Breast Neoplasms: Nielsen HJ

Sturgeon CM, Duffy MJ, Stenman UH, Lilja H, Brünner N, Chan DW, Babaian R, Bast RC, Dowell B, Esteva FJ, Haglund C, Harbeck N, Hayes DF, Holten-Andersen M, Klee GG, Lamerz R, Looijenga LH, Molina R, Nielsen HJ, Rittenhouse H, Semjonow A, Shih IeM, Sibley P, Sölétormos G, Stephan C, Sokoll L, Hoffman BR, Diamandis EP, Anonymous00039. · Department of Clinical Biochemistry, Royal Infirmary of Edinburgh, Edinburgh, UK. · Clin Chem. · Pubmed #19042984 No free full text.

Abstract: BACKGROUND: Updated National Academy of Clinical Biochemistry (NACB) Laboratory Medicine Practice Guidelines for the use of tumor markers in the clinic have been developed. METHODS: Published reports relevant to use of tumor markers for 5 cancer sites--testicular, prostate, colorectal, breast, and ovarian--were critically reviewed. RESULTS: For testicular cancer, alpha-fetoprotein, human chorionic gonadotropin, and lactate dehydrogenase are recommended for diagnosis/case finding, staging, prognosis determination, recurrence detection, and therapy monitoring. alpha-Fetoprotein is also recommended for differential diagnosis of nonseminomatous and seminomatous germ cell tumors. Prostate-specific antigen (PSA) is not recommended for prostate cancer screening, but may be used for detecting disease recurrence and monitoring therapy. Free PSA measurement data are useful for distinguishing malignant from benign prostatic disease when total PSA is <10 microg/L. In colorectal cancer, carcinoembryonic antigen is recommended (with some caveats) for prognosis determination, postoperative surveillance, and therapy monitoring in advanced disease. Fecal occult blood testing may be used for screening asymptomatic adults 50 years or older. For breast cancer, estrogen and progesterone receptors are mandatory for predicting response to hormone therapy, human epidermal growth factor receptor-2 measurement is mandatory for predicting response to trastuzumab, and urokinase plasminogen activator/plasminogen activator inhibitor 1 may be used for determining prognosis in lymph node-negative patients. CA15-3/BR27-29 or carcinoembryonic antigen may be used for therapy monitoring in advanced disease. CA125 is recommended (with transvaginal ultrasound) for early detection of ovarian cancer in women at high risk for this disease. CA125 is also recommended for differential diagnosis of suspicious pelvic masses in postmenopausal women, as well as for detection of recurrence, monitoring of therapy, and determination of prognosis in women with ovarian cancer. CONCLUSIONS: Implementation of these recommendations should encourage optimal use of tumor markers.

Brünner N, Nielsen HJ, Hamers M, Christensen IJ, Thorlacius-Ussing O, Stephens RW. · Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark. · APMIS. · Pubmed #10190293 No free full text.

Abstract: The cell surface plasminogen activation system functions in promoting tumor dissemination, and is facilitated by a glycolipid anchored three domain receptor for urokinase. This receptor can also be found in a soluble form (suPAR) in extracts of tumors, as well as in plasma from both healthy individuals and cancer patients. The suPAR in plasma consists of the intact three domain protein, but neither the precise mechanism of its release from cell surfaces, nor its biological function are understood. Increased levels of plasma suPAR have been found in patients with cancers of the lung, breast, ovary, and colon, and recent data now indicates that the level of the molecule is related to patient prognosis.

Usher PA, Sieuwerts AM, Bartels A, Lademann U, Nielsen HJ, Holten-Andersen L, Foekens JA, Brünner N, Offenberg H. · Department of Veterinary Pathobiology, Faculty of Life Sciences, University of Copenhagen, Ridebanevej 9, 1870 Frederiksberg C, Denmark. · Mol Oncol. · Pubmed #19383295 No free full text.

Abstract: TIMP-1 is a promising new candidate as a prognostic marker in colorectal and breast cancer. We now describe the discovery of two alternatively spliced variants of TIMP-1 mRNA. The two variants lacking exon 2 (del-2) and 5 (del-5), respectively, were identified in human cancer cell lines by RT-PCR. The del-2 variant was, furthermore, detected in extracts from 12 colorectal cancer tissue samples. By western blotting additional bands of lower molecular mass than full-length TIMP-1 were identified in tumor tissue, but not in plasma samples obtained from cancer patients. The two splice variants of TIMP-1 may hold important clinical information, and either alone or in combination with measurement of full-length TIMP-1 they may improve the prognostic and/or predictive value of TIMP-1 analyses.

Larsen JM, Christensen IJ, Nielsen HJ, Hansen U, Bjerregaard B, Talts JF, Larsson LI. · Division of Cell Biology, IBHV, Faculty of Life Sciences, University of Copenhagen, Copenhagen, Gronnegaardsvej 7, DK 1870 Frederiksberg C, Denmark. · Cancer Lett. · Pubmed #19327884 No free full text.

Abstract: The endogenous retroviral envelope protein syncytin is involved in cell fusions and has also been associated with immunomodulatory functions. Syncytin is currently known to be expressed in the placenta, testis and brain as well as in breast and endometrial carcinomas. Using a newly developed monoclonal syncytin antibody we have assessed syncytin expression in a retrospective series of 140 colorectal cancer patients. Variable degrees of syncytin expression were detected in both colonic and rectal tumors and the prognostic impact of such expression was analysed with the Kaplan-Meier method and the Cox proportional hazard model. Interestingly, increased syncytin expression was associated with decreased overall survival in rectal but not in colonic cancer patients. Thus, the prognostic impact of syncytin expression appears to vary with the tumor type.

Larsen MB, Stephens RW, Brünner N, Nielsen HJ, Engelholm LH, Christensen IJ, Stetler-Stevenson WG, Høyer-Hansen G. · The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark. · Scand J Immunol. · Pubmed #15882437 No free full text.

Abstract: Tissue inhibitor of metalloproteinases (TIMP)-2 is a highly conserved molecule, which binds both active and latent matrix metalloproteinase (MMP)-2. TIMP-2 is also involved in the activation of MMP-2 on the cell surface. A quantitative enzyme-linked immunosorbent assay (ELISA) was established and optimized for measurement of TIMP-2 in plasma. The capturing antibody in the ELISA was a monoclonal, while the detecting antibody was a chicken polyclonal antibody recognizing the native form of human TIMP-2. The levels of TIMP-2 were measured in ethylenediaminetetraacetic acid (EDTA) and citrate plasma from healthy donors. The median values were determined as 163 ng/ml (n = 186) with a range of 109-253 ng/ml for EDTA plasma and 139 ng/ml (n = 77) with a range of 95-223 ng/ml for citrate plasma. The TIMP-2 concentration in citrate plasma from 15 patients with advanced, stage IV breast cancer had a median value of 160 ng/ml, only slightly higher but statistically distinguishable from the level found in citrate plasma from the healthy donors. In addition, the TIMP-2 concentration in EDTA plasma from colorectal cancer patients revealed a significantly higher level in plasma from patients with Dukes stage A (P = 0.01) compared with patients with more advanced Dukes stages.

Mortensen K, Christensen IJ, Nielsen HJ, Hansen U, Larsson LI. · Division of Cell Biology, Department of Anatomy and Physiology, KVL, Gronnegaardsvej 7, Dk-1870 Frederiksberg C/Copenhagen, Denmark. · Cancer Lett. · Pubmed #15500954 No free full text.

Abstract: We have previously shown that a high frequency of microvessels expressing endothelial cell nitric oxide synthase (ecNOS) in the area surrounding the primary tumor (peritumoral ecNOS-expressing microvessel density: PEMVD) is a favorable prognostic indicator in breast cancer. Studies of a retrospective material of 186 colorectal tumors (Duke's stage B) now show that PEMVD is a significant and independent prognostic indicator for disease-free survival also in these patients. These data reinforce our hypothesis that a high level of expression of ecNOS in microvessels in the tumor-adjacent area protects against tumor metastasis.

Holten-Andersen MN, Christensen IJ, Nielsen HJ, Stephens RW, Jensen V, Nielsen OH, Sørensen S, Overgaard J, Lilja H, Harris A, Murphy G, Brünner N. · The Finsen Laboratory, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark. · Clin Cancer Res. · Pubmed #11801553 links to  free full text

Abstract: PURPOSE: The purpose of this study was to measure total levels of tissue inhibitor of metalloproteinases (TIMP-1) by ELISA in plasma from blood donors, patients with inflammatory bowel disease (IBD), and patients with cancer and to correlate the results to patient diagnosis. EXPERIMENTAL DESIGN: Total TIMP-1 plasma levels were measured by ELISA in blood samples from two different blood donor populations from IBD patients, and preoperative samples from patients with primary colon cancer (CC), rectal cancer (RC), or breast cancer. RESULTS: There were no significant differences in plasma TIMP-1 levels between healthy donors and IBD or breast cancer patients, whereas patients with CC or RC had significantly elevated TIMP-1 levels. Total TIMP-1 levels identified patients with CC with a sensitivity of 63% at 98% specificity, patients with early CC (Dukes' A+B) with a sensitivity of 56% at 98% specificity, and patients with right-sided CC with a sensitivity of 72% at 98% specificity. Combining carcinoembryonic antigen and TIMP-1 measurements increased the sensitivities obtained from TIMP-1 measurements alone. CONCLUSIONS: TIMP-1 was significantly elevated in plasma from CC and RC patients, including those with early-stage disease. Sensitivity and specificity were both sufficiently high to consider TIMP-1 as a marker for the early identification of CC patients, in particular, those with right-sided CC.

Pedersen AN, Brünner N, Høyer-Hansen G, Hamer P, Jarosz D, Larsen B, Nielsen HJ, Stephens RW. · The Finsen Laboratory, Rigshospitalet, Strandboulevarden 49, 2100 Copenhagen, Denmark. · Clin Chem. · Pubmed #10430786 links to  free full text

Abstract: BACKGROUND: The complex between urokinase (uPA) and its type-1 inhibitor (PAI-1) is formed exclusively from the active forms of these components; thus, the complex concentration in a biological sample may reflect the ongoing degree of plasminogen activation. Our aim was to establish an ELISA for specific quantification of the uPA:PAI-1 complex in plasma of healthy donors and breast cancer patients. METHODS: A kinetic sandwich format immunoassay was developed, validated, and applied to plasma from 19 advanced-stage breast cancer patients, 39 age-matched healthy women, and 31 men. RESULTS: The assay detection limit was <2 ng/L, and the detection of complex in plasma was validated using immunoabsorption, competition, and recovery tests. Eighteen cancer patients had a measurable complex concentration (median, 68 ng/L; range, <16 to 8700 ng/L), whereas for healthy females and males the median signal values were below the detection limit (median, <16 ng/L; range, <16 to 200 ng/L; P <0.0001). For patient plasma, a comparison with total uPA and PAI-1 showed that the complex represented a variable, minor fraction of the uPA and PAI-1 concentrations of each sample. CONCLUSION: The reported ELISA enables detection of the uPA:PAI-1 complex in blood and, therefore, the evaluation of the complex as a prognostic marker in cancer.

Holten-Andersen MN, Murphy G, Nielsen HJ, Pedersen AN, Christensen IJ, Høyer-Hansen G, Brünner N, Stephens RW. · The Finsen Laboratory, Copenhagen University Hospital, Denmark. · Br J Cancer. · Pubmed #10408859 No free full text.

Abstract: A kinetic enzyme-linked immunosorbent assay (ELISA) for plasma tissue inhibitor of metalloproteinase (TIMP)-1 was developed in order to examine the potential diagnostic and prognostic value of TIMP-1 measurements in cancer patients. The ELISA enabled specific detection of total TIMP-1 in EDTA, citrate and heparin plasma. The assay was rigorously tested and requirements of sensitivity, specificity, stability and good recovery were fulfilled. TIMP-1 levels measured in citrate plasma (mean 69.2+/-13.1 microg I(-1)) correlated with TIMP-1 measured in EDTA plasma (mean 73.5+/-14.2 microg I(-1)) from the same individuals in a set of 100 healthy blood donors (Spearman's rho = 0.62, P< 0.0001). The mean level of TIMP-1 in EDTA plasma from 143 patients with Dukes' stage D colorectal cancer was 240+/-145 microg I(-1) and a Mann-Whitney test demonstrated a highly significant difference between TIMP-1 levels in healthy blood donors and colorectal cancer patients (P < 0.0001). Similar findings were obtained for 19 patients with advanced breast cancer (mean 292+/-331 microg I(-1)). The results show that TIMP-1 is readily measured in plasma samples by ELISA and that increased levels of TIMP-1 are found in patients with advanced cancer. It is proposed that plasma measurements of TIMP-1 may have value in the management of cancer patients.

Cintin C, Johansen JS, Christensen IJ, Price PA, Sørensen S, Nielsen HJ. · Department of Surgical Gastroenterology, Hvidovre Hospital, University of Copenhagen, Denmark. · Br J Cancer. · Pubmed #10188896 No free full text.

Abstract: YKL-40 is a mammalian member of the chitinase protein family. Although the function of YKL-40 is unknown, the pattern of its expression suggests a function in remodelling or degradation of extracellular matrix. High serum YKL-40 has been found in patients with recurrent breast cancer and has been related to short survival. In the present study we analysed YKL-40 in preoperative sera from patients with colorectal cancer and evaluated its relation to survival. Serum YKL-40 was determined by RIA in 603 patients. Survival after operation was registered, and median follow-up time was 61 months. Three hundred and forty patients died. Sixteen per cent of the patients with Dukes' A, 26% with Dukes' B, 19% with Dukes' C and 39% with Dukes' D had high serum YKL-40 levels (adjusted for age). Analysis of serum YKL-40 as a continuous variable showed an association between increased serum YKL-40 and short survival (P < 0.0001). Patients with high preoperative serum YKL-40 concentration had significantly shorter survival than patients with normal YKL-40 (HR = 1.7; 95% CI: 1.3-2.1, P < 0.0001). Multivariate Cox analysis including serum YKL-40, serum CEA, Dukes' stage, age and gender showed that high YKL-40 was an independent prognostic variable for short survival (HR = 1.4; 95% CI: 1.1-1.8, P = 0.007). These results suggest that YKL-40 may play an important role in tumour invasion.