoma Res 9:155-161, 1999[Medline] 43. Boudreau N, Bissell MJ: Extracellular matrix signaling: Integration of form and function in normal and malignant cells. Curr Opin Cell Biol 10:640-646, 1998[CrossRef][Medline] 44. Dvorak HF: Tumors: Wounds that do not heal: Similarities between tumor stroma generation and wound healing. N Engl J Med 315:1650-1659, 1986[Medline] 45. Gregoire M, Lieubeau B: The role of fibroblasts in tumor behavior. Cancer Metastasis Rev 14:339-350, 1995[CrossRef][Medline] 46. Balkwill F, Mantovani A: Inflammation and cancer: Back to Virchow? Lancet 357:539-545, 2001[CrossRef][Medline] 47. Bingle L, Brown NJ, Lewis CE: The role of tumour-associated macrophages in tumour progression: Implications for new anticancer therapies. J Pathol 196:254-265, 2002[CrossRef][Medline] 48. Lin EY, Pollard JW: Role of infiltrated leucocytes in tumour growth and spread. Br J Cancer 90:2053-2058, 2004[CrossRef][Medline] 49. Pollard JW: Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 4:71-78, 2004[CrossRef][Medline] 50. Malinda KM, Ponce L, Kleinman HK, et al: Gp38k, a protein synthesized by vascular smooth muscle cells, stimulates directional migration of human umbilical vein endothelial cells. Exp Cell Res 250:168-173, 1999[CrossRef][Medline] 51. Nishikawa KC, Millis AJ: Gp38k (CHI3L1) is a novel adhesion and migration factor for vascular cells. Exp Cell Res 287:79-87, 2003[CrossRef][Medline] 52. Nutt CL, Betensky RA, Brower MA, et al: YKL-40 is a differential diagnostic marker for histologic subtypes of high-grade gliomas. Clin Cancer Res 11:2258-2264, 2005 53. Pelloski CE, Mahajan A, Maor M, et al: YKL-40 expression is associated with poorer response to radiation and shorter overall survival in glioblastoma. Clin Cancer Res 11:3326-3334, 2005 Submitted August 22, 2005; accepted October 27, 2005. This article has been cited by other articles:
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
median age), primary tumor site (limbs v other sites), ulceration (none v ulceration), Clark level (level II to III v IV to V), tumor thickness (log-transformed values), and histologic subtype (superficial spreading melanoma v others). Serum YKL-40 was considered both as a baseline and as an 
