Plasma Levels Of Tissue Inhibitor Research Articles

Left ventricle structure and function relations with the levels of plasma markers of fibrosis in hypertensive patients with NonSTEMI

Abstract Funding Acknowledgements Type of funding sources: None. Introduction. The myocardial fibrosis lies in the basis of left ventricle remodelling in patients with hypertension. Cardiomyocites hypertrophy, fibroblasts proliferation, enlargement of interstitial collagen volume and their ratio disorders may increase severity of stroke and myocardial infarction. Purpose. The purpose of the study is to evaluate relations between the plasma levels of myocardium fibrosis markers and left ventricle remodelling, systolic and diastolic function in hypertensive patients with NonSTEMI. Methods. Were examined 138 hypertensive patients (both men and women) with NonSTEMI. The mean age of patients was 51.2 (11.2) years. Patients with arrhythmias and conduction abnormalities, diabetes mellitus and autoimmune diseases were excluded form the study. In all patients was performed ECG in 12 standard leads; EchoCG (according to ASE/EACVI 2015 recommendations); evaluation plasma levels of tissue inhibitor of metalloproteinases-1 (TIMP-1) and insulin-like growth factor 1 (IGF-1). HF NYHA functional class was determined by performing 6MWT. Statistical significance was defined at the level of methods for p < 0,05. Results. The averaged levels for plasma markers of myocardium fibrosis were: TIMP-1 - 322.0 (250.0; 483.5) ng/mL; IGF-1 - 160.0 (141.0; 175.0) ng/mL. Results of correlative analysis revealed relations between IGF-1 and ILV mass (R=-0.59; p < 0.001), and weak correlation between IGF-1 and E/e" averaged (R=-0.19; p = 0.027) (Picture 1). These negative correlations may be explained by the growth in both fibroblasts and collagen production in myocardium. Also there were positive correlations between TIMP-1 and ILV mass (R = 0.63; p < 0.001) and TIMP-1 and E/e" average (R = 0.37; p < 0.001) (Picture 1) which may be due to an increase of myocardial stiffness as the result of fibrosis activity. The results of the comparison of TIMP-1 and ICF-1 plasma levels, structural and functional parameters of the LV in groups of patients with different types of LV geometry can be seen in Table 1. Conclusion. Thus, the results of the study show that plasma markers of fibrosis was significantly higher in patients with concentric and eccentric LV hypertrophy which may reflects the higher levels of myocardium stiffness. Abstract Table 1. Abstract Figure. Picture 1.

Plasma levels of tissue inhibitor of metalloproteinase-1 in patients with type 1 diabetes mellitus associate with early diabetic neuropathy and nephropathy.

Background:Tissue inhibitor of metalloproteinase-1 (TIMP-1) has been suggested as a marker for abnormal regulation of tissue remodelling in type 1 diabetes. Metalloproteinase-9 (MMP-9) has been associated with matrix turnover, and Neutrophil gelatinase associated lipocalin (NGAL) is a marker of tubular injury in diabetic nephropathy. The aim was to analyse these biomarkers to unmask early diabetic complications.Methods:Thirty-three type 1 diabetes patients, aged 20–35 years, and disease duration 20 ± 5.3 years were included. Along with clinical examination, neurophysiological measurements, routine biochemistry, plasma concentrations of TIMP-1, MMP-9 and NGAL were determined with immunoenzymatic techniques.Results:TIMP-1 correlated with abnormal unilateral and bilateral vibratory sense foot perception (r = −0.49 and r = −0.51, respectively), foot neuropathy impairment assessment score (NIA; r = −0.55), neuropathy symptom assessment score (r = 0.42), microalbuminuria (r = 0.50) and eGFR (r = −0.45). MMP-9 correlated with impaired foot NIA (r = 0.51). Multiple regression analysis showed an association for TIMP-1 (p = 0.004) with impaired neurophysiological examinations and renal dysfunction along with NGAL (p = 0.016 and p = 0.015 respectively).Conclusions:This study suggests that plasma levels of TIMP-1, MMP-9 and NGAL may serve as useful biomarkers in unravelling subclinical neuropathy and nephropathy in type 1 diabetes.

Hydroxytyrosol Supplementation Modifies Plasma Levels of Tissue Inhibitor of Metallopeptidase 1 in Women with Breast Cancer.

The etiology of breast cancer can be very different. Most antineoplastic drugs are not selective against tumor cells and also affect normal cells, leading to a wide variety of adverse reactions such as the production of free radicals by altering the redox state of the organisms. Therefore, the objective of this study was to elucidate if hydroxytyrosol (HT) (an antioxidant present in extra virgin olive oil) has a chemomodulatory effect when combined with the chemotherapeutic drugs epirubicin and cyclophosphamide followed by taxanes in breast cancer patients. Changes in plasma levels of matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinases 1 (TIMP-1) throughout the chemotherapy treatment were studied. Both molecules are involved in cell proliferation, apoptosis, neoangiogenesis, and metastasis in breast cancer patients. Women with breast cancer were divided into two groups: a group of patients receiving a dietary supplement of HT and a control group of patients receiving placebo. The results showed that the plasma levels of TIMP-1 in the group of patients receiving HT were significantly lower than those levels found in the control group after the epirubicin-cyclophosphamide chemotherapy.

Peripheral immune factors are elevated in women with current or recent alcohol dependence and associated with altered mood and memory

BackgroundThe adverse effects of alcohol on brain function result, in part, from inflammatory processes. The sex-specific neuropsychiatric consequences and inflammatory status of active alcohol dependence and early remission from dependence have not been investigated. MethodsNeuropsychiatric symptoms, inflammatory factors, and liver enzymes were compared in a prospective cohort study of adults with (n=51) or without (n=31) a current or recent history of alcohol dependence. ResultsNeuropsychiatric profiles were similar in adults with current or recent alcohol dependence regardless of sex. In male and female participants measures of depression (female p<0.05, male p<0.001), anxiety (female p<0.001, male p<0.001), and memory complaints (female p<0.001, male p<0.05) were elevated, relative to non-dependent controls. Significant sex×alcohol dependence history interactions were observed for plasma levels of tissue inhibitor of metalloproteinase 1 (TIMP-1) and brain derived neurotrophic factor (BDNF), with women in the alcohol dependent group exhibiting increased levels of both analytes (p<0.05) relative to controls. Positive correlations between TIMP-1 levels and measures of depression (r2=0.35, p<0.01), anxiety (r2=0.24, p<0.05) and memory complaints (r2=0.44, p<0.01) were found in female, but not male, participants. ConclusionsThough neuropsychiatric profiles were similar for men and women with current or recent alcohol dependence, plasma factors associated with increases in depression, anxiety, and memory impairment differed and support the need to tailor treatments based on sex.

Physical versus psychological social stress in male rats reveals distinct cardiovascular, inflammatory and behavioral consequences.

Repeated exposure to social stress can precipitate the development of psychosocial disorders including depression and comorbid cardiovascular disease. While a major component of social stress often encompasses physical interactions, purely psychological stressors (i.e. witnessing a traumatic event) also fall under the scope of social stress. The current study determined whether the acute stress response and susceptibility to stress-related consequences differed based on whether the stressor consisted of physical versus purely psychological social stress. Using a modified resident-intruder paradigm, male rats were either directly exposed to repeated social defeat stress (intruder) or witnessed a male rat being defeated. Cardiovascular parameters, behavioral anhedonia, and inflammatory cytokines in plasma and the stress-sensitive locus coeruleus were compared between intruder, witness, and control rats. Surprisingly intruders and witnesses exhibited nearly identical increases in mean arterial pressure and heart rate during acute and repeated stress exposures, yet only intruders exhibited stress-induced arrhythmias. Furthermore, re-exposure to the stress environment in the absence of the resident produced robust pressor and tachycardic responses in both stress conditions indicating the robust and enduring nature of social stress. In contrast, the long-term consequences of these stressors were distinct. Intruders were characterized by enhanced inflammatory sensitivity in plasma, while witnesses were characterized by the emergence of depressive-like anhedonia, transient increases in systolic blood pressure and plasma levels of tissue inhibitor of metalloproteinase. The current study highlights that while the acute cardiovascular responses to stress were identical between intruders and witnesses, these stressors produced distinct differences in the enduring consequences to stress, suggesting that witness stress may be more likely to produce long-term cardiovascular dysfunction and comorbid behavioral anhedonia while exposure to physical stressors may bias the system towards sensitivity to inflammatory disorders.

Detection of Biomarkers with Solid-Phase Proximity Ligation Assay in Patients with Colorectal Cancer

BACKGROUND: In the search for prognostic biomarkers, a significant amount of precious biobanked blood samples is needed for conventional analyses. Solid-phase proximity ligation assay (SP-PLA) is an analytic method with the ability to analyze many proteins at the same time in small amounts of plasma. The aim of this study was to explore the potential use of SP-PLA for biomarker validation in patients with colorectal cancer (CRC). MATERIAL AND METHODS: Plasma samples from patients with stage I to IV CRC, with (n = 31) and without (n = 29) disease dissemination at diagnosis or later, were analyzed with SP-PLA using 35 antibodies targeting an equal number of proteins in 5-μl plasma samples. Carcinoembryonic antigen (CEA), analyzed earlier in this cohort using a different technology, was used as a reference. RESULTS: A total of 21 of the 35 investigated proteins were detectable with SP-PLA. Patients in stage II to III with disseminated disease had lower plasma concentrations of HCC-4 (P = .025). Low plasma levels of tissue inhibitor of metalloproteinases–1 were seen in patients with disseminated disease stage II (P = .003). The level of CEA was higher in patients with disease dissemination compared with those without (P = .007). CONCLUSION: SP-PLA has the ability to analyze many protein markers simultaneously in a small amount of blood. However, none of the markers selected for the present SP-PLA analyses gave better prognostic information than CEA.

Subacute Cardiotoxicity of Yessotoxin: In Vitro and in Vivo Studies.

Yessotoxin (YTX) is a marine phycotoxin produced by dinoflagellates and accumulated in filter feeding shellfish. Although no human intoxication episodes have been reported, YTX content in shellfish is regulated by many food safety authorities due to their worldwide distribution. YTXs have been related to ultrastructural heart damage in vivo, but the functional consequences in the long term have not been evaluated. In this study, we explored the accumulative cardiotoxic potential of YTX in vitro and in vivo. Preliminary in vitro evaluation of cardiotoxicity was based on the effect on hERG (human ether-a-go-go related gene) channel trafficking. In vivo experiments were performed in rats that received repeated administrations of YTX followed by recordings of electrocardiograms, arterial blood pressure, plasmatic cardiac biomarkers, and analysis of myocardium structure and ultrastructure. Our results showed that an exposure to 100 nM YTX for 12 or 24 h caused an increase of extracellular surface hERG channels. Furthermore, remarkable bradycardia and hypotension, structural heart alterations, and increased plasma levels of tissue inhibitor of metalloproteinases-1 were observed in rats after four intraperitoneal injections of YTX at doses of 50 or 70 μg/kg that were administered every 4 days along a period of 15 days. Therefore, and for the first time, YTX-induced subacute cardiotoxicity is supported by evidence of cardiovascular function alterations related to its repeated administration. Considering international criteria for marine toxin risk estimation and that the regulatory limit for YTX has been recently raised in many countries, YTX cardiotoxicity might pose a health risk to humans and especially to people with previous cardiovascular risk.

Polymorphisms and Plasma Levels of Tissue Inhibitor of Metalloproteinase-3: Impact on Genetic Susceptibility and Clinical Outcome of Oral Cancer.

Oral cancer, the fourth most common cancer among men in Taiwan, is associated with environmental carcinogens. Tissue inhibitor of metalloproteinase-3 (TIMP3), a member of the TIMP family, is the only protein that binds to the extracellular matrix for suppressing cancer cell growth, angiogenesis, migration, and invasion. The association of TIMP3 polymorphism with oral cancer susceptibility, however, has not yet been reported. In this study, 1947 participants—1200 healthy male controls and 747 male patients with oral cancer—were recruited. Allelic discrimination of TIMP3 −1296 T > C (rs9619311), TIMP3 C > T (rs9862), and TIMP3 C > T (rs11547635) polymorphisms were assessed through real-time polymerase chain reaction. The authors discovered that individuals carrying the polymorphic rs9862 allele are more susceptible to oral cancer [odds ratio (OR), 1.5; 95% confidence interval (CI), 1.2-1.9; adjusted OR (AOR), 1.6; 95% CI, 1.2–2.1] after adjustment for betel quid chewing, alcohol, and tobacco consumption. Among 601 betel quid chewers, the TIMP3 polymorphism rs9862 T/T carriers had a 32.2-fold (95% CI, 20.2–51.3) increased oral cancer risk compared with those carrying C/C and not chewing betel quid. In addition, the authors observed a significant association between rs9862 variants and large tumors (OR, 1.5; 95% CI, 1.0–2.3) development. Moreover, TIMP3 plasma levels significantly increased in oral cancer patients who have large tumor or carry T allele rs9862 polymorphism. In conclusion, these results suggest that gene-environment interactions between the TIMP3 rs9862 polymorphisms and betel quid may alter oral cancer susceptibility and tumor growth in Taiwanese men.

Tissue Inhibitor Of Matrix Metalloproteinase-1 Is Required for High-Fat Diet-Induced Glucose Intolerance and Hepatic Steatosis in Mice.

BackgroundPlasma levels of tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) are elevated in obesity and obesity-related disorders, such as steatosis, but the metabolic role of TIMP-1 is unclear. Here we investigated how the presence or absence of TIMP-1 affected the development of diet-induced glucose intolerance and hepatic steatosis using the Timp1 null mice.Methods Timp1 knockout (TKO) and wild type (TWT) mice were fed chow, high-fat diet (HFD) or intermediate fat and sucrose diet (IFSD). We determined body weight, body composition, lipid content of the liver, energy intake, energy expenditure, oral glucose tolerance, as well as insulin tolerance. In addition, the histology of liver and adipose tissues was examined and expression of selected genes involved in lipid metabolism and inflammation in liver and adipose tissues was determined by RT-qPCR.ResultsTKO mice gained less weight and had lower energy efficiency than TWT mice when fed HFD, but not when fed chow or IFSD. Importantly, TKO mice were protected from development of HFD- as well as IFSD-induced glucose intolerance, hepatic steatosis, and altered expression of genes involved in hepatic lipid metabolism and inflammation.ConclusionCollectively, our results indicate that TIMP-1 contributes to the development of diet-induced hepatic steatosis and glucose intolerance and may be a potential therapeutic target.

Abstract P4-07-04: Preoperative Plasma Concentration of MMP-9/TIMP-1 Complexes Is Not Associated with Disease Outcome in Primary Breast Cancer (N=483)

Abstract Background: Plasma levels of Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) have been reported as predictors of poor prognosis. Indeed, in a previous study of 519 primary breast cancer patients we reported that high levels of TIMP-1 were associated with a poor prognosis (Würtz et al, 2008). In our previous study we quantified total levels of TIMP-1 in plasma; however, TIMP-1 is present in plasma in a non-complexed form and bound to various proteins. Thus, studying the different fractions might refine prognostic stratification and provide further insight into the role of TIMP-1 in tumor biology. Matrix Metalloproteinase-9 (MMP-9) is an important TIMP-1 binding partner and MMP-9 has previously been suggested as a breast cancer biomarker (Li et al, 2004; Somiari et al, 2006). Aim: The aim of the study was to analyze the concentration of MMP-9/TIMP-1 complexes in plasma from our previously studied primary breast cancer patients and evaluate whether these levels are associated with disease outcome. Materials and methods: Plasma concentrations of MMP-9/TIMP-1 complexes were measured using the human MMP-9/TIMP-1 Complex DuoSet® ELISA Development System (R&amp;D Systems, Inc.) The ELISA was thoroughly validated for measurements of MMP-9/TIMP-1 complexes in EDTA plasma. Samples included preoperatively obtained EDTA plasma from consecutively enrolled patients with primary breast cancer. Of the previously studied 519 patients, 483 had plasma samples available for analysis and follow-up data registered by the Danish Breast Cancer Cooperative Group and were included in the present study. The median follow-up time was 5.1 years. The relationship between MMP-9/TIMP-1 complexes and classical prognostic parameters was analyzed and the association with recurrence-free survival (RFS; includes breast cancer relapse, contralateral breast cancer, other malignant disease, and death without a previous relapse) was studied. Results: The ELISA was validated with acceptable results. The median TIMP-1 concentration was 2.06 ng/mL. For analysis, patients were grouped in quartiles of increasing MMP-9/TIMP-1 plasma concentrations. MMP-9/TIMP-1 complex levels were associated with menopausal status and with hormone receptor status; no significant associations with other clinico-pathological parameters (tumor size, nodal status, malignancy grade, age) were found. No statistically significant difference in survival was observed among TIMP-1 high and low groups (quartiles, log-rank analysis p=0.96). In a Cox multivariable analysis (including tumor size, nodal status, hormone receptor status, malignancy grade, menopausal status, age), only age (&amp;gt; 70 years) and hormone receptor status contributed significantly to the model for RFS (P&amp;lt;0.001). MMP-9/TIMP-1 complex concentration was not associated with RFS in this model. Conclusions: In this group of primary breast cancer patients we did notfind any association between MMP-9/TIMP-1 complex levels in plasma and RFS. Total TIMP-1 levels have previously been shown to correlate with prognosis in this patient cohort. Accordingly, our current results point to other TIMP-1 fractions, i.e. the fraction of free TIMP-1 or TIMP-1 in complex with other plasma proteins, as potential indicators of poor prognosis. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-07-04.

Elevated plasma levels of tissue inhibitors of metalloproteinase-1 and their overexpression in muscle in human and mouse muscular dystrophy

To investigate the role of tissue inhibitors of metalloproteinases (TIMPs) in muscular dystrophy, we examined the expression of TIMP-1 using plasma and biopsied muscle from patients with various muscular dystrophies by ELISA, immunohistochemistry, and Western blot analysis. TIMP-1 immunolocalization was also studied in mouse models of muscular dystrophy. Plasma TIMP-1 was elevated and correlated with TGF-β1 in Duchenne muscular dystrophy (DMD) and congenital muscular dystrophy (CMD), but not in Becker muscular dystrophy. In dystrophic human muscles, TIMP-1 was immunopositive in the regenerating and non-regenerating muscle fibers, and interstitial cells that consist of activated fibroblasts and macrophages. TIMP-1 immunoreactivity was also closely associated with TGF-β1. Western blot analysis showed elevated TIMP-1 protein in muscles in DMD. The semiquantitative analysis of TIMP-1 staining intensity and tissue fibrosis showed that TIMP-1 immunoreactivity is closely associated with the extent of tissue fibrosis in human and mouse dystrophic muscles. In conclusion, the present study implied that the TGF-β1–TIMP-1 pathway is activated in dystrophic muscles and the overexpression of TIMP-1 may result in increased deposition of extracellular matrix leading to tissue fibrosis.

Changes of Metalloproteinases Profile in Patients With Masked Hypertension

The aim of our study was to investigate whether collagen degradation is altered in participants with masked hypertension and whether this alteration could be related to disturbances in the matrix metalloproteinases plasma concentration and to compare the findings with those participants with normal blood pressure levels matched for age, sex, and body mass index. Twenty-four (11 men, 13 women) participants with masked hypertension [mean age 46 +/- 7 years and body mass index 25.9 +/- 2.1 kg/m(2) (group A)] and 106 healthy normotensives (49 men, 57 women) with normal blood pressure [mean age 44 +/- 6 years and body mass index 25.5 +/- 2.4 kg/m(2) (group B)]. The plasma levels of matrix metalloproteinase-9 were significantly higher, while the levels of tissue inhibitors of metalloproteinases-1 and -4 were significantly lower in group A compared with group B (matrix metalloproteinase-9: 569 +/- 135 vs. 282 +/- 117 ng/mL, TIMP-1: 169 +/- 42 vs. 230 +/- 37 ng/mL, P < .01, and TIMP-4: 2.1 +/- 1.3 vs. 4.2 +/- 1.98 ng/mL, P < .04, respectively). Patients with masked hypertension had significantly increased matrix metalloproteinase-9 plasma levels and significantly decreased plasma levels of tissue inhibitors of metalloproteinases-1 and -4 compared with participants with normal blood pressure. These findings need further investigation.

High plasma levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) and interleukin-8 (IL-8) characterize patients prone to ventricular fibrillation complicating myocardial infarction

Atherosclerotic plaques prone to cause thrombotic complications and plaque rupture account for the majority of fatal myocardial infarctions (MI), which may be complicated by ventricular fibrillation (VF). Matrix-degrading metalloproteinases (MMPs) and their inhibitors (TIMPs) are expressed in atherosclerotic lesions and contribute to plaque vulnerability. Interleukin-8 (IL-8) is one of the predominant chemokines interacting with MMPs and TIMPs and the coagulation system. The aim of the present study was to assess potential differences of levels of MMP-9, TIMP-1 and IL-8 in postmyocardial infarction patients with or without VF complicating acute MI. Blood samples were taken from 45 patients with VF complicating acute MI and from 88 patients without VF. All samples were collected during a symptom-free interval remote from the acute ischemic event with a median of 556 days. The markers of interest were TIMP-1, MMP-9 and IL-8. IL-8 and TIMP-1 levels were significantly higher among patients with VF than among patients without VF (p<0.001). In a logistic regression approach IL-8 was an independent indicator of patients prone to VF during MI (p=0.03). High levels of TIMP-1 (p=0.05), MMP-9 (p=0.03), the MMP-9/TIMP-1 ratio (p=0.049) and hypertension (p=0.02) were found to be indicators in patients with reinfarction or unstable angina pectoris during follow-up. Hypertension (p=0.02) and MMP-9 (p=0.03) were the only significant indicators characterizing patients undergoing coronary reinterventions, such as percutaneous coronary interventions and coronary bypass surgery. Higher TIMP-1 and IL-8 levels are present in patients with VF complicating MI. High TIMP-levels may be related to the degree of fibrosis which is a substrate for electrical instability and may contribute to the occurrence of VF. Patients prone to develop VF during MI seem to have an increased proinflammatory condition compared to patients without VF.

Tissue inhibitor of metalloproteinases-1 in the postoperative monitoring of colorectal cancer

The aim of this study was to investigate whether the pre- and postoperative plasma levels of tissue inhibitor of metalloproteinases-1 (TIMP-1) were associated with outcome in colorectal cancer (CRC). Pre- and postoperative plasma TIMP-1 from 280 curatively resected CRC patients and carcinoembryonic antigen (CEA) in corresponding serum samples were measured and correlated with patient outcome (death, local recurrence (LR) and distant metastases (DM)). The results showed that the course of plasma TIMP-1 from pre- to postoperative levels correlated with patient outcome ( P = 0.005). However, postoperative plasma TIMP-1 alone was strongly associated with patient outcome, high TIMP-1 predicting short survival ( P = 0.002). Combining postoperative TIMP-1 and CEA demonstrated that high TIMP-1 and CEA levels predicted poor outcome ( P < 0.0001); multivariate analysis identifying both parameters as strong prognostic factors for survival, LR and DM ( P < 0.0001). In conclusion, postoperative plasma TIMP-1 predicts patient outcome both alone and in combination with CEA. Postoperative TIMP-1 may be a marker of residual disease after primary surgery for CRC.

644 POSTER Plasma levels of tissue inhibitor of metalloproteinases 1 (TIMP-1) and tumor type M2 pyruvate kinase (TuM2-PK) for monitoring of advanced colorectal cancer

644 POSTER Plasma levels of tissue inhibitor of metalloproteinases 1 (TIMP-1) and tumor type M2 pyruvate kinase (TuM2-PK) for monitoring of advanced colorectal cancer

Plasma TIMP-1 in patients with colorectal adenomas: a prospective study

Colorectal cancer patients have increased plasma levels of tissue inhibitor of metalloproteinases-1 (TIMP-1). However, it remains unresolved whether colorectal adenomas are associated with increased plasma TIMP-1. Plasma TIMP-1 levels were determined using an immunoassay in 121 patients prospectively enrolled from surveillance colonoscopy programmes. TIMP-1 levels were correlated to various clinicopathological parameters. No significant associations were found between plasma TIMP-1 and size, macro- or microscopic morphology or grade of dysplasia of the adenomas. No significant differences in TIMP-1 levels were found between patients with adenomas ( n=36), hyperplastic polyps ( n=12) or no pathology ( n=68) of the large intestine. However, patients with colonic ( n=3) or rectal ( n=2) adenocarcinomas had significantly increased TIMP-1 levels ( P=0.02). The present study demonstrates that measurement of plasma TIMP-1 cannot be used for the identification of adenomatous or hyperplastic polyps of the large intestine.

Association between preoperative plasma levels of tissue inhibitor of metalloproteinases 1 and rectal cancer patient survival: a validation study

The level of the tissue inhibitor of metalloproteinases 1 (TIMP-1) has previously been demonstrated to predict the survival of early stage colorectal cancer patients. The present study was undertaken to further validate plasma TIMP-1 as a prognostic marker in rectal cancer. Preoperative plasma from 352 rectal cancer patients were analysed using an immunoassay for TIMP-1. The TIMP-1 immunoassay demonstrated robustness and good reproducibility with low interassay coefficients of variation (CV). The rectal cancer patients had a mean plasma TIMP-1 level of 184 μg/l (standard deviation (SD): 70 μg/l). There were no significant differences in TIMP-1 levels between patients with Dukes’ stage A, B or C disease, whereas Dukes’ stage D patients had significantly increased TIMP-1 levels (P<0.0001); however, high levels of TIMP-1 were not restricted to those with advanced disease. Univariate analysis demonstrated an increasing risk of mortality with increasing TIMP-1 levels Hazard Ratio (HR)=2.9; 95% Confidence Interval (CI): 1.7–5.0; P<0.0001). Including additional covariates, multivariate analysis identified plasma TIMP-1 as an independent prognostic marker (HR=2.2; 95% CI: 1.2–4.1 (P=0.01). This study showed a highly significant and independent association between preoperative plasma TIMP-1 levels and survival in rectal cancer patients, thus confirming our previous findings. Furthermore, the TIMP-1 immunoassay proved to be stable and reproducible in this confirmatory study.